Effects of Candesartan on Mortality and Morbidity in Patients With Chronic Heart Failure: The CHARM‐Overall Programme

Abstract

Background. Patients with chronic heart failure (chronic HF) are at high risk of cardiovascular death and recurrent hospital admissions. The authors aimed to find out whether the use of an angiotensin receptor blocker could reduce mortality and morbidity. Methods. In parallel, randomized, double-blind, controlled clinical trials, candesartan was compared with placebo in three distinct populations. The authors studied patients with left-ventricular ejection fraction (LVEF) ≤40% who were not receiving angiotensin-converting enzyme (ACE) inhibitors because of previous intolerance or who were currently receiving ACE inhibitors, and patients with LVEF >40%. Overall, 7601 patients (7599 with data) were randomly assigned candesartan (n=3803, titrated to 32 mg q.d.) or matching placebo (n=3796) and followed-up for at least 2 years. The primary outcome of the overall program was all-cause mortality, and the primary outcome for all the component trials was cardiovascular death or hospital admission for chronic HF. Analysis was by intention to treat. Findings. Median follow-up was 37.7 months. Eight hundred eighty-six (23%) patients in the candesartan group and 945 (25%) in the placebo group died (unadjusted hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.83–1.00; p=0.055; covariate adjusted HR, 0.90; 95% CI, 0.82–0.99; p=0.032), with fewer cardiovascular deaths (691 [18%] vs. 769 [20%], unadjusted HR, 0.88; 95% CI, 0.79– 0.97; p=0.012; covariate adjusted HR, 0.87; 95% CI, 0.78–0.96; p=0.006) and hospital admissions for chronic HF (757 [20%] vs. 918 [24%]; p<0.0001) in the candesartan group. There was no significant heterogeneity for candesartan results across the component trials. More patients discontinued candesartan than placebo because of concerns about renal function, hypotension, and hyperkalemia. Interpretation. Candesartan was generally well tolerated and significantly reduced cardiovascular deaths and hospital admissions for HF. Ejection fraction or treatment at baseline did not alter these effects.—Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362:759–766. Comment. The Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARMOverall) program is the largest trial program ever undertaken in chronic HF patients. The 7601-patient trial evaluated candesartan in addition to optimal treatment for HF and was made up of three smaller studies in separate populations: patients with left ventricular (LV) dysfunction intolerant to ACE inhibitors (the CHARM-Alternative trial),1 patients with LV dysfunction already taking ACE inhibitors (the CHARM-Added trial),2 and patients with preserved LV function (the CHARM-Preserved trial).3 These three different populations of patients with HF were studied individually and concurrently as a group. For this study design to be successful, each trial had to be similar in terms of inclusion and exclusion criteria, drug therapy utilized, and dose of drug used. This was necessary for data to be combined into the CHARM-Overall program to determine total mortality. In addition, each individual trial had adequate statistical power for analysis in each separate chronic HF population. For the CHARM-Alternative trial, investigators enrolled 2028 patients with symptomatic HF and LVEF ≤40% who were not receiving ACE inhibitors because of previous intolerance. Patients were randomly assigned candesartan (target dose 32 mg q.d.) or matching placebo. The primary outcome of the study was the composite of cardiovascular death or hospital admission for HF. Analysis was by intention to treat. The most common manifestation of ACE-inhibitor intolerance was cough (72%), followed by symptomatic hypotension (13%) and renal dysfunction (12%). During a median follow-up of 33.7 months, 334 (33%) of 1013 patients in the candesartan group and 406 (40%) of 1015 in the placebo group had cardiovascular death or hospital admission for chronic HF (unadjusted HR, 0.77; 95% CI, 0.67–0.89; p=0.0004; covariate adjusted HR, 0.70; 95% CI,0.60–0.81; p<0.0001). Each component of the primary outcome was reduced, as was the total number of hospital admissions for chronic HF. No statistical difference in overall drug discontinuations (21% candesartan vs. 19% placebo) was found, but there were significant increases in discontinuations due to hypotension (3.7% vs. 0.9%), increased creatinine levels (6.1% vs. 2.7%), and increased potassium levels (1.9% vs. 0.3%) in the candesartan group. Despite intolerance to ACE inhibitors, patients can tolerate candesartan and show a reduction in morbidity/mortality, but we still need to monitor hypotension, creatinine, and potassium. Candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic HF and intolerance to ACE inhibitors. Over the duration of the trial, 33% of candesartan compared with 40% of placebo patients had cardiovascular death or first admission to hospital for chronic HF. This absolute reduction of seven major events per 100 patients treated corresponds to the need to treat 14 patients with candesartan to prevent one patient from having cardiovascular death or hospital admission for HF. In addition, multiple chronic HF hospital admissions were reduced. Adequate attempts should be made to place patients with chronic HF and reduced LVEF on ACE inhibitors and β blockers; however, irrespective of the tolerance of an ACE inhibitor, the addition of candesartan improves outcome. In conclusion, candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic HF who were not receiving ACE inhibitors because of intolerance. For the CHARM-Added trial, the investigators enrolled 2548 patients with New York Heart Association functional class II-IV, chronic HF, LVEF ≤40%, and who were being treated with ACE inhibitors. They randomly assigned patients to candesartan (n=1276, target dose 32 mg q.d.) or placebo (n=1272). At baseline, 55% of patients were also treated with β blockers and 17% were treated with spironolactone. The primary outcome of the study was the composite of cardiovascular death or hospital admission for chronic HF. Analysis was done by intention to treat. The median follow-up was 41 months. Four hundred eighty-three (38%) patients in the candesartan group and 538 (42%) in the placebo group experienced the primary outcome (unadjusted HR, 0.85; 95% CI, 0.75–0.96; p=0.011; covariate adjusted p=0.010. Candesartan reduced each of the components of the primary outcome significantly, as well as the total number of hospital admissions for chronic HF. The benefits of candesartan were similar in all predefined subgroups, including patients receiving baseline β-blocker treatment. Overall, the addition of candesartan to ACE inhibitor and other treatment leads to a further clinically important reduction in relevant cardiovascular events in patients with chronic HF and reduced LVEF. The results of the CHARM-Added trial differ in some ways from those of the Valsartan Heart Failure Trial (Val-HeFT). Like the CHARM-Added trial, Val-HeFT studied the effect of an angiotensin receptor blocker in HF patients, 93% of whom also received treatment with an ACE inhibitor. While Val-HeFT did show a reduction in the combined end point of morbidity and mortality in valsartan patients compared with placebo, it did not show a significant decrease in total or cardiovascular mortality. Also, it demonstrated an increase in mortality in a subgroup of patients who were receiving a β blocker in addition to an ACE inhibitor and valsartan. It was postulated that extensive blockade of multiple neurohormonal systems in patients with chronic HF may be detrimental. In contrast, patients in the CHARM-Added trial who received the triple therapy combination of ACE inhibitor, β blocker, and angiotensin receptor blocker, the benefit was explained by the different angiotensin receptor blockers utilized or the dose of these agents employed. Another possible explanation is that subgroup analyses (like the one used in Val-HeFT) are often underpowered, and the results may have occurred due to chance. Candesartan had a similar rate of mortality compared with patients not treated with a β blocker. The CHARM-Preserved trial investigators randomly assigned 3023 patients to candesartan (n=1514, target dose 32 mg q.d.) or matching placebo (n=1509). Patients had New York Heart Association functional class II-IV, chronic HF, and LVEF >40%. The primary outcome was cardiovascular death or admission to a hospital for chronic HF. Analysis was done by intention to treat. Median follow-up was 36.6 months. Three hundred thirty-three (22%) patients in the candesartan and 366 (24%) in the placebo group experienced the primary outcome (unadjusted HR, 0.89; 95% CI, 0.77–1.03; p=0.118; covariate adjusted HR, 0.86; 95% CI, 0.74–1.0; p=0.051). Cardiovascular death did not differ between groups (170 vs. 170), but fewer patients in the candesartan group than in the placebo group were admitted to a hospital for chronic HF once (230 vs. 279; p=0.017) or multiple times. Composite outcomes that included nonfatal myocardial infarction and nonfatal stroke showed results similar to the primary composite (388 vs. 429; unadjusted HR, 0.88; 95% CI, 0.77–1.01; p=0.078; covariate adjusted HR, 0.86; 95% CI, 0.75–0.99; p=0.037). Candesartan has a moderate impact in preventing admissions for chronic HF among patients who have HF and LVEF >40%. The management of patients with preserved LVEF and HF is based on sparse data. This trial provides direct information on this large group of patients with HF. Among patients with preserved LVEF who have no contraindications, candesartan reduces the number of hospital admissions for chronic HF. It is not absolutely conclusive, but it is highly persuasive. We need more data on this group. This should be the beginning of many studies in this population, and the results of the Irbesartan in chronic HF Patients With Preserved LV Function (I-PRESERVE) trial are anxiously awaited. All patients were considered in the CHARM-Overall trial, with a primary end point of all-cause mortality. This was reduced by 9%, which was borderline significant in the unadjusted analysis (p=0.055); the p value dropped to 0.032 after adjustment for baseline variables. Cardiovascular death was also significantly reduced by 12%, and cardiovascular death and HF hospitalization, the primary end point of the component trials, was reduced by a highly statistically significant 16%, wagain mostly driven by a reduction in hospitalization. There was no effect of candesartan on myocardial infarction, stroke, or revascularization procedures, but a significant reduction in the development of new diabetes was seen with the angiotensin II blocker (7.6% placebo vs. 6.0% candesartan; HR, 0.78; p=0.02). In terms of side effects in the CHARMOverall program, as in the individual trials, candesartan was associated with significant increases in hypotension (3.5% vs. 1.7%), serum creatinine levels (6.2% vs. 3.0%), and hyperkalemia (2.2% vs. 0.6%). CHARM-Overall suggests that 23 patients need to be treated with candesartan for 3 years to prevent one cardiovascular death or chronic HF hospitalization. In an editorial in The Lancet, Dr. Harvey White of Green Lane Hospital, Auckland, New Zealand, calculates that over 3 years the treatment effect seen in CHARM equates to one death prevented per 63 patients treated, one first hospitalization with HF prevented per 23 patients treated, and one new case of diabetes prevented per 71 patients treated.