Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acceptance of the notion that physiologically specific interruption of the renin-angiotensin-aldosterone system (RAAS) is of considerable therapeutic benefit in the treatment of hypertension and congestive heart failure has generated great interest in the search for novel pharmacological inhibitors. The RAAS is expressed at the whole body, organ/tissue and cellular level through the action of the octapeptide angiotensin II (Ang II), the primary effector molecule of the RAAS. The availability of selective, potent, orally active and long-acting nonpeptide Ang II type 1 (AT1) receptor antagonists provided the opportunity to obtain the benefits of selectively blocking the RAAS at the level of the AT1 receptor that mediates most, if not all, of the important actions of Ang II, and avoid the nonspecificity of the Ang I converting enzyme (ACE) inhibitors. Losartan was the first, but by no means remained the only nonpeptide AT1 receptor antagonist. Numerous other "sartans" have emerged in the past several years and successfully completed clinical development. With the exception of Eprosartan, all others, i.e. Candesartan, Irbesartan, Saprisartan, Tasosartan, Telmisartan, Valsartan and Zolasartan, are based on modifications of Losartan's prototypic chemical structure. AT1 receptor antagonists represent the newest addition to the arsenal of cardiovascular therapeutics. The predominant role of the AT1 receptor in mediating the pathophysiological role of Ang II underlies the effectiveness of this novel class of agents to lower arterial blood pressure, reduce pre- and afterload, inhibit sympathetic nervous system activity and prevent cardiovascular hypertrophy and cardiac failure induced by inappropriate control of the RAAS.
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PMID:Angiotensin II receptor antagonists: an emerging new class of cardiovascular therapeutics. 1048 32

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 Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) will compare the efficacy of an ACE inhibitor (ramipril) with an angiotensin receptor blocker (telmisartan), and determine whether these treatments in combination will further reduce morbidity and mortality from cardiovascular disease.
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PMID:Angiotensin II and trials of cardiovascular outcomes. 1183 5

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 at high risk of complications from atherosclerosis.
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PMID:From the HOPE to the ONTARGET and the TRANSCEND studies: challenges in improving prognosis. 1183 7

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 generation.
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PMID:The ongoing telmisartan alone and in combination with ramipril global endpoint trial program. 1278 6

The use of angiotensin-receptor blockers has already been outlined in cardiology and diabetology. In extending clinical indications of this drug class their pleiotropic actions might play a role: they are improving endothelial function, and their antiatherogenic effect is not related to antihypertensive action. It may also be important that while some antihypertensive agents are impairing sexual function, angiotensin-receptor blocking agents seem to improve sexual activity in hypertensive men. As there is alternative route for angiotensin II synthesis, there are patients in whom blockade of angiotensin II actions do need more aggressive treatment for proper therapeutic results. The discovery of angiotensin-receptor blocking agents made possible to produce this blockade in the tissues as well, and suggested combined administration of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for better clinical results. In patients with congestive heart failure data from an earlier pilot study (RESOLVD) suggested that combined use of these two drug classes would lead for a more complete blockade of the renin-angiotensin system with better clinical results, especially in those patients in the higher dose ranges. Recent results showed that using this drug combination cardiovascular mortality and hospitalization because of worsening heart failure could significantly be decreased (CHARM-Added study). More important data are expected from the ongoing ONTARGET program (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial).
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PMID:[New possibilities in clinical use of angiotensin II receptor inhibitors]. 1472 9

Hypertension is one of the most important modifiable risk factors for cardiovascular pathology, such as atherosclerosis and cardiac left ventricular hypertrophy, including acute events such as stroke and myocardial infarction (MI). In particular, the risk of ischaemic and haemorrhagic stroke is directly and continuously related to high blood pressure levels. The renin-angiotensin system (RAS) plays an important role in volume homeostasis and blood pressure regulation. It also helps to prevent cell and organ damage from ischaemia during acute volume loss. However, angiotensin-II (A-II)--the main effector peptide of the RAS--also exerts a number of pathological effects, which are mediated by the AT 1 receptor. The Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial (ONTARGET) programme consists of two parallel trials where ONTARGET as a large, long-term study compares the efficacy of the angiotensin-receptor antagonist, telmisartan, the renin-angiotensin-converting enzyme (ACE) inhibitor, ramipril and combination therapy with telmisartan plus ramipril for reducing cardiovascular and cerebral risk. Telmisartan, due to its long duration of action, compares favourably with other angiotensin-receptor antagonists. In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril was shown to reduce the risk for MI and other cardiovascular events in patients at high risk for pathological cardiac events, but without heart failure or a low ejection fraction. The cardiovascular outcomes of high-risk patients using the same criteria as those of the HOPE study will be assessed in both trials. TRANSCEND differs from ONTARGET in that this trial will enrol patients who do not tolerate ACE inhibitors. This parallel study will therefore be able to compare telmisartan and placebo treatment. Both ONTARGET and TRANSCEND trials feature the same primary composite end point: death caused by cardiovascular disease, acute MI, stroke and hospitalisation because of congestive heart failure. The secondary end points will focus on reductions in the development of Type 2 diabetes mellitus, nephropathy, cognitive decrease and dementia as well as atrial fibrillation.
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PMID:Challenges in improving prognosis and therapy: the Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial programme. 1515 18

A progressive chain of pathophysiological events links cardiovascular risk factors to clinical manifestations of disease and life-threatening cardiovascular events. This chain--the cardiovascular continuum--underlies cardiovascular disease and holds the key to its prevention and treatment. Progressive tissue damage can result in morbidity from congestive heart failure, end-stage heart disease, nephrotic proteinuria and dementia and, eventually, death from cardio- or cerebrovascular causes. The renin-angiotensin-aldosterone system (RAAS) is involved at all stages of the cardiovascular continuum, because the effector molecules of the RAAS, angiotensin II in particular, have direct pathobiological effects on a variety of tissues, including the endothelium, vascular smooth muscle and the renal mesangium. Clinical trials of angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors have demonstrated the essential validity of this hypothesis. Interruption of the RAAS has been shown to reduce cardiovascular morbidity and mortality in patients with left ventricular hypertrophy, heart failure and post-myocardial infarction, as well as renal disease in patients with type 2 diabetes. Key questions remain, however. What are the clinical effects of combination ARB and ACE inhibitor treatment? How will combinations of RAAS blockade with other agents, such as statins, affect the cardiovascular continuum? Answers to these questions will require well-planned, adequately powered clinical trials, such as the Programme of Research tO evaluate Telmisartan End-organ proteCTION (PROTECTION) and the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) programmes. However, it is already clear that RAAS blockade is an essential part of blocking progression along the cardiovascular continuum.
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PMID:The cardiovascular continuum and renin-angiotensin-aldosterone system blockade. 1582 52

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.
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PMID:The ONTARGET/TRANSCEND Trial Programme: baseline data. 1586 20

Angiotensin receptor blockers (ARBs) were introduced after clinical trials showed angiotensin-converting enzyme inhibitors (ACEIs) to have extensive clinical benefits in a wide range of diseases. Consequently, it has been more difficult for clinical trials to demonstrate similar, enhanced or additive benefits of ARBs. However, ARBs were introduced with the hypothesis that they were likely a more effective method of interrupting the renin-angiotensin system and would result in enhanced outcomes. Clinical trials in high-risk vascular patients (after myocardial infarction), patients with heart failure and patients with nephropathy show the benefits of ACE inhibition. ARBs likely have similar benefits as ACEIs when used after myocardial infarction, in patients with heart failure and for management of diabetic nephropathy. However, ARBs generally remain a second-line treatment because it has been more difficult to demonstrate that ARBs prevent acute vascular events, such as myocardial infarction, together with the greater clinical trial evidence for ACE inhibition. The primary application of ACEIs over ARBs is reflected in the Canadian clinical guidelines for the management of patients with diabetes, hypertension, heart failure and following myocardial infarction. Until the completion of clinical trials, such as the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), that examine whether ARBs have vascular protective properties similar to ACEIs, it is unlikely that the clinical guidelines will change.
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PMID:Have angiotensin receptor blockers lived up to expectations? 1594 Mar 55

Endothelial dysfunction, characterized by impaired nitric oxide activity, constitutes an early step in the pathogenesis of atherosclerotic disease. Prospective studies have shown that impaired endothelium-dependent vasorelaxation and the vasodilatory response of coronary arteries to acetylcholine predict cardiovascular events. Microalbuminuria and estimated glomerular filtration rate, which are both deeply influenced by renal nitric oxide activity, are predictors of cardiovascular outcome and total mortality but develop at a later stage of renal impairment. Endothelial dysfunction reflects early stage renal involvement in the atherosclerotic processes. The Telmisartan versus Ramipril in renal ENdothelium DYsfunction (TRENDY) trial examined endothelial function of the renal vasculature as a therapeutic target in patients with hypertension and type 2 diabetes, but without albuminuria. The rationale was that blockade of the renin-angiotensin system (RAS) is cardio- and renoprotective at later stages of the disease, but the impact of blockade of the RAS at earlier stages of disease is unknown. The results of TRENDY indicate that the endothelial function, as assessed by basal nitric oxide activity, can be improved after RAS blockade. These data complement the results of the Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) trial, which demonstrated that telmisartan and enalapril similarly decelerate the progression of overt diabetic nephropathy. The results of TRENDY are in accordance with the observed changes in peripheral circulation. Endothelium-dependent vasorelaxation could be improved with angiotensin II receptor blockers, but not with diuretics or beta-blockers, in hypertensive patients. Intervention at the beginning of the renal and cardiovascular continuum offers the opportunity to prevent the fatal development towards renal and cardiac failure.
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PMID:Endothelial dysfunction: how can one intervene at the beginning of the cardiovascular continuum? 1660 59


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