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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

Heart failure remains a major and increasing cause of mortality and morbidity, even when the best available treatments are used. One of its key causes is neuroendocrine activation via the sympathetic nervous system and the renin-angiotensin system (RAS). Neuroendocrine blockers of the sympathetic nervous system (beta-blockers) and of the RAS (angiotensin-converting enzyme [ACE] inhibitors and angiotensin II type 1 [AT1] receptor blockers) therefore have an important potential therapeutic role in heart failure. The promising results from clinical trials with beta-blockers suggest that these drugs will become an established part of the future management of patients with mild to moderate symptomatic heart failure. Blockade of the RAS with ACE inhibitors has also been shown to be effective in reducing the risk of morbidity and mortality in patients with heart failure. Blockade of the AT1-receptor, with agents such as candesartan, produces more specific and, theoretically, more complete blockade of the major negative cardiovascular effects of angiotensin II than is possible using ACE inhibitors, whilst maintaining placebo-like tolerability. Furthermore, AT1-receptor blockade leads to increased stimulation of the angiotensin II type 2 (AT2) receptor, which, according to experimental data, may have favourable cardiovascular effects. Following encouraging results from two pilot studies, a major new international study programme - CHARM (Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity) - has been initiated to define the clinical benefits of candesartan cilexetil in a wide variety of patients with symptomatic heart failure. CHARM is the first study to accept all relevant heart failure patients who may benefit from RAS blockade, irrespective of their left ventricular function or tolerance of ACE inhibitors. The 6500 patients to be recruited will be divided among three integrated outcome studies. Two of these studies will examine the effect of candesartan cilexetil versus placebo in patients with an ejection fraction of 40% or less who are tolerant or intolerant of ACE inhibitors. The third study arm will examine the benefits of candesartan cilexetil in a previously seldom studied group: those with symptomatic heart failure, but with preserved left-ventricular systolic function. Recruitment of patients into the study has started.
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PMID:Exploring new treatment strategies in heart failure. 1105 37

The effectiveness of ACE inhibitors in reducing morbidity and mortality in patients with heart failure is largely attributable to their suppression of angiotensin II production. Despite chronic therapy with ACE inhibitors, angiotensin II levels may be incompletely suppressed and contribute to the high mortality of patients with heart failure. Recently, angiotensin receptor blockers, which block the effects rather than the production of angiotensin II, have become available. Angiotensin receptor blockers have been evaluated as both monotherapy and in combination with ACE inhibitors. In short term studies, angiotensin receptor blocker monotherapy appears to share many of the hemodynamic and clinical features of ACE inhibitors. In a long-term study, the Losartan Heart Failure Survival Study, angiotensin receptor blockers failed to demonstrate any beneficial effect over that seen with ACE inhibitors. The addition of an angiotensin receptor blocker to an ACE inhibitor appears to exert favorable short term hemodynamic, clinical, and neurohormonal effects. Four ongoing trials, Valsartan Heart Failure Trial, Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity, Optimal Therapy in Myocardial Infarction with Angiotensin II Antagonist Losartan study, and Valsartan In Acute Myocardial Infarction study, are evaluating the role of angiotensin receptor blockers either alone or in combination with ACE inhibitors in the management of left ventricular dysfunction. (c)2000 by CHF, Inc.
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PMID:The role of angiotensin receptor blockers in heart failure. 1202 95

Despite improvements in therapy, long-term mortality remains high in patients with heart failure and thus there remains a need for new treatment strategies to reduce the burden of mortality and morbidity associated with this condition. AT(1)-receptor blockers represent a rational approach to the management of heart failure, and have been shown to have beneficial effects on heart failure symptoms and exercise tolerance. However, the two outcome trials reported to date have not shown conclusive evidence of improvements in mortality. The potential benefits of AT(1)-receptor blockers in heart failure are currently being investigated in several trials. The CHARM programme (Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity) is the largest heart failure trial so far. This comprises three trials: CHARM Alternative, in patients with left ventricular dysfunction who are intolerant to ACE inhibitors; CHARM Added, in patients with left ventricular dysfunction who are also receiving ACE inhibitors; CHARM Preserved, in patients with preserved left ventricular systolic function (ejection fraction >40%). The primary end point will be a composite of cardiovascular mortality and hospitalisation for the treatment of heart failure. Other trials are currently investigating the effects of AT(1)-receptor blockers when used as an alternative or in addition to ACE inhibitors. The CHARM programme, together with other studies, should clarify the role of these agents in the management of heart failure.
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PMID:Current perspectives for AT(1)-receptor blockers in the management of heart failure. 1214 Jul 28

The purpose of this study was to investigate the effects of candesartan on arterial baroreflex sensitivity (BRS) and sympathetic activity in patients with mild heart failure (HF). Arterial pressure, heart rate, plasma renin activity, plasma angiotensin II and noradrenaline, and muscle sympathetic nerve activity (MSNA) were measured before therapy and after 4 weeks in 20 patients with mild HF. Patients were assigned to a candesartan group (n = 10) or a placebo group (n = 10). Baroreflex sensitivity was assessed by using phenylephrine. Candesartan induced an increase in plasma renin activity and plasma angiotensin II associated with a reduction in arterial pressure without affecting heart rate. Although plasma noradrenaline was unchanged (320 +/- 322 pg/ml to 339 +/- 104 pg/ml), MSNA decreased significantly (52 +/- 11 bursts/min to 42 +/- 9 bursts/min; p < 0.01)) and BRS increased significantly (6.9 +/- 3.6 msec/mm Hg to 10.2 +/- 3.3 msec/mm Hg; p < 0.01) after candesartan. However, there were no significant changes in the measured variables in the placebo group. These data indicate that candesartan treatment enhanced BRS and reduced sympathetic activity in patients with mild HF. Thus, the inhibitory effect of candesartan on sympathetic activity may, at least in part, contribute to the beneficial effect of angiotensin II receptor blockade in patients with mild HF.
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PMID:Candesartan and arterial baroreflex sensitivity and sympathetic nerve activity in patients with mild heart failure. 1245 20

To determine whether angiotensin receptor blockade decreases vascular tone in heart failure by improving endothelial-dependent vasorelaxation and increasing nitric oxide (NO) bioavailability, we treated infarcted adult male Sprague-Dawley rats with candesartan for 7 days or 8 weeks (10 mg/kg/day in drinking water). Candesartan, at both time points, lowered left ventricular (LV) systolic pressure (P < 0.05) (122 +/- 22 versus 74 +/- 16 and 73 +/- 10 mm Hg) and LV dP/dt (5914 +/- 1294 versus 2857 +/- 1672 versus 3175 +/- 769 mm Hg/s), but lowered LV end-diastolic pressure only at 8 weeks (16.9 +/- 9.7 versus 11.2 +/- 5.7 versus 6.9 +/- 5.3 mm Hg). The vasorelaxation response to acetylcholine (ACh) in thoracic aortic segments was decreased with infarction (P < 0.05), remained unchanged with 1 week of candesartan, but increased 84 and 86% at 10-4 and 10-5 M ACh (P < 0.05) at 8 weeks. The enhanced candesartan-induced vasorelaxation at 8 weeks was abolished with NG-nitro-l-arginine methyl ester (200 microM). In bovine pulmonary endothelial cells, 20 microM candesartan increased endothelial nitric-oxide synthase (eNOS) protein levels (P < 0.05) (28.9 +/- 2.6 versus 16.1 +/- 3.7 intensity units/microg of protein); the increased eNOS was abolished by a specific angiotensin subtype 2 (AT2) receptor antagonist, PD 123319. These data suggest that AT1 receptor blockade enhances vasorelaxation in heart failure by increasing NO bioavailability, in part via an AT2 receptor-mediated up-regulation of eNOS protein.
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PMID:Angiotensin subtype 1 rReceptor (AT1) blockade improves vasorelaxation in heart failure by up-regulation of endothelial nitric-oxide synthase via activation of the AT2 receptor. 1456 36

In parallel, randomized, double-blind, controlled clinical trials, candesartan (titrated to 32 mg once daily) was compared to placebo in 3 distinct populations: 1) patients with symptomatic heart failure (SHF) and left ventricular ejection fraction (LVEF) 40% or less who were not receiving an ACE inhibitor because of previous intolerance (CHARM-Alternative); 2) patients with SHF and LVEF 40% or less who were currently receiving an ACE inhibitor (CHARM-Added); 3) patients with SHF and LVEF higher than 40% (CHARM-Preserved). The primary outcome for the overall programme (CHARM-Overall) was all-cause mortality. For the component trials, it was a composite of cardiovascular death and hospital admission for CHF. Analysis was by intention to treat. In CHARM-Overall (placebo, n = 3796; candesartan, n = 3803; mean follow-up; 37.7 months), candesartan induced a 1.6% absolute reduction in all-cause mortality (unadjusted HR: 0.91; 95% CI 0.83-1.00; p = 0.055). In a prespecified analysis with covariate adjustment, this was statistically significant (HR: 0.90; 95% CI 0.82-0.94; p = 0;032). A highly significant reduction in the combined incidence of cardiovascular death and CHF hospital admission (HR: 0.84; 95% CI 0.77-0.91; p < 0.0001) was noted as well as a reduction of the number of patients developping a new diabetes (6% vs 7.4%: p = 0.02). In CHARM-Alternative, there were 1013 patients on candesartan and 1015 on placebo and the mean follow-up was 33.7 months. The combined incidence of cardiovascular death and CHF hospitalization was reduced by 23% (p = 0.0004). In CHARM-Added, 1276 patients received candesartan and 1272, placebo; mean follow-up was 41 months. The benefit induced by candesartan on the primary endpoint was 15% (p = 0.011). In those two studies the two components of the primary endpoint were significantly reduced. Candesartan was beneficial in all prespecified subgroups, including patients concomitantly treated by beta-blockers. In CHARM-Preserved (candesartan, n = 1514; placebo, n = 1509; mean follow-up: 36.6 months), neither the composite endpoint, nor cardiovascular death were reduced, but the number of admissions for heart failure was reduced. The clinical implications of these important results are discussed.
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PMID:[Clinical study of the month. The CHARM study]. 1467 27

The CHARM programme, which recruited 7,601 patients, compared the angiotensin-receptor blocker, candesartan, with a placebo in three different populations with class II-VI heart failure. Candesartan reduced cardiovascular mortality and/or hospitalization for heart failure in patients with heart failure and ejection fractions of greater than 40% or less, and total mortality was reduced in these patients as well. Similar benefits were seen whether or not background therapy with ACE inhibitors, beta blockers', or spironolactone was used. Pooled analysis of the three studies showed that candesartan provided a significant reduction in cardiovascular death and also demonstrated a positive trend in the overall reduction in all cause mortality. The major adverse effects were hyperkalemia, increase in creatinine concentration and hypotension.
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PMID:[Benefits of candesartan in the treatment of symptomatic heart failure--CHARM programme]. 1473 55

Risk factors of cardiovascular disease, such as hypertension, diabetes, and myocardial infarction, if left untreated, will increase the risk of the development of chronic heart failure. Much is known about the pathophysiology and effective treatments of chronic heart failure from left ventricular systolic dysfunction; however, little clinical trial evidence exists concerning benefits of treating patients with chronic heart failure and preserved systolic function, also known as left ventricular diastolic dysfunction. Rather, an understanding of the pathophysiology and patient signs and symptoms has usually dictated choice of treatments. With the results of ongoing trials, as well as the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Preserved and the Digitalis Investigation Group (DIG) trials, clinical evidence is accumulating to support effective treatments in patients with left ventricular diastolic dysfunction. The focus of this review is to discuss the risks of, identification of, and rationale for therapeutic choices being employed for treating left ventricular diastolic dysfunction and implications from studies that may support these choices.
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PMID:Left ventricular diastolic dysfunction: risks, identification, and treatment. 1501 55

The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) trials looked at the effects of candesartan in addition to best possible treatment for heart failure in 7601 patients. CHARM encompassed three studies in discrete populations, including patients with left ventricular dysfunction taking angiotensin-converting enzyme (ACE) inhibitors (CHARM-Added), patients with maintained left ventricular function (CHARM-Preserved), and patients with left ventricular dysfunction and an intolerance to ACE inhibitors (CHARM-Alternative). CHARM-Alternative was considered a success in that its participants experienced a significant reduction in each component of the study's primary end point, which was a composite of cardiovascular death or hospitalization for heart failure, over a median follow-up of 34 months. Candesartan was by and large well tolerated in these ACE-inhibitor intolerant patients; thus, the findings of this study provide additional support for the effectiveness of angiotensin receptor blocker therapy in heart failure patients poorly tolerant of an ACE inhibitor; however, candesartan was not convincingly shown to improve the incidence/severity of hypotension, hyperkalemia, and glomerular filtration rate reductions that were the basis for ACE inhibitor intolerance in approximately 25% of the study population.
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PMID:ACE inhibitor intolerance and lessons learned from the candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) trials. 1518 34


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