cardiovascular-agents and aliskiren

Aliskiren was shown to increase adverse events in patients with diabetes and concomitant renin-angiotensin blockade. We aim to investigate the efficacy and safety of aliskiren in patients with diabetes and increased cardiovascular risk or established cardiovascular disease.. MEDLINE and Embase were searched for prospective studies comparing addition of aliskiren to standard medical therapy in patients with diabetes and cardiovascular disease, or ⩾1 additional cardiovascular risk factor (hypertension, abnormal lipid profile, microalbuminuria/proteinuria, chronic kidney disease). Relative risk for efficacy (all-cause mortality, combined cardiovascular mortality and hospitalisation) and safety (hyperkalaemia, hypotension, renal impairment) outcomes was calculated.. Of 2151 studies identified in the search, seven studies enrolling 13,395 patients were included. Aliskiren had no effect on all-cause mortality (relative risk: 1.05, 95% confidence interval: 0.90 to 1.24, p = 0.53), or combined cardiovascular mortality or heart failure hospitalisation (relative risk: 1.07, 95% confidence interval: 0.81 to 1.40, p = 0.64). Patients receiving aliskiren had a greater risk of developing hyperkalaemia (relative risk: 1.32, 95% confidence interval: 1.14 to 1.53, p = 0.0003) and renal impairment (relative risk: 1.15, 95% confidence interval: 1.02 to 1.30, p = 0.03), but not hypotension.. Patients with diabetes and cardiovascular disease or cardiovascular risk do not benefit from the addition of aliskiren to standard medical therapy. Detrimental safety profile in pooled analysis supports current warnings.

Topics: Amides; Cardiovascular Agents; Cardiovascular Diseases; Chi-Square Distribution; Diabetes Mellitus; Fumarates; Humans; Odds Ratio; Renin-Angiotensin System; Risk Assessment; Risk Factors; Treatment Outcome

An estimated 5.1 million Americans have chronic heart failure and this is expected to increase 25% by 2030. Heart failure is a clinical syndrome that evolves from either functional or structural changes to the ventricles that lead to filling or ejection abnormalities. Thus far, pharmacotherapy has been show to be beneficial in patients only with reduced ejection fraction; however, new therapies have been developed in hopes of reducing the burden of heart failure. In this review, we will discuss current pharmacotherapies recommended in American College of Cardiology/American Heart Association guidelines, the evidence behind these recommendations as well as new and emerging therapies that have been developed.

Topics: Adrenergic beta-Antagonists; American Heart Association; Amides; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Antihypertensive Agents; Atrial Natriuretic Factor; Benzazepines; Biphenyl Compounds; Calcium Channel Blockers; Cardiology; Cardiotonic Agents; Cardiovascular Agents; Digoxin; Diuretics; Drug Combinations; Erythropoietin; Evidence-Based Medicine; Fumarates; Heart Failure; Hematinics; Humans; Hydralazine; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Iron; Isosorbide Dinitrate; Ivabradine; Mineralocorticoid Receptor Antagonists; Peptide Fragments; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Societies, Medical; Stroke Volume; Tetrazoles; United States; Valsartan; Vasodilator Agents

The renin–angiotensin–aldosterone system (RAAS) plays a pivotal role in regulating blood pressure, volume, and electrolytes. The final product of RAAS cascade is angiotensin II, which exerts diverse biological activities via binding to one of three known receptor types, with different binding consequences. Despite the success with conventional strategies to limit angiotensin II production and action, these agents promote a reflex rise in plasma renin activity, which is thought to be associated with an increased incidence of cardiovascular events. Several renin inhibitors have been synthesized in order to counteract deleterious consequences of renin activity and RAAS activation; aliskiren is the first of these new non-peptide direct renin inhibitors to be approved for the treatment of hypertension. The paper reviews pharmacokinetics of aliskiren and its role in hypertension, with particular regard to those studies that compared clinical efficacy of aliskiren in comparison and in addition to other antihypertensive drug strategies.

Topics: Amides; Cardiovascular Agents; Cardiovascular Diseases; Fumarates; Humans; Renin; Renin-Angiotensin System

The US Food and Drug Administration (FDA) has approved several new drugs in the past 2 years. This article provides an overview of some of the newer drugs that are likely to find wider use in the future. The drugs reviewed in this article can be used to treat cardiovascular system problems, diabetes mellitus, multiple sclerosis, hepatitis B infection, hyponatremia, Parkinson's disease, rheumatoid arthritis, pain, constipation, and insomnia. Another drug discussed can be used to help a patient stop smoking. The article also discusses Gardasil, the recombinant vaccine against human papilloma virus (types 6, 11, 16, and 18).

Topics: Abatacept; Acetanilides; Amides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antiparkinson Agents; Antirheumatic Agents; Antiviral Agents; Apomorphine; Benzazepines; Cardiovascular Agents; Fumarates; Hepatitis B; Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18; Humans; Hypoglycemic Agents; Immunoconjugates; Multiple Sclerosis; Natalizumab; Nucleosides; Papillomavirus Vaccines; Pharmacology, Clinical; Piperazines; Pyrazines; Pyrimidinones; Quinoxalines; Ranolazine; Sitagliptin Phosphate; Smoking Cessation; Telbivudine; Thymidine; Triazoles; Varenicline; Viral Vaccines

An association has been shown between plasma renin activity (PRA) and the risk of cardiovascular disease. There is also evidence that angiotensin II exerts detrimental effects on progression and instabilization of atherosclerotic plaque. The renin-angiotensin system (RAS) can be inhibited through inhibition of angiotensin I (Ang I) generation from angiotensinogen by direct renin inhibitors, inhibition of angiotensin II (Ang II) generation from angiotensin I by angiotensin-converting enzyme inhibitors and finally by direct inhibition of the action of Ang II receptor level. Aliskiren, the first direct renin inhibitor to reach the market, is a low-molecular-weight, orally active, hydrophilic nonpeptide. Aliskiren blocks Ang I generation, while plasma renin concentration increases because the drugs blocks the negative feed-back exerted by Ang II on renin synthesis. Because of its long pharmacological half-life, aliskiren is suitable for once-daily administration. Its through-to-peak ratio approximates 98% for the 300 mg/day dose. Because of its mechanism of action, aliskiren might offer the additional opportunity to inhibit progression of atherosclerosis at tissue level. Hypertension is an approved indication for this drug, which is also promising for the treatment of heart failure. The efficacy of this drug in reducing major clinical events is being tested in large ongoing clinical trials.

Topics: Amides; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Drug Administration Schedule; Fumarates; Humans; Prorenin Receptor; Protein Precursors; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Treatment Outcome; Vacuolar Proton-Translocating ATPases

Topics: Amides; Cardiovascular Agents; Etiocholanolone; Fumarates; Heart Failure; Humans; Neovascularization, Physiologic; Ventricular Remodeling

To: (i) describe the baseline characteristics of patients in ATMOSPHERE and the changes in the planned analysis of ATMOSPHERE resulting from the mandated discontinuation of study treatment in patients with diabetes; (ii) compare the baseline characteristics of patients in ATMOSPHERE with those in the Prospective comparison of Angiotensin Receptor neprilysin inhibitors with Angiotensin converting enzyme inhibitors to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF); and (iii) compare the characteristics of patients with and without diabetes at baseline in ATMOSPHERE.. A total of 7063 patients were randomized into ATMOSPHERE April 2009-April 2014 at 755 sites in 43 countries. Their average age was 63 years and 78% were men. ATMOSPHERE patients were generally similar to those in PARADIGM-HF although fewer had diabetes, renal dysfunction, and were treated with a mineralocorticoid receptor antagonist. In ATMOSPHERE, patients with diabetes differed in numerous ways from those without. Patients with diabetes were older and had worse heart failure status but a similar left ventricular ejection fraction (mean 28%); they had a higher body mass index and more co-morbidity, especially hypertension and coronary heart disease. Mean estimated glomerular filtration rate was slightly lower in those with diabetes compared with those without.. ATMOSPHERE will determine whether patients with HF and reduced ejection fraction (particularly those without diabetes) benefit from the addition of a direct renin inhibitor to standard background therapy, including an angiotensin-converting enzyme inhibitor, beta-blocker, and a mineralocorticoid receptor antagonist. ATMOSPHERE will also determine whether aliskiren alone is superior to, or at least non-inferior to, enalapril.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Diabetes Mellitus; Drug Therapy, Combination; Enalapril; Female; Fumarates; Heart Failure; Humans; Male; Middle Aged; Renin; Stroke Volume; Ventricular Dysfunction, Left

We assessed the relationship between diabetes and cardiac structure and function following myocardial infarction (MI) and whether diabetes influences the effect of direct renin inhibition on change in left ventricular (LV) size.. The ASPIRE trial enrolled 820 patients 2-8 weeks after MI with ejection fraction ≤ 45% and randomized them to the direct renin inhibitor aliskiren (n= 423) or placebo (n = 397) added to standard medical therapy. Echocardiography was performed at baseline and after 36 weeks in 672 patients with evaluable paired studies. Compared with non-diabetic patients, diabetic patients (n = 214) were at higher risk for a composite of cardiovascular (CV) death, heart failure hospitalization, recurrent MI, stroke, or aborted sudden death (14 vs. 7%; adjusted hazard ratio 1.63, 95% confidence interval 1.01-2.64, P= 0.045), despite similar left ventricular ejection fraction (37.9 ± 5.3 vs. 37.6 ± 5.2%, P= 0.48) and end-systolic volume (ESV) (84 ± 25 vs. 82 ± 28 mL, P= 0.46). Diabetic patients demonstrated greater concentric remodelling (relative wall thickness 0.38 ± 0.07 vs. 0.36 ± 0.07, P= 0.0002) and evidence of higher LV filling pressure (E/E' 11.1 ± 5.3 vs. 9.1 ± 4.3, P= 0.0011). At 36 weeks, diabetic patients experienced similar per cent reduction in ESV overall (-4.9 ± 17.9 vs. -5.5 ± 16.9, P= 0.67) but tended to experience greater reduction in ESV than non-diabetic patients when treated with aliskiren (interaction P = 0.08).. Compared with non-diabetic patients, diabetic patients are at increased risk of CV events post-MI despite no greater LV enlargement or reduction in systolic function. Diabetic patients demonstrate greater concentric remodelling and evidence of higher LV filling pressure, suggesting diastolic dysfunction as a potential mechanism for the higher risk observed among these patients.

Topics: Aged; Amides; Cardiovascular Agents; Diabetic Cardiomyopathies; Diastole; Double-Blind Method; Female; Fumarates; Humans; Male; Middle Aged; Myocardial Infarction; Renin; Systole; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

The renin-angiotensin system (RAS), which plays an important role in the progression of heart failure, is efficiently blocked by the inhibition of renin, the rate-limiting enzyme in the RAS cascade. In the present study, we investigated the cardioprotective effects of TAK-272 (SCO-272, imarikiren), a novel, orally effective direct renin inhibitor (DRI), and compared its efficacy with that of aliskiren, a DRI that is already available in the market. TAK-272 was administered to calsequestrin transgenic (CSQ-tg) heart failure mouse model that show severe symptoms and high mortality. The CSQ-tg mice treated with 300 mg/kg, the highest dose tested, of TAK-272 showed significantly reduced plasma renin activity (PRA), cardiac hypertrophy, and lung congestion. Further, TAK-272 reduced cardiomyocyte injury accompanied by an attenuation of the increase in NADPH oxidase 4 and nitric oxide synthase 3 expressions. TAK-272 also prolonged the survival of CSQ-tg mice in a dose-dependent manner (30 mg/kg: P = 0.42, 100 mg/kg: P = 0.12, 300 mg/kg: P < 0.01). Additionally, when compared at the same dose level (300 mg/kg), TAK-272 showed strong and sustained PRA inhibition and reduced the heart weight and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, a heart failure biomarker, while aliskiren showed a significant weaker PRA inhibition and failed to demonstrate any cardioprotective effects. Our results showed that TAK-272 is an orally active and persistent renin inhibitor, which reduced the mortality of CSQ-tg mice and conferred protection against cardiac hypertrophy and injury. Thus, TAK-272 treatment could provide a new therapeutic approach for heart failure.

Topics: Amides; Animals; Benzimidazoles; Cardiovascular Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fumarates; Heart; Heart Failure; Hypertrophy; Lung Diseases; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Morpholines; Piperidines; Protective Agents; Random Allocation; Renin

Chagas' disease is an important cause of cardiomyopathy in Latin America. We aimed to compare clinical characteristics and outcomes in patients with heart failure (HF) with reduced ejection fraction caused by Chagas' disease, with other etiologies, in the era of modern HF therapies.. This study included 2552 Latin American patients randomized in the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Aliskiren Trial to Minimize Outcomes in Patients With Heart Failure) trials. The investigator-reported etiology was categorized as Chagasic, other nonischemic, or ischemic cardiomyopathy. The outcomes of interest included the composite of cardiovascular death or HF hospitalization and its components and death from any cause. Unadjusted and adjusted Cox proportional hazards models were performed to compare outcomes by pathogenesis. There were 195 patients with Chagasic HF with reduced ejection fraction, 1300 with other nonischemic cardiomyopathy, and 1057 with ischemic cardiomyopathy. Compared with other etiologies, Chagasic patients were more often female, younger, and had lower prevalence of hypertension, diabetes mellitus, and renal impairment (but had higher prevalence of stroke and pacemaker implantation) and had worse health-related quality of life. The rates of the composite outcome were 17.2, 12.5, and 11.4 per 100 person-years for Chagasic, other nonischemic, and ischemic patients, respectively-adjusted hazard ratio for Chagasic versus other nonischemic: 1.49 (95% confidence interval, 1.15-1.94;. Despite younger age, less comorbidity, and comprehensive use of conventional HF therapies, patients with Chagasic HF with reduced ejection fraction continue to have worse quality of life and higher hospitalization and mortality rates compared with other etiologies.. PARADIGM-HF: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255; ATMOSPHERE: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658.

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Chagas Cardiomyopathy; Female; Fumarates; Heart Failure; Hospitalization; Humans; Kaplan-Meier Estimate; Latin America; Male; Middle Aged; Multicenter Studies as Topic; Quality of Life; Randomized Controlled Trials as Topic; Risk Factors; Stroke Volume; Time Factors; Treatment Outcome; Ventricular Function, Left

Topics: Amides; Animals; Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Female; Fumarates; Humans; Male; Myocardial Infarction; Renin; Ventricular Dysfunction, Left; Ventricular Remodeling

Topics: Adrenergic beta-Antagonists; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Drug Therapy, Combination; Fumarates; Humans; Molecular Targeted Therapy; Myocardial Infarction; Myocardium; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Treatment Outcome; Ventricular Remodeling