ramipril and Cardiovascular-Diseases

Topics: Aged; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Cardiovascular Diseases; Drug Combinations; Enalapril; Enzyme Inhibitors; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Myocardial Infarction; Neprilysin; Ramipril; Severity of Illness Index; Stroke Volume; Valsartan; Ventricular Dysfunction, Left

Renin inhibitors (RIs) reduce blood pressure more than placebo, with the magnitude of this effect thought to be similar to that for angiotensin converting enzyme (ACE) inhibitors. However, a drug's efficacy in lowering blood pressure cannot be considered as a definitive indicator of its effectiveness in reducing mortality and morbidity. The effectiveness and safety of RIs compared to ACE inhibitors in treating hypertension is unknown.. To evaluate the benefits and harms of renin inhibitors compared to ACE inhibitors in people with primary hypertension.. The Cochrane Hypertension Group Information Specialist searched the following databases for randomized controlled trials up to August 2020: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers about further published and unpublished work. The searches had no language restrictions.. We included randomized, active-controlled, double-blinded studies (RCTs) with at least four weeks follow-up in people with primary hypertension, which compared renin inhibitors with ACE inhibitors and reported morbidity, mortality, adverse events or blood pressure outcomes. We excluded people with proven secondary hypertension.. Two review authors independently selected the included trials, evaluated the risks of bias and entered the data for analysis.. We include 11 RCTs involving 13,627 participants, with a mean baseline age from 51.5 to 74.2 years. Follow-up duration ranged from four weeks to 36.6 months. There was no difference between RIs and ACE inhibitors for the outcomes: all-cause mortality: risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.18; 5 RCTs, 5962 participants; low-certainty evidence; total myocardial infarction: RR 0.86, 95% CI 0.22 to 3.39; 2 RCTs, 957 participants; very low-certainty evidence; adverse events: RR 0.98, 95% CI 0.93 to 1.03; 10 RTCs, 6007 participants;  moderate-certainty evidence; serious adverse events: RR 1.21, 95% CI 0.89 to 1.64; 10 RTCs, 6007 participants; low-certainty evidence; and withdrawal due to adverse effects: RR 0.85, 95% CI 0.68 to 1.06; 10 RTCs, 6008 participants; low-certainty evidence. No data were available for total cardiovascular events, heart failure, stroke, end-stage renal disease or change in heart rate. Low-certainty evidence suggested that RIs reduced systolic blood pressure: mean difference (MD) -1.72, 95% CI -2.47 to -0.97; 9 RCTs, 5001 participants;  and diastolic blood pressure: MD -1.18, 95% CI -1.65 to -0.72; 9 RCTs, 5001 participants,  to a greater extent than ACE inhibitors, but we judged this to be more likely due to bias than a true effect.  AUTHORS' CONCLUSIONS: For the treatment of hypertension, we have low certainty that renin inhibitors (RI) and angiotensin converting enzyme (ACE) inhibitors do not differ for all-cause mortality and myocardial infarction. We have low to moderate certainty that they do not differ for adverse events. Small reductions in blood pressure with renin inhibitors compared to ACE inhibitors are of low certainty.  More independent, large, long-term trials are needed to compare RIs with ACE inhibitors, particularly assessing morbidity and mortality outcomes, but also on blood pressure-lowering effect.

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Cause of Death; Female; Fumarates; Heart Rate; Humans; Irbesartan; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Myocardial Infarction; Patient Dropouts; Ramipril; Randomized Controlled Trials as Topic; Renin

The global epidemic of type 2 diabetes has prompted numerous studies and public health efforts to reduce its development. A variety of interventions, including lifestyle modifications and pharmacological agents directed at ameliorating the major risk factors for type 2 diabetes, are of proven efficacy in reducing the development of type 2 diabetes in people with impaired glucose tolerance. While prevention of the hyperglycaemia characteristic of diabetes is arguably an important, clinically relevant outcome, a more compelling outcome with greater clinical significance is the prevention or reduction of the relatively diabetes-specific microvascular and less-specific cardiovascular disease (CVD) complications associated with diabetes. These complications cause the majority of morbidity and excess mortality associated with diabetes. Any reduction in diabetes should, logically, also reduce the occurrence of its long-term complications; however, most diabetes prevention trials have not been of sufficient duration to allow such an evaluation. The limited long-term data, largely from the Da Qing Diabetes Prevention Study (DQDPS) and the Diabetes Prevention Program (DPP) and their respective follow-up studies (DQDPOS and DPPOS), suggest a reduction in microvascular complications and amelioration of CVD risk factors. Only the DQDPOS and Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) studies have shown a reduction in CVD events and only DQDPOS has demonstrated a decrease in CVD and overall mortality. While these limited data are promising, whether diabetes prevention directly reduces complication-related morbidity and mortality remains unclear. Longer follow-up of prevention studies is needed to supplement the limited current clinical trial data, to help differentiate the effects of diabetes prevention itself from the means used to reduce diabetes development and to understand the balance among benefits, risks and costs of prevention.

Topics: Atherosclerosis; Cardiovascular Diseases; Clinical Trials as Topic; Cost-Benefit Analysis; Diabetes Complications; Diabetes Mellitus, Type 2; Follow-Up Studies; Glucose Intolerance; Humans; Hypoglycemic Agents; Life Style; Metformin; Microcirculation; Preventive Medicine; Ramipril; Risk Factors; Rosiglitazone; Treatment Outcome

Studies have challenged the appropriateness of accepted blood pressure targets. We hypothesised that different levels of low blood pressure are associated with benefit for some, but harm for other outcomes.. In this analysis, we assessed the previously reported outcome data from high-risk patients aged 55 years or older with a history of cardiovascular disease, 70% of whom had hypertension, from the ONTARGET and TRANSCEND trials investigating ramipril, telmisartan, and their combination, with a median follow-up of 56 months. Detailed descriptions of randomisation and intervention have already been reported. We analysed the associations between mean blood pressure achieved on treatment; prerandomisation baseline blood pressure; or time-updated blood pressure (last on treatment value before an event) on the composite outcome of cardiovascular death, myocardial infarction, stroke, and hospital admission for heart failure; the components of the composite outcome; and all-cause death. Analysis was done by Cox regression analysis, ANOVA, and χ. Recruitment for ONTARGET took place between Dec 1, 2001, and July 31, 2008. TRANSCEND took place between Nov 1, 2001, and May 30, 2004. 30 937 patients were recruited from 733 centres in 40 countries and followed up for a median of 56 months. In ONTARGET, 25 127 patients known to be tolerant to angiotensin-converting-enzyme (ACE)-inhibitors were randomly assigned after a run-in period to oral ramipril 10 mg/day (n=8407), telmisartan 80 mg/day (n=8386), or the combination of both (n=8334). In TRANSCEND, 5810 patients who were intolerant to ACE-inhibitors were randomly assigned to oral telmisartan 80 mg/day (n=2903) or placebo (n=2907). Baseline systolic blood pressure (SBP) 140 mm Hg or higher was associated with greater incidence of all outcomes compared with 120 mm Hg to less than 140 mm Hg. By contrast, a baseline diastolic blood pressure (DBP) less than 70 mm Hg was associated with the highest risk for most outcomes compared with all DBP categories 70 mm Hg or more. In 4052 patients with SBP less than 120 mm Hg on treatment, the risk of the composite cardiovascular outcome (adjusted hazard ratio [HR] 1·14, 95% CI 1·03-1·26), cardiovascular death (1·29, 1·12-1·49), and all deaths (1·28, 1·15-1·42) were increased compared with those in whom SBP was 120-140 mm Hg during treatment (HR 1 for all outcomes, n=16099). No harm or benefit was observed for myocardial infarction, stroke, or hospital admission for heart failure. Mean achieved SBP more accurately predicted outcomes than baseline or time-updated SBP, and was associated with the lowest risk at approximately 130 mm Hg, and at 110-120 mm Hg risk increased for the combined outcome, cardiovascular death, and all-cause death except stroke. A mean DBP less than 70 mm Hg (n=5352) during treatment was associated with greater risk of the composite primary outcome (HR 1·31, 95% CI 1·20-1·42), myocardial infarction (1·55, 1·33-1·80), hospital admission for heart failure (1·59, 1·36-1·86) and all-cause death (1·16, 1·06-1·28) than a DBP 70-80 mm Hg (14 305). A pretreatment and mean on-treatment DBP of about 75 mm Hg was associated with the lowest risk.. Mean achieved SBP less than 120 mm Hg during treatment was associated with increased risk of cardiovascular outcomes except for myocardial infarction and stroke. Similar patterns were observed for DBP less than 70 mm Hg, plus increased risk for myocardial infarction and hospital admission for heart failure. Very low blood pressure achieved on treatment was associated with increased risks of several cardiovascular disease events. These data suggest that the lowest blood pressure possible is not necessarily the optimal target for high-risk patients, although it is not possible to rule out some effect of reverse causality.. Boehringer Ingelheim.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Cardiovascular Diseases; Drug Therapy, Combination; Female; Follow-Up Studies; Hospitalization; Humans; Hypertension; Hypotension; Male; Middle Aged; Multicenter Studies as Topic; Ramipril; Randomized Controlled Trials as Topic; Telmisartan

Lack of adherence may explain, at least in part, the poor cardiovascular risk factors control observed in patients with ischemic heart disease, increasing the risk of developing new events. Polypill improves medication adherence, which may actually reduce blood pressure and LDL cholesterol compared with the drugs given separately. The fixed combination of acetylsalicylic acid 100 mg + ramipril 2.5, 5, or 10 mg + either simvastatin 40 mg or atorvastatin 20 mg is the unique cardiovascular polypill that has been registered in 22 countries worldwide. The polypill-containing simvastatin has been specifically tested in a clinical trial including only patients with ischemic heart disease. The FOCUS study showed that patients treated with the polypill showed a higher adherence compared with those receiving separate medications.

Topics: Antihypertensive Agents; Aspirin; Atorvastatin; Cardiovascular Diseases; Drug Combinations; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Medication Adherence; Platelet Aggregation Inhibitors; Ramipril; Simvastatin

Recently, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure (BP) trial enrolled 4733 participants with type 2 diabetes and randomized them to a target systolic blood pressure (SBP) of less than 120 mm Hg or 140 mm Hg. Despite the significant difference in the achieved SBP, there was no significant difference in the incidence of primary outcomes. Based on this evidence, the target SBP for diabetics has been revised in the majority of major guidelines. However, there is a steeper association between SBP and stroke in Asians than other ethnicities, with stroke being the leading cause of cardiovascular mortality. This suggests that target BP in the Asian region should be tailored towards prevention of stroke. In the ACCORD study, the intensive BP treatment was associated with significant reductions in both total stroke and non-fatal stroke. The results from the ACCORD study are supported by a subgroup analysis from the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study, which showed that, in diabetic patients, the risk of stroke continues to decrease to a SBP value of 115 mm Hg with no evidence of J curve. As diabetes is highly associated with underlying coronary artery disease, there is a justified concern for adverse effects resulting from too much lowering of BP. In a post hoc analysis of 6400 diabetic subjects enrolled in the International Verapamil SR-Trandolapril (INVEST) study, subjects with SBP of less than 110 mm Hg were associated with a significant increase in all-cause mortality. In the ONTARGET study, at any levels of achieved SBP, diastolic blood pressure (DBP) below 67 mm Hg was associated with increased risk for cardiovascular outcomes. As such, a prudent approach would be to target a SBP of 130-140 mm Hg and DBP of above 60 mm Hg in diabetics with coronary artery disease. In conclusion, hypertension, in association with diabetes, has been found to be significantly correlated with an elevated risk for cardiovascular events. As the association between stroke and BP is stronger in Asians, compared to other ethnicities, consideration should be given for a target BP of 130/80 mm Hg in Asians.

Topics: Aged; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Cardiovascular Diseases; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Hypotension; Male; Middle Aged; Ramipril; Randomized Controlled Trials as Topic; Reference Values; Risk Factors; Stroke; Telmisartan

During the last decade, there has been a tremendous effort to develop different cardiovascular polypills in response to the upsurge in global cardiovascular disease worldwide. The pharmacological development of such a strategy has proven to be extremely complex from a formulation standpoint. Not all drugs are suitable for use in a polypill because of potential drug incompatibilities between them. Candidate agents must be safe, well tolerated, effective, guideline recommended and physiochemically compatible with the other components of the pill. The Fuster-CNIC-Ferrer cardiovascular (CV) polypill has been found to be the first-in-class polypill to be approved and commercialized in Europe and Latinamerican Countries. In this article, we review the pharmacological properties of its three components, including the clinical evidence supporting their use in patients with established cardiovascular disease, their pharmacokinetic properties, adverse effects, drug interactions and contraindications.

Topics: Aspirin; Atorvastatin; Cardiovascular Agents; Cardiovascular Diseases; Drug Combinations; Humans; Ramipril; Secondary Prevention

Angiotensin-converting enzyme (ACE) inhibitors are a heterogeneous class, varying in pharmacologic properties, which have different therapeutic impacts on patient profiles, including lipophilicity, tissue-ACE binding, duration of action, half-life, and increased bradykinin availability. Among the ACE inhibitor class, the agent perindopril, in particular, has pleiotropic effects that are not equally shared by other ACE inhibitors, including bradykinin site selectivity and subsequent enhancement of nitric oxide and inhibition of endothelial cell apoptosis. Moreover, there is a large amount of evidence to suggest that perindopril therapy may reduce cardiovascular event rates in patients, yet perindopril is rarely prescribed in the United States. Ramipril is another ACE inhibitor with both a favorable clinical profile and impressive outcomes data. Our review compares the pharmacologic and trial data among perindopril, ramipril, and other ACE inhibitors. In patients with or at high risk for coronary heart disease who do not have heart failure, or in patients with heart failure with preserved ejection fraction, perindopril should be among the preferred treatment agents in the ACE inhibitor class. Ramipril has an impressive track record of improving cardiovascular outcomes, too, and should be considered a preferred agent among the ACE inhibitor class.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Cardiovascular System; Coronary Disease; Heart Failure; Humans; Hypertension; Myocardial Infarction; Perindopril; Ramipril

To evaluate the efficacy and safety of the polypill for prevention of cardiovascular disease (CVD) and stroke and to present literature related to the polypill components (statin, aspirin, antihypertensive) for primary prevention of CVD and stroke.. A literature search was conducted in MEDLINE (1948-January 2011) and EMBASE (1974-January 2011) using the terms polypill and Polycap. When limited to clinical trials, systematic reviews, or meta-analyses, 7 studies were identified. Bibliographies of pertinent review articles and studies were scanned for additional references. A similar search was conducted to identify literature related to the use of polypill components for primary prevention of CVD and stroke.. Studies that evaluated the hypothetical benefits of a polypill and controlled trials that assessed a formulation of the polypill related to prevention of CVD and stroke were included. Studies were assessed for efficacy, safety, drug interactions, and clinical pharmacokinetics.. An initial study to predict benefit estimated that a hypothetical polypill would reduce diastolic blood pressure by 11 mm Hg and low-density lipoprotein cholesterol (LDL-C) by 70 mg/dL, thus reducing the relative risks of CVD and stroke by 88% and 80%, respectively. One clinical trial in patients at low risk for CVD and stroke found that diastolic blood pressure was reduced by 1.6 mm Hg and LDL-C was reduced by 17.7 mg/dL, correlating with 44% and 21% reduction in the relative risks of CVD and stroke, respectively. Studies in higher risk patients reported reductions in systolic blood pressure of up to 28.8 mm Hg and in LDL-C of up to 54 mg/dL, correlating with 62% and 60% relative reduction in risks of CVD and stroke, respectively.. Polypill study results have been more modest than originally theorized. However, results show promise in patients at higher risk for CVD and stroke.

Topics: Antihypertensive Agents; Aspirin; Atenolol; Cardiovascular Diseases; Drug Combinations; Humans; Hydrochlorothiazide; Hypolipidemic Agents; Platelet Aggregation Inhibitors; Primary Prevention; Ramipril; Simvastatin; Stroke

Angiotensin-receptor blockers (ARBs) offer superior tolerability to angiotensin-converting enzyme inhibitors, and are increasingly used in patient management. ARBs vary in their pharmacological profiles, which results in efficacy differences. Therefore, deciding between ARBs should be evidence-based and related to the specific requirements of the individual patient. For patients with hypertension but at low additional risk, an ARB that provides sustained, powerful 24-h reductions in blood pressure is suitable. For patients at very high additional risk (with heart failure), an ARB with demonstrated efficacy in this patient population is the preferred option. For patients at increased risk, telmisartan should be the ARB of choice based on the results from the Ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial (ONTARGET), which demonstrated for the first time that an ARB has equivalent protection to the reference angiotensin-converting enzyme inhibitor in a broad cross-section of at-risk patients but a better side-effect profile.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Biphenyl Compounds; Blood Pressure; Cardiovascular Diseases; Humans; Hypertension; Losartan; Ramipril; Risk Factors; Telmisartan; Tetrazoles

Increasing attention is being devoted to the use of combination therapy with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in order to achieve maximal blockade of the renin-angiotensin system (RAS) in patients at high risk of cardiovascular events. This approach has been adopted in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), which compared the effects of the ARB telmisartan and the ACE inhibitor ramipril, alone and in combination, on cardiovascular mortality and morbidity in high-risk patients with vascular disease or diabetes mellitus and end-organ damage. The results showed that telmisartan was as effective as ramipril for the primary cardiovascular outcome during a 56-month follow-up but was better tolerated. However, dual RAS blockade was not associated with any additional benefits, and the incidence of adverse events was greater with the combination. Based on these findings, optimal cardioprotective strategies in high-risk patients are likely to involve the addition of either telmisartan or ramipril on top of the patient's usual care, but not both. The choice of agent to be used in the long term could be based on other considerations, such as compliance and safety. Both cough and angioedema were higher with ramipril than telmisartan during the 56-month follow-up period in ONTARGET.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Diabetes Mellitus; Humans; Kidney Diseases; Ramipril; Risk Factors; Telmisartan

The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathogenesis of a variety of clinical conditions, including atherosclerosis, hypertension, left ventricular hypertrophy, myocardial infarction, and heart failure. Inhibition of the RAAS with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ARBs) has been shown to be effective in lowering blood pressure and reducing cardiovascular mortality and morbidity in various at-risk patient populations. A number of studies have shown that these 2 classes are effective in reducing the rate of renal disease progression in patients with diabetic nephropathy, although more long-term vascular outcome studies are needed in patients with chronic kidney disease. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) was the first study to show comparable reno- and cardioprotective effects between an ARB (telmisartan) and ramipril in a broad section of at-risk patients, on top of usual standard care. However, telmisartan showed better tolerability than ramipril in ONTARGET, with less cough and angioedema. This difference was obtained despite patients having been selected for tolerability to both drugs at study entry.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Diabetes Mellitus; Drug Therapy, Combination; Humans; Kidney Diseases; Ramipril; Telmisartan

Blockade of the renin-angiotensin system is an important approach in managing high blood pressure, and has increasingly been shown to affect cardiovascular disease processes mediated by angiotensin II throughout the cardiovascular and renal continua. Telmisartan is an angiotensin II receptor blocker (ARB) displaying unique pharmacologic properties, including a longer half life than any other ARB, that result in large and sustained reductions of blood pressure. In patients with mild-to-moderate hypertension, telmisartan has proved superior to other antihypertensive agents (valsartan, losartan, ramipril, perindopril, and atenolol) in controlling blood pressure particularly towards the end of the dosing interval. There is also clinical evidence that telmisartan reduces left ventricular hypertrophy, reduces arterial stiffness and the recurrence of atrial fibrillation, and confers renoprotection. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study has demonstrated that telmisartan has similar cardiovascular protective effects to ramipril in a large, high-risk patient population but was better tolerated. The powerful and sustained blood pressure control apparent in clinical trials, together with cardiovascular protection and tolerability demonstrated in ONTARGET means that telmisartan may be a preferred option for patients with hypertension.

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Calcium Channel Blockers; Cardiovascular Diseases; Cardiovascular System; Humans; Hypertension; Ramipril; Risk Factors; Telmisartan

Clinical trials have shown the efficacy of angiotensin II receptor blockers (ARBs) in patients with hypertension and have suggested that ARBs are noninferior to angiotensin-converting enzyme (ACE) inhibitors in patients with ischemic heart disease and heart failure. The Heart Outcomes Prevention Evaluation (HOPE), a landmark study in high cardiovascular risk management, demonstrated the cardioprotection of the ACE inhibitor ramipril. Thus, in the recent Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET®) ramipril was selected as a comparator when exploring the cardioprotective potential of telmisartan in the first head-to-head comparison of an ACE inhibitor and an ARB in a broad cross-sectional cohort of cardiovascular high-risk patients. ONTARGET showed that telmisartan is as effective as ramipril in the management of these patients but is better tolerated. The combination of ramipril and telmisartan did not confer a further benefit but did bring about an increased rate of adverse events such as renal dysfunction. In previous ARB outcome trials, cardiovascular risk profile, nature and severity of the underlying cardiovascular disease, dosing regimens and concomitant therapies, follow-up, and endpoints have varied greatly so that caution is warranted in extrapolating evidence gained from high-risk patients to other conditions such as acute myocardial infarction or chronic heart failure.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Cardiovascular System; Disease Progression; Humans; Ramipril; Risk Factors; Telmisartan; Treatment Outcome

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Endothelium, Vascular; Glomerular Filtration Rate; Heart Ventricles; Humans; Ramipril; Secondary Prevention

Renin-angiotensin-aldosterone system (RAAS) overactivity is associated with increased cardiovascular risk, a finding that may be explained by the key role of the RAAS in stimulating vascular and cardiac remodeling. Inhibition of RAAS activity with the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) has been shown to reduce cardiovascular mortality in patients with heart failure. ACE inhibitors have also been shown to reduce the incidence of stroke, myocardial infarction (MI), and heart failure in high-risk patients without heart failure. These findings led to the evaluation of the ARB telmisartan versus the ACE inhibitor ramipril in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), a cardioprotection trial conducted in high-risk patients without left ventricular dysfunction or heart failure. The results of this trial showed that the ACE inhibitor ramipril and the ARB telmisartan are equally effective in reducing the incidence of cardiovascular death, MI, stroke, and hospitalization for heart failure in patients without heart failure or left ventricular dysfunction but at high risk for cardiovascular disease (CVD). These results confirm that RAAS inhibition, using ACE inhibitors or ARBs, is an effective approach to reducing cardiovascular mortality and morbidity in patients without heart failure who are at high risk for CVD.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Cardiovascular Diseases; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Hypertension; Ramipril; Risk Reduction Behavior; Telmisartan

Cardiovascular disease (CVD) accounts for one of every three deaths in the United States. In recent years, a greater understanding of the renin-angiotensin-aldosterone system's (RAAS) contribution to CVD, particularly in the area of blood pressure regulation, has emerged. Thus, interrupting or blocking the RAAS has become a key component in the treatment of hypertension and other cardiovascular conditions. The role of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in reducing CVD in high-risk populations has been demonstrated by two recently completed major trials: the Ongoing Telmisartan Alone and in Combination with Ramipril Global endpoint Trial (ONTARGET) and the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease (TRANSCEND). This article describes these key studies and their outcomes and identifies critical issues that they raise for clinical practice in terms of choosing the most effective therapy for patients with existing CVD.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Drug Therapy, Combination; Humans; Ramipril; Randomized Controlled Trials as Topic; Telmisartan; Treatment Outcome; United States

The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) was a 25,620 patient study program comparing telmisartan with ramipril or the combination thereof in patients at increased cardiovascular risk. Ramipril had previously been proven to prevent cardiovascular events in a similar population within the HOPE-trial. However, ramipril and other ACE inhibitors (ACE-Is) may have limited tolerability that might restrict their use in patients requiring secondary prevention, whereas angiotensin receptor blockers (ARBs) are suggested to be better tolerated. However, no ARB had been compared with the standard treatment, ramipril, in these cardiovascular patients at increased risk. ONTARGET showed that telmisartan was as effective as ramipril in preventing cardiovascular events, but was better tolerated. The combination of ramipril and telmisartan was not superior to either monotherapy. Taken together, ONTARGET demonstrated that telmisartan is as effective as ramipril in a broad cardiovascular increased-risk population in the middle of the cardiovascular continuum. In these patients who are intolerant to ACE-Is or who do not achieve blood pressure control, the ARB with the best evidence for secondary prevention is telmisartan according to the results of the ONTARGET trial.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Agents; Cardiovascular Diseases; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Telmisartan; Treatment Outcome

The primary aim of the treatment in hypertension is to prevent cardiovascular complications. All hypertensives reduce the risk for cardiovascular events by providing effective blood pressure control. Besides blood pressure-lowering effect, the contribution of an antihypertensive agent to reduce the risk for cardiovascular events at high-risk patients was first demonstrated in 2000 in the HOPE study (Heart Outcomes Prevention Evaluation), which used an angiotensin-converting enzyme (ACE) inhibitor, ramipril 10 mg (N Engl J Med 2000;342:145-53). However, at the time the results of this study appeared, the use of angiotensin-receptor blockers (ARB) was gaining popularity in the treatment of hypertension as an alternative to ACE inhibitors. This raised the question as to whether an ARB would also offer benefit comparable to that derived from ramipril. A non-inferiority trial was planned by the same research group to test whether telmisartan 80 mg was as effective as ramipril 10 mg in a similar patient population. In order to obtain reliable results, 25,000 patients from all over the world had to be followed-up for five years (Am Heart J 2004;148:52-61). The results of the ONTARGET study (The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) which were presented at the annual meeting of the American College of Cardiology in March 2008 were suggestive of a new indication for telmisartan. In August, 2009, the U.S. Food and Drug Administration reported that a new indication might be justified for the use of telmisartan, an angiotensin-receptor blocker: In order to reduce the risk for cardiovascular diseases and if an ACE inhibitor (ramipril 10 mg) cannot be used, telmisartan 80 mg can be used in patients with a high cardiovascular risk profile (Press announcements, FDA). The aim of this review is to provide a comprehensive analysis of the course of this recent development in cardiovascular protection.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Ramipril; Renin-Angiotensin System; Telmisartan

Cardiovascular risk is determined by multiple risk factors. Blockade of the renin-angiotensin system is an important approach to the prevention of cardiovascular events. In the largest angiotensin receptor blocker cardiovascular outcome study to date, the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) program will compare the efficacy of therapy with telmisartan and ramipril, in reducing cardiovascular events in patients at high risk (history of coronary artery disease, stroke or transient ischemic attack, peripheral artery disease, or diabetes with evidence of end-organ damage). Recruited patients (n = 31,546) will be followed up for a period of 6 years, and more than 150,000 patient-years of data will be recorded. The primary endpoint is a composite of cardiovascular death, stroke, acute myocardial infarction, and hospitalization for congestive heart failure; secondary endpoints focus on reductions in newly diagnosed heart failure, new-onset type 2 diabetes, cognitive decline, atrial fibrillation, and nephropathy. In addition, an ambulatory blood pressure monitoring substudy will be conducted to assess the effect of treatment on endpoints after adjustment for 24-hour blood pressure values. Other substudies of the treatment effects on erectile dysfunction, blood markers, arterial stiffness, oral glucose tolerance, and the progression of target organ damage are also planned. The results of the ONTARGET program are due in 2008, and the findings are expected to have important clinical implications for the management of patients at high cardiovascular risk.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiotonic Agents; Cardiovascular Diseases; Clinical Trials as Topic; Drug Delivery Systems; Drug Therapy, Combination; Humans; Ramipril; Telmisartan; Treatment Outcome

The renin angiotensin system (RAAS) plays an important role in the pathophysiology of cardiovascular (CV) disease. Modulation of RAAS with angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and aldosterone inhibitors reduces a range of adverse CV outcomes in patients with or at risk of CV disease. Currently, there is incomplete evidence to show all RAAS modulators provide vascular protection by reducing the incidence of myocardial infarction (MI), stroke and CV death. In patients at high risk for CV events, studies with ACEi designed to test for long-term vascular protection, showed benefit. In contrast, studies of ARBs in patients with hypertension, heart failure, and renal disease have not consistently shown a reduction of CV outcomes. However, none of these studies was specifically designed to examine the impact of ARBs on the vascular protective outcomes of CV death, non-fatal MI, and stroke. The ONTARGET and TRANSCEND studies are designed to determine whether the ARB telmisartan is similar (or non-inferior) or superior to the ACEi ramipril in the reduction of CV events in patients with established CV disease or diabetes with target organ damage. The ONTARGET study has enrolled 25,620, and TRANSCEND 5,776 subjects. The subjects in both trials are similar to those studied in the HOPE study, yet there is greater ethnic diversity, a higher proportion of patients with cerebro-vascular disease, and a greater use of beta blockers and lipid-lowering treatment. The studies completed recruitment in 2004, and are due to complete follow-up and report the results in 2008. The ONTARGET and TRANSCEND studies will provide valuable comparative data on the efficacy of telmisartan and ramipril and their combination in patients at high risk for CV events. Although it is possible that enhanced benefits will be observed with dual therapy, the outcomes with ARB monotherapy remain uncertain.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Drug Therapy, Combination; Humans; Hypertension; Ramipril; Randomized Controlled Trials as Topic; Telmisartan

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Death, Sudden, Cardiac; Female; Follow-Up Studies; Humans; Male; Middle Aged; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Stroke

Ramipril is an oral, non-sulfhydryl ACE inhibitor thought to act in the renin-angiotensin-aldosterone system to decrease vasopressor activity, aldosterone secretion, and bradykinin degradation. Ramipril is generally well tolerated and effective in the treatment of patients aged > or =55 years at high risk for the development of cardiovascular (CV) events, in whom the risk of myocardial infarction (MI), stroke, and CV death can be significantly reduced. The risk of these CV outcomes may also be reduced with ramipril therapy in various subgroups; these include patients with diabetes mellitus, peripheral arterial disease (PAD) or renal insufficiency, and women. Thus, ramipril, in addition to lifestyle interventions, should be considered an important therapy in the prevention of CV outcomes in high-risk patients.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Female; Humans; Male; Middle Aged; Ramipril

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus; Diabetic Angiopathies; Humans; Premedication; Ramipril; Rosiglitazone; Thiazolidinediones; Treatment Outcome

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Double-Blind Method; Evidence-Based Medicine; Humans; Hypertension; Multicenter Studies as Topic; Myocardial Infarction; Placebos; Ramipril; Randomized Controlled Trials as Topic; Research Design; Risk Factors; Treatment Outcome

Ramipril is an angiotensin-converting enzyme inhibitor that has been extensively studied in randomised, controlled clinical trials in patients with cardiovascular diseases. Therapy with ramipril in patients with various cardiovascular disorders has demonstrated significant and clinically important reductions in cardiovascular death, myocardial infarction, stroke, congestive heart failure, progressive renal impairment and onset of diabetes. Ramipril is usually dosed at 2.5-10 mg/day. Beneficial effects of ramipril are observed in the treatment of hypertension and congestive heart failure, prevention of cardiovascular events in high-risk patients, prevention of congestive heart failure, diabetes and other vascular events.

Topics: Angiotensin-Converting Enzyme Inhibitors; Atherosclerosis; Cardiovascular Diseases; Carotid Arteries; Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Heart Failure; Humans; Hypertension; Proteinuria; Ramipril; Randomized Controlled Trials as Topic; Renal Insufficiency; Tissue Distribution

We review the evidence linking mild renal insufficiency (MRI) with increased cardiovascular risk. MRI is associated with a number of cardiovascular risk factors, including nighttime hypertension, and increased levels of lipoprotein (a), homocysteine, asymmetric dimethyl-arginine, and inflammation and insulin resistance markers and mediators. Epidemiologic evidence associates coronary artery disease and nephrosclerosis, a frequent cause of early renal insufficiency in the elderly. In a middle-aged general population MRI was found in 8% of women and 9% of men, but was not associated with cardiovascular disease. Nonetheless, in a representative sample of middle-aged British men the risk of stroke was 60% higher for the sub-group with MRI: in people at high cardiovascular risk (mostly coronary disease), the HOPE study found a 2-fold (unadjusted) or 1.4-fold (adjusted) higher incidence of cardiovascular outcomes with MRI. The combined incidence of cardiovascular death, myocardial infarction and stroke increased with the level of serum creatinine. Several studies have examined the cardiovascular risk associated with MRI in hypertension. In HDFP, as in HOPE, cardiovascular mortality increased with serum creatinine (five-fold difference in cardiovascular mortality between the lowest and the highest creatinine strata). The risk associated with renal insufficiency was independent of other classic cardiovascular risk factors. Two trials of hypertensives with low risk (HOT and a small Italian trial) found that cardiovascular outcomes approximately doubled in subjects with MRI. Another study (MRFIT) found that it was not baseline creatinine, but its increase on follow-up that predicted future cardiovascular disease. These observational data suggest that regardless of etiology MRI is a strong predictor of cardiovascular disease and is found in 10% of populations at low cardiovascular risk and in up to 30% of those at high risk. No prospective therapeutic trials aimed at reducing the cardiovascular burden in people with MRI are available. Subgroup analyses of the HOPE study indicate that angiotensin-converting enzyme (ACE) inhibition with ramipril is beneficial and does not increase the risk of such side effects as acute renal failure or hyperkalemia. Thus the frequent practice of withholding ACE inhibitors from patients with mild renal insufficiency is unwarranted, especially since MRI identifies a group at high risk that appears to benefit most from treatment. Moreove

Topics: Age Factors; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Creatinine; Diabetes Complications; Female; Follow-Up Studies; Humans; Hypertension; Incidence; Male; Middle Aged; Nephrosclerosis; Prognosis; Ramipril; Randomized Controlled Trials as Topic; Renal Insufficiency; Risk Factors; Sex Factors; Time Factors

Perindopril is a long-acting, once-daily lipophilic angiotensin-converting enzyme inhibitor with high tissue angiotensin-converting enzyme affinity, lowering angiotensin II and potentiating bradykinin. Efficacy, safety, and tolerability of perindopril are well established in the treatment of hypertension and heart failure. Moreover, large morbidity-mortality trials, such as the EUROPA, PROGRESS, and PREAMI have shown that treatment with perindopril reduces morbidity and mortality and prevents cardiovascular disease in a large range of patients with vascular diseases, whether or not they are hypertensive. Thus, the outcomes of these and other trials support the concept of cardiovascular protective properties of angiotensin-converting enzyme inhibition with perindopril in addition to the obvious blood-pressure-lowering effect. Considering its properties and the clinical evidence on efficacy and tolerability that has been gathered, perindopril should be considered a first-line therapeutic agent in hypertension, heart failure and acute myocardial infarction and a tool of secondary prevention of coronary artery disease.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Heart Failure; Humans; Hypertension; Indoles; Male; Middle Aged; Multicenter Studies as Topic; Myocardial Infarction; Perindopril; Prospective Studies; Ramipril; Randomized Controlled Trials as Topic; Risk; Risk Factors; Stroke; Time Factors

Results from experimental and epidemiologic studies suggest an influence of oxidative stress on development and progression of atherosclerosis in man. Prospective endpoint studies failed to support this hypothesis. The current literature is summarized in this review.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Antioxidants; Arteriosclerosis; Ascorbic Acid; Aspirin; beta Carotene; Cardiovascular Diseases; Controlled Clinical Trials as Topic; Double-Blind Method; Female; Follow-Up Studies; Free Radicals; Humans; Male; Nutritional Physiological Phenomena; Oxidative Stress; Placebos; Platelet Aggregation Inhibitors; Primary Prevention; Prospective Studies; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Time Factors; Tocopherols; Vitamins

Hypertension in combination with clinically overt diabetes mellitus is recognized as a particularly powerful combination of risk factors that greatly increases cardiovascular vulnerability. There is also evidence that presumed pre-diabetic conditions such as insulin resistance, hyperinsulinaemia and compensatory hyperglycaemia may amplify overall cardiovascular risk in patients with hypertension, especially when encountered as part of the condition known as metabolic syndrome X (Reaven's syndrome). The long-term benefits of antihypertensive therapy may be compromised if these drugs exert adverse effects on metabolic parameters such as insulin sensitivity, or if they promote a transition from pre-diabetes to overt diabetes. Class differences in the effects of antihypertensives on metabolic indices may therefore be an important consideration when choosing treatment for patients who exhibit these characteristics. Experience from clinical trials suggests that drugs that target the renin-angiotensin system may have metabolic advantages over drugs such as beta-blockers and diuretics, but this conclusion has not been proved definitively. Moxonidine, which selectively targets imidazoline type-1 receptors in the sympathetic vasomotor centres of the rostral-ventrolateral medulla, is an effective antihypertensive and has been reported to exert favourable metabolic effects in preclinical and clinical studies. The MARRIAGE study (Moxonidine And Ramipril Regarding Insulin And Glucose Evaluation) will extend these preliminary observations by comparing the effects of moxonidine and the ACE inhibitor ramipril--and the combination of both drugs--on metabolic and haemodynamic parameters in patients with hypertension and impaired fasting glycaemia. A description is provided of the design and conduct of MARRIAGE.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Hypertension; Imidazoles; Imidazoline Receptors; Insulin Resistance; Metabolic Syndrome; Ramipril; Receptors, Drug; Risk

Topics: Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; C-Reactive Protein; Cardiovascular Diseases; Humans; Inflammation; Myocardial Infarction; Prognosis; Ramipril; Risk Factors; Stroke

Treatment with angiotensin converting enzyme (ACE) inhibitors reduces mortality and morbidity among patients with heart failure, left-ventricular dysfunction after myocardial infarction and with hypertension. In addition, they have been shown to slow the progression of chronic kidney disease and reduce the recurrence of stroke and vascular events.. There has been an enormous interest in the potential cardioprotective effects of ACE inhibitors. This principle has been assessed in two landmark double blind placebo controlled clinical trials, HOPE and EUROPA. This article seeks to review and compare the important findings of these two clinical studies.. In the HOPE study, ramipril once daily produced a 22% reduction in the primary composite endpoint of myocardial infarction, stroke, or cardiovascular death (P < 0.001) among an older cohort (>55 years) of patients at high risk of future cardiovascular complications. The EUROPA study assessed the effects of the ACE inhibitor perindopril in a larger group of lower risk patients with established stable cardiovascular disease. In EUROPA, once daily treatment with perindopril lead to a significant 20% relative risk reduction in the combined primary endpoint (cardiovascular mortality, non-fatal myocardial infarction, and resuscitated cardiac arrest; p = 0.0003).. HOPE and EUROPA provide compelling evidence to suggest that all patients with evidence of stable cardiovascular disease or diabetes (plus one additional risk factor) should be treated with an ACE inhibitor.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Controlled Clinical Trials as Topic; Humans; Perindopril; Ramipril

To evaluate the effectiveness of ramipril in the prevention and treatment of cardiovascular disease and determine its need for inclusion on a formulary.. A MEDLINE and PubMed database search was conducted (1987-May 2002). Only journals written in the English language were selected for review. DATA EXTRACTION AND STUDY SELECTION: Articles reporting the use of ramipril in humans were evaluated. Emphasis was placed on randomized, controlled trials assessing efficacy.. Ramipril is an angiotensin-converting enzyme (ACE) inhibitor that exerts its effects through inhibition of the renin-angiotensin-aldosterone system. It exhibits a safety profile that is similar to that of other ACE inhibitors and is comparable in cost to the majority of the available agents. Clinical trials have proven the effectiveness of ACE inhibitors in the treatment of hypertension, heart failure, and nephropathy. Ramipril, however, is the only ACE inhibitor currently approved for the prevention of cardiovascular events in high-risk patients without evidence of left-ventricular dysfunction or heart failure, based on the results of the HOPE (Heart Outcomes Prevention Evaluation) trial. Whether this effect is specific to ramipril has yet to be proven. This article emphasizes the major trials involving ramipril including the AIRE (Acute Infarction Ramipril Efficacy), REIN (Ramipril Efficacy in Nephropathy), and HOPE trials.. Although similar to other ACE inhibitors in many aspects, it cannot be assumed that the benefits shown with ramipril in the HOPE trial are a class effect. Ongoing trials should help to clarify this matter. Until this time, current evidence justifies the inclusion of ramipril on a formulary.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Humans; Liver Diseases; Racial Groups; Ramipril; Randomized Controlled Trials as Topic; Renal Insufficiency

Costs of providing a particular medical service can be measured, but it is more difficult to assess whether the service provides good value for the money spent. Rigorous trials have demonstrated the health benefits connected with interventions for treatment and prevention of cardiovascular disease (CVD), and in-depth analyses of the costs associated with many of those interventions have been performed. Careful use of terminology clearly differentiating among cost-minimization (relative costs of proved equivalent therapeutics), cost-effectiveness (lives saved or years of life added), and cost-benefit (total net effect in monetary terms) analyses is warranted. Although trials commonly assess clinical effectiveness as reductions in mortality or CVD-specific outcomes, improvement in quality of life may be equally important and is expressed in quality-adjusted life-years. Comparisons between therapies can be assessed as a cost-effectiveness ratio. Extensive cost-effectiveness studies have been conducted on many important cardiovascular therapies: (1) beta-blockers and diuretics for multiple CVD outcomes, mortality, and prevention of recurrent myocardial infarction (MI); (2) statins for both primary and secondary prevention of CVD; (3) enalapril for prevention and treatment of congestive heart failure; (4) tissue plasminogen activator treatment of acute MI; (5) coronary artery bypass graft for left main, single-, and 2-vessel coronary artery disease, or severe angina; (6) physician counseling for smoking; and (7) radiofrequency ablation therapy for Wolff-Parkinson-White syndrome. Therapies considered economically attractive include (1) secondary prevention with statins in hyperlipidemia, (2) smoking cessation programs, (3) primary prevention in treatment of high blood pressure with diuretics and beta-blockers, (4) primary prevention with regular exercise programs, (5) secondary prevention with cardiac rehabilitation, and (6) postinfarction treatment with beta-blockers and angiotensin-converting enzyme (ACE) inhibitors. A recent cost-minimization analysis has been performed showing aspirin to be a "best buy" therapy for secondary prevention of CVD. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized Assessment Study in ACE-I Intolerant Patients with Cardiovascular Disease (TRANSCEND) program provide potential opportunities for both cost-minimization and cost-effectiveness analyses.

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Cost-Benefit Analysis; Drug Therapy, Combination; Humans; Life Expectancy; Models, Econometric; Ramipril; Survival Analysis; Telmisartan; United States

The renin-angiotensin system evolved to maintain volume homeostasis and blood pressure and to prevent ischemia during acute volume loss. But in the present age, these mechanisms are redundant, and the clinical significance of angiotensin II results from its pathologic effects, which are mediated by the angiotensin II type 1 (AT(1)) receptor. Activation of AT(1) receptors has been linked to pathologic processes that contribute to atherosclerosis and ischemic events, including oxidative stress, inflammatory processes, low-density lipoprotein cholesterol trafficking, and prothrombotic states. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) program will compare the efficacy of the angiotensin II receptor blocker (ARB) telmisartan, the angiotensin-converting enzyme (ACE) inhibitor ramipril, and combination therapy with telmisartan plus ramipril for reducing cardiovascular risk. The ARB telmisartan is distinguished by its long duration of action, which compares favorably with some other ARBs and conventional antihypertensives. Ramipril was shown in the Heart Outcomes Prevention Evaluation (HOPE) study to reduce the risk for myocardial infarction (MI) and other cardiovascular events in patients at high risk for cardiovascular events but without heart failure or a low ejection fraction. The ONTARGET program consists of 2 randomized, double-blind, multicenter international trials: a principal trial, ONTARGET, and a parallel trial, Telmisartan Randomized Assessment Study in ACE-I Intolerant Patients with Cardiovascular Disease (TRANSCEND). The treatment arms for the principal ONTARGET study are telmisartan 80 mg, ramipril 10 mg, and combination therapy with telmisartan 80 mg plus ramipril 10 mg; for the parallel study TRANSCEND, the treatment arms are telmisartan 80 mg and placebo. Both trials will assess cardiovascular outcomes in patients at high risk using the same criteria as that of the HOPE study, with a single exception: the TRANSCEND trial will enroll patients who do not tolerate ACE inhibitor treatment. The primary end points in both ONTARGET and TRANSCEND are death caused by cardiovascular disease, acute MI, stroke, and hospitalization because of congestive heart failure. The secondary end points include newly diagnosed heart failure, revascularization, new-onset type 2 diabetes mellitus, nephropathy, cognitive decrease and dementia, and newly diagnosed atrial fibrillation; these will be used for hypothesis

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Ramipril; Renin-Angiotensin System; Telmisartan

Ramipril (Altace)Use of tradenames is for product identification purposes only and does not imply endorsement.), an angiotensin-converting enzyme (ACE) inhibitor, is a prodrug which is rapidly hydrolyzed after absorption to the active metabolite ramiprilat. Earlier trials have shown that ACE inhibitors, when given to patients with low ejection fractions, have reduced the relative risk of myocardial infarction (MI) and other ischemic events by 14-23%. Subsequently, the double-blind, randomized, placebo-controlled, multicenter Heart Outcomes Prevention Evaluation (HOPE) study has shown that, in patients who are not known to have low ejection fraction or heart failure but are at increased risk for developing cardiovascular events, ramipril reduced the incidence of stroke, MI and death due to cardiovascular disease. Results from the HOPE study, in which 9297 patients were randomized to receive either ramipril 10 mg/day or placebo for a mean of 4.5 years, indicate that ramipril reduced the relative risk of the composite outcome of MI, stroke and cardiovascular death by 22%. The incidence of the composite outcome was significantly lower in the ramipril group than in the placebo group (14.0% vs 17.8%). Patients who received ramipril, compared with placebo recipients, had a significantly decreased incidence of stroke, MI or death due to cardiovascular disease (3.4% vs 4.9%, 9.9% vs 12.3% and 6.1% vs 8.1%, respectively). The relative risk of death from any cause was reduced among patients who received ramipril. In addition, treatment with ramipril reduced as the incidence of revascularization procedures, and, among patients with diabetes mellitus, ramipril reduced the incidence of complications related to diabetes mellitus, including the development of overt nephropathy. Moreover, in patients without a previous diagnosis of diabetes mellitus, ramipril, compared with placebo, significantly reduced the development of diabetes mellitus. Furthermore, compared with patients receiving placebo, patients receiving ramipril had a reduced rate of progression of carotid artery wall thickness.. Ramipril 10 mg/day can significantly reduce the incidence of MI, stroke or death from cardiovascular causes in patients aged > or =55 years who are at increased risk for the development of ischemic cardiovascular events due to a history of stroke, coronary artery disease (with controlled blood pressure), diabetes mellitus plus at least one other risk factor or peripheral vascular disease but no heart failure or low ejection fraction. Therefore, in addition to dietary and lifestyle modifications, ramipril should be an integral part of secondary prevention therapy in patients at increased risk for the development of cardiovascular events.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiovascular Diseases; Humans; Ramipril

When first introduced in 1981, angiotensin-converting enzyme (ACE) inhibitors were indicated only for treatment of refractory hypertension. Since then, they have been shown to reduce morbidity or mortality in congestive heart failure, myocardial infarction, diabetes mellitus, chronic renal insufficiency, and atherosclerotic cardiovascular disease. Pathologies underlying these conditions are, in part, attributable to the renin-angiotensin-aldosterone system. Angiotensin II contributes to endothelial dysfunction. altered renal hemodynamics, and vascular and cardiac hypertrophy. ACE inhibitors attenuate these effects. Clinical outcomes of ACE inhibition include decreases in myocardial infarction (fatal and nonfatal), reinfarction, angina, stroke, end-stage renal disease, and morbidity and mortality associated with heart failure. ACE inhibitors are generally well tolerated and have few contraindications. (Am Fam Physician 2002;66:473.)

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Captopril; Cardiovascular Diseases; Clinical Trials as Topic; Contraindications; Diabetic Nephropathies; Drug Costs; Enalapril; Fosinopril; Heart Failure; Humans; Hypertension; Indoles; Isoquinolines; Lisinopril; Meta-Analysis as Topic; Myocardial Infarction; Perindopril; Quinapril; Ramipril; Renin-Angiotensin System; Risk; Tetrahydroisoquinolines; United States

Patients with end-stage renal disease die from cardiovascular disease at a much younger age than people in the general population do. Here, we review the evidence linking early renal insufficiency (ERI) to an increased cardiovascular risk. A number of cardiovascular risk factors become prevalent with ERI, including night-time hypertension, increase in serum levels of lipoprotein (a), homocysteine and asymmetric dimethyl-arginine, and insulin resistance. Also, an epidemiologic association between coronary artery disease (CAD) and nephrosclerosis, a frequent cause of ERI in the elderly, is documented. In the middle-aged, general population ERI, found in 8% of women and 9% of men, was not associated with cardiovascular disease. However, in a representative sample of middle-aged British men the risk of stroke was 60% higher for the subgroup of individuals with ERI. In people at high cardiovascular risk (mostly CAD), the Heart Outcomes Prevention Evaluation (HOPE) study found a 2-fold (unadjusted) or 1.4-fold (adjusted) higher incidence of cardiovascular outcomes with ERI. The incidence of primary outcome increased with the level of serum creatinine. At least four studies have determined the cardiovascular risk associated with ERI in hypertension. In Hypertension Detection and Follow-up Program, as in HOPE, cardiovascular mortality increased with higher serum creatinine levels (5-fold difference in cardiovascular mortality between the lowest and the highest creatinine strata). In patients with hypertension with low risk, the Hypertension Optimal Treatment and a small Italian trial found about a doubling in cardiovascular outcomes in ERI. However, in the Multiple Risk Factor Intervention Trial, not baseline serum creatinine level, but its increase on follow-up predicted future cardiovascular disease. These observational data suggest that ERI, independent of etiology, is a strong predictor of cardiovascular disease, present in 10% of a population at low, and up to 30% at high, cardiovascular risk. No prospective therapeutic trials aimed at reducing the cardiovascular burden in individuals with ERI are available. Subgroup analyses of the HOPE study indicate that ACE inhibition with ramipril is beneficial without an increased risk of adverse effects like acute renal failure or hyperkalemia. Thus the frequent practice of withholding ACE inhibitors from patients with mild renal insufficiency is unwarranted, especially since this identifies a group at high risk who a

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Kidney Failure, Chronic; Ramipril; Risk Factors; Treatment Outcome

Proven cardiovascular benefit from angiotensin-converting enzyme (ACE) inhibition is a cornerstone of evidence-based medicine. The first study to show dramatic benefits from ACE inhibition was the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS-I), in which a 31% decrease in the rate of death was observed in patients with severe heart failure at the end of 1 year of enalapril treatment (p = 0.001). This result led to large long-term studies-including Survival and Ventricular Enlargement (SAVE), Acute Infarction Ramipril Efficacy (AIRE), Trandolapril Cardiac Evaluation (TRACE), and Study of Left Ventricular Dysfunction (SOLVD)-which verified that ACE inhibition decreases heart failure, myocardial infarction (MI), and mortality, and that striking benefit could be observed within 30 days. Short-term studies of patients in the acute phase of a heart attack verified that ACE inhibition provided rapid benefits. A meta-analysis of short-term (up to 8 weeks) studies of ACE inhibition (including CONSENSUS-II, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico [GISSI]-3, International Study of Infarct Survival [ISIS]-4, and the Chinese Captopril Study [CCS]-1) demonstrated that post-MI risk was reduced by 10% within the first day of treatment. The immediacy of the benefit suggested that ACE inhibition not only improved cardiovascular function in failing hearts but also affected important mechanisms in patients without overt heart failure. Effects on more general mechanisms of heart disease suggested that patients with problems other than hypertension or heart failure might benefit from ACE inhibitors. The Heart Outcomes Prevention Evaluation (HOPE) study investigated the hypothesis that ACE inhibition would confer benefits to patients who were at high risk for cardiovascular events, but who were without left ventricular dysfunction or heart failure. Long-term reductions in MI, stroke, cardiac arrest, and heart failure, as well as improvements in mortality, were observed in this population after treatment with ACE inhibitors. Substudies of the HOPE study revealed that ACE inhibition reduced progression of atherosclerosis and improved myocardial remodeling. Taken together, these studies provide evidence that supports treatment of a broad population of patients at risk for cardiovascular events with ACE inhibitors. The next step is to combine ACE inhibition with other treatments to maximize patient benefit. The Ongoing Telmisa

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Clinical Trials as Topic; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Ramipril; Survival Rate; Telmisartan; Treatment Outcome

The Heart Outcomes Prevention Evaluation (HOPE) study conclusively demonstrated that ramipril, an angiotensin-converting enzyme (ACE) inhibitor, reduces the risk of cardiovascular death, myocardial infarction (MI), and death in patients at risk for cardiovascular events but without heart failure. The Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE) substudy demonstrated that ramipril also reduced atherosclerosis. These results suggest that the renin-angiotensin system (RAS) has a more important role in the development and progression of atherosclerosis than previously believed, and they indicate the need for further clinical studies to define the range of benefits available from modifying the RAS. Achieving maximum benefit may require treatment with both an ACE inhibitor and an angiotensin II type-1 receptor blocker (ARB). The Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) study indicated that combining an ACE inhibitor with an ARB decreased blood pressure and improved the ejection fraction more than treatment with either drug alone in patients with congestive heart failure. The Valsartan in Heart Failure Trial (Val-HeFT) showed that the combination of an ACE inhibitor and an ARB reduced hospitalization for heart failure in patients with congestive heart failure by 27.5%, although no decrease in all-cause mortality was observed. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) is a large, long-term study (23,400 patients, 5.5 years). It will compare the benefits of ACE inhibitor treatment, ARB treatment, and treatment with an ACE inhibitor and ARB together, in a study population with established coronary artery disease, stroke, peripheral vascular disease, or diabetes with end-organ damage. Patients with congestive heart failure will be excluded. In a parallel study, patients unable to tolerate an ACE inhibitor will be randomized to receive telmisartan or placebo (the Telmisartan Randomized Assessment Study in ACE-I Intolerant Patients with Cardiovascular Disease [TRANSCEND]). The primary endpoint for both trials is a composite of cardiovascular death, MI, stroke, and hospitalization for heart failure. Secondary endpoints will investigate reductions in the development of diabetes mellitus, nephropathy, dementia, and atrial fibrillation. These 2 trials are expected to provide new insights into the optimal treatment of patients

Topics: Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Carotid Artery Diseases; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Prognosis; Ramipril; Receptor, Angiotensin, Type 1; Telmisartan; Treatment Outcome; Ultrasonography; Ventricular Dysfunction, Left

Diabetes has long been recognized as a risk factor for heart disease. Recent evidence has brought to light complex interactions that seem to influence both the renal and the vascular complications of diabetes. The use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been shown to ameliorate renal and cardiac risks in both type 1 and type 2 diabetes to a degree that is disproportionate to blood pressure-lowering effects. The judicious use of these agents can materially improve the prognosis for patients with diabetes.

Topics: Albuminuria; Amlodipine; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biphenyl Compounds; Calcium Channel Blockers; Captopril; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Humans; Irbesartan; Kidney Diseases; Losartan; Prognosis; Ramipril; Tetrazoles

Ramipril, an angiotensin-converting enzyme (ACE) inhibitor, is a prodrug which is rapidly hydrolysed after absorption to the active metabolite ramiprilat. Earlier trials have shown that ACE inhibitors, when given to patients with low ejection fractions, have reduced the relative risk of myocardial infarction (MI) and other ischaemic events by 14 to 23%. Subsequently, the double-blind, randomised, placebo-controlled, multicentre Heart Outcomes Prevention Evaluation (HOPE) study has shown that, in patients who are not known to have low ejection fraction or heart failure but are at increased risk for developing cardiovascular events, ramipril reduced the incidence of stroke, MI and death due to cardiovascular disease. Results from the HOPE study, in which 9297 patients were randomised to receive either ramipril 10 mg/day or placebo for a mean of 4.5 years, indicate that ramipril reduced the relative risk of the composite outcome of MI, stroke and cardiovascular death by 22%. The incidence of the composite outcome was significantly lower in the ramipril group than in the placebo group (14.0 vs 17.8%). Patients who received ramipril, compared with placebo recipients, had a significantly decreased incidence of stroke, MI or death due to cardiovascular disease (3.4 vs 4.9%, 9.9 vs 12.3% and 6.1 vs 8.1%, respectively). The relative risk of death from any cause was reduced among patients who received ramipril. In addition, treatment with ramipril reduced as the incidence of revascularisation procedures, and, among patients with diabetes mellitus, ramipril reduced the incidence of complications related to diabetes mellitus, including the development of overt nephropathy. Moreover, in patients without a previous diagnosis of diabetes mellitus, ramipril, compared with placebo, significantly reduced the development of diabetes mellitus. Furthermore, compared with patients receiving placebo, patients receiving ramipril had a reduced rate of progression of carotid artery wall thickness.. Ramipril 10 mg/day can significantly reduce the incidence of MI, stroke or death from cardiovascular causes in patients aged > or =55 years who are at increased risk for the development of ischaemic cardiovascular events due to a history of stroke, coronary artery disease (with controlled blood pressure), diabetes mellitus plus at least one other risk factor or peripheral vascular disease but no heart failure or low ejection fraction. Therefore, in addition to dietary and lifestyle modifications, ramipril should be an integral part of secondary prevention therapy in patients at increased risk for the development of cardiovascular events.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiovascular Diseases; Disease Progression; Humans; Ramipril; Randomized Controlled Trials as Topic

The Heart Outcomes Prevention Evaluation study was a landmark study employing the angiotensin-converting enzyme inhibitor ramipril in a patient population pre-destined for vascular events. This study found that a 10 mg dose of ramipril in comparison with placebo reduced the incidence of death, myocardial infarction, stroke, and death from cardiovascular causes by 22%. This improvement in outcome was viewed as a direct consequence of ramipril, although the fact that blood pressure was reduced with ramipril has cast some considerable doubt on this supposition. Whether the observed findings in this study are a 'class effect' for all angiotensin-converting enzyme inhibitors is unclear. To its credit, ramipril is the first angiotensin-converting enzyme inhibitor shown to prevent ischemic events in high-risk patients without discernible left ventricular dysfunction. Other similar trials are underway, which are studying similar populations to those included in this landmark study and should resolve the question of whether the cardioprotective effects of angiotensin-converting enzyme inhibitors are a 'class effect'.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Controlled Clinical Trials as Topic; Evaluation Studies as Topic; Humans; Multicenter Studies as Topic; Myocardial Infarction; Ramipril; Stroke

The unique findings from the HOPE (Heart Outcomes Prevention Evaluation) study strongly support extending the use of the angiotensin-converting enzyme (ACE) inhibitor ramipril as a preventive agent for patients at high risk of cardiovascular events with normal left ventricular function. In addition, ramipril provides significant benefit in diabetic patients. These findings will impact on how ramipril is used in primary care, where ACE inhibitors are currently underprescribed. Patients reflecting the inclusion criteria of the HOPE study should be considered as suitable candidates for long-term ramipril therapy as an addition to their existing drug regimen. Screening should include control of kidney function (by serum creatinine), particularly within the first two weeks of treatment, in addition to regular monitoring of serum potassium. However, the HOPE study shows that ramipril is well tolerated at high doses and over a long treatment period. The effectiveness of therapy should also be regularly reviewed and dose adjustments made where necessary. If concern remains, referral to a specialist--a cardiologist or a diabetologist--may ultimately be necessary.

Topics: Adrenergic beta-Antagonists; Algorithms; Angiotensin-Converting Enzyme Inhibitors; Anticholesteremic Agents; Aspirin; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Complications; Family Practice; Female; Humans; Male; Platelet Aggregation Inhibitors; Practice Patterns, Physicians'; Ramipril

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Drug Therapy, Combination; Hemodynamics; Humans; Kidney Diseases; Kidney Function Tests; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Vitamin E

Ramipril is a long-acting, lipophylic angiotensin converting enzyme inhibitor, its principle action is to inhibit the conversion of angiotensin I to the active angiotensin II. Ramipril is indicated in the treatment of hypertension, congestive cardiac failure (including that following acute myocardial infarction), nephropathy (with and without diabetes mellitus) and now, following the findings of the HOPE study, in the prevention of cardiovascular events (including myocardial infarction) in high risk individuals. This article concentrates on reviewing the evidence supporting ramipril's use in these indications.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus; Heart Failure; Humans; Hypertension; Myocardial Infarction; Proteinuria; Ramipril

Based on the results of large clinical trials, ACE inhibitors are established as routine treatment after acute myocardial infarction accompanied by heart failure. Pathophysiologically, the benefit of ACE inhibitors has been attributed to an effect on remodelling of the left ventricle. In the past decade, it has been suggested that ACE inhibitors might have other important mechanisms of action and accordingly be useful for other conditions than those they have been used for until now.. We reviewed clinical studies of ACE inhibitors with special emphasis on the use of these agents in the acute phase of myocardial infarction and in the follow-up period. These studies were assessed together with the recently published Heart Outcomes Prevention Evaluation (HOPE) study.. In the HOPE study it was found that ACE inhibition protected against cardiovascular events in patients at high risk due to atherosclerotic disease, but without dysfunction of the left ventricle. The effect is most likely a retarding of the atherothrombotic process in the coronary arteries.. The latest results are important for clinical practice. Other post-infarction patients than those with myocardial failure may benefit from treatment with ACE inhibitors. We also discuss the timing of ACE inhibitor treatment, the importance of an adequate ACE inhibitor dose, and combination with other treatment regimens used in secondary prevention.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Controlled Clinical Trials as Topic; Follow-Up Studies; Humans; Myocardial Infarction; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Vitamin E

The Heart Outcomes Prevention Evaluation (HOPE) study was designed to test the hypotheses that two preventive intervention strategies, namely angiotensin-converting enzyme (ACE) inhibition or vitamin E, would improve morbidity and mortality in patients at high risk of cardiovascular events compared with placebo. This review addresses the ACE inhibitor (ACE-I) (ramipril) arm of the study, both on the trial population as a whole, and on the large diabetic subgroup. Patients were included in the study who were considered to be at high risk of future fatal or non-fatal cardiovascular events, by virtue of their age (>55 years), existing or previous cardiovascular disease, or diabetes. Diabetics had at least one other risk factor, either known vascular disease or other factors such as cigarette smoking, high cholesterol or hypertension. Ramipril or placebo was added to concomitant medication, which included, in a substantial proportion of patients, antihypertensive drugs (excluding ACE-I), lipid-lowering agents or aspirin. As a result, despite a history of hypertension in nearly 50% of patients, blood pressure (BP) at baseline was normal and the reduction in BP attributable to ramipril modest (a fall of 3-4 mmHg systolic BP and 1-2 mmHg diastolic). The trial was stopped early on the advice of the Data Monitoring Committee because of convincing evidence of the benefit of ramipril treatment on the combined primary endpoint of cardiovascular death, non-fatal myocardial infarct (MI) and non-fatal stroke (14% vs. 17.8% on ramipril and placebo, respectively; relative risk reduction 22%, p<0.001). This comprised a risk reduction of 32% for stroke, 20% for MI, 26% for cardiovascular death and 16% for all-cause mortality, as well as a reduction in the risk of several other endpoints including heart failure and revascularisation procedures. The results among the 3577 diabetic subjects were even more striking, with a reduction of 25% in the combined primary endpoint. This reduction in the combined endpoint and in particular the reduction in MI far exceeded that which would be expected from the modest fall in BP. Furthermore, a multiple regression analysis of the diabetic subgroup showed similar relative risk reductions even after allowing for the effects of the fall in BP. Possible explanations for the non BP-mediated benefits of ramipril include reduction of angiotensin II-induced intimal and vascular smooth muscle proliferation and possible plaque stabilisation. The HOP

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Controlled Clinical Trials as Topic; Diabetic Angiopathies; Humans; Ramipril; Risk Factors; Vascular Diseases

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiovascular Diseases; Diabetic Angiopathies; Humans; Hypertension; Ramipril; Randomized Controlled Trials as Topic; Renin-Angiotensin System

Ramipril is a long acting angiotensin converting enzyme (ACE) inhibitor, which exhibits similar pharmacodynamic properties to captopril and enalapril. Like enalapril it is a prodrug, which is hydrolysed after absorption to form the active metabolite ramiprilat which has a long elimination half-life, permitting once daily administration. In hypertensive patients daily doses in the range 2.5 to 20 mg are usually effective in reducing high blood pressure and maintaining satisfactory control during long term treatment. Patients who do not respond adequately to monotherapy with ramipril usually respond with the addition of a diuretic such as hydrochlorothiazide or piretanide. Ramipril 5 to 10 mg once daily shows comparable antihypertensive efficacy to usual therapeutic dosages of captopril, enalapril and atenolol in patients with mild to moderate essential hypertension. Preliminary data indicate that ramipril may be effective in indications such as severe essential hypertension and renal hypertension. It has also displayed beneficial effects in patients with moderate to severe congestive heart failure. Ramipril has been well tolerated and exhibits an adverse effect profile typical of ACE inhibitors as a class. In conclusion, ramipril will likely represent a useful alternative ACE inhibitor for use in patients with hypertension or congestive heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Ramipril

A polypill that includes key medications associated with improved outcomes (aspirin, angiotensin-converting-enzyme [ACE] inhibitor, and statin) has been proposed as a simple approach to the secondary prevention of cardiovascular death and complications after myocardial infarction.. In this phase 3, randomized, controlled clinical trial, we assigned patients with myocardial infarction within the previous 6 months to a polypill-based strategy or usual care. The polypill treatment consisted of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg). The primary composite outcome was cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization. The key secondary end point was a composite of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischemic stroke.. A total of 2499 patients underwent randomization and were followed for a median of 36 months. A primary-outcome event occurred in 118 of 1237 patients (9.5%) in the polypill group and in 156 of 1229 (12.7%) in the usual-care group (hazard ratio, 0.76; 95% confidence interval [CI], 0.60 to 0.96; P = 0.02). A key secondary-outcome event occurred in 101 patients (8.2%) in the polypill group and in 144 (11.7%) in the usual-care group (hazard ratio, 0.70; 95% CI, 0.54 to 0.90; P = 0.005). The results were consistent across prespecified subgroups. Medication adherence as reported by the patients was higher in the polypill group than in the usual-care group. Adverse events were similar between groups.. Treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse cardiovascular events than usual care. (Funded by the European Union Horizon 2020; SECURE ClinicalTrials.gov number, NCT02596126; EudraCT number, 2015-002868-17.).

Topics: Angiotensin-Converting Enzyme Inhibitors; Aspirin; Atorvastatin; Cardiovascular Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ischemic Stroke; Myocardial Infarction; Platelet Aggregation Inhibitors; Ramipril; Secondary Prevention

In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking.. We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident heart failure (outpatient symptomatic heart failure or heart failure leading to hospitalization), whichever occurred first.. A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril-valsartan and 2831 to receive ramipril. Over a median of 22 months, a primary-outcome event occurred in 338 patients (11.9%) in the sacubitril-valsartan group and in 373 patients (13.2%) in the ramipril group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P = 0.17). Death from cardiovascular causes or hospitalization for heart failure occurred in 308 patients (10.9%) in the sacubitril-valsartan group and in 335 patients (11.8%) in the ramipril group (hazard ratio, 0.91; 95% CI, 0.78 to 1.07); death from cardiovascular causes in 168 (5.9%) and 191 (6.7%), respectively (hazard ratio, 0.87; 95% CI, 0.71 to 1.08); and death from any cause in 213 (7.5%) and 242 (8.5%), respectively (hazard ratio, 0.88; 95% CI, 0.73 to 1.05). Treatment was discontinued because of an adverse event in 357 patients (12.6%) in the sacubitril-valsartan group and 379 patients (13.4%) in the ramipril group.. Sacubitril-valsartan was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril among patients with acute myocardial infarction. (Funded by Novartis; PARADISE-MI ClinicalTrials.gov number, NCT02924727.).

Topics: Aged; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Cardiovascular Diseases; Double-Blind Method; Drug Combinations; Female; Heart Failure; Hospitalization; Humans; Hypotension; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Ramipril; Stroke Volume; Valsartan; Ventricular Dysfunction, Left

To compare the pharmacodynamics of the CNIC polypill (atorvastatin 40mg/ramipril 10mg/aspirin 100mg) in terms of low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP), with the corresponding reference products (atorvastatin and ramipril).. This was a multicenter, randomized, open-label, and parallel 3-arm study comparing the effect of the CNIC polypill vs ramipril 10mg and atorvastatin 40mg on SBP and LDL-C. The coprimary endpoints were differences in the adjusted mean 24-hour SBP (using ambulatory BP measurement) and LDL-C during the study period estimated using an ANCOVA model.. Of the 241 patients included in the per protocol population, 84 received the CNIC polypill (group A), 84 atorvastatin (group B), and 73 ramipril (group C). SBP decreased from 139.3±12.5 to 133.2±12.9mmHg in group A and from 138.1±11.9 to 134.0±12.8mmHg in group C (baseline adjusted mean difference for the decrease in SBP was 1.77mmHg (90%CI, -0.5 to 4.0) in favor of group A, without reaching statistical significance. LDL-C was reduced by 33.9±21.6 and 29.2±25.8mg/dL in groups A and B, respectively (baseline adjusted mean difference for the decrease in LDL-C was 7.0% (90%CI, 1.5-12.4), a significantly greater decrease with the polypill). The 3 treatments were well tolerated.. The results of this study rule out a negative effect on blood pressure of the interaction between the components of the CNIC polypill. The reduction in LDL-C was greater in the CNIC polypill group, suggesting a synergistic effect of the components.

Topics: Aspirin; Atorvastatin; Cardiovascular Diseases; Cholesterol, LDL; Drug Combinations; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ramipril; Treatment Outcome

Eggs are a rich source of essential nutrients, but they are also a source of dietary cholesterol. Therefore, some guidelines recommend limiting egg consumption. However, there is contradictory evidence on the impact of eggs on diseases, largely based on studies conducted in high-income countries.. Our aim was to assess the association of egg consumption with blood lipids, cardiovascular disease (CVD), and mortality in large global studies involving populations from low-, middle-, and high-income countries.. We studied 146,011 individuals from 21 countries in the Prospective Urban Rural Epidemiology (PURE) study. Egg consumption was recorded using country-specific validated FFQs. We also studied 31,544 patients with vascular disease in 2 multinational prospective studies: ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial) and TRANSCEND (Telmisartan Randomized Assessment Study in ACEI Intolerant Subjects with Cardiovascular Disease). We calculated HRs using multivariable Cox frailty models with random intercepts to account for clustering by study center separately within each study.. In the PURE study, we recorded 14,700 composite events (8932 deaths and 8477 CVD events). In the PURE study, after excluding those with history of CVD, higher intake of egg (≥7 egg/wk compared with <1 egg/wk intake) was not significantly associated with blood lipids, composite outcome (HR: 0.96; 95% CI: 0.89, 1.04; P-trend = 0.74), total mortality (HR: 1.04; 95% CI: 0.94, 1.15; P-trend = 0.38), or major CVD (HR: 0.92; 95% CI: 0.83, 1.01; P-trend = 0.20). Similar results were observed in ONTARGET/TRANSCEND studies for composite outcome (HR 0.97; 95% CI: 0.76, 1.25; P-trend = 0.09), total mortality (HR: 0.88; 95% CI: 0.62, 1.24; P-trend = 0.55), and major CVD (HR: 0.97; 95% CI: 0.73, 1.29; P-trend = 0.12).. In 3 large international prospective studies including ∼177,000 individuals, 12,701 deaths, and 13,658 CVD events from 50 countries in 6 continents, we did not find significant associations between egg intake and blood lipids, mortality, or major CVD events. The ONTARGET and TRANSCEND trials were registered at clinicaltrials.gov as NCT00153101. The PURE trial was registered at clinicaltrials.gov as NCT03225586.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Eggs; Female; Humans; Lipids; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Ramipril; Telmisartan

Studies have shown a non-linear relationship between systolic blood pressure (SBP) and diastolic blood pressure (DBP) and outcomes, with increased risk observed at both low and high blood pressure (BP) levels. We hypothesized that the BP-risk association is different in individuals with and without diabetes at high cardiovascular risk.. We identified patients with (N = 11 487) or without diabetes (N = 19 450), from 30 937 patients, from 133 centres in 44 countries with a median follow-up of 56 months in the ONTARGET/TRANSCEND studies. Patients had a prior history of stroke, myocardial infarction (MI), peripheral artery disease, or were high-risk diabetics. Patients in ONTARGET had been randomized to ramipril 10 mg daily, telmisartan 80 mg daily, or the combination of both. Patients in TRANSCEND were ACE intolerant and randomized to telmisartan 80 mg daily or matching placebo. We analysed the association of mean achieved in-trial SBP and DBP with the composite outcome of cardiovascular death, MI, stroke and hospitalization for congestive heart failure (CHF), the components of the composite, and all-cause death. Data were analysed by Cox regression and restricted cubic splines, adjusting for risk markers including treatment allocation and accompanying cardiovascular treatments. In patients with diabetes, event rates were higher across the whole spectrum of SBP and DBP compared with those without diabetes (P < 0.0001 for the primary composite outcome, P < 0.01 for all other endpoints). Mean achieved in-trial SBP ≥160 mmHg was associated with increased risk for the primary outcome [diabetes/no diabetes: adjusted hazard ratio (HR) 2.31 (1.93-2.76)/1.66 (1.36-2.02) compared with non-diabetics with SBP 120 to <140 mmHg], with similar findings for all other endpoints in patients with diabetes, and for MI and stroke in patients without diabetes. In-trial SBP <120 mmHg was associated with increased risk for the combined outcome in patients with diabetes [HR 1.53 (1.27-1.85)], and for cardiovascular death and all-cause death in all patients. In-trial DBP ≥90 mmHg was associated with increased risk for the primary outcome [diabetes/no diabetes: HR 2.32 (1.91-2.82)/1.61 (1.35-1.93) compared with non-diabetics with DBP 70 to <80 mmHg], with similar findings for all other endpoints, but not for CHF hospitalizations in patients without diabetes. In-trial DBP <70 mmHg was associated with increased risk for the combined outcome in all patients [diabetes/no diabetes: HR 1.77 (1.51-2.06)/1.30 (1.16-1.46)], and also for all other endpoints except stroke.. High on treatment BP levels (≥160 or ≥90 mmHg) are associated with increased risk of cardiovascular outcomes and death. Also low levels (<120 or <70 mmHg) are associated with increased cardiovascular outcomes (except stroke) and death. Patients with diabetes have consistently higher risks over the whole BP range, indicating that achieving optimal BP goals is most impactful in this group. These data favour guidelines taking lower BP boundaries into consideration, in particular in diabetes.. http://clinicaltrials.gov.Unique identifier: NCT00153101.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Determination; Cardiovascular Diseases; Case-Control Studies; Diabetes Mellitus; Diastole; Drug Therapy, Combination; Heart Failure; Hospitalization; Humans; Hypertension; Myocardial Infarction; Peripheral Arterial Disease; Ramipril; Retrospective Studies; Risk Factors; Stroke; Systole; Telmisartan

Current guidelines of hypertensive management recommend upper limits for systolic (SBP) and diastolic blood pressure (DBP). J-curve associations of BP with risk exist for some outcomes suggesting that lower limits of DBP goals may also apply. We examined the association between mean attained DBP and cardiovascular (CV) outcomes in patients who achieved an on-treatment SBP in the range of 120 to <140 mmHg in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND) trials on patients with high CV risk. This SBP range was associated with the lowest CV risk.. We analysed the outcome data from patients age 55 years or older with CV disease from the ONTARGET and TRANSCEND trials that randomized high-risk patients to ramipril, telmisartan, and the combination. In patients with controlled SBP (on-treatment 120 to <140 mmHg), the composite outcome of CV death, myocardial infarction, stroke and hospital admission for heart failure, the components thereof, and all-cause mortality were analysed according to mean on-treatment DBP as categorical (<70, 70 to <80, 80 to <90, and ≥90 mmHg) and continuous variable as well as the change of DBP according to baseline DBP. Pulse pressure (PP) was related to outcomes as a continuous variable.. In 16 099 of 31 546 patients, mean achieved SBP was 120 to <140 mmHg. The nominally lowest risk for all outcomes was observed at an achieved DBP of 70 to <80 mmHg. A higher achieved DBP was associated with a higher risk for the outcomes of stroke and of hospitalization for heart failure (≥80 mmHg) and myocardial infarction (≥90 mmHg). A lower achieved DBP (<70 mmHg) was associated with a higher risk for the primary outcome [hazard ratio (HR) 1.29, 95% confidence interval (95% CI) 1.15-1.45; P < 0.0001], myocardial infarction HR 1.54 (95% CI 1.26-1.88, P < 0.0001) and hospitalization for heart failure HR 1.81 (95% CI 1.47-2.24, P < 0.0001) and all-cause death (HR 1.19, 95% CI 1.04-1.35; P < 0.0001) while there was no signal for stroke and CV death compared to DBP 70 to <80 mmHg. A decrease of DBP was associated with lower risk when baseline DBP was >80 mmHg. The associations to outcomes were similar when patients were divided to SBP 120 to <130 mmHg or 130 to <140 mmHg for DBP or PP.. Compared to a DBP of 70 to <80 mmHg, lower and higher DBP was associated with a higher risk in patients achieving a SBP of 120 to <140 mmHg. Associations of DBP and PP to risk were similar notably at controlled SBP. These data suggest at optimal achieved SBP, risk is still defined by low or high DBP. These findings support guidelines which take DBP at optimal SBP control into consideration.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Drug Therapy, Combination; Female; Follow-Up Studies; Heart Failure; Hospitalization; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Ramipril; Risk Assessment; Single-Blind Method; Stroke; Telmisartan; Treatment Outcome

It is hypothesized that in individuals without clinical cardiovascular disease (CVD), but at increased CVD risk, a 50% to 60% reduction in CVD risk could be achieved using fixed dose combination (FDC) therapy (usually comprised of multiple blood-pressure agents and a statin [with or without aspirin]) in a single "polypill". However, the impact of a polypill in preventing clinical CV events has not been evaluated in a large randomized controlled trial.. TIPS-3 is a 2x2x2 factorial randomized controlled trial that will examine the effect of a FDC polypill on major CV outcomes in a primary prevention population. This study aims to determine whether the Polycap (comprised of atenolol, ramipril, hydrochlorothiazide, and a statin) reduces CV events in persons without a history of CVD, but who are at least at intermediate CVD risk. Additional interventions in the factorial design of the study will compare the effect of (1) aspirin versus placebo on CV events (and cancer), (2) vitamin D versus placebo on the risk of fractures, and (3) the combined effect of aspirin and the Polycap on CV events.. The study has randomized 5713 participants across 9 countries. Mean age of the study population is 63.9 years, and 53% are female. Mean INTERHEART risk score is 16.8, which is consistent with a study population at intermediate CVD risk.. Results of the TIP-3 study will be key to determining the appropriateness of FDC therapy as a strategy in the global prevention of CVD.

Topics: Adrenergic beta-1 Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atenolol; Cardiovascular Diseases; Diuretics; Double-Blind Method; Drug Combinations; Female; Global Health; Humans; Hydrochlorothiazide; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Male; Middle Aged; Primary Prevention; Ramipril; Retrospective Studies; Simvastatin

Although orthostatic hypotension (OH) is often considered a contraindication to blood pressure (BP) treatment, evidence is lacking. We examined the effect of BP goal or initial medication choice on OH in AASK (African American Study of Kidney Disease and Hypertension), a 2×3 factorial trial. Blacks with chronic kidney disease attributed to hypertension were randomly assigned 1 of 2 BP goals: intensive (mean arterial pressure, ≤92 mm Hg) or standard (mean arterial pressure, 102-107 mm Hg) and 1 of 3 initial medications (ramipril, metoprolol, and amlodipine). Postural changes in systolic BP, diastolic BP, or heart rate (HR) were determined after 2 minutes and 45 seconds of standing. OH was assessed each visit and defined using the consensus definition (drop in systolic BP ≥20 mm Hg or diastolic BP ≥10 mm Hg). Median follow-up was 4 years. Outcomes were congestive heart failure, stroke, nonfatal cardiovascular disease (CVD), fatal CVD, any CVD (composite of preceding events), and all-cause mortality. There were 1094 participants (mean age, 54.5±10.7 years; 38.8% female; OH was assessed at 52 864 visits). Mean seated systolic BP, diastolic BP, and HR were 150.3±23.9 mm Hg, 95.5±14.2 mm Hg, and 72.0±12.6 bpm, respectively. A more intensive BP goal did not alter the distributions of standing BP and was not associated with OH, but metoprolol was associated with systolic OH compared with ramipril (odds ratio, 1.68; 95% CI, 1.15-2.46) and amlodipine (odds ratio, 1.94; 95% CI, 1.09-3.44). Although consensus OH was associated with stroke (HR, 5.01; 95% CI, 1.80-13.92), nonfatal CVD (HR, 2.28; 95% CI, 1.21-4.30), and any CVD event (HR, 2.12; 95% CI, 1.12-3.98), neither BP goal or medication altered this risk. Concerns about causing OH or its CVD consequences should not deter a lower BP goal among adults with chronic kidney disease attributed to hypertension.

Topics: Amlodipine; Antihypertensive Agents; Blood Pressure; Blood Pressure Determination; Cardiovascular Diseases; Drug Monitoring; Female; Humans; Hypertension; Hypotension, Orthostatic; Male; Metoprolol; Middle Aged; Outcome Assessment, Health Care; Ramipril; United States

In 28 790 patients recruited for the ONTARGET (Ongoing Treatment Alone and in Combination With Ramipril Global End Point Trials) and TRANSCEND (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease) trials, we investigated the prognostic value for cardiovascular events (primary outcome) of (1)on-treatment visit-to-visit systolic blood pressure (SBP) variability versus mean SBP and (2) the 2 measures together. SBP variability was measured by the coefficient of variation (CV) of mean SBP to which it was unrelated. Confounders such as variable time and number of visits from which to calculate SBP-CV were avoided by using the same number of visits at identical times in all patients. The covariate-adjusted risk of the primary outcome (Cox models) increased as SBP-CV or mean on-treatment quintile SBP increased, but only for mean on-treatment SBP, the relationship achieved statistical significance: global test for trend,. URL: http//www.clinicaltrial.gov. Unique identifier: NCT00153101

Topics: Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Pressure Determination; Cardiovascular Diseases; Female; Humans; Hypertension; Male; Middle Aged; Observer Variation; Office Visits; Predictive Value of Tests; Prognosis; Ramipril; Risk Assessment; Risk Factors

Initiation of blockade of the renin-angiotensin system may cause an acute decrease in glomerular filtration rate (GFR): the prognostic significance of this is unknown. We did a post hoc analysis of patients with, or at risk for, vascular disease, in two randomized controlled trials: Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND), whose median follow-up was 56 months. In 9340 patients new to renin-angiotensin system blockade, who were then randomized to renin-angiotensin system blockade, a fall in GFR of 15% or more at 2 weeks after starting renin-angiotensin system blockade was seen in 1480 participants (16%), with persistence at 8 weeks in 700 (7%). Both acute increases and decreases in GFR after initiation of renin-angiotensin system blockade were associated with tendencies, mostly not statistically significant, to increased risk of cardiovascular outcomes, which occurred in 1280 participants, and of microalbuminuria, which occurred in 864. Analyses of creatinine-based outcomes were suggestive of regression to the mean. In more than 3000 patients randomized in TRANSCEND to telmisartan or placebo, there was no interaction between acute change in GFR and renal or cardiovascular benefit from telmisartan. Thus, both increases and decreases in GFR on initiation of renin-angiotensin system blockade are common, and may be weakly associated with increased risk of cardiovascular and renal outcomes. Changes do not predict increased benefit from therapy.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Disease Progression; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Odds Ratio; Ramipril; Renin-Angiotensin System; Risk Factors; Telmisartan; Time Factors; Treatment Outcome

Avoidance of death, disability, dementia, and cognitive dysfunction (DDCD) are high priorities for people in aging societies. Evidence is mounting that these conditions are associated with impaired glycemic control.. The aim of this study was to assess the strength of relationship between the degree of glucose elevation and the development of the composite elements of DDCD that impede successful/healthy aging in a population at high risk for cardiovascular disease. DESIGN, SETTING, PARTICIPANTS, AND MAIN OUTCOME MEASURE: The relationship between baseline fasting plasma glucose values and DDCD was determined among 31 227 participants of the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE intolerant Subjects With Cardiovascular Disease studies followed up for a median of 4.7 years. Several statistical models were used for the entire cohort and for those with and without normal fasting plasma glucose (ie, < 5.6 mmol/L) or a history of diabetes mellitus.. After adjusting for age and sex, a diagnosis of diabetes mellitus was associated with an approximately 1.6 greater odds of DDCD; every 1 mmol/L higher baseline fasting plasma glucose value was associated with a 1.09 (95% confidence interval 1.07, 1.10) greater odds. These associations persisted in the multivariate models (a 1.08 95% confidence interval 1.07, 1.1 greater odds after adjustment for age, sex, education, and depression).. In individuals with high cardiovascular risk, a direct relationship exists between levels of dysglycemia and the risk of DDCD. Further research is needed to understand the mechanisms underlying such an association and whether benefits can be derived from preventative strategies.

Topics: Aged; Aged, 80 and over; Aging; Benzimidazoles; Benzoates; Cardiovascular Diseases; Chronic Disease; Cognition Disorders; Dementia; Disabled Persons; Female; Glucose Metabolism Disorders; Humans; Male; Middle Aged; Ramipril; Risk Factors; Telmisartan

To examine the association between Mini-Mental State Examination (MMSE) score and motor vehicle crash (MVC) risk in a large cohort of community-dwelling participants with cardiovascular disease (CVD) or diabetes mellitus.. Prospective observational study.. Participants enrolled in the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial and Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease clinical trial, which included individuals aged 55 and older with CVD or diabetes mellitus.. Totally 17,538 frequent drivers (defined as driving at least once per week) who had completed a baseline MMSE.. Involvement in a MVC as the driver.. Baseline MMSE score was divided into four categories: 30, 27-29, 24-26, and <24. The median MMSE score was 29 (interquartile range 27-30), and 726 (4.1%) has a MMSE score of less than 24 at baseline. After a mean follow-up of 4.5 years, 1,068 (6.1%) participants were drivers in a MVC. Lower scores were not associated with future MVCs (MMSE score 29-27, hazard ratio (HR)=1.06, 95% confidence interval (CI)=0.93-1.22); MMSE score 26-24, HR=0.96, 95% CI=0.78-1.19; MMSE score<24, HR=0.72, 95% CI=0.50-1.05) on multivariable analysis. A MVC within the previous 2 years (HR=2.68, 95% CI=2.29-3.13) was the strongest predictor of future MVCs. Other clinical factors associated with greater MVC risk were depression, falls within the previous year, sleep apnea, and lower baseline systolic blood pressure.. In a population of frequent drivers, the MMSE does not predict MVCs. Other clinical factors have a stronger association with MVC risk.

Topics: Accidents, Traffic; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Automobile Driving; Benzimidazoles; Benzoates; Cardiovascular Diseases; Dementia; Diabetes Complications; Female; Humans; Male; Neuropsychological Tests; Predictive Value of Tests; Prospective Studies; Ramipril; Risk; Telmisartan

Dietary sodium, the main determinant of the pharmacodynamic response to renin-angiotensin system blockade, influences the pharmacokinetics of various cardiovascular drugs. We compared the effect of contrasted sodium diets on the pharmacokinetics of single oral doses of 8 mg candesartan cilexetil, 160 mg valsartan, 10 mg ramipril, and 50 mg atenolol administered to 64 (16 per group) normotensive male subjects randomly assigned to sodium depletion (SD) or sodium repletion (SR) in a crossover study. Pharmacodynamic response was assessed as the increase in plasma renin concentration for renin-angiotensin system blockers and electrocardiographic changes in PR interval duration for atenolol. The area under the curve (AUC) for plasma candesartan and atenolol concentrations was significantly lower for SR than for SD (respective ratios of AUC0-∞: 0.74; [90% CI, 0.66-0.82] and 0.69 [90% CI, 0.54-0.88], respectively), indicating a lack of bioequivalence between SR and SD. SR did not affect the pharmacokinetics of valsartan or ramipril. The increase in plasma renin concentration with the 3 renin-angiotensin system blockers was 10 times lower during the SR than the SD period. In the multiple regression analysis, the AUC0-24 of plasma drug concentration explained <1% and 21% of the variance of the AUC0-24 of delta plasma renin concentration for candesartan (P=0.8882/P=0.0368) during the SR and SD periods, respectively. The atenolol-induced lengthening of PR interval was fully reversed by SR. Thus, sodium balance modulates the pharmacokinetics of candesartan cilexetil and atenolol, with measurable effects on the selected pharmacodynamic end points.

Topics: Adolescent; Adrenergic beta-1 Receptor Antagonists; Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Atenolol; Benzimidazoles; Biphenyl Compounds; Cardiovascular Diseases; Chromatography, Liquid; Cross-Over Studies; Diet, Sodium-Restricted; Dose-Response Relationship, Drug; Electrocardiography; Humans; Immunoradiometric Assay; Male; Ramipril; Reference Values; Renin; Renin-Angiotensin System; Sodium, Dietary; Tetrazoles; Treatment Outcome; Young Adult

The impact of nonpersistence on events and of events on persistence is unclear. We studied the effects of nonpersistence on outcomes and events on nonadherence in a randomized placebo controlled trial in 40 countries on 25,620 patients.. In the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), persistent patients (n = 20,991) were compared with individuals who had permanently stopped study medications (n = 4,629).. Older age, female gender, less physical activity, less education, and history of stroke/transient ischemic attack, depression, and diabetes were associated with nonpersistence. After adjustment, nonpersistence was associated with the composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure (hazard ratio 1.24, 99% CI 1.09-1.40, P < .0001), cardiovascular death alone (1.87, 1.60-2.19, P < .0001), and heart failure hospitalization alone (1.32, 1.04-1.67, P = .0023). Cardiovascular events increased when medications were stopped, whereas noncardiovascular outcomes did not. Nonpersistence rapidly increased within the first year after nonfatal events such as myocardial infarction (hazard ratio 3.37, 99% CI 2.72-4.16, P < .0001), stroke (3.25, 2.59-4.07, P < .0001), and hospitalization for heart failure (3.67, 2.95-4.57, P < .0001). Persistence was poorer with more frequent and earlier events. Patients stopping medication after an event were at greater risk for subsequent events.. Improving medications persistence could interrupt this vicious circle and may improve outcomes.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Drug Therapy, Combination; Female; Humans; Male; Medication Adherence; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Ramipril; Risk; Telmisartan

The microvascular circulation plays an important role in bone health. This study examines whether albuminuria, a marker of renal microvascular disease, is associated with incident hip and pelvic fractures.. This study reanalyzed data from the Ongoing Telmisartan Alone and in combination with Ramipril Global End Point Trial/Telmisartan Randomized Assessment Study in Angiotensin-Converting Enzyme Intolerant Subjects with Cardiovascular Disease trials, which examined the impact of renin angiotensin system blockade on cardiovascular outcomes (n=28,601). Albuminuria was defined as an albumin-to-creatinine ratio≥30 mg/g (n=4597). Cox proportional hazards models were used to determine the association of albuminuria with fracture risk adjusted for known risk factors for fractures, estimated GFR, and rapid decline in estimated GFR (≥5%/yr).. There were 276 hip and pelvic fractures during a mean of 4.6 years of follow-up. Participants with baseline albuminuria had a significantly increased risk of fracture compared with participants without albuminuria (unadjusted hazard ratio=1.62 [1.22, 2.15], P<0.001; adjusted hazard ratio=1.36 [1.01, 1.84], P=0.05). A dose-dependent relationship was observed, with macroalbuminuria having a large fracture risk (unadjusted hazard ratio=2.01 [1.21, 3.35], P=0.007; adjusted hazard ratio=1.71 [1.007, 2.91], P=0.05) and microalbuminuria associating with borderline or no statistical significance (unadjusted hazard ratio=1.52 [1.10, 2.09], P=0.01; adjusted hazard ratio=1.28 [0.92, 1.78], P=0.15). Estimated GFR was not a predictor of fracture in any model, but rapid loss of estimated GFR over the first 2 years of follow-up predicted subsequent fracture (adjusted hazard ratio=1.47 [1.05, 2.04], P=0.02).. Albuminuria, especially macroalbuminuria, and rapid decline of estimated GFR predict hip and pelvic fractures. These findings support a theoretical model of a relationship between underlying causes of microalbuminuria and bone disease.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Fractures, Bone; Glomerular Filtration Rate; Hip Fractures; Humans; Pelvic Bones; Prospective Studies; Ramipril; Risk Factors; Telmisartan; Time Factors

We sought to determine whether the blood pressure (BP) levels at which cardiovascular (CV) protection is achieved differ between diabetic and nondiabetic patients from the ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial).. Greater absolute benefits of BP reductions have been claimed for diabetic as compared with nondiabetic patients.. A total of 25,584 patients (9,603 diabetic), older than 55 years, at high CV risk were randomized to ramipril, telmisartan, or both and observed for 4.6 years. We pooled the treatment arms to examine the relationships between BP and the primary composite outcome (CV death, nonfatal myocardial infarction or stroke, or hospitalized heart failure) and its components.. The primary outcome occurred in 1,938 (20.2%) diabetic patients and in 2,276 (14.2%) nondiabetic patients. Compared with nondiabetic patients, diabetic patients had a significantly higher risk for the primary endpoint (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.38 to 1.57) and CV death (HR: 1.56; 95% CI: 1.42 to 1.71); myocardial infarction (HR: 1.30 (95% CI: 1.17 to 1.46); stroke (HR: 1.39; 95% CI: 1.23 to 1.56); and congestive heart failure hospitalization (HR: 2.06; 95% CI: 1.82 to 2.32). The CV risk was significantly higher in diabetic than in nondiabetic patients regardless of the systolic BP changes during treatment. In both diabetic and nondiabetic patients, progressively greater systolic BP reductions were accompanied by reduced risk for the primary outcome only if baseline systolic BP levels ranged from 143 to 155 mm Hg; except for stroke, there was no benefit in fatal or nonfatal CV outcomes by reducing systolic BP below 130 mm Hg.. The relationship between BP and overall CV risk had a similar pattern in diabetic and nondiabetic patients over a wide range of baseline and in-treatment BP values although, for the same systolic BP, a higher risk is observed in diabetic patients.

Topics: Aged; Benzimidazoles; Benzoates; Blood Pressure Determination; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypertension; Hypotension; Kaplan-Meier Estimate; Male; Middle Aged; Patient Safety; Ramipril; Reference Values; Risk Assessment; Survival Rate; Telmisartan; Treatment Outcome

Evidence on new-onset atrial fibrillation in high-risk vascular patients without heart failure is limited. New-onset atrial fibrillation was a prespecified secondary objective of the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) studies.. We studied 30 424 ONTARGET/TRANSCEND patients (mean age ± SD, 66.4 ± 7.0) with vascular disease or complicated diabetes who were in sinus rhythm at entry. A copy of ECG was sent to central office every time new atrial fibrillation was detected by investigators.. During a median follow-up period of 4.7 years, new atrial fibrillation occurred in 2092 patients (15.1 per 1000  patient-years). Risk of atrial fibrillation increased with age, SBP and pulse pressure, left ventricular hypertrophy, BMI, serum creatinine and history of hypertension, coronary artery disease and cerebrovascular disease (all P < 0.01). After adjustment for BMI and other variables, atrial fibrillation risk increased with hip circumference. History of hypertension was associated with a 34% higher risk of new atrial fibrillation. New atrial fibrillation portended an increased risk of congestive heart failure [hazard ratio 2.89, 95% confidence interval (CI) 2.45-3.40, P < 0.01] and cardiovascular death (hazard ratio 1.22, 95% CI 1.05-1.41, P < 0.01). Risk of stroke was unaffected (hazard ratio 1.14, 95% CI 0.93-1.40), whereas that of myocardial infarction was reduced (hazard ratio 0.64, 95% CI 0.50-0.82). Patients with new atrial fibrillation were more likely to receive vitamin K antagonists (P < 0.01), statins (P < 0.05) and β-blockers (P < 0.01) than those in sinus rhythm.. New atrial fibrillation is common in high-risk vascular patients and is associated with several risk factors including history of hypertension. Hip circumference was the strongest anthropometric predictor. Despite extensive use of modern therapies, new atrial fibrillation carries a high risk of congestive heart failure and death over a relatively short term.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Anthropometry; Atrial Fibrillation; Benzimidazoles; Benzoates; Body Mass Index; Cardiovascular Diseases; Diabetes Complications; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertrophy, Left Ventricular; Male; Middle Aged; Placebos; Ramipril; Risk; Risk Factors; Stroke; Telmisartan; Vitamin K

Angiotensin receptor blockers (ARB) and angiotensin converting enzyme (ACE) inhibitors are known to reduce proteinuria. Their combination might be more effective than either treatment alone, but long-term data for comparative changes in renal function are not available. We investigated the renal effects of ramipril (an ACE inhibitor), telmisartan (an ARB), and their combination in patients aged 55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage.. The trial ran from 2001 to 2007. After a 3-week run-in period, 25,620 participants were randomly assigned to ramipril 10 mg a day (n = 8,576), telmisartan 80 mg a day (n = 8,542), or to a combination of both drugs (n = 8,502; median follow-up was 56 months), and renal function and proteinuria were measured. The primary renal outcome was a composite of dialysis, doubling of serum creatinine, and death. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00153101.. 784 patients permanently discontinued randomised therapy during the trial because of hypotensive symptoms (406 on combination therapy, 149 on ramipril, and 229 on telmisartan). The number of events for the composite primary outcome was similar for telmisartan (n = 1,147 [13.4%]) and ramipril (1,150 [13.5%]; hazard ratio [HR] 1.00, 95% CI 0.92-1.09), but was increased with combination therapy (1,233 [14.5%]; HR 1.09, 1.01-1.18, p = 0.037). The secondary renal outcome, dialysis or doubling of serum creatinine, was similar with telmisartan (189 [2.21%]) and ramipril (174 [2.03%];HR 1.09, 0.89-1.34) and more frequent with combination therapy (212 [2.49%]: HR 1.24,1.01-1.51, p = 0.038). Estimated glomerular filtration rate (eGFR) declined least with ramipril compared with telmisartan (-2.82 [SD 17.2] mL/min/1.73 m² vs -4.12 [17.4], p < 0.0001) or combination therapy (-6.11 [17.9], p < 0.0001). The increase in urinary albumin excretion was less with telmisartan (p = 0.004) or with combination therapy (p=0.001) than with ramipril.. In people at high vascular risk, telmisartans effects on major renal outcomes are similar to ramipril. Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal outcomes.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Clinical Trials as Topic; Drug Therapy, Combination; Glomerular Filtration Rate; Humans; Middle Aged; Multicenter Studies as Topic; Proteinuria; Ramipril; Telmisartan

A daily single capsule (polycap) of 3 blood pressure (BP) lowering drugs (hydrochlorthiazide, 12.5 mg; atenolol, 50 mg; ramipril, 5 mg) at low doses, simvastatin (20 mg), and aspirin (100 mg) has been demonstrated to be well tolerated and to reduce BP and low-density lipoprotein cholesterol. We examined the incremental effects of 2 (full dose) plus K(+) supplementation versus single polycap (low dose) on risk factors and tolerability.. After a run-in period, 518 individuals with previous vascular disease or diabetes mellitus from 27 centers in India were randomly assigned to a single-dose polycap or to 2 capsules of the polycap plus K(+) supplementation for 8 weeks. The effects on BP, heart rate (HR), serum lipids, serum and urinary K(+), and tolerability were assessed using an intention-to-treat analysis. The full-dose polycap (plus K(+) supplementation) reduced BP by a further 2.8 mm Hg systolic and 1.7 mm Hg diastolic, compared with that observed with the low-dose polycap (P=0.003; P=0.001), but there were no differences in HR (0.1 bpm). The differences in total and low-density lipoprotein cholesterol between the full-dose and low-dose polycap was 7.2 mg/dL (P=0.014) and 6.6 mg/dL (P=0.006), respectively, but there were no differences in high-density lipoprotein cholesterol or triglycerides. The rates of discontinuation of the study drug after randomization were similar in the 2 groups (6.9% low dose versus 7.8% full dose).. The full-dose polycap (plus K(+) supplementation) reduces BP and low-density lipoprotein cholesterol to a greater extent compared with the low dose, with similar tolerability. Therefore, the full-dose polycap should potentially lead to larger benefits. Clinical Trial Registration- URL: http://www.ctri.nic.in. Unique identifier: CTRI/2010/091/000054.

Topics: Administration, Oral; Aged; Analysis of Variance; Antihypertensive Agents; Aspirin; Atenolol; Biomarkers; Blood Pressure; Capsules; Cardiovascular Diseases; Cholesterol, LDL; Creatinine; Dietary Supplements; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Female; Heart Rate; Humans; Hydrochlorothiazide; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypertension; India; Male; Middle Aged; Platelet Aggregation Inhibitors; Polypharmacy; Potassium; Ramipril; Risk Assessment; Risk Factors; Simvastatin; Tablets; Time Factors; Treatment Outcome

cardiovascular risk factors are associated with dementia and cognitive decline. We investigated the effects of renin-angiotensin system blockade on cognitive function in patients aged 55 years and older with established atherosclerotic cardiovascular disease or diabetes with end-organ damage in two clinical trials.. in the main study, ONTARGET, a double-blind, double-dummy, randomised controlled trial, the effects on cardiovascular outcomes of standard doses of an angiotensin-converting enzyme (ACE) inhibitor (ramipril), an angiotensin-receptor blocker (telmisartan), and a combination of the drugs were evaluated in 25 620 participants. In the parallel TRANSCEND trial, the effects of telmisartan were compared with those of placebo in 5926 participants intolerant to ACE inhibitors. Secondary outcomes included cognitive impairment (defined by investigator-reported diagnosis of dementia or significant cognitive dysfunction, or a score of ≤ 23 on the Mini-Mental State Examination [MMSE]) and cognitive decline (a decrease of ≤ 3 points on the MMSE from baseline during follow-up). Analyses were by intention to treat. We pooled data from these studies to identify baseline predictors of cognitive impairment and its frequency according to mean systolic blood pressure during follow-up. These studies were registered with ClinicalTrials.gov, number NCT00153101.. During a median duration of 56 months (IQR 51-64) of follow-up in ONTARGET, cognitive impairment occurred in 652 (8%) of 7865 patients allocated ramipril, 584 (7%) of 7797 allocated telmisartan, and 618 (8%) of 7807 allocated combination treatment (combination vs ramipril, odds ratio [OR] 0·95, 95% CI 0·85-1·07, p= 0·39; telmisartan vs ramipril, OR 0·90, 0·80-1·01, p = 0·06). Corresponding figures for cognitive decline were 1314 (17%), 1279 (17%), and 1240 (17%) in each of the groups, respectively (telmisartan vs ramipril, OR 0·97, 0·89-1·06, p= 0·53; combination vs ramipril, OR 0·95, 0·88-1·04, p=0·28). In TRANSCEND, cognitive impairment occurred in 239 (9%) of 2694 participants allocated telmisartan compared with 245 (9%) of 2689 allocated placebo (OR 0·97, 0·81-1·17, p= 0·76). The corresponding figures for cognitive decline were 454 (17%) and 412 (16%; OR 1·10, 0·95-1·27, p= 0·22).. In patients with cardiovascular disease or diabetes, different approaches to blocking of the renin-angiotensin system had no clear effects on cognitive outcomes. Although patients with the lowest systolic blood pressure had the greatest preservation of cognitive function, meta-regression analyses did not show any benefits of blood-pressure lowering on cognition over several years of treatment.

Topics: Aged; Aged, 80 and over; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Cognition Disorders; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Mental Status Schedule; Neuropsychological Tests; Odds Ratio; Ramipril; Renin-Angiotensin System; Telmisartan; Treatment Outcome

Most patients miss occasional doses of antihypertensives. The use of 'forgiving' drugs (i.e. drugs with duration of action longer than the 24-h dosing interval) may allow an adequate blood pressure (BP) reduction to be maintained despite missed doses.. To quantify the effects of adherence level and duration of action on estimated mean systolic BP (SBP) reduction and cardiovascular disease (CVD) risk.. For 1250 patients, we simulated 256-day dosing histories with realistically distributed drug holidays based on a study of electronically monitored dosing records. Adherence was set to the desired level by altering the proportion of doses missed. Mean office SBP-lowering effect (aliskiren 300 mg, -14.1 mmHg; irbesartan 300 mg, -13.3; ramipril 10 mg, -10.1 mmHg) and the rate of SBP increase after stopping treatment (off-rate; aliskiren, 1.0 mmHg/day; irbesartan, 3.6 mmHg/day; ramipril, 4.0 mmHg/day) were taken from the results of a randomised, double-blind trial. SBP was averaged over time and patient to estimate mean reductions in SBP and 10-year CVD risk (Framingham risk equation, baseline absolute 10-year CVD risk: 27%).. Predicted reductions in SBP and CVD risk with aliskiren were larger and less affected by imperfect adherence than the reductions with irbesartan or ramipril. For aliskiren, reducing adherence from 90% to 60% led to a predicted rise in SBP of 1.0 mmHg and three additional CVD events per 1000 treated patients; larger predicted differences were observed for irbesartan (2.5 mmHg; 7.5 events/1000 treated patients) and ramipril (2.2 mmHg; 6.7 events/1000 treated patients).. To offset the effects of imperfect adherence, a common challenge with antihypertensives, for better BP management it may be prudent to prescribe 'forgiving' drugs.

Topics: Aged; Amides; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Cardiovascular Diseases; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Irbesartan; Male; Medication Adherence; Ramipril; Risk Factors; Tetrazoles; Treatment Outcome

This study investigated the effects of pioglitazone (PIO), ramipril (RAM), or their combination (PIRA) on low-grade inflammation in nondiabetic hypertensive patients with increased cardiovascular risk.. Patients enrolled in this placebo-controlled, double-blind, randomized, parallel trial (72 male, 77 female, aged 60 ± 9 years, body mass index 30.4 ± 4.7 kg/m(2), duration of hypertension 9 ± 8 years) were treated with either 30/45 mg PIO (dose titration), 2.5/5 mg RAM, or their combination for 12 weeks. A reduction in high-sensitivity C-reactive protein was observed with PIO (-0.89 ± 1.98 mg/liter; -25%) and PIRA (-0.49 ± 2.11 mg/liter; -16%), while an increase was seen with RAM (0.58 ± 2.13 mg/liter; +20%, p < .05 vs PIO and PIRA). The 24-hour blood pressure profile showed a small increase with both monotherapies but a decrease with PIRA (p < .05 vs PIO). Improvements in biomarkers of chronic systemic inflammation and insulin resistance (IR) were observed in the PIO and PIRA arms only [PIO/RAM/PIRA: homeostasis model of assessment of IR: -0.78 ± 1.39 (-29%)/0.15 ± 1.03 (+5%)/ -1.44 ± 2.83 (-40%); adiponectin: 8.51 ± 5.91 (+104%)/ 0.09 ± 2.63 (+1%)/ 8.86 ± 6.37 mg/liter (+107%); matrix metallo-proteinase-9: -48 ± 127 (-12%)/-1 ± 224 (0%)/-60 ± 210 ng/ml (-13%), p < .05 for RAM vs PIO or PIRA in all cases].. Our 3-month study in nondiabetic hypertensive patients showed a decrease in biomarkers of IR and chronic systemic inflammation with the PIO monotherapy and the PIRA combination only, which may help to explain some findings in other cardiovascular outcome trials.

Topics: Adult; Aged; Antihypertensive Agents; Biomarkers; Blood Vessels; Cardiovascular Diseases; Diabetes Complications; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Inflammation; Male; Middle Aged; Pioglitazone; Placebos; Ramipril; Risk Factors; Severity of Illness Index; Thiazolidinediones; Up-Regulation

Hypertension treatment guidelines recommend that blood pressure (BP) be lowered to <140/90 mm Hg, but that a reduction to <130/80 mm Hg be adopted in patients at high cardiovascular (CV) risk. We investigated the CV and renal benefits associated with these BP targets in the high-CV-risk population of the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET).. Patients were divided into 4 groups according to the proportion of in-treatment visits before the occurrence of an event (<25%->75%) in which BP was reduced to <140/90 or <130/80 mm Hg. After adjustment for demographic and clinical variables, a progressive increase in the proportion of visits in which BP was reduced to <140/90 or <130/80 mm Hg was associated with a progressive reduction in the risk of stroke, new onset of microalbuminuria or macroalbuminuria, and return to normoalbuminuria in albuminuric patients. An increased frequency of BP control to either target did not have any consistent effect on the adjusted risk of myocardial infarction and heart failure. The adjusted risk of CV events was reduced by increasing the frequency of BP control to <140/90 mm Hg, but not to <130/80 mm Hg. Similar findings were obtained for the achievement of the BP target in the visit preceding a CV event.. The more frequent achievement of the BP targets recommended by guidelines led to cerebrovascular and renal protection, but did not increase cardiac protection. Overall, CV protection was favorably affected by the less tight but not by the tighter BP target. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00153101.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Pressure; Cardiovascular Diseases; Dose-Response Relationship, Drug; Drug Therapy, Combination; Guidelines as Topic; Humans; Incidence; Kidney Diseases; Middle Aged; Ramipril; Risk; Stroke; Telmisartan

Although erectile dysfunction (ED) is associated with cardiovascular risk factors and atherosclerosis, it is not known whether the presence of ED is predictive of future events in individuals with cardiovascular disease. We evaluated whether ED is predictive of mortality and cardiovascular outcomes, and because inhibition of the renin-angiotensin system in high-risk patients reduces cardiovascular events, we also tested the effects on ED of randomized treatments with telmisartan, ramipril, and the combination of the 2 drugs (ONTARGET), as well as with telmisartan or placebo in patients who were intolerant of angiotensin-converting enzyme inhibitors (TRANSCEND).. In a prespecified substudy, 1549 patients underwent double-blind randomization, with 400 participants assigned to receive ramipril, 395 telmisartan, and 381 the combination thereof (ONTARGET), as well as 171 participants assigned to receive telmisartan and 202 placebo (TRANSCEND). ED was evaluated at baseline, at 2-year follow-up, and at the penultimate visit before closeout. ED was predictive of all-cause death (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.21 to 2.81, P=0.005) and the composite primary outcome (HR 1.42, 95% CI 1.04 to 1.94, P=0.029), which consisted of cardiovascular death (HR 1.93, 95% CI 1.13 to 3.29, P=0.016), myocardial infarction (HR 2.02, 95% CI 1.13 to 3.58, P=0.017), hospitalization for heart failure (HR 1.2, 95% CI 0.64 to 2.26, P=0.563), and stroke (HR 1.1, 95% CI 0.64 to 1.9, P=0.742). The study medications did not influence the course or development of ED.. ED is a potent predictor of all-cause death and the composite of cardiovascular death, myocardial infarction, stroke, and heart failure in men with cardiovascular disease. Trial treatment did not significantly improve or worsen ED.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT 00153101.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Double-Blind Method; Drug Therapy, Combination; Erectile Dysfunction; Humans; Male; Mortality; Predictive Value of Tests; Ramipril; Telmisartan; Treatment Outcome

The Polycap (polypill; aspirin [acetylsalicylic acid], ramipril, simvastatin, atenolol, and hydrochlorothiazide) was found to be safe and effective for reducing multiple cardiovascular risk factors in The Indian Polycap Study (TIPS).. We evaluated the bioavailability of each ingredient of the Polycap and determined any drug-drug interactions relative to single component reference preparations.. The bioavailability of the ingredients of the Polycap (T; test) when formulated as a single capsule was compared with that of identical capsules with each of its ingredients administered separately (R; reference) in a five-arm, randomized, single-dose, two-period, two-treatment, two-sequence, crossover trial with at least a 2-week washout period in a total of 195 healthy volunteers. Plasma concentrations of each drug and, where applicable, its active metabolite were measured using validated liquid chromatography-tandem mass spectrometry and ultra-performance liquid chromatography. Mean pharmacokinetic parameters and their standard deviations were computed for each analyte.. Comparative bioavailability was computed and no drug-drug interactions and no difference in comparative bioavailability were concluded for each ingredient based on point estimates of the T/R ratio of the geometric means falling within 80-125% for peak plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC(t)), and AUC from time zero to infinity (AUC(infinity)). The T/R ratio for C(max), AUC(t) and AUC(infinity) was within 80-125% for atenolol, hydrochlorothiazide, ramipril, ramiprilat and dose-normalized salicylic acid. However, for simvastatin, the T/R point estimates for C(max), AUC(t) and AUC(infinity) for Ln-transformed data were significantly lower ( approximately 3-4%) than the lower bound of 80%. For its active metabolite, simvastatin acid, these estimates were significantly higher ( approximately 25-35%) than the higher bound of 125%. Thus, the increased bioavailability of active simvastatin acid appeared to compensate for the loss of bioavailability of simvastatin.. The Polycap was found to be effective and safe in the previously published TIPS trial. The present study in healthy volunteers establishes that Polycap is safe (no serious adverse events) and well tolerated, and that there is no indication of pharmacokinetic drug-drug interactions for any of the ingredients, with their bioavailabilities being well preserved.

Topics: Administration, Oral; Adolescent; Adult; Antihypertensive Agents; Area Under Curve; Aspirin; Atenolol; Biological Availability; Capsules; Cardiovascular Diseases; Chromatography, Liquid; Cross-Over Studies; Drug Combinations; Drug Interactions; Humans; Hydrochlorothiazide; Hypolipidemic Agents; Male; Middle Aged; Platelet Aggregation Inhibitors; Ramipril; Risk Factors; Simvastatin; Tandem Mass Spectrometry; Young Adult

Results of the recently published ONTARGET study (The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) showed that telmisartan (80 mg/day) was non-inferior to ramipril (10 mg/day) in reducing cardiovascular events. Clinicians in Asia doubt tolerability of these doses for their patients. We therefore analyzed data from this study and a parallel study TRANSCEND (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease). Our objectives were to compare Asians and non-Asians with respect to the following: 1) Effectiveness of telmisartan vs. ramipril in reducing cardiovascular events;2) Proportions who reached the full dose of telmisartan, ramipril or placebo; and3) Proportions of overall discontinuations, and discontinuations due to adverse effects.. The ONTARGET study randomized 25,620 patients at risk of cardiovascular events to ramipril, telmisartan, or their combination. The primary composite endpoint was death caused by cardiovascular disease, acute MI, stroke, and hospitalization because of congestive heart failure. TRANSCEND randomized 5926 high-risk patients with a history of intolerance to ACE-inhibitors to telmisartan or placebo. The primary outcome was the same. In this substudy, we compared Asians and non-Asians as to how well they tolerated telmisartan (given in both studies) and ramipril (given in ONTARGET).. 1) Telmisartan was non-inferior to ramipril in lowering the primary endpoint among Asians (RR = 0.92; 95% CI: 0.74, 1.13); 2) more Asians achieved the full dose of either drug; 3) less withdrew (overall); and 4) less withdrew for adverse effects. Furthermore, telmisartan was better tolerated than ramipril. This advantage was greater among Asians.. Although Asians had lower BMI than non-Asians, Asians tolerated both drugs better. Regulatory agencies require reporting of safety and effectiveness data by ethnicity, but few comply with this requirement. This study shows that safety data in ethnic subgroups can help assess applicability of results to specific populations.. ClinicalTrials.gov NCT00153101.

Topics: Angiotensin-Converting Enzyme Inhibitors; Asia; Benzimidazoles; Benzoates; Body Mass Index; Cardiovascular Diseases; Double-Blind Method; Ethnicity; Humans; Patient Compliance; Placebos; Ramipril; Risk; Telmisartan; Treatment Outcome

Topics: Administration, Oral; Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Aspirin; Atenolol; Capsules; Cardiovascular Agents; Cardiovascular Diseases; Diuretics; Double-Blind Method; Drug Combinations; Drug Costs; Humans; Hydrochlorothiazide; Hydroxymethylglutaryl-CoA Reductase Inhibitors; India; Platelet Aggregation Inhibitors; Primary Prevention; Ramipril; Research Design; Secondary Prevention; Simvastatin; Treatment Outcome

The prognostic significance of left and right bundle branch block (LBBB and RRBB) in patients with chronic stable cardiovascular (CV) disease is not well characterized and was evaluated in the Heart Outcomes Prevention Evaluation (HOPE) study cohort.. Observational analysis of data prospectively collected in the HOPE trial.. HOPE was a multicenter, international trial, which evaluated ramipril and vitamin E in 9,541 patients aged > or = 55 years with CV disease or diabetes with > or = 1 CV risk factor(s) but without heart failure (HF) or known left ventricular systolic dysfunction. Follow-up extended for a median of 4.5 years. Electrocardiograms were obtained at baseline in all study participants and were read centrally.. Major CV events (defined as CV death, myocardial infarction, or stroke), heart failure, CV death, all-cause death, and sudden death.. Baseline LBBB was present in 246 (2.6%) patients and was associated with increased risk for major CV events (HR = 1.54; 95% CI, 1.18-2.02), CV death (HR 2.29; 95% CI, 1.63-3.20), heart failure (HR 2.99; 95% CI, 2.31-3.87), sudden death (HR 3.17; 95% CI, 2.13-4.73), and all-cause death (HR = 2.10; 95% CI, 1.59-2.77). In multivariate models, LBBB remained an independent predictor of heart failure, sudden death, CV death, and all-cause death (P < or = 0.002 for all). Baseline RBBB was present in 428 (4.5%) of patients and was not associated with increased CV risk.. In patients with stable chronic CV disease, LBBB but not RBBB is an independent predictor of heart failure, sudden death, CV death, and all-cause death.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Bundle-Branch Block; Cardiovascular Diseases; Chronic Disease; Death, Sudden; Double-Blind Method; Drug Therapy, Combination; Electrocardiography; Europe; Female; Heart Failure; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; North America; Proportional Hazards Models; Prospective Studies; Ramipril; Risk Assessment; Risk Factors; Stroke; Time Factors; Treatment Outcome; Vascular Diseases; Vitamin E

The recently published Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) in patients with vascular disease or high-risk diabetes, as the largest published comparative trial of these agent classes, provides further evidence concerning the comparison between the angiotensin-receptor blockers (ARBs) and the angiotensin-converting enzyme inhibitors (ACEIs). In this trial, telmisartan (an ARB) was non-inferior to ramipril (an ACEI) in reducing fatal and nonfatal cardiovascular events. Moreover, ONTARGET is an example of a high-quality noninferiority trial. However, the combination of the 2 agents was associated with more adverse effects without an increase in benefit. The study differed from several other comparative studies in which the dose and choice of ACEI was left to individual physicians. Further, in ONTARGET, the ACEI was not titrated to the maximum dose and patients with heart failure were excluded.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Global Health; Humans; Incidence; Male; Ramipril; Risk Factors; Telmisartan; Treatment Outcome

The combination of three blood-pressure-lowering drugs at low doses, with a statin, aspirin, and folic acid (the polypill), could reduce cardiovascular events by more than 80% in healthy individuals. We examined the effect of the Polycap on blood pressure, lipids, heart rate, and urinary thromboxane B2, and assessed its tolerability.. In a double-blind trial in 50 centres in India, 2053 individuals without cardiovascular disease, aged 45-80 years, and with one risk factor were randomly assigned, by a central secure website, to the Polycap (n=412) consisting of low doses of thiazide (12.5 mg), atenolol (50 mg), ramipril (5 mg), simvastatin (20 mg), and aspirin (100 mg) per day, or to eight other groups, each with about 200 individuals, of aspirin alone, simvastatin alone, hydrochlorthiazide alone, three combinations of the two blood-pressure-lowering drugs, three blood-pressure-lowering drugs alone, or three blood-pressure-lowering drugs plus aspirin. The primary outcomes were LDL for the effect of lipids, blood pressure for antihypertensive drugs, heart rate for the effects of atenolol, urinary 11-dehydrothromboxane B2 for the antiplatelet effects of aspirin, and rates of discontinuation of drugs for safety. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00443794.. Compared with groups not receiving blood-pressure-lowering drugs, the Polycap reduced systolic blood pressure by 7.4 mm Hg (95% CI 6.1-8.1) and diastolic blood pressure by 5.6 mm Hg (4.7-6.4), which was similar when three blood-pressure-lowering drugs were used, with or without aspirin. Reductions in blood pressure increased with the number of drugs used (2.2/1.3 mm Hg with one drug, 4.7/3.6 mm Hg with two drugs, and 6.3/4.5 mm Hg with three drugs). Polycap reduced LDL cholesterol by 0.70 mmol/L (95% CI 0.62-0.78), which was less than that with simvastatin alone (0.83 mmol/L, 0.72-0.93; p=0.04); both reductions were greater than for groups without simvastatin (p<0.0001). The reductions in heart rate with Polycap and other groups using atenolol were similar (7.0 beats per min), and both were significantly greater than that in groups without atenolol (p<0.0001). The reductions in 11-dehydrothromboxane B2 were similar with the Polycap (283.1 ng/mmol creatinine, 95% CI 229.1-337.0) compared with the three blood-pressure-lowering drugs plus aspirin (350.0 ng/mmol creatinine, 294.6-404.0), and aspirin alone (348.8 ng/mmol creatinine, 277.6-419.9) compared with groups without aspirin. Tolerability of the Polycap was similar to that of other treatments, with no evidence of increasing intolerability with increasing number of active components in one pill.. This Polycap formulation could be conveniently used to reduce multiple risk factors and cardiovascular risk.

Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Aspirin; Atenolol; Cardiovascular Diseases; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Humans; Hydrochlorothiazide; Hydroxymethylglutaryl-CoA Reductase Inhibitors; India; Middle Aged; Platelet Aggregation Inhibitors; Ramipril; Risk Factors; Risk Reduction Behavior; Simvastatin; Treatment Outcome

The ONTARGET and TRANSCEND clinical trials were designed to investigate the cardioprotective effects of telmisartan 80 mg and ramipril 10 mg, alone and in combination, in patients at high risk of cardiovascular disease. Cardiac MRI enables investigation of mechanistic effects of these agents on cardiac structural and functional variables. Here, we report the design, analysis protocol, reproducibility and relevant quality control procedures, and baseline patient characteristics of the ONTARGET/TRANSCEND cardiac MRI substudy. MRI was undertaken in 330 subjects enrolled in ONTARGET, and 38 subjects in TRANSCEND, across eight centers in six countries. Analyses were performed by two independent analysts using guide-point modeling. Cases with discrepancies in LV mass (LVM) of >5% were independently reanalyzed. Cases with discrepancies in end-diastolic volume (EDV) of >5%, or end-systolic volume (ESV) of >12%, were then reconciled by consensus.. Baseline characteristics were broadly similar to the main ONTARGET/TRANSCEND trials, except for a higher frequency of coronary artery disease and Asian ethnicity in the substudy. Reproducibility of MRI analyses (mean +/- SD) were 2.8 +/- 3.7 ml in EDV, -0.3 +/- 3.6 ml in ESV, 3.1 +/- 3.3 ml in SV, 1.1 +/- 1.8% in EF, and 0.4 +/- 4.5 g in LVM. Subgroup analyses revealed increased ESV and LVM, and reduced EF, in subjects with a history of either coronary artery disease or myocardial infarction.. The ONTARGET/TRANSCEND cardiac MRI substudy protocol provides for a reliable assessment of the effects of telmisartan and ramipril, alone and in combination, on cardiac structural and functional parameters over a 2-year follow-up period.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Clinical Protocols; Double-Blind Method; Drug Therapy, Combination; Female; Heart Ventricles; Humans; Magnetic Resonance Imaging; Male; Prospective Studies; Quality Control; Ramipril; Reproducibility of Results; Retrospective Studies; Stroke Volume; Telmisartan; Treatment Outcome; Ventricular Dysfunction, Left

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers reduce left ventricular hypertrophy (LVH). The effect of these drugs on LVH in high-risk patients without heart failure is unknown.. In the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET), patients at high vascular risk and tolerant of ACE inhibitors were randomly assigned to ramipril, telmisartan, or their combination (n=23 165). In the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND), patients intolerant of ACE inhibitors were randomized to telmisartan or placebo (n=5343). Prevalence of LVH at entry in TRANSCEND was 12.7%. It was reduced by telmisartan (10.5% and 9.9% after 2 and 5 years) compared with placebo (12.7% and 12.8% after 2 and 5 years) (overall odds ratio, 0.79; 95% confidence interval [CI], 0.68 to 0.91; P=0.0017). New-onset LVH occurred less frequently with telmisartan compared with placebo (overall odds ratio, 0.63; 95% CI, 0.51 to 0.79; P=0.0001). LVH regression was similar in the 2 groups. In ONTARGET, prevalence of LVH at entry was 12.4%. At follow-up, it occurred slightly less frequently with telmisartan (odds ratio, 0.92; 95% CI, 0.83 to 1.01; P=0.07) and the combination (odds ratio, 0.93; 95% CI, 0.84 to 1.02; P=0.12) than with ramipril, but differences between the groups were not significant. New-onset LVH was associated with a higher risk of primary outcome during follow-up (hazard ratio, 1.77; 95% CI, 1.50 to 2.07).. In patients at high vascular risk, telmisartan is more effective than placebo in reducing LVH. New-onset LVH is reduced by 37%. The effect of combination of the 2 drugs on LVH is similar to that of ramipril alone.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Cardiovascular Diseases; Diastole; Double-Blind Method; Drug Therapy, Combination; Drug Tolerance; Electrocardiography; Female; Humans; Hypertrophy, Left Ventricular; Male; Odds Ratio; Placebos; Prevalence; Proportional Hazards Models; Ramipril; Regression Analysis; Systole; Telmisartan

The prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure study addresses the issue of whether progression to manifest hypertension in patients with high-normal blood pressure can be prevented with treatment.. A total of 1008 participants with high-normal office blood pressure were randomized to ramipril treatment group (n = 505) and a control group (n = 503). The patients were followed up for 3 years. Primary endpoint was to prevent or delay the progression to manifest hypertension. Secondary endpoints were reduction in the incidence of cerebrovascular and cardiovascular events, as well as the development of hypertension as defined by ambulatory blood pressure monitoring.. One hundred and fifty-five patients (30.7%) in the ramipril group, and 216 (42.9%) in the control group reached the primary endpoint (relative risk reduction 34.4%, P = 0.0001). Ramipril also proved to be more effective in reducing the incidence of manifest office hypertension in patients with baseline ambulatory blood pressure monitoring high-normal blood pressure. The incidence of cerebrovascular and cardiovascular events showed no statistically significant differences between the two groups. Cough was more frequent in the ramipril group (4.8 vs. 0.4%).. There is now good clinical evidence that patients with high-normal blood pressure (prehypertension) are more likely to progress to manifest hypertension than patients with optimal or normal blood pressure. Additional ambulatory blood pressure monitoring seems to be essential to achieve correct diagnosis. Treatment of patients with high-normal office blood pressure with the angiotensin-converting enzyme inhibitor was well tolerated, and significantly reduced the risk of progression to manifest hypertension.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cardiovascular Diseases; Disease Progression; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Ramipril

ONTARGET ("ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial") compared the angiotensin converting enzyme inhibitor ramipril (10 mg/day), the angiotensin-receptor blocker telmisartan 80 mg/day, and the combination of the two drugs in 25,620 patients with vascular disease or high-risk diabetes. After a median follow up of 56 months, no significant differences were observed between the three groups neither in the primary composite outcome (death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure), nor in each of its components, total mortality and other secondary outcomes. Telmisartan was equivalent to ramipril (non inferiority criterion), but was better tolerated (less cough and angioedema). The combination of the two drugs in this population (without congestive heart failure and proteinuric nephropathy) did not bring increased benefit (no superiority), but was associated with more adverse events (hypotension, syncope and renal dysfunction). In this population, the choice of the molecule in monotherapy remains optional and the use of a dual blockade is not justified in order to have a better cardiovascular protection.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Diabetes Complications; Drug Therapy, Combination; Humans; Ramipril; Risk Factors; Telmisartan; Treatment Outcome; Vascular Diseases

Angiotensin receptor blockers (ARB) and angiotensin converting enzyme (ACE) inhibitors are known to reduce proteinuria. Their combination might be more effective than either treatment alone, but long-term data for comparative changes in renal function are not available. We investigated the renal effects of ramipril (an ACE inhibitor), telmisartan (an ARB), and their combination in patients aged 55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage.. The trial ran from 2001 to 2007. After a 3-week run-in period, 25 620 participants were randomly assigned to ramipril 10 mg a day (n=8576), telmisartan 80 mg a day (n=8542), or to a combination of both drugs (n=8502; median follow-up was 56 months), and renal function and proteinuria were measured. The primary renal outcome was a composite of dialysis, doubling of serum creatinine, and death. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00153101.. 784 patients permanently discontinued randomised therapy during the trial because of hypotensive symptoms (406 on combination therapy, 149 on ramipril, and 229 on telmisartan). The number of events for the composite primary outcome was similar for telmisartan (n=1147 [13.4%]) and ramipril (1150 [13.5%]; hazard ratio [HR] 1.00, 95% CI 0.92-1.09), but was increased with combination therapy (1233 [14.5%]; HR 1.09, 1.01-1.18, p=0.037). The secondary renal outcome, dialysis or doubling of serum creatinine, was similar with telmisartan (189 [2.21%]) and ramipril (174 [2.03%]; HR 1.09, 0.89-1.34) and more frequent with combination therapy (212 [2.49%]: HR 1.24, 1.01-1.51, p=0.038). Estimated glomerular filtration rate (eGFR) declined least with ramipril compared with telmisartan (-2.82 [SD 17.2] mL/min/1.73 m(2)vs -4.12 [17.4], p<0.0001) or combination therapy (-6.11 [17.9], p<0.0001). The increase in urinary albumin excretion was less with telmisartan (p=0.004) or with combination therapy (p=0.001) than with ramipril.. In people at high vascular risk, telmisartan's effects on major renal outcomes are similar to ramipril. Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal outcomes.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Creatinine; Diabetes Mellitus; Double-Blind Method; Drug Therapy, Combination; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kidney; Middle Aged; Proteinuria; Ramipril; Telmisartan

In patients who have vascular disease or high-risk diabetes without heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and morbidity from cardiovascular causes, but the role of angiotensin-receptor blockers (ARBs) in such patients is unknown. We compared the ACE inhibitor ramipril, the ARB telmisartan, and the combination of the two drugs in patients with vascular disease or high-risk diabetes.. After a 3-week, single-blind run-in period, patients underwent double-blind randomization, with 8576 assigned to receive 10 mg of ramipril per day, 8542 assigned to receive 80 mg of telmisartan per day, and 8502 assigned to receive both drugs (combination therapy). The primary composite outcome was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure.. Mean blood pressure was lower in both the telmisartan group (a 0.9/0.6 mm Hg greater reduction) and the combination-therapy group (a 2.4/1.4 mm Hg greater reduction) than in the ramipril group. At a median follow-up of 56 months, the primary outcome had occurred in 1412 patients in the ramipril group (16.5%), as compared with 1423 patients in the telmisartan group (16.7%; relative risk, 1.01; 95% confidence interval [CI], 0.94 to 1.09). As compared with the ramipril group, the telmisartan group had lower rates of cough (1.1% vs. 4.2%, P<0.001) and angioedema (0.1% vs. 0.3%, P=0.01) and a higher rate of hypotensive symptoms (2.6% vs. 1.7%, P<0.001); the rate of syncope was the same in the two groups (0.2%). In the combination-therapy group, the primary outcome occurred in 1386 patients (16.3%; relative risk, 0.99; 95% CI, 0.92 to 1.07); as compared with the ramipril group, there was an increased risk of hypotensive symptoms (4.8% vs. 1.7%, P<0.001), syncope (0.3% vs. 0.2%, P=0.03), and renal dysfunction (13.5% vs. 10.2%, P<0.001).. Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema. The combination of the two drugs was associated with more adverse events without an increase in benefit. (ClinicalTrials.gov number, NCT00153101 [ClinicalTrials.gov].).

Topics: Aged; Angioedema; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Pressure; Cardiovascular Diseases; Creatinine; Diabetes Mellitus; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Ramipril; Risk; Telmisartan

Cardiovascular (CV) disease is the leading cause of death in the elderly. The use of ACE-inhibitors in elderly patients with chronic stable vascular disease has not been previously reported.. The HOPE trial evaluated the effects of ramipril and vitamin E in high-risk vascular disease patients. We report the effects of ramipril in the elderly HOPE study patients, defined as those > or =70 years of age. A total of 2755 elderly patients with vascular disease or diabetes and at least one additional CV risk factor and without heart failure or low ejection fraction were randomized to ramipril 10 mg daily or placebo. Those assigned to ramipril had fewer major vascular events compared to those assigned to placebo [18.6 vs. 24.0%, hazard ratio (HR) = 0.75, P = 0.0006], CV deaths (9.3 vs. 13.0%, HR = 0.71, P = 0.003), myocardial infarctions (12.0 vs. 15.6%, HR = 0.75, P = 0.006), and strokes (5.4 vs. 7.7%, HR = 0.69, P = 0.013). Treatment was safe and generally well tolerated.. Ramipril reduces the risk of major vascular events in elderly patients with vascular disease and is safe and well tolerated by most.

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cardiovascular Diseases; Female; Humans; Long-Term Care; Male; Middle Aged; Ramipril; Risk Factors; Single-Blind Method; Treatment Outcome; Withholding Treatment

Ramipril has been used in twice daily dose of 5 mg in most heart failure trials, whereas the dose used in Heart Outcomes Prevention Evaluation (HOPE) study was 10 mg once at bedtime. The HOPE investigators in an ambulatory blood pressure (ABP) substudy observed a fall of nighttime but not daytime blood pressure (BP). We examined the effects of once daily ramipril 10 mg versus 5 mg twice a day. Twenty-nine patients were recruited based on the original criteria for the HOPE study and were given ramipril either in twice-daily dose (5 mg b.d.) or once daily (10 mg o.d.) each morning in randomized, prospective crossover trial. Twenty-four hour ABP recordings were taken just before commencement of ramipril therapy and after treatment with twice-daily and once-daily ramipril. Our results show that ramipril causes a significant reduction of BP over 24-h period as compared with baseline. The mean baseline ABP was 124/73 mm Hg, which reduced to 117/69 mm Hg for the twice-a-day regimen (P<0.001) and 115/68 mm Hg for the once a day regimen (P<0.001). Both regimes effectively lower BP to a similar extent. Ramipril causes significant BP reduction in both once- and twice-daily dosing. The fall in BP after daytime dosing is greater than that observed in the HOPE study (including ABP substudy). Once-daily dosing in the morning seems to be effective in causing a significant reduction in the ABP profile of patients at high-risk of a future vascular event.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cardiovascular Diseases; Cross-Over Studies; Diabetes Mellitus; Female; Humans; Male; Middle Aged; Prospective Studies; Ramipril

Erectile dysfunction (ED) is a common disorder in middle-aged men and is significantly influenced by cardiovascular risk factors (CVRFs) and cardiovascular disease. The substudy of the ONTARGET/TRANSCEND trials evaluates the relationship of erectile function to baseline characteristics and current treatment in cardiovascular high-risk patients who have been enrolled in these trials. The effects of treatment with telmisartan and ramipril, alone or in combination, including a telmisartan versus placebo arm will be determined prospectively during a follow-up of 4 years.. One thousand three hundred fifty-seven patients were evaluated in 13 countries at baseline, 2 years, and 4 years, with ED determined using the ED score of the Cologne Male Survey (Kölner [Cologne] Evaluation of Erectile Dysfunction) and the 5-item International Index of Erectile Function. Erectile dysfunction scores were related to CVRF and the use of cardiovascular drugs.. Prevalence of ED was 50.7% (Kölner [Cologne] Evaluation of Erectile Dysfunction) and 54.3% (5-item International Index of Erectile Function), respectively, with a decline of sexual activity after the diagnosis of cardiovascular disease. In multivariate analysis, diabetes mellitus (P < .00001), stroke (P = .00026), pelvic surgery (P = .025), and age of >65 years (P < .00001) correlated with the degree of ED. No significant associations were observed for cholesterol levels, hypertension, and smoking status as well as current treatment with angiotensin-converting enzyme inhibitors, angiotensin I antagonists, diuretics, beta-blockers, or calcium-channel blockers.. The ONTARGET/TRANSCEND-ED substudy shows a significant influence of cardiovascular disease on erectile function. In contrast to prior smaller studies, drug therapy and CVRF seem to play a minor role in cardiovascular high-risk patients. Follow-up data will provide information whether angiotensin-converting enzyme inhibitors, angiotensin I antagonists, or a combination thereof are able to improve erectile function.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Drug Therapy, Combination; Erectile Dysfunction; Global Health; Humans; Male; Middle Aged; Multivariate Analysis; Patient Satisfaction; Prospective Studies; Ramipril; Risk Factors; Telmisartan

Microalbuminuria independently predicts increased cardiovascular risk in hypertensive patients, especially in those with concomitant diabetes or established cardiovascular disease. Drugs that target the renin-angiotensin-aldosterone system reduce microalbuminuria regardless of diabetic status. The Irbesartan in the Management of PROteinuric patients at high risk for Vascular Events was a multicenter, randomized, double-blind, placebo-controlled paralleled group study in which hypertensive patients with microalbuminuria and increased cardiovascular risk were randomized to 20 weeks treatment with ramipril plus irbesartan or to ramipril plus placebo. Patients discontinued or tapered previous antihypertensive therapy during a 14-day placebo lead-in period. Change in albumin excretion rate from baseline to week 20 was the primary end point. Adjusted week 20 baseline geometric ratios for ramipril plus irbesartan and ramipril plus placebo were not significantly different. Although differences in blood pressure reductions were observed between the two treatments, these changes did not affect microalbuminuria. More patients on dual therapy achieved target blood pressure goals at week 20 than with monotherapy. The incidence of adverse effects and treatment-related adverse effects was similar in both groups. Our results suggest that patients with cardiovascular risk and relatively low albumin excretion rates in early-stage disease may only require monotherapy with renin-angiotensin-aldosterone blocking agents.

Topics: Aged; Aged, 80 and over; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Cardiovascular Diseases; Female; Humans; Hypertension; Irbesartan; Male; Middle Aged; Ramipril; Tetrazoles; Treatment Outcome

To evaluate the impact of microalbuminuria (MAU) or tubular proteinuria (TPU) on cardiovascular and cerebrovascular events and all-cause mortality, and to assess whether a normalization of MAU and/or TPU induced by angiotensin-converting enzyme-inhibitor-based antihypertensive treatment with ramipril improves cerebrovascular prognosis in essential hypertensive patients without diabetes mellitus.. A prospective, controlled, multicenter study was performed involving 3529 hypertensive participants (average follow-up 42.5 months). Ramipril was the basic antihypertensive medication. Proteinuria analysis (albumin, alpha 1-microglobulin, SDS electrophoresis) was performed by quantitative measurement every year. Ambulatory blood pressure monitoring was performed once yearly. The main outcome determined was cardiovascular and cerebrovascular events and all-cause mortality.. In patients with TPU and/or MAU, the risk for endpoints increased significantly compared with normal (TPU, 30.0%; MAU, 54.7%; MAU + TPU, 64.0%; macroproteinuria, 74.4%). A change of protein excretion either from pathologic to normal or from normal to pathologic showed a clear trend to correlate with cerebrovascular endpoints (P = 0.056 and P = 0.055). Normal protein excretion at baseline and during follow-up indicated a significantly better prognosis than pathologic proteinuria at baseline and during follow-up. (P < 0.0001). TPU normalized in 31.9%, MAU in 30.6%, MAU + TPU in 29.3%, and macroproteinuria in 10.2% of patients. A total of 445 (25.4%) patients with normal protein excretion developed pathologic proteinuria during follow-up.. In non-diabetic hypertensive patients, MAU as well as TPU increases the incidence of cardiovascular events. Normalization of MAU, TPU or macroproteinuria during angiotensin-converting enzyme-inhibitor-based treatment correlates with a reduction of cardiovascular events. Beyond blood pressure control, normalization of MAU and TPU should be considered as a further therapeutic goal. There is a need for further studies to optimize treatment if proteinuria is unresponsive to angiotensin-converting enzyme inhibitors.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Blood Pressure; Cardiovascular Diseases; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Proteinuria; Ramipril; Stroke

Ramipril is an oral, non-sulfhydryl ACE inhibitor thought to act in the renin-angiotensin-aldosterone system to decrease vasopressor activity, aldosterone secretion, and bradykinin degradation. Ramipril is generally well tolerated and effective in the treatment of patients aged > or =55 years at high risk for the development of cardiovascular (CV) events, in whom the risk of myocardial infarction (MI), stroke, and CV death can be significantly reduced. The risk of these CV outcomes may also be reduced with ramipril therapy in various subgroups; these include patients with diabetes mellitus, peripheral arterial disease (PAD) or renal insufficiency, and women. Thus, ramipril, in addition to lifestyle interventions, should be considered an important therapy in the prevention of CV outcomes in high-risk patients.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Female; Humans; Male; Middle Aged; Ramipril

In recent large cardiovascular trials done in stable patients, 14-31% of the participants were smokers; the consequences of smoking in these trials using medications known to reduce cardiovascular events, have not been assessed.. We evaluated the cardiovascular outcomes according to smoking status of men and women participating in the Heart Outcomes Prevention Evaluation trial.. The occurrence of cardiovascular events was documented among participants who did not change their smoking status during the trial. There were 2728 'never smokers', 5241 'former smokers' and 936 'current smokers', and all had stable cardiovascular disease or diabetes with at least one other risk factor. None had previous congestive heart failure or known left ventricular ejection fraction < 0.40.. During the 4.5-year follow-up, there were 641 cardiovascular deaths, 978 myocardial infarctions, 358 strokes and 1021 deaths. In comparison to 'never smokers', smokers had relative risks adjusted for confounding variables including medications known to reduce cardiovascular mortality and morbidity, for cardiovascular death of 1.65 [95% confidence interval (CI), 1.28-2.14], for myocardial infarction of 1.26 (95% CI, 1.01-1.58), for stroke of 1.42 (95% CI, 1.00-2.04), and for total mortality of 1.99 (95% CI, 1.63-2.44). The rates of these events among 'former smokers' were not different from those of 'never smokers'.. Smoking increased the risk of mortality and morbidity among high-risk patients despite the use of medications known to reduce cardiovascular events. Smoking cessation programs should be reinforced even for patients participating in clinical trials.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Cardiovascular Diseases; Female; Humans; Incidence; Male; Middle Aged; Morbidity; Myocardial Infarction; Preventive Medicine; Ramipril; Risk Factors; Smoking; Stroke; Treatment Outcome; Vitamin E

Both hyper- and hypokalemia increase cardiovascular risk. Modest hyperkalemia is common with angiotensin-converting enzyme inhibition. We studied post-hoc the association of an initial, on-treatment serum potassium measurement with subsequent cardiovascular outcomes over 4.5 years in 9297 individuals at high cardiovascular risk, randomized to an ACE inhibitor or to placebo.. Post-hoc analysis of cardiovascular outcomes, as related to serum potassium levels, in the HOPE (Heart Outcomes and Prevention Evaluation) study which compared ramipril to placebo, and included 692 patients with a serum potassium level >5.0 mM and 137 with a serum potassium level <3.5 mM, defined as hyper- and hypokalemia, respectively. Serum potassium was measured 1 month after start of randomized treatment.. With hyperkalemia, the primary event rate was unchanged compared to normokalemia (15.5 vs 15.7%, p > 0.4, respectively), with hypokalemia, the primary event rate was higher (22.6% vs 15.5%, respectively, p = 0.023). The hazard ratio for the primary outcome associated with this initial hypokalemia was 1.44 (1.00-2.06) on multivariate analysis. The combined primary outcome (myocardial infarction, cardiovascular death, stroke) was not different throughout deciles of serum potassium but the lowest and highest deciles included many with normokalemia. Randomized treatment was withheld because of hyperkalemia in 8 and 6 people allocated to ramipril and placebo, respectively. The benefit of ramipril on cardiovascular outcomes was independent of serum potassium, but ramipril reduced hypokalemia in the entire cohort (1.15 vs 1.86% with placebo, p = 0.005), particularly in those participants on diuretics (3.8% vs 6.5%, p = 0.07).. In patients at high cardiovascular risk, modest hypokalemia predicts a less favorable outcome while modest hyperkalemia does not. Ramipril reduces hypokalemia and decreases risk.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Female; Humans; Hyperkalemia; Hypokalemia; Male; Middle Aged; Potassium; Ramipril; Risk Factors; Treatment Outcome

Cardiovascular risk is determined by multiple risk factors, all of which greatly increase the chance of morbidity and mortality. So-called "normal" levels of these factors are not biologically normal, so current strategy is based on estimations of a person's global cardiovascular risk, and then using appropriate combinations of treatments in higher-risk people. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) provide multiple actions against many of the risk factors for cardiovascular disease and also show some evidence of an effect that is independent of blood pressure reduction. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) is designed to clarify whether an ARB (telmisartan), an ACE inhibitor (ramipril) or a combination of both confers blood pressure-independent cardioprotection in high-risk patients whose blood pressure is well controlled. The Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) trial has the same endpoints, but will compare telmisartan with placebo in patients who are intolerant to an ACE inhibitor. Primary endpoints for both trials are the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalisation for heart failure. Recruitment is now complete, with 25 620 patients randomised in ONTARGET and 5926 in TRANSCEND. Baseline patient characteristics are similar to those in the Heart Outcomes Prevention Evaluation (HOPE) study, except that the current trials have greater ethnic diversity (including an important cohort from Asia). The subjects are slightly older and mean blood pressure at randomisation is again normal, but slightly lower than in HOPE. The use of beta-blockers and lipid-lowering therapy, known to reduce mortality and morbidity, is also higher in ONTARGET/TRANSCEND. These trials are the largest comparisons to date of ARB and ACE-inhibitor therapy in high-risk patients with controlled blood pressure, and the results will contribute significantly to the future treatment of cardiovascular disease.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Female; Humans; Hypertension; Male; Prospective Studies; Ramipril; Telmisartan

A cost-effectiveness analysis was conducted in Italy of preventive treatment with ramipril (an angiotensin converting enzyme [ACE] inhibitor) compared to no treatment in patients at high risk of cardiovascular death. The analysis was based on data extracted from the HOPE trial.. The current life table method was used in order to model a lifetime time horizon for outcomes and costs. The cohorts used were 1000 subjects on ramipril, and 1000 subjects on placebo enrolled in the HOPE trial. Kaplan-Meier curves at 5 years of the clinical study were fitted using an exponential model over a lifetime horizon, the outcome variables being myocardial infarction, stroke, revascularization and death. Total direct medical costs have been considered from a third-party payer's perspective--the Italian National Health Service. Resources involved in each event/activity were estimated using the modified Delphi technique with a panel of six clinicians. Types of resources reported included drug therapies, laboratory and imaging tests, physician visits, outpatient and inpatient rehabilitation, as well as medical and surgical hospital admissions. The incremental cost per life year gained was the main measure of the analysis.. ICER (incremental cost-effectiveness ratio) decreases with the length of the treatment period. After the first year the ICER is 55,062 euros and subsequently decreases to about 12,770 euros at 5 years, 5945 euros at 10 years and 3726 euros at 20 years. The two ways sensitivity analysis showed that at 5 years ICERs range from a saving of 4059 euros to a cost of 22,929 euros (at 20 years they are 1814 euros and 4434 euros), mainly depending on the cost of drug and cost of events. Previous analyses in other countries based on the HOPE study obtained ICER values which are comparable with our results, when taking into account the different cost structure of the health care systems.. On the basis of these results, the use of ramipril is likely to represent an efficient use of public health expenditure in the Italian healthcare system.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Cost-Benefit Analysis; Delphi Technique; Female; Humans; Italy; Male; Middle Aged; Outcome Assessment, Health Care; Placebos; Ramipril; Risk Factors; Survival Analysis

Emerging data suggest that different indices of glycaemia are risk factors for clinical events. The aim of this analysis was to investigate the relationship between fasting plasma glucose or glycated haemoglobin (GHb) levels and incident cardiovascular (CV) outcomes, death, heart failure and overt nephropathy in diabetic and non-diabetic individuals enrolled in the Heart Outcomes Prevention Evaluation (HOPE) study.. The adjusted 4.5-year risk of CV events (myocardial infarction or stroke or CV death), heart failure, death and overt nephropathy was analysed in relation to baseline and updated GHb levels (in 3,529 diabetic HOPE study participants) and baseline fasting plasma glucose levels (in 1,937 non-diabetic and 1,013 diabetic participants).. In diabetic participants, a 1% absolute rise in the updated GHb predicted future CV events (relative risk [RR]=1.07, 95% CI 1.01-1.13; p=0.014), death (RR=1.12, 95% CI 1.05-1.19; p=0.0004), heart failure (RR=1.20, 95% CI 1.08-1.33; p=0.0008) and overt nephropathy (RR=1.26, 95% CI 1.17-1.36; p<0.0001) after adjusting for age, sex, diabetes duration, blood pressure, WHR, hyperlipidaemia and ramipril. Similarly, a 1 mmol/l rise in fasting plasma glucose was related to an increased risk of CV outcomes (RR=1.09, 95% CI 1.05-1.13; p<0.0001), death (RR=1.06, 95% CI 1.01-1.12; p=0.017), heart failure (RR=1.16, 95% CI 1.06-1.13; p=0.0007) and overt nephropathy (RR=1.34, 95% CI 1.23-1.45; p<0.0001) in the group composed of diabetic and non-diabetic individuals. The significant relationship between fasting plasma glucose and CV outcomes persisted after adjustment for diabetes status (RR=1.06, 95% CI 1.00-1.12; p=0.043).. There is an independent progressive relationship between indices of glycaemia and incident CV events, renal disease and death. Clinical trials of glucose lowering to prevent these outcomes in diabetic and non-diabetic individuals are indicated.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus; Diabetic Angiopathies; Fasting; Female; Glycated Hemoglobin; Humans; Kidney Diseases; Male; Placebos; Ramipril; Reference Values; Risk Factors; Vitamin E

We have previously demonstrated that ramipril reduces vascular events and new diagnoses of diabetes when given for a 4.5-year period. However, it is not known whether the benefits are observed in subgroups of patients at varying risk or on other proven therapies and whether the benefits are sustained beyond the current trial. The 2 aims of this investigation were to assess whether the benefits observed during the HOPE trial were (1) maintained after trial cessation during an additional 2.6 years of follow-up and (2) observed in subgroups based on risk and ancillary treatments.. Of the initial 267 study centers and 9297 patients, 174 centers and 4528 patients agreed to further follow-up. The rates of use of angiotensin-converting-enzyme inhibitors (ACEIs) in the 2 groups (72% ramipril versus 68% placebo) were similar after the end of the trial. During the posttrial follow-up, patients allocated to ramipril had a 19% further lower relative risk (RR) of myocardial infarction (95% confidence interval [CI], 0.65 to 1.01), a 16% lower RR (95% CI, 0.70 to 0.99) of revascularization, and a 34% lower RR of a new diagnosis of diabetes (95% CI, 0.46 to 0.95). Similar RR reductions in vascular events were observed during and after the active phase of the trial, regardless of baseline risk (RR of 0.76, 0.89, and 0.83 for low-, medium-, and high-risk patients, respectively) or ancillary treatments (RR of 0.90 for aspirin, 0.76 for beta-blockers, and 0.84 for lipid-lowering medication).. The benefits of ramipril observed during the active period of the HOPE trial were maintained during posttrial follow-up for cardiovascular death, stroke, and hospitalization for heart failure. Additional reductions in myocardial infarction, revascularization, and the development of diabetes were observed during the follow-up phase despite similar rates of ACEI use in the 2 randomized groups. These benefits were consistent regardless of patient risk or ancillary treatments.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus; Female; Follow-Up Studies; Humans; Male; Ramipril; Treatment Outcome

To evaluate the hypothesis that angiotensin-converting enzyme inhibitor therapy with ramipril reduces baseline levels of C-reactive protein in patients at high cardiovascular risk.. Secondary prevention patients were screened for eligibility and treated with ramipril for 6 month. Baseline and 6-month highly sensitive C-reactive protein levels were determined.. A total of 77 patients were analyzed. The median highly sensitive C-reactive protein concentration at baseline was 2.17 mg/l (interquartile interval 0.97-4.54); whereas in post-treatment, the median was 1.70 mg/l (interquartile interval 0.88-3.41), P=0.0009. Patients were stratified according to risk level determined by baseline highly sensitive C-reactive protein levels: low-risk (<1 mg/l), intermediate risk (1-3 mg/l) and high risk (>3 mg/l) The reduction in highly sensitive C-reactive protein occurred at the expense of the high-risk group (baseline 5.02 mg/l, post-treatment 3.3 mg/l, P<0.0001), with no differences in the other groups. In multiple regression analysis, the reduction observed in the high-risk group could not be explained by baseline treatment or change in any of the variables analyzed.. Highly sensitive C-reactive protein levels were reduced after a 6-month ramipril therapy in secondary prevention patients, suggesting an anti-inflammatory effect of angiotensin-converting enzyme inhibitors. Future investigations will be done to confirm these results, and to investigate how angiotensin-converting enzyme inhibitor treatment elicits anti-inflammatory effects.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; C-Reactive Protein; Cardiovascular Diseases; Drug Therapy, Combination; Female; Humans; Inflammation; Male; Middle Aged; Ramipril; Risk Factors; Secondary Prevention

Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve cardiovascular disease outcomes in high-risk patients, but evidence for the cardio-protective effects of angiotensin II receptor blockers (ARBs) is less extensive. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the parallel Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease (TRANSCEND)--which together form The ONTARGET Trial Programme--are long-term, large-scale, double-blind, multinational outcome studies with the primary objectives of determining if the combination of the ARB telmisartan 80 mg and the ACE inhibitor ramipril 10 mg is more effective than ramipril 10 mg alone, and if telmisartan is at least as effective as ramipril (in the case of ONTARGET), and if telmisartan is superior to placebo (in the case of TRANSCEND), in providing cardiovascular protection for high-risk patients. A pre-defined substudy is being conducted within The ONTARGET Trial Programme to compare the effects of these agents, alone and in combination, on cardiac structure and function. The substudy overcomes criticisms of many previous studies, which have been performed in small numbers of patients using suboptimal methodology, by evaluating changes in left ventricular structure and function using sophisticated technology provided by magnetic resonance imaging (MRI). Some 300 randomized patients within ONTARGET, recruited from selected centres in Australia, Canada, Germany, Hong Kong, New Zealand and Thailand, will have MRI undertaken at baseline and at 2-year follow-up. As this method of assessing left ventricular dysfunction is somewhat timeconsuming, expensive and complex, and in the light of current interest in the role of B-type natriuretic peptide (BNP) as a simple, inexpensive diagnostic and prognostic tool, the substudy will also examine whether changes in BNP during follow-up correlated with changes in left ventricular dysfunction.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Double-Blind Method; Drug Therapy, Combination; Follow-Up Studies; Humans; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging; Middle Aged; Natriuretic Peptide, Brain; Patient Selection; Ramipril; Research Design; Telmisartan; Time Factors

The purpose of this study was to assess the effects of ramipril on left ventricular mass (LVM) and function in vascular disease patients with controlled blood pressure (BP) and with preserved left ventricular ejection fraction (LVEF).. Increased LVM and left ventricular (LV) volume and decreased LVEF predict clinical events. Angiotensin-converting enzyme inhibitors reduce LVM and LV volume and preserve LVEF in patients with hypertension and/or LV dysfunction, but have not been studied in patients with controlled BP and preserved LVEF.. We compared the effects of two doses of ramipril (10 mg/day and 2.5 mg/day) versus placebo in 506 patients with vascular disease on echocardiographic measures of LVM and LV function.. Baseline BP and LVEF were similar, 131/76 mm Hg and 58%, in all treatment groups. After four years, LVM index increased by 3.98 +/- 2.08 g/m2 in the placebo and by 4.16 +/- 1.86 g/m2 in the ramipril 2.5 mg/day groups and decreased by 2.02 +/- 2.25 g/m2 in the ramipril 10 mg/day group (p = 0.02). The changes in LV end-diastolic and end-systolic volumes were 4.16 +/- 2.55 ml and 5.31 +/- 1.67 ml in the placebo, -0.43 +/- 2.75 ml and 2.90 +/- 1.45 ml in the ramipril 2.5 mg/day, and -5.90 +/- 2.93 ml and -1.90 +/- 1.55 ml in the ramipril 10 mg/day groups (p = 0.02 and p = 0.001). The changes in LVEF were -2.02 +/- 0.72%, -1.54 +/- 0.74%, and -0.17 +/- 0.72%, respectively (p = 0.01).. Ramipril has beneficial effects on LV structure and function in vascular patients with controlled BP and with preserved LVEF.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Canada; Cardiovascular Diseases; Diastole; Dose-Response Relationship, Drug; Double-Blind Method; Echocardiography; Female; Follow-Up Studies; Heart Ventricles; Humans; Male; Middle Aged; Patient Compliance; Ramipril; Stroke Volume; Systole; Treatment Outcome; Ventricular Dysfunction, Left

Angiotensin-converting enzyme (ACE) inhibitors reduce mortality, myocardial infarction, stroke, heart failure, need for revascularization, nephropathy, and diabetes and its complications. Although angiotensin-II receptor blockers (ARBs) have been less extensively evaluated, theoretically they may have "protective" effects similar to those of ACE inhibitors, but with better tolerability. Currently, there is uncertainty about the role of ARBs when used alone or in combination with an ACE inhibitor in high-risk populations with controlled hypertension.. Primary objectives of the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) are to determine if the combination of the ARB telmisartan and the ACE inhibitor ramipril is more effective than ramipril alone, and if telmisartan is at least as effective as ramipril. The Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease (TRANSCEND) will determine if telmisartan is superior to placebo in patients who are intolerant of ACE inhibitors. The primary outcome for both trials is the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure.. High-risk patients with coronary, peripheral, or cerebrovascular disease or diabetes with end-organ damage are being recruited and followed for 3.5 to 5.5 years in 2 parallel, randomized, double-blind clinical trials.. Recruitment from 730 centers in 40 countries for ONTARGET (n = 25,620) was completed in July 2003. For TRANSCEND, 5776 patients (out of a projected total of 6000) have been recruited (by May 10, 2004). Baseline patient characteristics are comparable to the Heart Outcomes Prevention Evaluation (HOPE) trial, the basis of the design of the current study, confirming that patients are at high-risk.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Diabetes Mellitus; Double-Blind Method; Drug Therapy, Combination; Humans; Middle Aged; Patient Selection; Ramipril; Randomized Controlled Trials as Topic; Research Design; Telmisartan

In people with diabetes, renal disease tends to progress from microalbuminuria to clinical proteinuria to renal insufficiency. Little evidence has been published for the nondiabetic population. This study retrospectively analyzed changes of proteinuria over 4.5 yr in the HOPE (Heart Outcomes and Prevention Evaluation) study, which compared ramipril's effects to placebo in 9297 participants, including 3577 with diabetes and 1956 with microalbuminuria. This report is restricted to 7674 participants with albuminuria data at baseline and at follow-up. Inclusion criteria were known vascular disease or diabetes plus one other cardiovascular risk factor, exclusion criteria included heart failure or known impaired left ventricular function, dipstick-positive proteinuria (>1+), and serum creatinine >2.3 mg/dl (200 microM). Baseline microalbuminuria predicted subsequent clinical proteinuria for the study participants overall (adjusted odds ratio [OR], 17.5; 95% confidence interval [CI], 12.6 to 24.4), in participants without diabetes (OR, 16.7; 95% CI, 8.6 to 32.4), and in participants with diabetes (OR, 18.2; 95% CI, 12.4 to 26.7). Any progression of albuminuria (defined as new microalbuminuria or new clinical proteinuria) occurred in 1859 participants; 1542 developed new microalbuminuria, and 317 participants developed clinical proteinuria. Ramipril reduced the risk for any progression (OR, 0.87; 95% CI, 0.78 to 0.97; P = 0.0146). People without and with diabetes who are at high risk for cardiovascular disease are also at risk for a progressive rise in albuminuria. Microalbuminuria itself predicts clinical proteinuria in nondiabetic and in diabetic people. Ramipril prevents or delays the progression of albuminuria.

Topics: Aged; Albuminuria; Antihypertensive Agents; Cardiovascular Diseases; Diabetic Nephropathies; Disease Progression; Female; Follow-Up Studies; Humans; Male; Middle Aged; Predictive Value of Tests; Ramipril; Renal Insufficiency; Risk Factors

The Heart Outcomes Prevention Evaluation (HOPE), a Canadian-led, multicentre, randomized controlled trial, demonstrated the effectiveness of the ACE inhibitor ramipril in the secondary prevention of cardiovascular disease in patients who were at high risk for cardiovascular events but did not have left ventricular dysfunction or heart failure. We studied whether HOPE affected the prescribing of ACE inhibitors generally, and ramipril specifically, in Ontario, where the trial was coordinated.. We used linked administrative databases to examine prescribing patterns for ACE inhibitors in the 1.29 million to 1.54 million elderly (aged 66 and over) residents of Ontario during the study period and specifically those with diabetes or congestive heart failure. For all new prescriptions for these drugs filled between Jan. 1, 1993, and Mar. 31, 2001, we conducted time-series analyses to measure any association with the release of the HOPE results.. The monthly number of new prescriptions for ramipril from the time it was introduced in 1995 until HOPE's early termination, in April 1999, peaked at 58 per 100,000 elderly Ontario residents. The rate increased to 92/100,000 in May, coincident with newspaper coverage of the trial's early termination, then fell back to 63/100,000 in August. After HOPE's results were formally released, starting Aug. 31, the rate increased significantly; it peaked at 304/100,000 in May 2000 (p < 0.01). The market share of ramipril among ACE inhibitors also increased significantly (p < 0.01), both overall and among patients with diabetes or congestive heart failure.. HOPE led to a striking and unprecedented increase, over 400%, in ramipril prescribing to elderly Ontario residents, including those not eligible for the trial. Many physicians are now prescribing ramipril for patients with diabetes or congestive heart failure.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Databases, Factual; Drug Utilization; Humans; Ontario; Ramipril; Treatment Outcome

Previous trials in the prevention of heart failure have been restricted to patients with low ejection fraction or hypertension. We assessed an angiotensin-converting enzyme (ACE) inhibitor, ramipril, to prevent the development of heart failure in high-risk patients without known low ejection fraction or heart failure.. We randomly assigned 9297 patients to receive double-blind ramipril (10 mg daily) or matching placebo for 4.5 years. Death attributable to heart failure, hospitalization for heart failure, initiation of open-label ACE inhibitor for heart failure, or development of typical signs or symptoms of heart failure developed in 951 patients and was associated with a 4.01-fold increase in the risk of death (P<0.0001). The rate of developing heart failure was significantly increased with coronary disease (risk ratio, 2.17), microalbuminuria (1.82), left ventricular hypertrophy (1.47), increasing age (by decade, 1.37), and diabetes (1.36). Ramipril reduced new-onset heart failure rate from 11.5% to 9.0% (relative risk, 0.77; 95% CI, 0.68 to 0.87; P<0.0001). Ramipril consistently reduced heart failure rate both in those with (relative risk, 0.87) and those without an interim myocardial infarction (relative risk, 0.78). Ramipril also reduced the heart failure rate more in patients with baseline systolic pressure above the median (139 mm Hg) (relative risk, 0.67) compared with those below the median (relative risk, 0.91; P=0.024 for interaction of group by treatment).. Ramipril significantly reduces the rate of development of heart failure in patients at high risk of cardiovascular events.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Double-Blind Method; Follow-Up Studies; Heart Failure; Humans; Incidence; Myocardial Infarction; Ramipril; Treatment Outcome

We evaluated the effects of long-term therapy with the angiotensin-converting enzyme (ACE) inhibitor ramipril on major cardiovascular (CV) outcomes in high-risk women.. The effect of long-term ACE inhibitor therapy in high-risk women without heart failure and with preserved left ventricular (LV) systolic function has not been previously reported.. The Heart Outcomes Prevention Evaluation (HOPE) trial is a large, randomized clinical trial that evaluated ramipril and vitamin E in high-risk patients. We present the preplanned analysis of the effects of ramipril in women in the HOPE study. The study randomized 2,480 women aged >or=55 years with vascular disease or diabetes and at least one additional CV risk factor and without heart failure or a known low LV ejection fraction to ramipril (10 mg/day) or placebo. The primary outcome was the composite of myocardial infarction, stroke or CV death. Average follow-up was 4.5 years.. Treatment with ramipril resulted in reduced primary end point rates (11.3% vs. 14.9% in the placebo arm; relative risk [RR] 0.77, 95% confidence interval [CI] 0.62 to 0.96; p = 0.019), fewer strokes (3.1% vs. 4.8%; RR 0.64, 95% CI 0.43 to 0.96; p = 0.029) and fewer CV deaths (4.2% vs. 6.9%; RR 0.62, 95% CI 0.44 to 0.88; p = 0.0068). There were trends toward reduced rates of myocardial infarction, heart failure and all-cause death. The beneficial effect of ramipril was similar in women and men.. Treatment with ramipril reduces the CV risk in high-risk women without heart failure and with preserved LV systolic function.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Female; Follow-Up Studies; Humans; Middle Aged; Myocardial Infarction; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Treatment Outcome

This study compares the effect of estrogens and ACE inhibition on plasminogen activator inhibitor-1 (PAI-1) concentrations in healthy postmenopausal women, genotyped for a 4G/5G polymorphism in the PAI-1 promoter, a polymorphism shown to influence PAI-1 concentrations. Methods and Results- Morning estradiol, PAI-1, tissue plasminogen activator, plasma renin activity, angiotensin II, and aldosterone were measured in 19 postmenopausal women (5G/5G:4G/5G:4G4G=5:10:4, respectively) at baseline and during randomized, single-blind, crossover treatment with conjugated equine estrogens 0.625 mg per os per day, ramipril 10 mg per os per day, and combination estrogens and ramipril. Estradiol (P<0.005) and angiotensin II (P<0.01) were significantly higher during estrogens. Plasma renin activity was significantly increased during ACE inhibition (P<0.05). Both conjugated estrogens [PAI-1 antigen from 12.5 (7.6, 17.4) [mean (95% CI)] baseline to 6.6 (2.6, 10.7) ng/mL, P<0.01] and ACE inhibition [8.3 (4.9, 11.7) ng/mL, P<0.005] decreased PAI-1 without decreasing tissue plasminogen activator. The effect of combined therapy on PAI-1 [5.6 (2.3, 8.8) ng/mL] was significantly greater than that of ramipril alone (P<0.05). There was a significant effect of PAI-1 4G/5G genotype on baseline PAI-1 concentrations (P=0.001) and a significant interactive effect of 4G/5G genotype and treatment, such that genotype influenced the change in PAI-1 during ramipril (P=0.011) or combined therapy (P=0.006) but not during estrogens (P=0.715).. ACE inhibition with ramipril and conjugated estrogens similarly decrease PAI-1 antigen concentrations in postmenopausal women. Larger studies that use clinical outcomes are needed to determine whether PAI-1 4G/5G genotype should influence the choice of conjugated estrogens or ACE inhibition for the treatment of healthy postmenopausal women.

Topics: Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cardiovascular Diseases; Cross-Over Studies; Drug Therapy, Combination; Estradiol; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Female; Humans; Middle Aged; Plasminogen Activator Inhibitor 1; Polymorphism, Genetic; Postmenopause; Ramipril; Renin; Single-Blind Method; Tissue Plasminogen Activator

To evaluate if long-term treatment with ramipril is cost-effective in patients at high risk of cardiovascular events.. Randomized double-blind and placebo controlled. Information was gathered prospectively for a number of direct medical, direct nonmedical and indirect costs.. This is a sub-study to the Heart Outcomes Prevention Evaluation (HOPE) study performed in Swedish patients. All Swedish centres (19; n= 554) were invited to take part and 18 centres agreed to do so (n=537). The patients were managed in a specialist setting with a mean follow-up period of 4.5 years. Main outcome measures. The number of life-years saved was derived from the global HOPE study (n=9297) and subsequently the estimated life expectancy of those who completed the clinical study alive was added to the calculation. Direct medical costs related to cardiovascular disease only were considered in the primary analysis, whilst all kinds of costs and costs for all kinds of diseases were included in subsequent analyses. The cost of added years of life, according to the future cost method, was included in sensitivity analyses.. The cost per life-year gained was SEK 16 600 (Euro 1940) when direct medical costs for cardiovascular reasons only were considered and SEK 45 400 (Euro 5300) when direct medical costs for all diseases were considered. The corresponding costs when direct nonmedical and indirect cost were added to the estimate were SEK 16 100 (Euro 1880) and SEK 54 600 (Euro 6380), respectively. When the future cost method was applied, the cost per life-year gained was SEK 208 300 (Euro 24 300).. Ramipril is highly cost-effective in the treatment of patients at high risk of cardiovascular events.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Cost-Benefit Analysis; Direct Service Costs; Female; Hemodynamics; Hospitalization; Humans; Life Expectancy; Male; Multicenter Studies as Topic; Prospective Studies; Ramipril; Randomized Controlled Trials as Topic; Sweden

Albuminuria has been shown to identify patients with an increased cardiovascular risk, and in clinical studies ACE inhibitors reduce the urinary protein excretion. It was the primary aim of this intensified monitoring project to determine whether these results can be reproduced in a clinical practice setting. Micro- (2.7-22.6 mg albumin/mmol creatinine) or macroalbuminuria (>22.6 mg/mmol) was confirmed by a central laboratory in 598 out of 773 patients with hypertension who had albuminuria >50 mg/l on a Micral Test II performed by 147 general practitioners. Coronary heart disease (prevalence rates 15% in patients with normalbuminuria, 33% in patients with microalbuminuria, and 40% in patients with macroalbuminuria), heart failure (prevalence rates 19, 29, and 32%, respectively), left ventricular hypertrophy (prevalence rates 30, 42, and 38%, respectively), and peripheral vascular disease (prevalence rates 7, 15, and 20%, respectively) were significantly more common in patients with elevated urinary albumin excretion. 230 patients with microalbuminuria and 202 subjects with macroalbuminuria were treated with the angiotensin-converting enzyme inhibitor ramipril for 6 months. The treatment significantly lowered mean arterial blood pressure (from a median value of 120 mm Hg, quartiles 113-125 mm Hg, to 103 mm Hg, quartiles 100-109 mm Hg) as well as urinary albumin excretion (from a median value of 18 mg/mmol creatinine, quartiles 7.2-54.6 mg/mmol creatinine, to 6.5 mg/mmol creatinine, quartiles 1.6-23.1 mg/mmol creatinine). The treatment efficacy was unaffected by age, body mass index, and smoking status. Patients with diabetes mellitus type II and heart failure also had a significant, although less pronounced reduction of albuminuria. In summary, we conclude that ramipril is able to reduce the urinary albumin excretion in a clinical practice setting, as has been shown in clinical studies. However, the treatment response is not completely uniform, as special patient populations seem to be more resistant to therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Austria; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Creatinine; Female; Glycated Hemoglobin; Humans; Lipids; Male; Middle Aged; Monitoring, Physiologic; Proteinuria; Ramipril; Risk Factors

The cardiovascular risk associated with early renal insufficiency is unknown. Clinicians are often reluctant to use angiotensin-converting enzyme inhibitors in patients with renal insufficiency.. To determine whether mild renal insufficiency increases cardiovascular risk and whether ramipril decreases that risk.. Post hoc analysis.. The Heart Outcomes and Prevention Evaluation (HOPE) study, a randomized, double-blind, multinational trial involving 267 study centers.. 980 patients with mild renal insufficiency (serum creatinine concentration >/= 124 micromol/L [>/=1.4 mg/dL]) and 8307 patients with normal renal function (serum creatinine concentration < 124 micromol/L [<1.4 mg/dL]) Patients with a baseline serum creatinine concentration greater than 200 micromol/L (2.3 mg/dL) were excluded.. The primary outcome measure was incidence of cardiovascular death, myocardial infarction, or stroke.. Cumulative incidence of the primary outcome was higher in patients with renal insufficiency than in those without (22.2% vs. 15.1%; P < 0.001) and increased with serum creatinine concentration. Patients with renal insufficiency had a substantially increased risk for cardiovascular death (11.4% vs. 6.6%) and total mortality (17.8% vs. 10.6%) (P < 0.001 for both comparisons). The effect of renal insufficiency on the primary outcome (adjusted hazard ratio, 1.40 [95% CI, 1.16 to 1.69]) was independent of known cardiovascular risks and treatment. Ramipril reduced the incidence of the primary outcome in patients with and those without renal insufficiency (hazard ratio, 0.80 vs. 0.79; P > 0.2 for the difference).. In patients who had preexisting vascular disease or diabetes combined with an additional cardiovascular risk factor, mild renal insufficiency significantly increased the risk for subsequent cardiovascular events. Ramipril reduced cardiovascular risk without increasing adverse effects.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Creatinine; Diabetes Complications; Double-Blind Method; Female; Follow-Up Studies; Humans; Middle Aged; Prognosis; Ramipril; Regression Analysis; Renal Insufficiency; Risk Factors; Statistics, Nonparametric; Vascular Diseases

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Creatinine; Diabetes Complications; Double-Blind Method; Female; Follow-Up Studies; Humans; Middle Aged; Prognosis; Ramipril; Renal Insufficiency; Risk Factors; Vascular Diseases

Type 2 diabetes is a growing clinical and public health problem. Preventive efforts related to lifestyle modification are not always successful; therefore, alternative prevention strategies need to be studied.. To investigate the effectiveness of ramipril, an angiotensin-converting enzyme inhibitor, in preventing diabetes among high-risk persons.. The randomized, controlled Heart Outcomes Prevention Evaluation trial of 5720 patients older than 55 years without known diabetes but with vascular disease who were followed up for a mean of 4.5 years. The study included 267 hospitals in 19 countries and was conducted between 1994 and 1999.. Patients were randomly assigned to receive ramipril, up to 10 mg/d (n = 2837), or placebo (n = 2883).. Diagnosis of diabetes determined from self-report at follow-up visits every 6 months, compared between the 2 groups.. One hundred and two individuals (3.6%) in the ramipril group developed diabetes compared with 155 (5.4%) in the placebo group (relative risk [RR], 0.66; 95% confidence interval [CI], 0.51-0.85, P<.001). Similar results were noted when different diagnostic criteria were used; in the ramipril group, the RR for diagnosis of diabetes and hemoglobin A(1c) greater than 110% was 0.60 (95% CI, 0.43-0.85), for initiation of glucose-lowering therapy, 0.56 (95% CI, 0.41-0.77), and for both, 0.51 (95% CI, 0.34-0.76). These effects were also consistently seen in several subgroups examined.. Ramipril is associated with lower rates of new diagnosis of diabetes in high-risk individuals. Because these results have important clinical and public health implications, this hypothesis requires prospective confirmation.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus; Female; Humans; Male; Middle Aged; Proportional Hazards Models; Ramipril; Randomized Controlled Trials as Topic; Survival Analysis

In the HOPE-trial, the ACE inhibitor ramipril significantly reduced cardiovascular morbidity and mortality in patients at high risk for cardiovascular events. The benefit could only partly be attributed to the modest mean reduction of office blood pressure (OBP) during the study period (3/2 mm Hg). However, because according to the HOPE protocol ramipril was given once daily at bedtime and blood pressure was measured during the day, the 24-hour reduction of blood pressure may be underestimated based on OBP. Thirty-eight patients with peripheral arterial disease enrolled in the HOPE study underwent 24-hour ambulatory blood pressure (ABP) measurement before randomization and after 1 year. OBP was measured in the sitting position immediately before fitting the ABP measuring equipment to the patients. Ramipril did not significantly reduce OBP (8/2 mm Hg, P=NS) or day ABP (6/2 mm Hg, P=NS) after 1 year. Twenty-four-hour ABP was significantly reduced (10/4 mm Hg, P=0.03), mainly because of a more pronounced blood pressure lowering effect during nighttime (17/8 mm Hg, P<0.001). The night/day ratio was also significantly lowered in the ramipril group. ABP shows greater falls, especially at night, than OBP during treatment with ramipril given once daily at bedtime. Although, OBP is the correct comparator when comparing with previous large intervention trials and epidemiological studies, the effects on cardiovascular morbidity and mortality seen with ramipril in the HOPE study may, to a larger extent than previously ascribed, relate to effects on blood pressure patterns over the 24-hour period.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure Monitoring, Ambulatory; Cardiovascular Diseases; Circadian Rhythm; Female; Humans; Hypertension; Male; Peripheral Vascular Diseases; Ramipril

Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction, whether or not they have heart failure. We assessed the role of an angiotensin-converting-enzyme inhibitor, ramipril, in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure.. A total of 9297 high-risk patients (55 years of age or older) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were randomly assigned to receive ramipril (10 mg once per day orally) or matching placebo for a mean of five years. The primary outcome was a composite of myocardial infarction, stroke, or death from cardiovascular causes. The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper.. A total of 651 patients who were assigned to receive ramipril (14.0 percent) reached the primary end point, as compared with 826 patients who were assigned to receive placebo (17.8 percent) (relative risk, 0.78; 95 percent confidence interval, 0.70 to 0.86; P<0.001). Treatment with ramipril reduced the rates of death from cardiovascular causes (6.1 percent, as compared with 8.1 percent in the placebo group; relative risk, 0.74; P<0.001), myocardial infarction (9.9 percent vs. 12.3 percent; relative risk, 0.80; P<0.001), stroke (3.4 percent vs. 4.9 percent; relative risk, 0.68; P<0.001), death from any cause (10.4 percent vs. 12.2 percent; relative risk, 0.84; P=0.005), revascularization procedures (16.3 percent vs. 18.8 percent; relative risk, 0.85; P<0.001), cardiac arrest (0.8 percent vs. 1.3 percent; relative risk, 0.62; P=0.02), [corrected] heart failure (9.1 percent vs. 11.6 percent; relative risk, 0.77; P<0.001), and complications related to diabetes (6.4 percent vs. 7.6 percent; relative risk, 0.84; P=0.03).. Ramipril significantly reduces the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Double-Blind Method; Female; Humans; Male; Middle Aged; Myocardial Infarction; Ramipril; Risk Factors; Stroke; Treatment Outcome

Diabetes mellitus is a strong risk factor for cardiovascular and renal disease. We investigated whether the angiotensin-converting-enzyme (ACE) inhibitor ramipril can lower these risks in patients with diabetes.. 3577 people with diabetes included in the Heart Outcomes Prevention Evaluation study, aged 55 years or older, who had a previous cardiovascular event or at least one other cardiovascular risk factor, no clinical proteinuria, heart failure, or low ejection fraction, and who were not taking ACE inhibitors, were randomly assigned ramipril (10 mg/day) or placebo, and vitamin E or placebo, according to a two-by-two factorial design. The combined primary outcome was myocardial infarction, stroke, or cardiovascular death. Overt nephropathy was a main outcome in a substudy.. The study was stopped 6 months early (after 4.5 years) by the independent data safety and monitoring board because of a consistent benefit of ramipril compared with placebo. Ramipril lowered the risk of the combined primary outcome by 25% (95% CI 12-36, p=0.0004), myocardial infarction by 22% (6-36), stroke by 33% (10-50), cardiovascular death by 37% (21-51), total mortality by 24% (8-37), revascularisation by 17% (2-30), and overt nephropathy by 24% (3-40, p=0.027). After adjustment for the changes in systolic (2.4 mm Hg) and diastolic (1.0 mm Hg) blood pressures, ramipril still lowered the risk of the combined primary outcome by 25% (12-36, p=0.0004).. Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes. The cardiovascular benefit was greater than that attributable to the decrease in blood pressure. This treatment represents a vasculoprotective and renoprotective effect for people with diabetes.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Complications; Diabetic Angiopathies; Diabetic Nephropathies; Female; Humans; Hypertension; Male; Ramipril; Risk Factors

The Heart Outcomes Prevention Evaluation (HOPE) study found that the ACE inhibitor ramipril can lower the risk of atherosclerotic disease events and death in patients without heart failure but with known atherosclerosis or with diabetes plus at least one cardiovascular risk factor. This benefit was independent of ramipril's effect on blood pressure. Additional benefits were a reduced risk of diabetic nephropathy in diabetic patients, and a lower likelihood of newly diagnosed diabetes. On the other hand, vitamin E in the doses and duration studied (400 IU/day for 4.5 years) did not lower risk significantly.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Complications; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Ramipril; Risk Factors; Treatment Outcome; Vitamin E

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Placebos; Prospective Studies; Ramipril; Risk Factors; Stroke; Time Factors

Whether ACE inhibition is useful for type 2 diabetic patients with micro- and macroalbuminuria remains unknown. The Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria, Cardiovascular Events and Ramipril (DIABHYCAR) Study was set up to address this issue through a multicenter double-blind parallel placebo-controlled > or = 3-year trial in Europe and North Africa. In this article, we report the characteristics of the randomized patients.. The main selection criteria were as follows: men or women aged > or = 50 years with type 2 diabetes treated with oral antidiabetic drugs, with or without hypertension, with a plasma creatinine level < 150 mumol/l, and with persistent micro- or macroalbuminuria, as assessed centrally by two successive urine samples containing a urinary albumin concentration > or = 20 mg/l. Patient characteristics were studied by comparing patients who were randomized to those who were not, taking their geographical origin into account.. There were 25,455 patients screened for urinary albumin (20,296 from France, 918 from Germany, 1,019 from Northwest Europe, 969 from Central Europe, 959 from Mediterranean Europe, and 1,294 from North Africa). Of these patients, 4,937 were randomized. Compared with the nonrandomized patients, the randomized patients were older, more often men, more obese, had higher systolic/diastolic blood pressure and plasma glucose, smoked more tobacco, drank more alcohol, and had complications more frequently. Using a logistic regression analysis, all the above-mentioned items appeared as independent determinants for randomization into the study, with the exception of alcohol intake. The contribution of each item varied slightly from one geographical origin to another.. The physical, biological, and behavioral characteristics create a poor renal and cardiovascular prognosis for the type 2 diabetic patients randomized to the DIABHYCAR Study because of micro- and macroalbuminuria. Testing the usefulness of ACE inhibition for the type 2 diabetic patients with microalbuminuria seems feasible through the DIABHYCAR Study.

Topics: Africa, Northern; Albuminuria; Alcohol Drinking; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Double-Blind Method; Europe; Female; Humans; Male; Middle Aged; Obesity; Placebos; Ramipril; Smoking

The non-insulin-dependent DIABetes, HYpertension, microalbuminuria or proteinuria, CARdiovascular events, and Ramipril (DIABHYCAR) study is a randomized, prospective, double-blind, placebo-controlled, multicenter international trial of the ACE inhibitor ramipril (1.25 mg/day) in patients with type II diabetes and micro- or macroalbuminuria. The main outcome of the study is the time to first occurrence of either death from a cardiovascular origin, including sudden death, nonfatal myocardial infarction, stroke, or congestive heart failure, or requirement of hemodialysis or renal transplantation. The study was launched in France in early 1995 with the participation of general practitioners only, but had to be extended to 15 other countries in 1997 due to difficulties in recruitment. Since 2.5 years after the beginning of the trial the observed event rate was much less than anticipated, it was decided to increase recruitment and follow-up duration and to include congestive heart failure in the definition of the main outcome to keep the study power at a satisfactory level. Recruitment ended on April 1, 1998 with 4937 randomized patients. Following the early discontinuation for efficacy of another study of ramipril in high cardiovascular risk patients, the Heart Outcomes Prevention Evaluation study (HOPE), the second interim analysis of DIABHYCAR was performed early (when 406 instead of 500 patients presented a main outcome) and the Data Safety and Monitoring Board recommended that the study continue. Follow-up is planned to end on March 31, 2001.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Clinical Trials as Topic; Data Interpretation, Statistical; Diabetes Mellitus, Type 2; Europe; Female; France; Humans; Male; Multicenter Studies as Topic; Patient Selection; Ramipril; Randomized Controlled Trials as Topic; Research Design; Sample Size

The HOPE study investigated the hypothesis that inhibition of the RAS with the ACE inhibitor, ramipril, prevents cardiovascular events in patients with a high cardiovascular risk. The primary endpoint of the double-blind, placebo-controlled study was the combination of myocardial infarction, stroke and cardiovascular death. The result was a significant reduction in the number of myocardial infarctions (9.9 vs. 12.2%), cardiovascular deaths (6.1 vs. 8.1%), strokes (3.4 vs. 4.9%) and revascularizations (16.0 vs. 18.6%) under the ACE inhibitor. The cough rate was raised (by 5%). The cardio- and nephroprotective benefits of ramipril were largely independent of the reduction in blood pressure achieved by the ACE inhibitor. The effects of rampipril in terms of micro- and macrovascular complications benefitted in particular type 2 diabetics with additional cardiovascular risk factors, so that this group should not be denied ramipril. The level of albumin excretion in the urine is directly coupled with the rate of cardiovascular events.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Ramipril; Risk Factors; Survival Rate

The results of the HOPE ("Heart Outcomes Prevention Evaluation") study were presented at the XXIst Congress of the European Society of Cardiology in Barcelona (August 28-September 1, 1999). In addition, results obtained in the large diabetic sub-population (38% of the 9541 patients included in the trial) were reported at the XXXVth Congress of the European Association for the Study of Diabetes in Brussels (September 28-October 2, 1999). The HOPE trial was terminated early because of a reduction of the relative risk (-22%, p < 0.000002) of major cardiovascular events in the group treated with ramipiril compared to the group receiving placebo. Such a favourable effect of ramipril was observed in non-diabetic subjects in secondary prevention and in diabetic patients in secondary or primary prevention. In the latter population, a significant reduction in the incidence of microangiopathic complications (nephropathy and retinopathy) was also demonstrated.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Complications; Humans; Ramipril; Treatment Outcome

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Humans; Ramipril

To describe the design of the HOPE (Heart Outcomes Prevention Evaluation) study.. Description of the key design features of HOPE, a large, simple randomized trial of two widely applicable treatments--ramipril, an angiotensin-converting enzyme inhibitor; and vitamin E, a naturally occurring antioxidant vitamin--in the prevention of myocardial infarction, stroke or cardiovascular death.. Two-hundred and sixty-seven hospitals, physician offices and clinics in Canada, the United States, Mexico, Europe and South America.. Over 9000 women and men aged 55 years and above at high risk for cardiovascular events such as myocardial infarction and stroke were recruited over 18 months.. A 2X2 factorial design with ramipril and vitamin E with follow-up for up to four years.. HOPE will be one of the largest trials of two new interventions to prevent myocardial infarction, stroke or cardiovascular death in high risk patients. The results of HOPE will have direct public health impact and are likely to be readily incorporated into clinical practice. Key design features of HOPE are inclusion of individuals at high risk of cardiovascular disease, inclusion of a substantial proportion of patients with diabetes (36%) and women (27%), and detailed substudies to provide data on mechanisms of benefit.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Female; Humans; Male; Middle Aged; Patient Selection; Ramipril; Research Design; Risk Factors; Vitamin E

To describe the rationale and design of a large international study (microalbuminuria, cardiovascular, and renal outcomes [MICRO] in the HOPE [Heart Outcomes Prevention Evaluation] study) of an ACE inhibitor and vitamin E for the prevention of diabetic nephropathy (DN) and cardiovascular disease (CVD) in patients with diabetes and microalbuminuria (MA).. A total of 3,657 diabetic subjects, including 1,129 with MA, are randomly allocated to receive the ACE inhibitor ramipril (or placebo) and vitamin E (or placebo) for 4 years in a two-by-two factorial design. Diabetic subjects are a subset of the 9,541 subjects enrolled in the HOPE study.. The development of DN in microalbuminuric diabetic subjects and the development of MA in normoalbuminuric subjects, as well as cardiovascular death, myocardial infarction, and storke, are the main outcomes. The correlation of changes in albuminuria with changes in carotid atherosclerosis documented in a subset of subjects will also be analyzed.. The effect of both an ACE inhibitor and vitamin E on the progression of renal and CVD in patients with diabetes is being assessed in the MICRO-HOPE study.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Factor Analysis, Statistical; Humans; Middle Aged; Placebos; Ramipril; Research Design; Risk Factors; Time Factors; Vitamin E

Microalbuminuria and proteinuria are strong independent predictors for increased cardiovascular mortality in non-insulin-dependent diabetic (NIDDM) patients. In such patients, angiotensin converting enzyme (ACE) inhibition improves the evolution of diabetic nephropathy; however, no data are currently available on the effects of such intervention on cardiovascular morbidity and mortality. The aim of the Diab-Hycar study is to test the hypothesis that ACE inhibition with a low daily dose of 1.25 mg ramipril, which has no significant effect on blood pressure, may reduce cardiovascular morbidity and/or mortality in normotensive or hypertensive NIDDM patients with persistent albuminuria. Selected and followed by general practitioners, 4000 patients will receive their usual oral antidiabetic treatment and if necessary antihypertensive treatment (ACE inhibitors excluded). In addition in a randomized, double-blind trial they will be given either a placebo or 1.25 mg ramipril daily. The follow-up is currently scheduled to last 3 years. The efficacy of ACE-inhibition will be assessed by the following major end-points: cardiovascular death, sudden death, myocardial infarction, stroke, renal replacement therapy. The Diab-Hycar study started on 3 February 1995. By 1 September 1995, 11,000 urine samples were tested. The prevalence of persistent albuminuria was 23%, 964 patients were initially included in the study, with 619 eligible patients included soon after. Different strategies have been developed to record cardiovascular events correctly and to minimize the number of patients lost to follow-up.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Clinical Protocols; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Patient Selection; Proteinuria; Ramipril

Ramipril is a long acting angiotensin converting enzyme (ACE) inhibitor, which exhibits similar pharmacodynamic properties to captopril and enalapril. Like enalapril it is a prodrug, which is hydrolysed after absorption to form the active metabolite ramiprilat which has a long elimination half-life, permitting once daily administration. In hypertensive patients daily doses in the range 2.5 to 20 mg are usually effective in reducing high blood pressure and maintaining satisfactory control during long term treatment. Patients who do not respond adequately to monotherapy with ramipril usually respond with the addition of a diuretic such as hydrochlorothiazide or piretanide. Ramipril 5 to 10 mg once daily shows comparable antihypertensive efficacy to usual therapeutic dosages of captopril, enalapril and atenolol in patients with mild to moderate essential hypertension. Preliminary data indicate that ramipril may be effective in indications such as severe essential hypertension and renal hypertension. It has also displayed beneficial effects in patients with moderate to severe congestive heart failure. Ramipril has been well tolerated and exhibits an adverse effect profile typical of ACE inhibitors as a class. In conclusion, ramipril will likely represent a useful alternative ACE inhibitor for use in patients with hypertension or congestive heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Ramipril

Cardiovascular disease is a leading cause of death globally, responsible for nearly 18 million deaths worldwide in 2017. Medications to reduce the risk of cardiovascular events are prescribed based on evidence from clinical trials which explore treatment effects in an indicated sample of the general population. However, these results may not be fully generalisable because of trial eligibility criteria that generally restrict to younger patients with fewer comorbidities. Therefore, evidence of effectiveness of medications for groups underrepresented in clinical trials such as those aged ≥75 years, from ethnic minority backgrounds or with low kidney function may be limited.Using individual anonymised data from the Ongoing Telmisartan Alone and the Ramipril Global Endpoint Trial (ONTARGET) trial, in collaboration with the original trial investigators, we aim to investigate clinical trial replicability within a real-world setting in the area of cardiovascular disease. If the original trial results are replicable, we will estimate treatment effects and risk in groups underrepresented and excluded from the original clinical trial.. We will develop a cohort analogous to the ONTARGET trial within the Clinical Practice Research Datalink between 1 January 2001 and 31 July 2019 using the trial eligibility criteria and propensity score matching. The primary outcome is a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalisation for congestive heart failure. If results from the cohort study fall within pre-specified limits, we will expand the cohort to include under represented and excluded groups.. Ethical approval has been granted by the London School of Hygiene & Tropical Medicine Ethics Committee (Ref: 22658). The study has been approved by the Independent Scientific Advisory Committee of the UK Medicines and Healthcare Products Regulatory Agency (protocol no. 20_012). Access to the individual patient data from the ONTARGET trial was obtained by the trial investigators. Findings will be submitted to peer-reviewed journals and presented at conferences.

Topics: Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Clinical Trials as Topic; Cohort Studies; Drug Therapy, Combination; Electronic Health Records; Ethnicity; Humans; Minority Groups; Ramipril; Telmisartan; United Kingdom

Herein, UV spectrophotometry assisted by multivariate chemometric analysis have been presented for quantitative determination of complex quinary therapy containing atenolol, ramipril, hydrochlorothiazide, simvastatin and aspirin without any prior separation. Such combination is very useful for treating various cardiovascular diseases (CVD) including high blood pressure, hypercholesterolemia in addition to its antiplatelet aggregating activity. Calibration (15 samples) and validation (10 samples) sets were prepared of different concentrations for these drugs via implementing partial factorial experimental design. The zero order UV spectra of these sets were recorded and then subjected for further chemometric analysis. Partial least square (PLS) with/without variable selection procedure i.e. genetic algorithm (GA) were employed to untangle the UV spectral overlapping of these mixtures. The performance of these chemometric techniques were compared in terms of accuracy and predictive abilities using cross-validation and external validation methods. It was found that PLS provides good recoveries with prompt predictive ability albeit GA-PLS exhibited better analytical performance owing to its capability to remove redundant variables i.e. the number of absorbance variables had been reduced to about 19-28%. The developed methods allowed reliable determination of such complex therapy in its laboratory prepared mixtures and pharmaceutical preparation within comparable results to those reported by HPLC method, posing these chemometric methods as valuable and indispensable analytical tools in in-process testing and quality control analysis of many pharmaceutical compounds targeting CVD.

Topics: Algorithms; Aspirin; Atenolol; Capsules; Cardiovascular Diseases; Chromatography, High Pressure Liquid; Humans; Hydrochlorothiazide; Least-Squares Analysis; Ramipril; Simvastatin; Spectrophotometry, Ultraviolet

There is underutilization of appropriate medications for secondary prevention of cardiovascular disease (CVD).. Usual care (UC) was compared to polypill-based care with 3 versions using a validated micro-simulation model in the NHANES population with prior CVD. UC included individual prescription of up to 4 drug classes (antiplatelet agents, beta-blockers, renin-angiotensin-aldosterone inhibitors and statins). The polypills modeled were aspirin 81 mg, atenolol 50 mg, ramipril 5 mg, and either simvastatin 40 mg (Polypill I), atorvastatin 80 mg (Polypill II), or rosuvastatin 40 mg (Polypill III). Baseline medication use and adherence came from United Healthcare claims data.. When compared to UC, there were annual reductions of 130,000 to 178,000 myocardial infarctions and 54,000 to 74,000 strokes using Polypill I and II, respectively. From a health sector perspective, in incremental analysis the ICERs for Polypill I and II were $20,073/QALY and $21,818/QALY respectively; Polypill III was dominated but had a similar cost-effectiveness ratio to Polypill II when compared directly to usual care. From a societal perspective, Polypill II was cost-saving and dominated all strategies. Over a 5-year period, those taking Polypill I and II compared to UC saved approximately $12 and $6 per-patient-per-year alive, respectively. Polypill II was the preferred strategy in 98% of runs at a willingness to pay of $50,000 in the probability sensitivity analysis.. Use of a polypill has a favorable cost profile for secondary CVD prevention in the United States. Reductions in CVD-related healthcare costs outweighed medication cost increases on a per-patient-per-year basis, suggesting that a polypill would be economically advantageous to both patients and payers.

Topics: Adrenergic beta-Antagonists; Aspirin; Atenolol; Budgets; Cardiovascular Diseases; Cost Savings; Cost-Benefit Analysis; Drug Combinations; Drug Costs; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Life Expectancy; Male; Medication Adherence; Middle Aged; Nutrition Surveys; Platelet Aggregation Inhibitors; Ramipril; Renin-Angiotensin System; Secondary Prevention; Stroke; United States

Manufacturers of US Food and Drug Administration-approved prescription drugs often apply for additional indications based on randomized clinical trials. Real-world database analyses on a medication's use and outcomes in routine settings of care might help to inform decision making regarding such supplemental indications.. To examine whether longitudinal data from a health care database can support the results of a randomized clinical trial that led to a supplemental indication for telmisartan.. This cohort study of patients newly prescribed telmisartan or ramipril used insurance claims data from a nationwide health care database from January 1, 2003, through September 30, 2009, to compare patient outcomes. This study replicated the inclusion and exclusion criteria used in the Ongoing Telmisartan Alone and in Combination with Ramipril Global End-point Trial (ONTARGET) and used propensity score matching to balance 74 patient characteristics. Data analysis was performed from February 15, 2017, to May 24, 2017.. Telmisartan use vs ramipril use.. The primary outcome was a composite of myocardial infarction, stroke, or hospitalization for congestive heart failure.. Of the 640 951 patients included in the study, 48 053 were newly prescribed ramipril (mean [SD] age, 68.29 [9.52] years; 31 940 male [66.5%]) and 4665 were newly prescribed telmisartan (mean [SD] age, 69.43 [9.60] years; 2413 male [51.7%]). After propensity score matching, a total of 4665 patients were newly prescribed telmisartan (mean [SD] age, 69.43 [9.60] years; 2413 [51.7%]), and 4665 patients were newly prescribed ramipril (mean [SD] age, 69.36 [9.67] years; 2343 male [50.2%]). As seen in ONTARGET, the composite risk of stroke, myocardial infarction, and hospitalization for congestive heart failure was similar for the 2 medications (hazard ratio, 1.0; 95% CI, 0.9-1.1). In addition, the study found that telmisartan was associated with a substantially decreased risk of angioedema (hazard ratio, 0.1; 95% CI, 0.03-0.56) compared with ramipril.. Real-world data analyses of patients receiving routine care provided findings similar to those found in the randomized clinical trial that established telmisartan's supplemental indication. In certain situations, database studies may support supplemental applications for effectiveness for already approved medications.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Clinical Trials as Topic; Delivery of Health Care; Drug Approval; Drug Prescriptions; Follow-Up Studies; Humans; Ramipril; Retrospective Studies; Telmisartan; United States

Topics: Acrylamides; Afatinib; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cardiotonic Agents; Cardiovascular Diseases; Gefitinib; Humans; Lung Neoplasms; Middle Aged; Nebivolol; Piperazines; Protein Kinase Inhibitors; Quinazolines; Ramipril

Topics: Angiotensin-Converting Enzyme Inhibitors; Atorvastatin; Cardiovascular Diseases; Consensus; Drug Combinations; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ramipril; Secondary Prevention

To estimate the health benefits and cost-effectiveness of a polypill intervention (aspirin 100 mg, atorvastatin 20 mg, ramipril 10 mg) compared with multiple monotherapy for secondary prevention of cardiovascular events in adults with a history of myocardial infarction from the perspective of the Spanish National Health System.. An adapted version of a recently published Markov model developed and validated in Microsoft Excel was used to compare the cost-effectiveness of the polypill with that of its combined monocomponents over a 10-year time horizon. The population included in the model had a mean age of 64.7 years; most were male and had a history of myocardial infarction. The input parameters were obtained from a systematic literature review examining efficacy, adherence, utilities, and costs. The results of the model are expressed in events avoided, incremental costs, incremental life years, incremental quality-adjusted life years, and the incremental cost-effectiveness ratio.. Over a 10-year period, use of the cardiovascular polypill instead of its monocomponents simultaneously would avoid 46 nonfatal and 11 fatal cardiovascular events per 1000 patients treated. The polypill would also be a more effective and cheaper strategy. Probabilistic analysis of the base case found a 90.9% probability that the polypill would be a cost-effective strategy compared with multiple monotherapy at a willingness-to-pay of 30 000 euros per quality-adjusted life year.. The polypill would be a cost-effective strategy for the Spanish National Health System with potential clinical benefits.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Aspirin; Atorvastatin; Cardiovascular Diseases; Cost-Benefit Analysis; Drug Costs; Drug Therapy, Combination; Female; Follow-Up Studies; Forecasting; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Male; Markov Chains; Medication Adherence; Middle Aged; Platelet Aggregation Inhibitors; Quality-Adjusted Life Years; Ramipril; Retrospective Studies; Secondary Prevention; Spain

Cardiovascular disease is a chronic disorder which is usually already at an advanced stage when the first symptoms develop. The fact that the initial clinical presentation can be lethal or highly incapacitating emphasizes the need for primary and secondary prevention. It is estimated that the ratio of patients with good adherence to secondary prevention of cardiovascular disease is low and also decreases gradually over time. The Polypill for secondary prevention of cardiovascular disease is the first fixed-dose combination therapy of salicylic acid, atorvastatin and ramipril approved in Spain. The purpose of this consensus document was to define and recommend, through the evidence available in the literature and clinical expert opinion, the impact of treatment adherence in the secondary prevention of cardiovascular disease and the use of the Polypill in daily clinical practice as part of a global strategy including adjustments in patient lifestyle. A RAND/UCLA methodology based on scientific evidence, as well as the collective judgment and clinical expertise of an expert panel was used for this assessment. As a result, a final report of recommendations on the impact of the lack of adherence to treatment of secondary prevention of cardiovascular disease and the effect of using a Polypill in adherence of patients was produced. The recommendations included in this document have been addressed to all those specialists, cardiologists, internists and primary care physicians with competence in prescribing and monitoring patients with high and very high cardiovascular risks.

Topics: Atorvastatin; Cardiovascular Agents; Cardiovascular Diseases; Drug Combinations; Humans; Medication Adherence; Ramipril; Salicylic Acid; Secondary Prevention

In the SMILE-4 study, zofenopril + acetyl salicylic acid (ASA) was more effective than ramipril + ASA on 1-year prevention of major cardiovascular events (MACE) in patients with acute myocardial infarction complicated by left ventricular dysfunction. In this retrospective analysis, we evaluated drug efficacy in subgroups of patients, according to a history of diabetes mellitus.. The primary study endpoint was 1-year combined occurrence of death or hospitalization for cardiovascular causes. Diabetes was defined according to medical history (previous known diagnosis).. A total of 562 of 693 (81.0%) patients were classified as nondiabetics and 131 (18.9%) as diabetics. The adjusted rate of MACE was lower under zofenopril than under ramipril in both nondiabetics [27.9% vs. 34.9% ramipril; odds ratio, OR and 95% confidence interval: 0.55 (0.35, 0.86)] and diabetics [30.9% vs. 41.3%; 0.56 (0.18, 1.73)], although the difference was statistically significant only for the nondiabetic group (P = 0.013). Zofenopril was superior to ramipril as regards to the primary study endpoint in the subgroup of 157 patients with uncontrolled blood glucose (≥ 126 mg/dL), regardless of a previous diagnosis of diabetes [0.31 (0.10, 0.90), P = 0.030]. Zofenopril significantly reduced the risk of hospitalization for cardiovascular causes in both nondiabetics [0.64 (0.43, 0.96), P = 0.030] and diabetics [0.38 (0.15, 0.95), P = 0.038], whereas it was not better than ramipril in terms of prevention of cardiovascular deaths.. This retrospective analysis of the SMILE-4 study confirmed the good efficacy of zofenopril plus ASA in the prevention of long-term MACE also in the subgroup of patients with diabetes mellitus.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Aspirin; Captopril; Cardiovascular Diseases; Diabetic Cardiomyopathies; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Ramipril; Randomized Controlled Trials as Topic; Retrospective Studies; Systole; Ventricular Dysfunction, Left

Topics: Angiotensin-Converting Enzyme Inhibitors; Aspirin; Atorvastatin; Cardiovascular Diseases; Drug Combinations; Europe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Medication Adherence; Patient Selection; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Ramipril; Secondary Prevention; Spain

The present study investigated the effects of switching to different products of the same off-patent active substance (brand name or generic) on therapy discontinuation or substitution with another molecule of the same class, in patients with cardiovascular disease treated with statins and antihypertensives in a 'real-world' setting.. A retrospective cohort study in a 'real-world' setting.. Analysis of data performed by integrating administrative databases that included approximately two million individuals who are assisted by the National Health System from three Local Health Units located in three different regions of Italy.. All patients aged ≥18 years with at least one prescription of simvastatin, ramipril or amlodipine in the period 1 January to 31 December 2010 were included and followed up for 2 years.. Prescription refills occurring during follow-up were evaluated. Frequency of discontinuation of therapy or substitution with another molecule of the same class (eg, from simvastatin to a different statin) during follow-up was identified.. During follow-up, therapy discontinuation or substitution was found to be more frequent in patients switching to a different product of the same active substance compared with non-switching patients (11.5% vs 10.8% and 22.2% vs 20.8% (p=0.002), respectively, in the simvastatin group; 4.0% vs 3.5% and 24.6% vs 22.7% (p<0.001), respectively, in the amlodipine group). In the ramipril group, 8% of patients undertook a therapy substitution to another molecule; no trend towards a lower percentage of substitution was observed in the non-switching group, while 18% of patients discontinued treatment, with a significant difference in favour of patients not switching. These findings were partially confirmed by multivariate analysis.. Switches among products of the same active substance are quite common in patients with cardiovascular disease. Our study suggests that switching may expose patients to a higher risk of therapy discontinuation or substitution.

Topics: Aged; Amlodipine; Antihypertensive Agents; Cardiovascular Diseases; Databases, Factual; Drug Substitution; Drugs, Generic; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Italy; Male; Medication Adherence; Middle Aged; Multivariate Analysis; Ramipril; Retrospective Studies; Simvastatin

Elevated systolic blood pressure (SBP) correlates to cognitive decline and incident dementia. The effects of heart rate (HR), visit to visit HR variation, and visit to visit SBP variation are less well established. Patients without preexisting cognitive dysfunction (N=24 593) were evaluated according to mean SBP, SBP visit to visit variation (coefficient of variation [standard deviation/mean×100%], CV), mean HR, and visit to visit HR variation (HR-CV) in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease. Cognitive function was assessed with mini mental state examination. Cognitive dysfunction (fall in mini mental state examination ≤24 points), important cognitive decline (drop of ≥5 points), and cognitive deterioration (drop of >1 point per year or decline to <24 points) were assessed. SBP and HR were measured over 10.7±2.2 (mean±SD) visits. Mean SBP, mean HR, and SBP-CV were associated with cognitive decline, dysfunction, and deterioration (all P<0.01, unadjusted). After adjustment, only SBP-CV (P=0.0030) and mean HR (P=0.0008) remained predictors for cognitive dysfunction (odds ratios [95% confidence intervals], 1.32 [1.10-1.58] for 5th versus 1st quintile of SBP-CV and 1.40 [1.18-1.66] for 5th versus 1st quintile of mean HR). Similar effects were observed for cognitive decline and deterioration. SBP-CV and mean HR showed additive effects. In conclusion, SBP-CV and mean HR are independent predictors of cognitive decline and cognitive dysfunction in patients at high CV risk.. http://www.clinicaltrials.gov. Unique identifier: NCT 00153101.

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Cardiovascular Diseases; Cognition Disorders; Drug Therapy, Combination; Female; Follow-Up Studies; Heart Rate; Humans; Hypertension; Incidence; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Ramipril; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Telmisartan

Some angiotensin converting enzyme (ACE) inhibitors are efficiently removed from circulation by hemodialysis ('high dialyzability'), whereas others are not ('low dialyzability'). In patients receiving hemodialysis, this may influence the effectiveness of ACE inhibitors.. Using linked healthcare databases we identified older patients receiving chronic hemodialysis who filled new ACE inhibitor prescriptions. The low dialyzability group (n = 3,369) included fosinopril and ramipril. The high dialyzability group (n = 5,974) included enalapril, lisinopril, and perindopril. The primary outcome was all-cause mortality within 180 days of first ACE inhibitor prescription.. There were 361 deaths among 5,974 patients (6.0%) prescribed with low dialyzability ACE inhibitors and 179 deaths among 3,369 patients (5.3%) prescribed with high dialyzability ACE inhibitors (relative risk 1.1, 95% CI 0.9-1.3, p = 0.6).. In this study of older patients receiving hemodialysis, the dialyzability of ACE inhibitors was not associated with mortality or cardiovascular outcomes.

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Cardiotonic Agents; Cardiovascular Diseases; Enalapril; Female; Fosinopril; Hemorheology; Humans; Kidney Failure, Chronic; Kidneys, Artificial; Lisinopril; Male; Middle Aged; Perindopril; Ramipril; Renal Dialysis; Retrospective Studies; Survival Analysis

The aim of this nation-wide cohort study was to assess the association of using an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) therapy on the prognosis of hypertensive patients with chronic kidney disease (CKD). We used Cox's proportional hazard regression model to estimate hazard ratios (HRs) for the risk of end-stage renal disease (ESRD), all-cause mortality, cardiovascular mortality, and first hospitalization for cardiovascular disease (CVD) for losartan and ramipril versus conventional antihypertensive agents. In total, 136,266 hypertensive patients with CKD in Taiwan were followed up from 2001 to 2008. In an average follow-up of 5.9 years, 7364 (5.40%) patients reached ESRD, 4165 (3.06%) patients died, and 6163 (4.52%) patients had their first hospitalization for CVD. Use of losartan or ramipril was associated with a lower risk of the endpoints compared with the conventional group. In the losartan group, the risks of ESRD, all- and cardiovascular-cause mortality, and first hospitalization for CVD were decreased by 9.2% (P = 0.01), 24.6% (P < 0.001), 12.4% (P = 0.03), and 36.0% (P = 0.01), respectively. In the ramipril group, these risks decreased by 7.6% (P = 0.02) for ESRD, 56.9% (P < 0.001) for all-cause mortality, 7.5% (P = 0.04) for cardiovascular mortality, and 24.7% (P < 0.001) for first hospitalization. This study indicated that losartan and ramipril had distinct association on the prognosis of hypertensive patients with CKD, and was first to disclose that the mean time to reach each endpoint for patients in the losartan, ramipril, and conventional group was not significantly different. However, further study is needed to confirm results of the present study.

Topics: Adolescent; Adult; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Cohort Studies; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Hospitalization; Humans; Hypertension; Losartan; Male; Middle Aged; Proportional Hazards Models; Ramipril; Renal Insufficiency, Chronic; Taiwan; Young Adult

The present study was carried out to study the effect of spironolactone, atenolol, metoprolol, ramipril and perindopril on cardiovascular complications in neonatal model of diabetes in rats, induced by administering 90 mg/kg streptozotocin (STZ), i.p. in 2-day-old rats. Our data suggest that spironolactone, metoprolol and perindopril prevent not only the STZ-induced metabolic abnormalities but also cardiovascular complications as evident from the reduction in cholesterol, triglyceride and decrease in cardiac hypertrophy which are the initial symptoms of congestive heart failure. Metoprolol and perindopril appears to be beneficial agents as compared to atenolol and ramipril.

Topics: Animals; Animals, Newborn; Antihypertensive Agents; Atenolol; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Metoprolol; Perindopril; Ramipril; Rats, Wistar; Spironolactone

Topics: Antihypertensive Agents; Benzimidazoles; Benzoates; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypertension; Ramipril; Randomized Controlled Trials as Topic; Telmisartan

The execution of the dosing regimen in Polish primary health care is unknown. The aim of the study was to appraise the medication adherence in patients with hypertension of various cardiovascular risk.. A prospective interviewer questionnaire-based study included 1,467 consecutive patients with arterial hypertension with the pharmacotherapy containing ramipril in the daily dose of 10 mg. The mean observation period was 30.3 +/- 7.0 days (20-56 days). At the followup visit the study participants filled the Morisky-Green test appraising the medication non-adherence.. As many as 60.9% of the study participants have ever forgotten to take their medicine, 60.7% are sometimes neglectful in regard to their medicine hours, 32.4% skip their medicine hours when they are feeling well and 37.4% skip the drugs when they feel badly due to the medicine. Drug adherence was observed in 26.0% of patients. The level of adherence varied between different cardiovascular risk groups and was higher in the groups of lower cardiovacular risk. A very weak correlation between cardiovascular risk level and non-adherence to medication assessed with Morisky-Green scale was observed (r = 0.078, p = 0.047). No relation of non-compliance to medication to age and gender was noted.. Drug adherence in patients with hypertension treated in Polish primary healthcare is very low regardless of the cardiovascular risk level.

Topics: Antihypertensive Agents; Cardiovascular Diseases; Female; Humans; Hypertension; Male; Medication Adherence; Middle Aged; Patient Compliance; Poland; Primary Health Care; Prospective Studies; Ramipril; Risk Factors; Surveys and Questionnaires

Ramipril - a drug with a large evidence base. Various aspects of choosing a drug in cardiology from the standpoint of evidence-based medicine are risen from his example.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Clinical Trials as Topic; Evidence-Based Medicine; Humans; Outcome and Process Assessment, Health Care; Ramipril; Therapeutic Equivalency

We evaluated the cost-effectiveness of administering a daily "polypill" consisting of three antihypertensive drugs, a statin, and aspirin to prevent cardiovascular disease among high-risk patients in Latin America. We found that the lifetime risk of cardiovascular disease could be reduced by 15 percent in women and by 21 percent in men if the polypill were used by people with a risk of cardiovascular disease equal to or greater than 15 percent over ten years. Attaining this goal would require treating 26 percent of the population at a cost of $34-$36 per quality-adjusted life-year. Offering the polypill to women at high risk and to men age fifty-five or older would be the best approach and would yield acceptable incremental cost-effectiveness ratios. The polypill would be very cost-effective even in the country with the lowest gross national income in our study. However, policy makers must weigh the value of intervention with the polypill against other interventions, as well as their country's willingness and ability to pay for the intervention.

Topics: Aged; Antihypertensive Agents; Aspirin; Atenolol; Cardiovascular Diseases; Cohort Studies; Cost-Benefit Analysis; Developing Countries; Drug Combinations; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Latin America; Male; Markov Chains; Middle Aged; Quality-Adjusted Life Years; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Simvastatin; Sodium Chloride Symporter Inhibitors

Previous randomized controlled trials demonstrated a protective effect of renin angiotensin system blocking agents for the development of type-2 diabetes in patients with pre-diabetes. However, there are no real-world data available to illustrate the relevance for clinical practice.. Open, prospective, parallel group study comparing patients with an ACE inhibitor versus a diuretic based treatment. The principal aim was to document the first manifestation of type-2 diabetes in either group.. A total of 2,011 patients were enrolled (mean age 69.1±10.3 years; 51.6% female). 1,507 patients were available for the per-protocol analysis (1,029 ramipril, 478 diuretic group). New-onset diabetes was less frequent in the ramipril than in the diuretic group over 4 years. Differences were statistically different at a median duration of 3 years (24.4% vs 29.5%; p<0.05). Both treatments were equally effective in reducing BP (14.7±18.0/8.5±8.2 mmHg and 12.7±18.1/7.0±8.3 mmHg) at the 4 year follow-up (p<0.001 vs. baseline; p=n.s. between groups). In 38.6% and 39.7% of patients BP was below 130/80 mmHg (median time-to-target 3 months). There was a significant reduction of cardiovascular morbidity and mortality in favour of ramipril (p=0.033). No significant differences were found for a change in HbA1c as well as for fasting blood glucose levels during follow-up. The rate of adverse events was higher in diuretic treated patients (SAE 15.4 vs. 12.4%; p<0.05; AE 26.6 vs. 25.6%; p=n.s).. Ramipril treatment is preferable over diuretic based treatment regimens for the treatment of hypertension in pre-diabetic patients, because new-onset diabetes is delayed.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Disease Progression; Diuretics; Female; Germany; Glycated Hemoglobin; Humans; Hypertension; Incidence; Male; Middle Aged; Prediabetic State; Prospective Studies; Ramipril; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Topics: Atrial Fibrillation; Benzimidazoles; Benzoates; Cardiovascular Diseases; Female; Humans; Male; Ramipril; Telmisartan

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Comprehension; Education, Medical; Evaluation Studies as Topic; Humans; Publications; Ramipril; Reading; Research Design; Treatment Outcome

To examine the impact of tissue selectivity of angiotensin-converting enzyme (ACE) inhibitors on mortality and morbidity in patients following acute myocardial infarction (AMI).. A retrospective cohort study using a Medicaid claims database was conducted. Patients hospitalized for an AMI and subsequently filling a prescription for an ACE inhibitor were followed longitudinally for the occurrence of cardiovascular-related hospitalizations and all-cause mortality. A subanalysis was also conducted to account for switching/discontinuation of ACE inhibitor therapy. Stepwise (forward conditional) Cox-proportional hazards models were used to analyze the effect of tissue selectivity on study outcomes.. The final study sample consisted of 689 AMI and the results indicated that tissue-selective ACE inhibitors had a protective effect against hospitalization due to stroke/transient ischemic attack (TIA) (hazard ratio [HR] = 0.265; 95% confidence interval [CI] = 0.101-0.698). A similar lower rate in hospitalizations due to heart failure was observed in the group using tissue-selective ACE inhibitors; however, the results were not statistically significant (HR = 0.681; 95% CI = 0.436-1.063). A protective effect was also observed on the combined outcome of hospitalization due to any cardiovascular condition (HR = 0.712; 95% CI = 0.536-0.945). Hospitalizations due to recurrent AMI, need for coronary revascularization procedures, and mortality were not significantly different between patients using tissue-selective and non-tissue-selective ACE inhibitors. The completer subanalysis provided similar findings regarding the impact of tissue selectivity on study outcomes.. Tissue-selective ACE inhibitors may have a protective effect against hospitalization due to stroke/TIA or heart failure when compared to non-tissue-selective ACE inhibitors for patients following AMI.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Comorbidity; Enalapril; Female; Heart Failure; Humans; Lisinopril; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Organ Specificity; Proportional Hazards Models; Ramipril; Retrospective Studies; Secondary Prevention; Stroke; Survival Analysis

Reanalysis of incurred samples showed that the bioanalytical method for the quantification of ramipril and ramiprilat was generating irreproducible results for ramiprilat.. An additional peak interfering with ramiprilat was observed in the incurred samples but not in the calibrant and quality control samples. A similar interference was detected for ramipril, but it was chromatographically separated. Interferences were produced during sample preparation, which involves strong cation exchanger cartridges. The interfering products corresponded to the methylation of ramipril and ramiprilat glucuronide.. Following this discovery, a reproducible method was developed and successfully validated for ramipril and ramiprilat. Additional stability tests were performed in the presence of glucuronide and diketopiperazine metabolites of ramipril and ramiprilat to demonstrate the method specificity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Artifacts; Calibration; Cardiovascular Diseases; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Diketopiperazines; Glucuronides; Guidelines as Topic; Humans; Mass Spectrometry; Methylation; Ramipril; Reference Standards; Reproducibility of Results; Sensitivity and Specificity; Specimen Handling; Validation Studies as Topic

No more effective than ramipril in a trial including 25620 patients; two unconvincing placebo-controlled trials in a total of about 26 200 patients.

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Ramipril; Risk Factors; Telmisartan

Some aspects of the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) study are briefly commented on in this article. The three main topics of interest related to the study that require further analysis are the following: the influence of blood pressure control, and in particular, the target blood pressure for patients with established cardiovascular disease such as those admitted in the ONTARGET study, the renal aspects of the study, which are of great interest but do not adequately clarify, in particular, concerns over the dual blockade of the renin-angiotensin-aldosterone system (RAAS) with telmisartan and ramipril, and finally, and probably most importantly, the role of statins in the outcome of the study. A high percentage of patients receiving this type of therapy at the end of the study, which probably contributed to obtaining a residual risk similar to that in the Heart Outcomes Prevention Evaluation (HOPE) study in the absence of treatment with RAAS blockers in approximately two-thirds of patients included in the ONTARGET trial.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Pressure; Cardiovascular Diseases; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Ramipril; Telmisartan

The recently published ONTARGET trial found that telmisartan was non-inferior to ramipril in reducing CV death, MI, stroke, or heart failure in patients with vascular disease or high-risk diabetes. The cost implications of ramipril and telmisartan monotherapy use based on the ONTARGET study are reported here.. Only healthcare system costs were considered. Healthcare resource utilization was collected for each patient during the trial. The authors obtained country-specific unit costs to the different healthcare care resources consumed (i.e., hospitalizations events, procedures, non-study, and study drugs) for all enrolled patients. Purchasing power parities were used to convert country-specific costs into US dollars (US$ 2008). The total undiscounted costs of the study for the telmisartan group was $12,762 per patient and is higher than the ramipril group at $12,007 per patient, an un-discounted difference of $755 (95% confidence interval [CI], $218-$1292); The discounted costs for the telmisartan group was $11,722 compared with $11,019 for the ramipril group; a difference of $703 (95% CI, $209-$1197). The difference in costs is exclusively related to the acquisition cost of telmisartan over generic ramipril.. This analysis only considered direct healthcare system costs. Costs accrued outside the hospital were not collected. Combination therapy was excluded since it would likely be more expensive than ramipril alone, with no additional benefit and a risk of some harm.. Based on these results, it is suggested that for the ONTARGET patients, the use of telmisartan instead of ramipril increases costs by 6.3%. These findings suggest that the choice to put patients on telmisartan should be justified based on the patient?s susceptibility to specific adverse events to minimize the cost implications.

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Cost of Illness; Diabetes Complications; Health Services; Heart Failure; Humans; Multicenter Studies as Topic; Myocardial Infarction; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Telmisartan

Topics: Benzimidazoles; Benzoates; Blood Pressure; Cardiovascular Diseases; Guidelines as Topic; Humans; Kidney Diseases; Ramipril; Telmisartan

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Cardiovascular System; Humans; Ramipril; Renin-Angiotensin System; Telmisartan

To assess the cross-sectional associations of the measures of glycemia and cognitive function in subjects at high cardiovascular risk.. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and concurrent Telmisartan Randomized Assessment Study in ACE intolerant Subjects with Cardiovascular Disease (TRANSCEND) are multi-center, randomized, controlled investigations of different approaches to angiotensin receptor blockade in over 30,000 high CV risk subjects. Baseline data in both trials was used to analyze relationships between measures of glycemic control and cognition.. The univariate and multivariate relationships between diabetes status, fasting plasma glucose (FPG), and scores on the Mini-Mental State Examination (MMSE) were assessed.. In subjects with diabetes, the mean MMSE score was 0.4 units lower than in those without diabetes (P<0.0001). In all subjects, a 1 mmol/L higher FPG value was associated with a MMSE score that was 0.06 units lower (P<0.0001). The association persisted after adjustment for several cardiovascular risk factors.. Dysglycemia is a risk factor for impaired cognitive function in this broadly representative, high-risk study population. Prospective studies can more reliably discern temporal associations, including the effects of glucose lowering in this clinical group.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Glucose; Cardiovascular Diseases; Cognition; Cognition Disorders; Cross-Sectional Studies; Depression; Diabetes Mellitus; Diabetic Angiopathies; Drug Therapy, Combination; Female; Glucose Intolerance; Humans; Male; Middle Aged; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Telmisartan

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Cardiovascular Diseases; Clinical Trials as Topic; Comorbidity; Drug Interactions; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Multicenter Studies as Topic; Myocardial Ischemia; Ramipril; Renal Insufficiency; Risk; Stroke; Telmisartan; Treatment Outcome

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Cardiovascular Diseases; Double-Blind Method; Drug Therapy, Combination; Humans; Hypertension; Ramipril; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Research Design; Risk Factors; Telmisartan; Treatment Outcome

Blockade of the renin-angiotensin system (RAS) has become an integral component of the treatment of patients at increased cardiovascular risk. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) studied 23 400 high-risk cardiovascular patients and compared the effectiveness of telmisartan with that of ramipril and showed that the two drugs were 'therapeutically equivalent'. Telmisartan is now the only angiotensin II blocker with clinical trial evidence of cardiovascular protection equivalent to that of ramipril, which is widely regarded as the 'reference' drug for RAS blockade in patients at increased cardiovascular risk. Despite the prior exclusion of patients intolerant of angiotensin-converting enzyme inhibitors drugs, there were fewer discontinuations in the telmisartan group, and so telmisartan had a superior overall efficacy/tolerability ratio.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Female; Humans; Male; Ramipril; Renin-Angiotensin System; Telmisartan

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Humans; Hypertension; Ramipril; Renin-Angiotensin System; Risk Factors; Telmisartan

The Heart Outcomes Prevention Evaluation study established the angiotensin-converting enzyme inhibitor ramipril, versus placebo, for prevention of cardiovascular events in high-risk patients. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) was later conducted in similar high-risk patients using multifactorial treatment to control hypertension, platelet aggregation, and dyslipidemia, while comparing ramipril, telmisartan, or their combination, without placebo. In ONTARGET, the first angiotensin II receptor blocker-based study to be performed in a broader population of patients without congestive heart failure and/or left ventricular hypertrophy/dysfunction, telmisartan provided cardiovascular protection that was noninferior to ramipril. However, greater blockade of the renin-angiotensin system, using their combination, was not superior to ramipril alone. Telmisartan was better tolerated than ramipril in this high-risk population: notably, the incidence of cough and angioedema was significantly lower with telmisartan alone. Thus, telmisartan provides comparable efficacy to ramipril with less adverse events, which may encourage patient compliance.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Ramipril; Retrospective Studies; Risk Factors; Telmisartan

Angiotensin II has diverse effects on cardiovascular structure and function, and hence drugs that inhibit the formation or activity of this peptide have attained a central position in the prevention of morbidity and mortality from cardiovascular causes. The recent ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) has shown that, in patients with vascular disease or patients with diabetes who were at high risk of cardiovascular events, the angiotensin II receptor blocker telmisartan is noninferior to the angiotensin-converting enzyme inhibitor ramipril in preventing such events, despite the ONTARGET patients receiving better background preventive therapy than those enrolled in the earlier Heart Outcomes Prevention Evaluation (HOPE) study. In addition, telmisartan offers superior tolerability to that of ramipril. Moreover, the finding in this study that combination therapy with telmisartan and ramipril produced no further reduction in cardiovascular events than either drug alone, despite producing greater reductions in blood pressure, highlights the potential importance of endothelial effects of renin-angiotensin system blockade in cardiovascular protection.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Drug Therapy, Combination; Humans; Hypertension; Ramipril; Renin-Angiotensin System; Risk Factors; Telmisartan

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Creatinine; Diabetes Mellitus; Disease Progression; Drug Therapy, Combination; Glomerular Filtration Rate; Humans; Kidney; Multicenter Studies as Topic; Proteinuria; Ramipril; Randomized Controlled Trials as Topic; Telmisartan

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Drug Therapy, Combination; Humans; Hypertension; Multicenter Studies as Topic; Ramipril; Randomized Controlled Trials as Topic; Telmisartan; Treatment Outcome

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Drug Therapy, Combination; Humans; Ramipril; Randomized Controlled Trials as Topic; Telmisartan

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Body Size; Cardiovascular Diseases; Humans; Life Style; Metabolic Syndrome; Obesity; Ramipril; Renin-Angiotensin System; Risk Assessment; Risk Factors; Telmisartan

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Multicenter Studies as Topic; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Telmisartan

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus; Drug Therapy, Combination; Humans; Ramipril; Telmisartan

Topics: Angioedema; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Drug Therapy, Combination; Humans; Hypotension; Ramipril; Telmisartan

The results of the 'Ongoing telmisartan alone and in combination with ramipril global eendpoint trial' (ONTARGET) have recently been published. In this trial, which was performed in patients with a high cardiovascular risk, it was investigated whether angiotensin II receptor blockade with telmisartan is equally effective as angiotensin converting enzyme (ACE) inhibition with ramipril and whether the combination oftelmisartan and ramipril (dual blockade) is more effective than ACE-inhibition alone to reduce cardiovascular morbidity and mortality and hospitalization for heart failure. On the basis of the ONTARGET results it can be concluded that dual blockade has no place in the treatment of high cardiovascular risk patients without heart failure, because this approach gives no additional reduction of cardiovascular risk and may even be associated with increased mortality. It also has more side effects. Since telmisartan was equally effective and safe as ramipril, one can choose from both agents in the treatment of patients with a high cardiovascular risk.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Drug Therapy, Combination; Humans; Ramipril; Telmisartan; Treatment Outcome

ONTARGET has established the efficacy of the angiotensin receptor blocker (ARB) telmisartan to slow disease progression and delay or prevent morbid events in patients with atherosclerosis. Although the study failed to confirm additive efficacy of telmisartan and the angiotensin-converting-enzyme (ACE) inhibitor ramipril, caution should be exercised in assuming that the mean response in a clinical trial applies to individual patients who might benefit from combination therapy. Physicians should also recognize that the design of the study, in which full doses of the ACE inhibitor and the ARB were administered, might not replicate clinical practice, where one drug is usually added to the other.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Atherosclerosis; Benzimidazoles; Benzoates; Cardiovascular Diseases; Disease Progression; Drug Therapy, Combination; Humans; Ramipril; Randomized Controlled Trials as Topic; Research Design; Telmisartan; Treatment Outcome

Topics: Aged; Angioedema; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Drug Therapy, Combination; Humans; Hypotension; Ramipril; Risk Assessment; Risk Factors; Telmisartan

Topics: Albuminuria; Antihypertensive Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; DNA Transposable Elements; Humans; Hypertension; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Prognosis; Ramipril; Sequence Deletion

To assess the safety and tolerability of ramipril 10 mg in patients at high risk of cardiovascular (CV) events by observing the levels of blood pressure (BP) and by recording the incidence of cough in these patients, a study was conducted in a total of 1048 patients who participated in the registry. Eligible patients in this prospective, observational, longitudinal, multicentre registry included all normotensives--including treated hypertensives--with BP <140/90 mm Hg, a history of coronary aritery disease and a history of cerebrovascular disease, peripheral arterial disease or diabetes (with micro-albuminuria) or dyslipidaemia, in whom ramipril was indicated for CV risk reduction and had been prescribed by the treating physician. The primary outcome was the effect on BP at 8 weeks, and the secondary outcome was the incidence of cough at 8 weeks. Ramipril was initiated at 2.5 mg once daily (OD) for a week, followed by 5 mg OD for 3 weeks and was then increased to 10 mg OD. Data was analysed using ANOVA and Chi-square test. A total of 1,048 patients participated in this registry; 868 (82.82%) continued with the treatment till the end of the registry (ie, 8 weeks). At baseline, systolic BP was 130.10 +/- 5.38 mm Hg, while diastolic BP was 81.07 +/- 4.36 mm Hg. At 8 weeks, these values changed non-significantly to 123.41 +/- 6.33 mm Hg and 79.03 +/- 4.84 mm Hg, respectively. At week 1, 41 patients had cough, which increased non-significantly to 58 by week 8. Only 6 patients complained of severe cough at week 8, which did not lead to treatment discontinuation. Tolerability of the treatment was assessed to be 'excellent' or 'good' by 63.3% patients and 67% physicians. Treatment with ramipril 10 mg daily in patients with high risk of CV events and normal/ controlled BP produced neither a significant fall in BP nor significant adverse events in real-world clinical practice and was well tolerated.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Cough; Diastole; Drug-Related Side Effects and Adverse Reactions; Humans; Hypertension; Longitudinal Studies; Product Surveillance, Postmarketing; Prospective Studies; Ramipril; Risk Factors; Risk Reduction Behavior; Systole

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Drug Therapy, Combination; Evidence-Based Medicine; Follow-Up Studies; Humans; Multicenter Studies as Topic; Ramipril; Randomized Controlled Trials as Topic; Telmisartan

Clinical Pharmacology is commonly accepted to be a bridging discipline between basic science observations and clinical practice. Today, it should be a major task of the clinical pharmacologist in academia to provide support in the interpretation of preclinical and clinical study data, to develop evidence-based treatment guidelines and to serve as drug expert supporting all disciplines of clinical medicine with specific pharmacological and therapeutic knowledge. The results of the ONTARGET-trial confront both researchers and clinicians with the unexpected truth that AT(1)-receptor-blockade with an angiotensin-receptor-blocker (ARB) does not seem to have superior therapeutic benefit compared with an ACE-inhibitor (ACE-I) at reducing fatal and nonfatal cardiovascular events. The combination of the two drugs was associated with more adverse events without an increase in benefit. Therefore, the crucial question 'ACE-I, ARB, or both?' requires a new and critical appraisal depending on the medical indication for which these renin-angiotensin-system (RAS)-inhibitors are used: In a population of high-risk patients suffering from cardiovascular disease or diabetes mellitus, the evidence to favor an ARB over an ACE-I is still limited after ONTARGET and because of the higher costs for ARBs one can rather support the old therapeutic advice that ARBs are equally effective as ACE-Is and therefore therapeutic alternatives for patients with ACE-I intolerance. With respect to a very moderate additive BP-lowering effect of dual therapy with an ACE-I and an ARB seen in metaanalysis which was not even clearly attributable to dual RAS-inhibition and the increased adverse event rate in the combination treatment group of ONTARGET, this regimen seems not to be recommendable for the treatment of hypertension. Dual-RAS-blockade using an ACE-I-ARB-combination is an effective therapy to treat proteinuria and might be of therapeutic benefit especially in diabetic patients without concomitant diseases. There may be a therapeutic rationale to prefer ARBs over ACE-Is in well-selected patients with congestive heart failure (CHF) because a considerable amount of angiotensin II (Ang II) is produced independent of angiotensin-conversion-enzyme (ACE) in the failing heart and is therapeutically unaffected by ACE-I treatment. The results of the Val-HeFt and the CHARM-added-study revealed additive effects of an ARB on heart failure related morbidity and mortality when added to existing therapy w

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Benzimidazoles; Benzoates; Cardiovascular Diseases; Drug Therapy, Combination; Humans; Kidney Diseases; Ramipril; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Telmisartan

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Follow-Up Studies; Humans; Perindopril; Ramipril; Randomized Controlled Trials as Topic

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Pressure; Cardiovascular Diseases; Drug Therapy, Combination; Humans; Ramipril; Research Design; Telmisartan; Tetrazoles; Valine; Valsartan

Economic analyses of randomized clinical trials often focus only on the results that are observed during the study. However, for many preventive interventions, associated costs and benefits will accrue over a patient's remaining lifetime. To determine the importance of the chosen time horizon, the cost-effectiveness (C/E) of ramipril therapy was calculated and compared in the Heart Outcomes Prevention Evaluation (HOPE), the Microalbuminuria, Cardiovascular, and Renal Outcomes in HOPE (MICRO-HOPE) and the Acute Infarction Ramipril Efficacy (AIRE) study versus the entire life expectancy (L/E) of potential patients.. The Cardiovascular Disease Life Expectancy model, a validated Markov model, was calibrated to accurately forecast the results of each trial. These results were then extrapolated over the remaining L/E of hypothetical patients 55 to 75 years of age. The predicted change in L/E and associated direct health care costs for Canadians were calculated and discounted 3% annually.. In HOPE, the forecasted increased L/E averaged 0.06 years during the five-year study versus 1.3 years over the remaining years of L/E. The associated C/E of ramipril was $15,000 per year of life saved (YOLS) over the study duration and $8,500/YOLS over the remaining lifetime. For hypothetical patients, the C/E of ramipril over 4.5 years ranged from $6,700/YOLS to more than $58,300/YOLS and was lowest among elderly men. When the remaining L/E was considered, the C/E of ramipril was similar for men and women of all ages, ranging from $8,100/YOLS to $10,200/YOLS. The analyses of MICRO-HOPE and AIRE provided similar results.. The estimated efficacy and associated C/E of ramipril in HOPE, MICRO-HOPE and the AIRE study is extremely sensitive to the selected time horizon. Economic analyses beyond the duration of randomized clinical trials are required to fully evaluate the potential costs and benefits of long-term preventive therapies.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Canada; Cardiovascular Diseases; Cost-Benefit Analysis; Drug Costs; Female; Humans; Life Expectancy; Male; Markov Chains; Middle Aged; Outcome Assessment, Health Care; Ramipril; Randomized Controlled Trials as Topic; Value of Life

Protected learning time (PLT) schemes have been set up in primary care across the UK. There is little published evidence of their effectiveness.. To investigate the effect of a PLT intervention for general practice to increase prescribing of ramipril for prevention of cardiovascular outcomes.. Quasi-experimental, interrupted time series.. Lincolnshire, UK.. Prescribing data were analysed one year before and after the education for change in rate of increase of prescribing of ramipril, whether change in prescribing was related to postulated explanatory variables and to determine intervention costs.. The primary outcome was the rate of change of ramipril (10 mg) prescription items 12 months after compared with before the educational intervention. Secondary outcomes included cost.. Ramipril prescribing at therapeutic dosage increased significantly (odds ratio 1.50, 95% CI 1.07-1.93) following education by 52,345 items (31,132 items at 10 mg) at a cost of pound 292k to pound 460k depending on formulation. This occurred despite a background of secular change. Most practices were represented by GPs, nurses or both during the education. Single-handed GPs were less likely to attend. Practices showed considerable variation in response to the educational intervention. The only predictor of whether practices increased in prescribing rate after the education was whether a practice nurse had undertaken specific diabetes training. Total list size, dispensing, training or single-handed status and GP attendance did not predict a change in prescribing.. PLT schemes can contribute to beneficial changes in prescribing across a large geographical area.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Diabetes Complications; Drug Utilization; Education, Medical, Continuing; England; Family Practice; Humans; Learning; Medical Audit; Practice Patterns, Physicians'; Primary Health Care; Program Evaluation; Ramipril; Retrospective Studies; Risk Factors; Staff Development; Time

Diabetes mellitus is associated with a specific cardiomyopathy. We compared the cardioprotective effects of an endothelin-A receptor blocker (ET(A)-RB) with those of an angiotensin-converting enzyme inhibitor (ACE-I) in rats with streptozotocin (STZ)-induced diabetes.. Diabetic rats were left untreated or received either the ET(A)-RB atrasentan or the ACE-I ramipril (each 3 mg kg(-1) per day) orally for 8 weeks. Isolated isovolumic heart function was studied during normoxia and in response to ischaemia-reperfusion. Cardiac fibrosis, tissue oxidative stress and tissue nitric oxide synthase (NOS) activity were determined.. Basal left ventricular systolic contractility was lower in diabetic compared to nondiabetic hearts and ET(A)-RB or ACE-I treatment significantly antagonised the decline. Following 15 min of no-flow ischaemia, reperfusion systolic function was depressed and left-ventricular end-diastolic pressure (LVEDP) was elevated in diabetic hearts. ET(A)-RB or ACE-I treatment significantly improved recovery of reperfusion systolic and diastolic function, without differences between groups. Hydroxyproline (an index of tissue fibrosis) and malondialdehyde (a measure of tissue oxidative stress) were elevated at the end of reperfusion in diabetic, compared to nondiabetic hearts. Either treatment reduced hydroxyproline and malondialdehyde to control level. Constitutive NOS activity was similar in nondiabetic and diabetic hearts and unaffected by ET(A)-RB or ACE-I treatment.. These results suggest that in experimental type 1 diabetes ET(A)-RB is as effective as an ACE-I in ameliorating myocardial functions during normoxia and ischaemia-reperfusion. Combining the two treatments neither afforded additive effects, nor diminished any protection effect seen with either drug.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrasentan; Cardiovascular Diseases; Diabetes Mellitus, Experimental; Endothelin A Receptor Antagonists; Female; Fibrosis; Myocardial Reperfusion Injury; Nitric Oxide Synthase; Oxidative Stress; Pyrrolidines; Ramipril; Rats; Rats, Sprague-Dawley; Streptozocin; Ventricular Function, Left; Ventricular Pressure

The results of the HOPE study, a randomized clinical trial, provide strong evidence that 1) ramipril prevents the composite outcome of cardiovascular death, myocardial infarction or stroke in patients who are at high risk of a cardiovascular event and 2) ramipril is cost-effective at a threshold willingness-to-pay of $10,000 to prevent an event of the composite outcome. In this report the concept of the expected value of information is used to determine if the information provided by the HOPE study is sufficient for decision making in the US and Canada.. and results Using the cost-effectiveness data from a clinical trial, or from a meta-analysis of several trials, one can determine, based on the number of future patients that would benefit from the health technology under investigation, the expected value of sample information (EVSI) of a future trial as a function of proposed sample size. If the EVSI exceeds the cost for any particular sample size then the current information is insufficient for decision making and a future trial is indicated. If, on the other hand, there is no sample size for which the EVSI exceeds the cost, then there is sufficient information for decision making and no future trial is required. Using the data from the HOPE study these concepts are applied for various assumptions regarding the fixed and variable cost of a future trial and the number of patients who would benefit from ramipril.. Expected value of information methods provide a decision-analytic alternative to the standard likelihood methods for assessing the evidence provided by cost-effectiveness data from randomized clinical trials.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Cost-Benefit Analysis; Decision Making; Humans; Middle Aged; Ramipril; Randomized Controlled Trials as Topic; Sample Size

Economic analyses of drug therapies are highly dependent on the clinical indications for treatment. The cost effectiveness of ramipril has been evaluated in numerous studies, usually based on the results of one specific clinical trial. We estimated the cost effectiveness of this drug across a range of currently accepted therapeutic indications, using a single health economic model and adjusted for quality of life, to compare the different outcomes observed in four clinical trials.. The cardiovascular life expectancy model, a validated Markov model, was calibrated to accurately forecast the results of four trials including AIRE, HOPE, Micro-HOPE, and REIN. We then extrapolated these results over the remaining life expectancy of the patients enrolled in each study and adjusted for the quality of life associated with the observed outcomes. The cost per quality-adjusted life-year (QALY) was then calculated from the perspective of the Canadian healthcare system incorporating the estimated direct healthcare costs associated with treatments and outcomes.. After discounting all costs and outcomes 3% annually, the benefits associated with ramipril ranged from 0.74 QALYs in the AIRE study to 1.22 QALYs in Micro-HOPE. Treatment was estimated to be cost-saving for some patient groups, such as those in REIN. The highest cost-effectiveness ratio was observed among individuals enrolled in HOPE ($Can20 000 per QALY in 2002).. Treatment with ramipril appears to be economically attractive across a wide range of patient groups, including those with increased coronary risk and/or diabetes mellitus (HOPE and Micro-HOPE), those with congestive heart failure (AIRE), and those with non-diabetic nephropathy (REIN).

Topics: Angiotensin-Converting Enzyme Inhibitors; Canada; Cardiovascular Diseases; Clinical Trials as Topic; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Female; Heart Failure; Humans; Male; Middle Aged; Models, Economic; Proteinuria; Quality of Life; Quality-Adjusted Life Years; Ramipril; Treatment Outcome

In the DREAM trial, involving more than 5000 patients with "impaired glucose tolerance", ramipril had no preventive effect, while rosiglitazone had cardiac adverse effects.

Topics: Antihypertensive Agents; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Incidence; Ramipril; Randomized Controlled Trials as Topic; Thiazolidinediones; Treatment Outcome

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Cardiovascular Diseases; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Ramipril; Randomized Controlled Trials as Topic; Telmisartan

Increasing evidence suggests that angiotensin converting enzyme (ACE) inhibitors exert antithrombotic effects. Based on the assumption of differential effects of various ACE inhibitors on coagulation, the aim of the present study was to evaluate the coagulative activities of cardiovascular (CV) patients treated with either ramipril, captopril, and enalapril, and to compare these with patients treated with established antithrombotics such as aspirin (ASA) and clopidogrel or none of these medication.. Blood samples of 320 CV patients with coronary artery disease and/or arterial hypertension were analyzed by wholeblood aggregometry. Platelet aggregation was determined by measuring the increase in impedance across paired electrodes in response to the aggregatory agents collagen and adenosine diphosphate (ADP), respectively. These data were correlated with medical treatment.. Platelet aggregation was attenuated ex vivo by ramipril and captopril as well as by ASA and clopidogrel. While collagen-induced platelet aggregation was significantly reduced by ramipril (35%; P <0.01) and captopril (27%; P = 0.01), no change was seen with enalapril. After induction with ADP, platelet aggregation was reduced in the presence of captopril therapy by 46% (P <0.05). There was a trend of inhibition with ramipril (32%, P = n.s.), whereas no antithrombotic effect was seen with enalapril.. Our findings demonstrate that ACE inhibitors decrease platelet aggregation ex vivo. The differential antiaggregatory profile may explain at least in part different effects of ACE inhibitors on cardiovascular endpoints as observed in large clinical trials.

Topics: Adenosine Diphosphate; Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Aspirin; Captopril; Cardiovascular Diseases; Clopidogrel; Collagen; Coronary Artery Disease; Electric Impedance; Enalapril; Female; Fibrinolytic Agents; Germany; Humans; Hypertension; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Prospective Studies; Ramipril; Ticlopidine; Treatment Outcome

This study compares the effect of two different strategies to inhibit the renin-angiotensin system in the setting of acute myocardial infarction (MI). Male Wistar rats were treated with placebo, the angiotensin-converting enzyme (ACE) inhibitor ramipril (1 mg/kg/day), or the AT1 receptor antagonist, olmesartan (1 mg/kg/day), both initiated 1 week before induction of MI and continued for 6 weeks after MI. The inflammatory reaction in the heart was investigated 7 days post-MI by determination of macrophage infiltration and the expression of tumor necrosis factor (TNF-alpha), interleukin (IL)-1beta and IL-6 at mRNA and protein levels. Six weeks post-MI, cardiac function was measured following chronic implantation of catheters in the LV and femoral artery, and cardiac morphology and coronary structure were investigated in picrosirius-red stained hearts. In placebo-treated rats, macrophage infiltration was accompanied by upregulation of IL-1beta and IL-6 mRNA in the peri-infarct zone. TNF-alpha and IL-1beta mRNA and protein were also upregulated in the non-infarcted myocardium. Whereas both treatment regimes significantly reduced IL-6 upregulation, olmesartan additionally reduced macrophage infiltration and IL-1beta expression. Six weeks post-MI, placebo-treated MI animals developed an impaired cardiac function with structural remodeling of the myocardium and coronaries. While olmesartan and ramipril both improved cardiac function and reduced infarct size and myocardial/coronary remodeling, olmesartan was more effective not only in increasing vascular perimeter, inner vascular diameter and septal thickness but also in lowering media thickness of coronary arteries, inner left ventricular diameter, left ventricular circumference and left ventricular end-diastolic pressure than ramipril. Thus, following MI the AT1 receptor blocker, olmesartan, attenuated cardiac inflammatory reactions and protected myocardial/coronary structure and function of the failing heart proving to be of similar, in some cases superior effectiveness in this respect than the ACE inhibitor, ramipril.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Cardiovascular Diseases; Cardiovascular System; Disease Models, Animal; Dose-Response Relationship, Drug; Imidazoles; Inflammation; Interleukin-1; Interleukin-6; Male; Myocardial Infarction; Placebos; Ramipril; Rats; Rats, Wistar; Renin-Angiotensin System; RNA, Messenger; Tetrazoles; Tumor Necrosis Factor-alpha

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypertension; Metabolic Syndrome; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Telmisartan; Time Factors

The HOPE TIPS study assessed the practicality and tolerability of ramipril titration to a target dose of 10 mg (as achieved in definitive efficacy studies) in a clinical practice setting. 3881 patients at high cardiovascular risk (HOPE study criteria) were recruited in primary and specialist care settings in 9 countries by 439 investigators. Dose titration of ramipril from 2.5 mg to 10 mg daily took place over 9-12 weeks. The mean age of the patients was 64 years, 60% were male and 79% Asian. The target dosage of 10 mg daily was reached in 73% of patients with 96% of patients achieving 5 mg or 10 mg daily. During the study period uncontrolled hypertension (> 160/90) was recorded in 15% of patients, myocardial infarction or unstable angina 1.6%, heart failure 0.4%, new diabetes 0.6%. Only 9.8% of patients discontinued treatment with 5.9% attributed to treatment side-effects and 4% related to cough. The large majority of patients in a wide range of clinical practice settings with high cardiovascular risk can be treated with ramipril titrated to 10 mg daily with good tolerability.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Cough; Female; Humans; Male; Middle Aged; Prospective Studies; Ramipril

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure Determination; Cardiovascular Diseases; Humans; Hypertension; Myocardial Infarction; Placebos; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Treatment Outcome

The Heart Outcomes Prevention Evaluation (HOPE) study demonstrated that the angiotensin-converting enzyme inhibitor, ramipril, significantly reduces mortality, myocardial infarction and stroke in high-risk cardiovascular patients, beyond the benefits from blood pressure lowering. The tolerability of ramipril 10 mg/day has been an important concern when applying these results. Following the same criteria as the HOPE study, we investigated the adverse effects profile and tolerability of 10 mg ramipril in high-risk patients at our institution. In total, 92 patients with high cardiovascular risk were eligible for this study. Initially, ramipril was prescribed 2.5 mg orally once daily, and then titrated up to 5.0, 7.5, and 10.0 mg/day at 1-month intervals. The target maintenance dose was 10 mg/day. All adverse events were recorded during at least 3 months of follow-up. After 4-6 months of the titration protocol, only 18 patients (25.3%) reached and remained on ramipril 10 mg/day; 11 (15.5%), 22 (30.9%), and 20 patients (28.2%) remained on 2.5, 5.0, and 7.5 mg/day, respectively. Twenty-one patients (22.6%) had at least one adverse event. Twelve patients (13.0%) stopped treatment because of adverse effects. A total of 23 episodes of adverse events were reported, including cough (15.1%), dizziness (6.0%), and hypotension (2.4%). Ramipril was relatively well tolerated in our study population. However, only one-quarter of our patients reached the target maintenance dose of 10 mg/day. Dry cough, dizziness, and hypotension were the major side effects. About 15% of our patients discontinued ramipril treatment, which is comparable with previous reports.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Cough; Female; Humans; Male; Middle Aged; Patient Compliance; Ramipril; Risk

Ramipril may prevent cardiovascular death, myocardial infarction and stroke in patients without evidence of left ventricular dysfunction or heart failure who are at high risk for cardiovascular events. In the present study we assessed the cost-effectiveness of ramipril in patients with an increased risk of cardiovascular events from a third party payer's perspective in Switzerland. In addition, the cost-effectiveness of ramipril in the subgroup of diabetic patients was assessed.. We developed a decision analytic cost-effectiveness model to estimate the incremental costs (in 2001 in Swiss Francs [CHF]), incremental effects (in terms of life-years gained [LYG]) and incremental cost-effectiveness (CHF per LYG) of ramipril versus placebo. Clinical input parameters were derived from the Heart Outcomes Prevention Evaluation (HOPE) study. Cost data were extracted from the literature. Deterministic sensitivity analysis was used to assess the impact of varying the input parameters on the cost effectiveness of the intervention. In addition, first order Monte Carlo simulation was used to capture patient-to-patient variability, presented as cost-effectiveness acceptability curves.. The incremental cost-effectiveness ratio of ramipril versus placebo was CHF 6,005 per life-year gained in the base case analysis. In diabetic patients the cost-effectiveness ratio was CHF 3,790 per life-year gained. Varying the price of ramipril in a deterministic sensitivity analysis only had a moderate impact on the cost-effectiveness ratio in the overall population (range: CHF 3,652-15,418 per LYG) as well as in diabetic patients (range: CHF 2,370-9,468 per LYG).. Ramipril in patients at high risk for cardiovascular events represents an efficient use of scarce health care resources in Switzerland and is cost-effective under reasonable assumptions. Ramipril is even more cost-effective in the subgroup of diabetic patients.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Cost of Illness; Cost-Benefit Analysis; Decision Support Techniques; Diabetic Angiopathies; Humans; Monte Carlo Method; Ramipril; Switzerland

In the HOPE (Heart Outcomes Prevention Evaluation) trial, ramipril (compared with placebo) significantly reduced cardiovascular death and all-cause mortality as well as the incidence of costly cardiovascular events, such as myocardial infarction, revascularisation, stroke, cardiac arrest, hospitalisation due to heart failure and worsening angina pectoris, new-onset diabetes mellitus and microvascular diabetic complications.. Data from the HOPE study were used in a cost-effectiveness analysis to determine the additional cost per life-year gained (LYG) when the ACE inhibitor ramipril was added to the current medication of patients at high risk for cardiovascular events. The aim was to establish the incremental cost-effectiveness ratio (ICER) of ramipril versus placebo from the perspective of the Statutory Health Insurance (SHI) provider in Germany, for both the study population as a whole and for the subgroup of patients with diabetes.. A modelling approach was used, based on secondary analysis of published data and retrospective application of costs. In the base-case analysis, average case-related expenses of the SHI were applied and LYG were quantified using the average of the difference between the survival rates in the ramipril and placebo groups during the HOPE trial. LYG beyond the trial duration were estimated by the method of declining exponential approximation of life expectancy.. After a treatment period of 4.5 years, the ICER of ramipril versus placebo was Euros 4074/LYG and Euros 2486/LYG (discounted at 5% per annum and in 1998-2002 values; Euro 1 approximately USD 0.88; first quarter 2002 values) for the HOPE study population as a whole and the subgroup of patients with diabetes, respectively. To test the model's robustness, the influence of the model variables on the results was quantified using a deterministic model, and a best-case/worst-case scenario analysis. The effect of random variables was investigated in a Monte Carlo simulation. The acquisition cost for ramipril had the greatest impact on the ICER of ramipril (2.2-fold greater than the impact of the number of LYG). In 95% of the 10,000 simulation steps, the ICER of ramipril after 4.5 years of treatment was between Euros 1290 and Euros 9005 per LYG for the entire HOPE study population and between Euros 290 and Euros 6115 per LYG in the diabetic subgroup.. Results of this evaluation suggest that ramipril is likely to be cost effective in secondary prevention of cardiovascular events from the perspective of the SHI (third-party payer) in Germany. The estimated ICER of ramipril compares well with other ICERs of widely accepted treatments used for the management of cardiovascular diseases, such as HMG-CoA reductase inhibitors.

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Cost-Benefit Analysis; Female; Humans; Male; Middle Aged; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Female; Humans; Hypertension; Losartan; Male; Middle Aged; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Stroke

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Canada; Cardiovascular Diseases; Humans; Ramipril; Risk Factors

Topics: Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Combinations; Felodipine; Follow-Up Studies; Humans; Hypertension; Prediabetic State; Ramipril

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Cardiovascular Diseases; Humans; Hypertension; Ramipril; Randomized Controlled Trials as Topic

To estimate differences in direct costs attributable to avoided hospitalizations and procedures during the years of the HOPE (Heart Outcomes Prevention Evaluation) study after the cost of treatment with ramipril or alternative angiotensin-converting enzyme inhibitor therapy was taken into account.. A decision analytical model was developed to estimate the economic impact of reductions in hospitalizations and/or procedures both at annual increments and over the first 4 years of the HOPE study. The analysis compared the number of cardiovascular events per endpoint per year in the intervention and placebo group with hospitalization and procedural costs. Cost data were derived from the literature and inflated to the appropriate index year using the consumer price index.. For approximately 9000 patients studied, the gross estimated savings in direct costs for 297 events avoided were more than $5 million over 4 years. After the cost of treatment was deducted for both groups, the net estimated savings were $871 000 over 4 years.. The results demonstrate that the use of ramipril provides cost-effective treatment for high-risk cardiovascular patients with an ejection fraction >40%.

Topics: Angioplasty, Balloon, Coronary; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Coronary Artery Bypass; Cost Savings; Cost-Benefit Analysis; Decision Support Techniques; Heart Failure; Hospitalization; Humans; Middle Aged; Multicenter Studies as Topic; Myocardial Infarction; Ramipril; Risk Factors; Stroke

Angiotensin-converting enzyme (ACE) inhibitors are used to treat cardiovascular diseases, major causes of death in Canada. The HOPE (Heart Outcomes Prevention Evaluation) study showed that ramipril benefits patients at high risk for cardiovascular disease. We analyzed ACE inhibitor use and costs in Canada before and after publication of HOPE.. We obtained pharmacy and hospital sales data for 1985-2001 from IMS Canada for all ACE inhibitors (Anatomical Therapeutic Category code C09A0) and for the 3 largest provinces (i.e., British Columbia, Quebec, Ontario). Prescription numbers, total costs, cost/prescription, and market share of individual ACE inhibitors were plotted over time and analyzed using regression. Canadian dollars were used to report costs.. We examined 10 drugs; captopril was the first, introduced in 1985. Overall, prescriptions increased consistently from 356 000 in 1985 to 11.5 million in 2001, representing an annual increase of 660 000 (y = 661 410x-510 360; r(2) = 0.99). Total costs increased linearly from 1985 (14.5 million US dollars) to 2001 (513 million US dollars): Y = 29.3.10(6)x - 29.9.10(6); r(2) = 0.99. Provincial utilization patterns were also similar. Ramipril's national use increased dramatically from 1999 (822 000 prescriptions, 9.2% of all ACE inhibitors) to 2001 (3.8 million, 32.8% of all ACE inhibitors). National costs for ramipril increased exponentially (y = 1.08e(0.6248x)) to a total of 157 million US dollars in 2001, with the 3 major provinces accounting for 78.9%. Costs per prescription followed no observable trend (range 39.45-46.20 US dollars).. The number of prescriptions and the total cost of ACE inhibitors increased over the period studied. Ramipril use increased in concert with publication of the HOPE trial, while the growth rates of other ACE inhibitors remained constant.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Canada; Captopril; Cardiovascular Diseases; Drug Utilization; Female; Humans; Logistic Models; Male; Ramipril; Time Factors

In the Heart Outcomes Prevention Evaluation (HOPE) Study, the angiotensin-converting enzyme (ACE) inhibitor ramipril was shown to significantly reduce the relative risk of stroke by 32% in high-risk cardiovascular patients (P < 0.001). However, the study did not examine the economic implications of these findings.. The purpose of this economic analysis was to estimate the potential economic benefits of the differences in direct health care costs attributable to the prevention of first and recurrent strokes in the HOPE Study patient population through the use of ramipril.. The epidemiologic component of the model examined the incidence of first and recurrent strokes in the HOPE Study population, assessed at annual increments, for the years 1995 through 1997. An economic decision model was constructed by the application of costs to the epidemiologic foundation. Direct costs for stroke hospitalization and follow-up were calculated based on estimates provided by Samsa et al (1999). The estimated cost of ramipril treatment was based on the average wholesale price for the corresponding year of the analysis. The Samsa index costs are given in 1991 US $; they were converted to study-year US $ using the Consumer Price Index for the corresponding year.. The mean age of the patient population was 69 years, with >70% of patients aged >/=65 years. When ACE-inhibitor treatment costs were included in the calculation of treatment costs, the expense to avert 1 stroke was estimated at $13,766 for years 1 to 2 after randomization and $12,281 for years 2 to 3. By years 3 to 4, ramipril treatment resulted in 21 fewer strokes and produced an estimated savings of $52,861.. Ramipril 10 mg/d was a cost-effective means of preventing first and recurrent ischemic strokes in the HOPE Study patient population.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Data Collection; Direct Service Costs; Hospitalization; Humans; Middle Aged; Models, Economic; Ramipril; Randomized Controlled Trials as Topic; Secondary Prevention; Treatment Outcome

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Ramipril

Topics: Angiotensin-Converting Enzyme Inhibitors; Canada; Cardiovascular Diseases; Clinical Trials as Topic; Cost-Benefit Analysis; Humans; Ramipril

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Complications; Female; Humans; Male; Middle Aged; Patient Selection; Ramipril; Randomized Controlled Trials as Topic

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus; Follow-Up Studies; Humans; Kidney Diseases; Placebos; Prospective Studies; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Time Factors

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Cost Savings; Drug Costs; Drugs, Generic; Germany; Heart Failure; Humans; Hypertension; Ramipril

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Cardiovascular Diseases; Diabetes Complications; Drug Therapy, Combination; Humans; Myocardial Infarction; Placebos; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Telmisartan; Time Factors

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Losartan; Ramipril; Risk Factors

Analysing specific non-fatal events in isolation may lead to spurious conclusions about efficacy unless the events considered are combined with all-cause mortality. The use of combined endpoints has therefore become widespread, at least in cardiovascular disease trials. Combining all-cause mortality with selected non-fatal events is useful because event-free survival, an important criterion in therapy evaluation, is addressed in this manner. In many clinical trials, symptoms, signs or paraclinical measures (for example, blood pressure, exercise duration, quality of life scores) are used as endpoints. If the patient died before the endpoint was measured, or it was otherwise not possible to perform follow-up assessments as planned, the effect of treatment on these endpoints may be distorted if the patients concerned are ignored in the analysis. Examples are given of how distortion can be avoided by including all patients randomized in an analysis that uses a ranked combined endpoint based both on clinical events and on paraclinical measures. A distinction is made between a pseudo intention-to-treat analysis that disregards study medication status at the time of endpoint assessment but is confined to patients with data, and a true intention-to-treat analysis that takes into account all patients randomized based on a ranked combined endpoint.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiotonic Agents; Cardiovascular Diseases; Disease-Free Survival; Humans; Metoprolol; Phenethylamines; Potassium Channel Blockers; Pyridazines; Ramipril; Randomized Controlled Trials as Topic; Sulfonamides; Survival Analysis; Treatment Outcome

The cost-effectiveness of adding ramipril to the regular treatment of patients at high risk of suffering cardiovascular events was calculated.. A retrospective pharmacoeconomic model was used. The clinical data were obtained from a randomized clinical trial of 9,297 patients (the HOPE study). Information about resource use and the associated costs was obtained from Spanish sources. The analysis was undertaken from the perspective of the National Health System, focusing on drug costs and the primary and secondary complications of cardiovascular events.. The incremental cost per life-year gained in the base case was 10,329 euros (6% discount rate). A sensitivity analysis showed that the results were more sensitive to changes in estimated post-trial life expectancy than to any other variable. The estimated number of cases of myocardial infarction, stroke, or cardiovascular death prevented in five years ranged from 19,000 to 39,000.. The addition of Ramipril to the conventional treatment of patients at high cardiovascular risk is cost-effective and less expensive per life-year gained than several treatments currently financed by the Spanish National Health System.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Cost-Benefit Analysis; Economics, Pharmaceutical; Female; Humans; Life Expectancy; Male; Models, Economic; Ramipril; Retrospective Studies; Spain

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus; Humans; Ramipril; Risk

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus; Humans; Ramipril; Risk

We investigated the effects of MDL-100,240 in a transgenic rat model (TGRen2) of hypertension with severe cardiovascular damage (CVD) due to enhanced tissue synthesis of angiotensin II (Ang II). Male heterozygous TGRen2 rats (5 weeks old) were allocated to receive MDL-100,240, ramipril (RAM) or placebo (PLAC) for 4 weeks, during which blood pressure (BP) was measured. We then evaluated: 1) left ventricle (LV) and right ventricle (RV), brain, kidney and adrenals weight; 2) structural changes in the aorta and the mesenteric arterioles wall; 3) tension responses of segments of the aorta to phenylephrine, KCl, and endothelin-1; and 4) creatinine, aldosterone, atrial natriuretic peptide (ANP), and cyclic GMP (cGMP) plasma levels. Compared to PLAC, both MDL-100,240 and RAM significantly (P < .001) lowered BP (after 4 weeks: 255 +/- 15 mm Hg PLAC, v 174 +/- 6 MDL-100,240, v 166 +/- 5 RAM). They hindered LV hypertrophy (3.73 +/- 0.25 mg/g body weight (PLAC) v 2.71 +/- 0.22 (MDL-100,240) P < .001; v 2.36 +/- 0.2 (RAM), P < .001). MDL-100,240 also prevented aortic dilatation and hypertrophy of the mesenteric arterioles (media thickness, 25.3 +/- 0.5 microm PLAC, v 21.1 +/- 0.9 MDL-100,240, P < .007; v 20.2 +/- 1.5 RAM, P = .033) and lowered the tension responses to phenylephrine (P < .01), KCl (P < .01), and endothelin-1 (P < .001). Plasma aldosterone (710 +/- 153 pmol/L PLAC, v 237 +/- 61 MDL-100,240, v 180 +/- 22 RAM) and creatinine levels (0.69 +/- 0.33 mg/dL PLAC, v 0.41 +/- 0.02 MDL-100,240, v 0.41 +/- 0.04 RAM) were also decreased (P < or = .001). Compared to PLAC, plasma ANP levels were 11% and 2.4% higher in MDL-100,240 and RAM, respectively (both P = not significant); cGMP levels were unaffected. Thus, severe hypertension and related CVD were regressed by MDL-100,240, which resulted to be as effective as a full dosage of ramipril in TGRen2.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Aorta; Benzazepines; Blood Pressure; Body Weight; Cardiovascular Diseases; Hypertension; In Vitro Techniques; Male; Neprilysin; Organ Size; Pyridines; Ramipril; Rats; Vasoconstriction

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzothiadiazines; Blood Pressure; Cardiovascular Diseases; Diuretics; Humans; Ramipril; Risk Factors; Sodium Chloride Symporter Inhibitors

Topics: Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Electrocardiography; Humans; Hypertrophy, Left Ventricular; Ramipril; Risk

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cardiovascular Diseases; Confounding Factors, Epidemiologic; Female; Humans; Male; Ramipril; Randomized Controlled Trials as Topic; Risk Factors

Topics: Cardiovascular Diseases; Evaluation Studies as Topic; Humans; Public Health; Ramipril; Research; Treatment Outcome; Vitamin E

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Cardiovascular Diseases; Clinical Trials as Topic; Enalapril; Heart Failure; Humans; Indoles; Isoquinolines; Myocardial Infarction; Perindopril; Prodrugs; Quinapril; Ramipril; Stroke; Stroke Volume; Tetrahydroisoquinolines; Treatment Outcome; Ventricular Dysfunction, Left

To assess the cost effectiveness of ramipril treatment in patients at low, medium, and high risk of cardiovascular death.. Population based cost effectiveness analysis from the perspective of the health care provider in the UK. Effectiveness was modelled using data from the HOPE (heart outcome prevention evaluation) trial. The life table method was used to predict mortality in a medium risk cohort, as in the HOPE trial (2.44% annual mortality), and in low and high risk groups (1% and 4.5% annual mortality, respectively).. UK population using 1998 government actuary department data.. Cost per life year gained at five years and lifetime treatment with ramipril.. Cost effectiveness was pound36 600, pound13 600, and pound4000 per life year gained at five years and pound5300, pound1900, and pound100 per life year gained at 20 years (lifetime treatment) in low, medium, and high risk groups, respectively. Cost effectiveness at 20 years remained well below that of haemodialysis ( pound25 000 per life year gained) over a range of potential drug costs and savings. Treatment of the HOPE population would cost the UK National Health Service (NHS) an additional pound360 million but would prevent 12 000 deaths per annum.. Ramipril is cost effective treatment for cardiovascular risk reduction in patients at medium, high, and low pretreatment risk, with a cost effectiveness comparable with the use of statins. Implementation of ramipril treatment in a medium risk population would result in a major reduction in cardiovascular deaths but would increase annual NHS spending by pound360 million.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Cost of Illness; Cost-Benefit Analysis; Drug Costs; Health Care Costs; Humans; Life Tables; Male; Middle Aged; Ramipril; Risk Assessment; United Kingdom; Value of Life

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Humans; Ramipril; Renal Insufficiency; Risk Factors; Vascular Diseases

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Complications; Humans; Ramipril

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Anticholesteremic Agents; Cardiovascular Diseases; Clinical Trials as Topic; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Middle Aged; Ramipril; Risk

The MICRO-HOPE substudy demonstrated that when ramipril treatment was added to people with Type 2 diabetes and additional cardiovascular risk factors cardiovascular events were reduced by 25% in 4.5 years. We wished to determine the proportion of people with Type 2 diabetes and additional cardiovascular risk factors registered with a hospital diabetes service.. Non-proteinuric people (n = 1370) with Type 2 diabetes identified on our diabetes register were subject to analysis. Anticipated reductions in cardiovascular events due to ramipril treatment were based on reductions observed in the MICRO-HOPE substudy.. Non-proteinuric people (n = 1075 (78%)) with Type 2 diabetes had at least one additional cardiovascular risk factor. Twenty-nine percent were already taking an angiotensin-converting enzyme inhibitor. The remaining 764 patients were similar to ramipril-treated participants in the MICRO-HOPE substudy. Treatment with ramipril for 4.5 years would be anticipated to reduce cardiovascular deaths by 26, revascularization procedures by 19 and admissions for myocardial infarction and stroke by 18 and 26, respectively.. Of non-proteinuric people with Type 2 diabetes, 78% have additional cardiovascular risk factors. Only a small proportion currently receive treatment with an angiotensin-converting enzyme inhibitor. The incidence of cardiovascular events could be reduced if more patients were treated with ramipril and other cardiovascular risk factors were addressed.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Middle Aged; Proteinuria; Ramipril; Risk Factors

The HOPE (Heart Outcomes and Prevention Evaluation) study has demonstrated a clear and beneficial effect of ramipril on cardiovascular events and disease progression. The cost-effectiveness of treatment with ramipril remains an important question that is being addressed by analysis of data from the main HOPE study and from a Swedish substudy. Data from the main HOPE study indicate that hospital costs per patient were reduced in the ramipril group compared with the placebo group. The net effect indicates that ramipril is cost neutral or could even be cost saving in US non-Medicare patients. In the Swedish health economic substudy, a separate protocol and separate case record forms were utilised to generate more specific data from the 537 Swedish patients taking part in HOPE. In this analysis, costs and effects associated with each treatment group were assessed and incremental cost-effectiveness ratios were calculated. The primary analysis was cost per life year gained which amounted to 29,000 Swedish Kroner. In a world with a growing prevalence of cardiovascular disease and with additional constraints on healthcare expenditure, analysis of the cost-effectiveness of preventive and curative medications is increasingly important. In this context, the early observations on the cost-effectiveness of ramipril appear very hopeful.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Cost-Benefit Analysis; Economics, Pharmaceutical; Humans; Ramipril

Over a 4.5 year follow-up period, the HOPE (Heart Outcomes Prevention Evaluation) trial, and the MICRO-HOPE (Microalbuminuria, Cardiovascular, and Renal Outcomes) and SECURE (Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E) substudies have all demonstrated a large benefit of ramipril versus placebo in patients over 55 years at high risk (by reason of a prior vascular event), or by being diabetic subjects with one additional risk factor. The baseline blood pressure on average was normal, at 139/79 mmHg, and was modestly reduced by 3.3/1.4 mmHg. Patients with known left ventricular dysfunction were excluded, as were those with uncontrolled hypertension. The incidence of stroke was reduced by 32%, myocardial infarction by 20% and cardiovascular death by 25%. The benefits conferred were in addition to, and largely independent of, other conventional treatments such as aspirin, lipid-lowering agents, beta-blockers, diuretics and calcium channel blockers. The relative risk reduction was very similar whether or not the patient was a known hypertensive at baseline. High dose ACE inhibition with ramipril is applicable to a far wider population of patients at high risk of cardiovascular events than the current indications of hypertension and left ventricular dysfunction.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cardiovascular Diseases; Cardiovascular System; Drug Therapy, Combination; Humans; Middle Aged; Patient Selection; Ramipril

Diabetic nephropathy is a glomerular disease, which causes most of premature mortality observed in diabetic patients. The risk of diabetic nephropathy is not entirely accounted for by diabetes duration and control. Diagnosis has been improved by sensitive assays for urinary albumin (microalbuminuria). Treatment relies up on early and liberal use of several antihypertensive agents. Among them, angiotensin I converting enzyme inhibitors rank first, because of their efficacy.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diuretics; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Primary Prevention; Prognosis; Prospective Studies; Proteinuria; Ramipril; Renin-Angiotensin System; Risk Factors; Time Factors

Cardiovascular risk reduction in diabetic patients is a multidimensional task. Long-term decrease of glycaemia by the use of insulin or sulfonylureas had disappointing effects on cardiovascular events, whereas metformin effects are ambiguous. On the contrary, controlling risk factors like hypertension or hypercholesterolaemia decrease the incidence of cardiovascular events in diabetic as in non-diabetic patients. Similarly, clinical trials have shown the efficacy of treatments that decrease cardiovascular risk whatever the cause, such as antiplatelet drugs in secondary prevention and high-dose ramipril in secondary prevention or in hypertensive patients. The absolute benefit conferred by efficient therapies is higher in diabetic patients because they are at an increased risk of events compared with their non-diabetic counterparts.

Topics: Angiotensin-Converting Enzyme Inhibitors; Anticholesteremic Agents; Antihypertensive Agents; Blood Glucose; Cardiovascular Diseases; Cholesterol; Confidence Intervals; Diabetes Mellitus, Type 2; Humans; Hypercholesterolemia; Hypertension; Meta-Analysis as Topic; Obesity; Platelet Aggregation Inhibitors; Primary Prevention; Prospective Studies; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Time Factors

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Humans; Myocardial Infarction; Ramipril; Risk Factors; Stroke

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Diabetic Nephropathies; Female; Humans; Male; Ramipril

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Heart Diseases; Humans; Ramipril; Risk Factors

The results of the HOPE ("Heart Outcomes Prevention Evaluation") study, recently published in the New England Journal of Medicine, demonstrated a highly significant cardiovascular protection by an angiotensin converting enzyme inhibitor, ramipril at a dose of 10 mg/day, after a mean follow-up of 4.5 years, but not of vitamin E supplements at a dose of 400 UI/day in high-risk patients (> 55 years old) who had evidence of vascular disease (secondary prevention) or combined diabetes mellitus and another cardiovascular risk factor (primary prevention).

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Complications; Humans; Middle Aged; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome; Vitamin E

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Dietary Supplements; Humans; Middle Aged; Multicenter Studies as Topic; Ramipril; Randomized Controlled Trials as Topic; Vitamin E

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Humans; Middle Aged; Prognosis; Ramipril; Randomized Controlled Trials as Topic

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Complications; Humans; Hypertension; Ramipril

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Costs and Cost Analysis; Diabetes Complications; Humans; Hypertension; Middle Aged; Ramipril

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypertension; Ramipril

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Humans; Middle Aged; Ramipril; Risk Factors; Ventricular Dysfunction, Left

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Ramipril; Risk Factors

Topics: Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Cardiovascular Diseases; Humans; Ramipril

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anticholesteremic Agents; Aspirin; Cardiovascular Diseases; Humans; Ramipril

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Determination; Cardiovascular Diseases; Humans; Ramipril; Sphygmomanometers

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus; Female; Humans; Incidence; Male; Middle Aged; Ramipril; Risk Factors; Treatment Outcome

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Humans; Male; Middle Aged; Myocardial Infarction; Ramipril; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Adverse Drug Reaction Reporting Systems; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Fasciitis; Female; Foot Diseases; Heel; Humans; Male; Microwaves; Pain; Pain Management; Prostatic Hyperplasia; Ramipril; Ultrasonic Therapy; Ultrasonics; United States; United States Food and Drug Administration

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Complications; Humans; Obesity; Ramipril

Topics: Angiotensin-Converting Enzyme Inhibitors; Aspirin; Cardiovascular Diseases; Humans; Multicenter Studies as Topic; Myocardial Ischemia; Oximes; Piperidines; Platelet Aggregation Inhibitors; Ramipril; Randomized Controlled Trials as Topic

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Female; Humans; Male; Multicenter Studies as Topic; Ramipril

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Female; Health Education; Humans; Male; Middle Aged; Myocardial Infarction; Ramipril; Risk Factors; Stroke; United States

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Humans; Ramipril

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiac Surgical Procedures; Cardiology; Cardiovascular Diseases; Congresses as Topic; Europe; Fibrinolytic Agents; Humans; Ramipril; Randomized Controlled Trials as Topic