Associate Professor/Director of Studies
Department of Medicine
Karolinska University Hospital
The incidence of chronic heart failure (CHF) has increased, probably as a consequence of the ageing Western population.(1) Treatment with angiotensin-converting enzyme (ACE) inhibitors(2) and beta-blockers(3–5) is effective in patients with impaired left ventricular ejection fraction (LVEF). Despite these advances, mortality and morbidity in low-LVEF heart failure remains very high, and further improvements in the treatment of these patients are needed.
A large proportion of patients with CHF have preserved LV systolic function.(6) However, there is very limited information on which to base therapeutic decisions in this group.
Candesartan is an angiotensin-II type I (AT(1)) receptor blocker that binds tightly to and dissociates slowly from the receptor.(7) The renin–angiotensin–aldosterone system (RAAS), which is activated in patients with heart failure and contributes to disease progression, is thus inhibited by candesartan. By blocking the effects of angiotensin-II at the receptor level, blockade of the effects of the RAAS is possible without the adverse effects, such as cough, which are observed when inhibiting the ACE. Furthermore, the combination of an ACE inhibitor and an AT(1)-receptor blocker might be advantageous in situations where a more complete blockade of the RAAS is indicated.
Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) was a research programme consisting of double-blind, placebo-controlled trials.(8–11) A total of 7,601 patients with NYHA class II–IV heart failure on standard baseline therapy were randomised to candesartan (titrated from 4mg or 8mg once daily to a target dose of 32mg once daily) or placebo and followed up for two to four years.
The CHARM–Alternative trial included patients with LVEF </=40% not receiving an ACE inhibitor due to prior intolerance. The CHARM–Added trial included patients with LVEF </=40% receiving an ACE inhibitor. Finally, the CHARM–Preserved trial included patients with LVEF >40%. Most patients were on background diuretic therapy, and approximately 55% were on a beta-blocker in all three trials.
The primary endpoint in each of the three trials was cardiovascular (CV) mortality or hospitalisation for heart failure. Other endpoints included other cardiovascular events, as well as effects on NYHA functional class and incidence of diabetes mellitus. The initial dose of candesartan was 4mg for 80% of patients, the mean daily dose was 24mg, and 63% of patients were titrated to the target dose of 32mg once daily.
In the CHARM–Alternative trial,9 the use of candesartan resulted in a 23% (p<0.001) relative risk reduction in the primary endpoint of CV death or heart failure hospitalisation. There was a 32% relative risk reduction (p<0.001) in CHF hospitalisations as a first event, and a reduction in the total number of CHF hospitalisations (445 vs 608, p<0.001). Symptoms of heart failure as assessed by NYHA functional class significantly improved in patients treated with candesartan (p=0.008).
In the CHARM-Added trial,(10) candesartan produced a 15% relative risk reduction (p=0.011) of CV death or heart failure hospitalisation. This favourable effect was evident both in patients receiving ACE inhibitors at doses recommended for heart failure and in patients on lower doses. A beneficial effect was also evident with concomitant use of an ACE inhibitor, a beta-blocker and candesartan. The use of candesartan resulted in a 17% relative risk reduction (p=0.014) for CHF hospitalisations as a first event, and a reduction in the total number of CHF hospitalisations (607 vs 836, p=0.002). Symptoms of heart failure as assessed by NYHA functional class improved with candesartan (p=0.020).
In the CHARM-Preserved trial,(11) the use of candesartan resulted in an 11% (p=0.118) relative risk reduction of CV death or heart failure hospitalisation. Although the drug had no apparent effect on cardiovascular mortality, there was a trend in reducing the relative risk for CHF hospitalisations as a first event (p=0.072), and a reduction in total heart failure hospitalisations (402 vs 566, p=0.013). The incidence of reported new-onset diabetes mellitus decreased by 40% with candesartan treatment (p=0.005).
In an analysis of the pooled data from the three component trials,(8) treatment with candesartan resulted in a 9% relative risk reduction (p=0.055) in all-cause death, attributable to a 12% relative risk reduction (p=0.011) in CV death. The incidence of a new diagnosis of diabetes was reduced by 22% with candesartan (p=0.020). In a prespecified analysis of the pooled results of the 4,576 patients with a LVEF </=40%, the use of candesartan resulted in a 12% relative risk reduction in all-cause mortality (p=0.018).(12) This improvement in survival was attributable to a 16% relative risk reduction in CV deaths (p=0.005). Candesartan also demonstrated a 24% relative risk reduction in hospitalisations for heart failure as a first event (p<0.001), and a reduction in the total number of CHF hospitalisations (1,052 vs 1,444, p<0.001). Symptoms of heart failure as assessed by NYHA functional class improved (p<0.001).
Candesartan was generally well tolerated, but in the CHARM studies discontinuations due to renal dysfunction, hyperkalaemia or hypotension were more common with candesartan than with placebo.(8) However, it is interesting to note that in patients with previous intolerance to ACE inhibitors, candesartan was tolerated almost to the same extent as placebo.(9) However, monitoring of blood pressure, serum creatinine and potassium is indicated in patients with heart failure during dose escalation of candesartan, and at regular intervals thereafter.
The CHARM programme has shown that candesartan has beneficial effects on CV mortality and morbidity in patients with heart failure and an impaired LVEF. There is a clear benefit of candesartan in patients unable to tolerate an ACE inhibitor, and this benefit is of a similar magnitude to that obtained with an ACE inhibitor.(9) The effect is present also when candesartan is used in combination with an ACE inhibitor and/or a beta-blocker. This added efficacy is particularly noteworthy, since a subgroup analysis from Val-HeFT (Valsartan Heart Failure Trial) suggested the lack of benefit of the AT(1)-receptor blocker valsartan in patients already receiving beta-blockers and ACE inhibitors.(13)
For patients with heart failure and an impaired LV function, the use of candesartan is implicated both in patients intolerant of ACE inhibitors and as an add-on to treatment with ACE inhibitors and beta-blockers. For these patients, candesartan reduces both mortality and morbidity.
For patients with heart failure and a preserved LVEF, candesartan may reduce the risk of hospitalisation for heart failure and the risk of diabetes. For this group of patients, there is currently no other evidence-based therapy.
- Stewart S, et al. Heart failure and the aging population: An increasing burden in the 21st century? Heart 2003;89:49-53.
- Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995;273:1450-6.
- CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9-13.
- MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-7.
- Packer M, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651-8.
- Redfield MM. Heart failure – an epidemic of uncertain proportions. N Engl J Med 2002;347:1442-4.
- Nishikawa K, et al. Candesartan cilexetil: a review of its preclinical pharmacology. J Hum Hypertens 1997;11 Suppl:S9-17.
- Pfeffer M, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall Programme. Lancet 2003;362:759-66.
- Granger C, et al. Effects of candesartan in patients with chronic heart failure and reduced left ventricular systolic function and intolerant to ACE inhibitors: the CHARM-Alternative trial. Lancet 2003;362:767-71.
- McMurray J, et al. Effects of candesartan in patients with chronic heart failure and reduced left ventricular systolic function treated with an ACE inhibitor: the CHARM-Added trial. Lancet 2003;362:772-6.
- Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and left ventricular ejection fraction above 40%: the CHARM-Preserved trial. Lancet 2003;362:777-81.
- Young J, et al. Mortality and morbidity reduction with candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low left ventricular ejection fraction trials. Circulation 2004;110:2618-26.
- Cohn J, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in CHF. N Engl J Med 2001;345:1667-75.