ramipril and Hypotension

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

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

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

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

The purpose of this study was to compare the effects of continuation versus discontinuation of the angiotensin-converting enzyme (ACE) inhibitor ramipril and assess the efficacy of prophylactic vasopressin infusion on hemodynamic stability and vasoactive drug requirements in patients undergoing coronary artery bypass graft (CABG) surgery.. A prospective, randomized, double-blinded, single-center clinical study.. Tertiary care hospital.. Forty-seven patients on the ACE inhibitor ramipril for 6 weeks before undergoing elective primary CABG surgery on cardiopulmonary bypass (CPB).. Patients were randomly divided into 3 groups: group A (n = 16), patients discontinued ramipril 24 hours before surgery; group B (n = 16), patients continued ramipril until the morning of surgery; and group C (n = 15), patients continued ramipril until the morning of surgery and received vasopressin infusion (0.03 U/min) from the onset of rewarming until the hemodynamics were stable without vasopressor agents. The anesthetic technique and conduct of CPB were standardized for all the groups. Hemodynamic parameters and vasoactive drug requirements were recorded for 3 days postoperatively.. Patients in group A maintained stable mean arterial pressure (MAP) and systemic vascular resistance (SVR). In group B, MAP and SVR decreased after the induction of anesthesia and remained so throughout surgery (p < 0.05). In group C, MAP and SVR decreased upon the induction of anesthesia (p < 0.05) but normalized after CPB.. Preoperative ACE inhibitor continuation predisposed to hypotension upon the induction of anesthesia and in the post-CPB period. Prophylactic low-dose vasopressin infusion prevented post-CPB hypotension. Low-dose vasopressin can be considered as potential therapy in these patients.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Coronary Artery Bypass; Double-Blind Method; Female; Heart Rate; Humans; Hypotension; Male; Middle Aged; Prospective Studies; Ramipril; Vasopressins

In a placebo-controlled, double-blinded, randomized study we evaluated the effect of ramipril prior to thrombolysis on the course of PAI-1 plasma levels and on the frequency of postinfarct ischemic events in patients with acute myocardial infarction. Fifty-one out of 99 patients received 2.5 mg ramipril orally prior to thrombolysis and 12 h later. The blood samples for determination of PAI-1 plasma levels were collected on admission and 2, 4, 8, 12 and 24 h after thrombolysis. Postinfarct ischemic events were registered until coronary angiography was performed and defined as recurrent chest pain and/or evidence of ischemic signs on the ECG (ST-depression or ST-segment elevation of 1 mm in one or more inferior or anterior leads). Coronary angiography was performed within 7 days after the onset of myocardial infarction. Patients were classified into two groups: those without reperfusion of the infarct-related artery (TIMI grade 0 or 1) and those with reperfusion of the infarct-related artery (TIMI grade 2.3). On admission, PAI-1 plasma levels were similar in both groups (ramipril: 47.1 [4.8] ng/ml; placebo: 49.1 [4.8] ng/ml). The PAI-1AUC was 77.2 [6.7] ng/ml/h in the ramipril group and 95.4 [6.2] ng/ml/h in the placebo group (p = 0.013). Significant differences between groups were observed at 4, 8 and 12 h after thrombolysis (4 h: 85.5 (11.3) vs. 116 (12.3) ng/ml, p < 0.01; 8 h: 79.1 (11.2) vs. 100.9 (9.3) ng/ml, p < 0.01; 12 hrs: 71.3 (9.5) vs. 87.4 (7.7) ng/ml, p < 0.05). The relative frequency of postinfarct ischemic events was significantly lower in the ramipril group (2.5% versus 7.1%, p = 0.001). Additionally, we observed a significant higher rate of TIMI grade 2 and 3 of the infarct-related artery in patients receiving oral ramipril compared to the placebo group (73% versus 54%; p = 0.035). Our study demonstrates a favorable effect of ramipril on the fibrinolytic system after thrombolysis associated with a lower rate of postinfarct ischemic events within the first days after myocardial infarction. Therefore, the application of ramipril prior to thrombolysis appears to be a reasonable concomitant treatment which may reduce early infarct-related complications.

Topics: Adult; Aged; Cause of Death; Double-Blind Method; Drug Therapy, Combination; Emergency Medical Services; Female; Hemodynamics; Humans; Hypotension; Ischemia; Middle Aged; Myocardial Infarction; Plasminogen Activator Inhibitor 1; Ramipril; Thrombolytic Therapy

Angiotensin-converting enzyme inhibitors are associated with deleterious hypotension during anesthesia and shock. Because the pharmacologic effects of angiotensin-converting enzyme inhibitors are partly mediated by increased bradykinin B2 receptor activation, this study aimed to determine the impact of acute B2 receptor blockade during hemorrhagic shock in angiotensin-converting enzyme inhibitor-treated mice.. In vivo study.. University research unit.. C57/Bl6 mice.. The hemodynamic effect of B2 receptor blockade using icatibant (B2 receptor antagonist) was studied using a pressure-targeted hemorrhagic shock and a volume-targeted hemorrhagic shock. Animals were anesthetized with ketamine and xylazine (250 mg/kg and 10 mg/kg, respectively), intubated using intratracheal cannula, and ventilated (9 mL/kg, 150 min). Five groups were studied: 1) sham-operated animals, 2) control shocked mice, 3) shocked mice treated with ramipril for 7 days (angiotensin-converting enzyme inhibitors) before hemorrhagic shock, 4) shocked mice treated with angiotensin-converting enzyme inhibitors and a single bolus of icatibant (HOE-140) immediately before anesthesia (angiotensin-converting enzyme inhibitors + icatibant), and 5) shocked mice treated with a single bolus of icatibant. One hour after volume-targeted hemorrhagic shock, blood lactate was measured to evaluate organ failure.. During pressure-targeted hemorrhagic shock, the mean blood volume withdrawn was significantly lower in the angiotensin-converting enzyme inhibitor group than in the other groups (p < 0.001). During volume-targeted hemorrhagic shock, icatibant prevented blood pressure lowering in the angiotensin-converting enzyme inhibitor group (p < 0.001). Blood lactate was significantly higher in the angiotensin-converting enzyme inhibitor group than in the other groups, particularly the HOE groups.. During hemorrhagic shock, acute B2 receptor blockade significantly attenuates the deleterious hemodynamic effect of angiotensin-converting enzyme inhibitor treatment in mice. This beneficial effect of B2 receptor blockade is rapidly reached and sustained with a single bolus of icatibant. This benefit could be of interest in angiotensin-converting enzyme inhibitor-treated patients during both emergency anesthesia and resuscitation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Disease Models, Animal; Hypotension; Mice; Mice, Inbred C57BL; Ramipril; Shock, Hemorrhagic

The hypertension is a civilization disease, slowly destroying the cardio-vascular system and leading to serious complications, which may result in patient death. Critical factors enhancing the proper functioning of the body are: properly selected pharmacotherapy and the self-control of the blood pressure.. was to evaluate the effectiveness and safety of the hypertension treatment with generic and original formulations of angiotensin converting enzyme (ACE) inhibitors.. To the study, which consisted of an interview and completed a joint survey were enrolled 120 patients with hypertension therapy based on formulations of ACE inhibitors group. Data for the analysis were obtained from surveys conducted in: Department of Angiology, Hypertension and Diabetology, Department and Clinic of Endocrinology, Diabetology and Isotope Therapy and its Clinic for Diabetic Outpatients, in the period from 03/02/2011 to 20/04/2011.. Out of 120 surveyed hypertensive patients treated with ACEI, 79 persons (66%) received the original preparations and 41 (34%) generic medications. Most preparations contained ramipril: 78 patients, of whom 50 received the original formulations and 28 a generic one. In this population no differences were found in the reduction of the systolic and the diastolic blood pressure between groups of patients receiving original and generic formulations. The most common adverse effects (AE) reported by patients were cough (n = 16), hypotension (n = 7), paresthesia (n = 6), skin lesions (n = 6), weakness (n = 5), headache and dizziness (n = 5). Some of these, i.e.: cough, weakness, headaches and dizziness, occurred more frequently in patients receiving therapy with generic preparations.. Both the reference and generic preparations showed similar efficacy in reducing systolic and diastolic pressure. The therapy with original drugs leads less frequently to adverse effects such as cough, weakness, headaches and dizziness.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cough; Dizziness; Drug Eruptions; Drugs, Generic; Female; Headache; Humans; Hypertension; Hypotension; Male; Muscle Weakness; Paresthesia; Population Surveillance; Ramipril

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

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

The physiological effects of ACE inhibitors may act in part through a kinin-dependent mechanism. We investigated the effect of chronic ACE-inhibitor treatment on functional kinin B(1)- and B(2)-receptor expression, which are the molecular entities responsible for the biological effects of kinins.. Rats were subjected to different 6-week treatments using various mixtures of the following agents: ACE inhibitor, angiotensin AT(1)-receptor antagonist, and B(1)- and B(2)-receptor antagonists. Chronic ACE inhibition induced both renal and vascular B(1)-receptor expression, whereas B(2)-receptor expression was not modified. Furthermore, with B(1)-receptor antagonists, it was shown that B(1)-receptor induction was involved in the hypotensive effect of ACE inhibition. Using microdissection, we prepared 10 different nephron segments and found ACE-inhibitor-induced expression of functional B(1)-receptors in all segments. ACE-inhibitor-induced B(1)-receptor induction involved homologous upregulation, because it was prevented by B(1)-receptor antagonist treatment. Finally, using B(2)-receptor knockout mice, we showed that ACE-inhibitor-induced B(1)-receptor expression was B(2)-receptor independent.. This study provides the first evidence that chronic ACE-inhibitor administration is associated with functional vascular and renal B(1)-receptor induction, which is involved in ACE-inhibitor-induced hypotension. The observed B(1)-receptor induction in the kidney might participate in the known renoprotective effects of ACE inhibition.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Dinoprostone; Drug Administration Schedule; Enzyme Activation; Hypotension; Irbesartan; Kidney; Male; Mice; Mice, Knockout; Nephrons; Organ Specificity; Ramipril; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin; RNA, Messenger; Tetrazoles; Time