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

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%; p40%. 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.