THE LANCET 2003;362:767-771

Background: Angiotensin II which plays a role in ventricular remodeling and progression of heart failure can be produced by pathways independent of angiotensin convening enzyme. Preliminary studies showed that the combination of angiotensin II blockers with angiotensin-converting enzyme inhibitors (ACEi) improves hemodynamics and reduces ventricular remodeling.

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The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Added trial sough to assess if adding the angiotensin-receptor blocker (ARB), candesartan, to ACEi could improve outcomes in patients with systolic heart failure.

Patients: Eligible patients had left ventricular ejection fraction of 40% or less within the previous 6 months, and NYHA class II, III or IV symptoms. Patients with NYHA class II symptoms had to have cardiac-related hospitalization within 6 months. Patients also had to have treatment with ACEi at a constant dose for at least 30 days.

Exclusion criteria were not provided in the main manuscript.

Baseline characteristics: Patients were recruited from 618 centers in 26 countries. The trial randomized 2,548 patients – 1,276 randomized to receive candesartan and 1,272 to receive placebo.

The average age of patients was 64 years and 79% were men. The average left ventricular ejection fraction was 28%. Cardiomyopathy was ischemic in 62% of the patients. The NYHA class was II in 24% of the patients, III in 73% and IV in 3%.

Approximately 48% had hypertension, 30% had diabetes, 56% had prior myocardial infarction, 9% had stroke, 27% had atrial fibrillation and 17% were current smokers.

At the time of enrollment, 90% were taking a diuretic, 58% were taking digoxin, 55% were taking beta-blockers, 17% were taking spironolactone and all but two patients were taking ACEi.

Procedures: The trial was double-blinded. Patients were assigned in a 1:1 ratio to receive candesartan starting at 4 or 8mg once daily or placebo. The treatment was doubled every two weeks to a target dose of 32mg once daily.

After randomization, follow up occurred at 2, 4, and 6 weeks, 6 months and every 4 months thereafter.

Endpoints: The primary outcome was a composite of cardiovascular death or heart failure hospitalizations. All deaths were classified as cardiovascular unless there was a clear non-cardiac cause.

Analysis was performed based on the intention-to-treat principle. The estimated sample size to have 80% power at 5% alpha was 2,300 patients. The sample size calculation assumed 16% relative risk reduction in the primary outcome with candesartan assuming an 18% annual event rate in the placebo arm.

Results: The median follow up time was 41 months. The mean candesartan daily dose was 24mg at 6 months.

Candesartan reduced the primary endpoint of cardiovascular death or heart failure hospitalizations (37.9% vs 42.3%, adjusted HR: 0.85, 95% CI: 0.75 – 0.96; p= 0.01). Candesartan reduced the individual components of the primary outcome - (23.7% vs 27.3%; p= 0.021) for cardiovascular death and (24.2% vs 28.0%; p= 0.018) for heart failure hospitalizations. There was no significant reduction in all-cause death (29.5% with candesartan vs 32.4%; p= 0.105). The number of patients who had any hospitalization was similar in both groups (66.8% with candesartan vs 67.5%; p= 0.7), however, the total number of hospitalizations was lower with candesartan (2,462 vs 2,798; p= 0.023).

Serum creatinine at least doubled in 7% of the patients in the candesartan group vs 6% in the placebo group. In the subset of patients taking spironolactone, serum creatinine at least double in 11% of the patients taking candesartan compared to 4% of the patients taking placebo.

Hyperkalemia, defined as serum potassium of 6 mmol/L or higher, occurred in 3% of the patients in the candesartan group vs 1% in the placebo group. In the subset of patients taking spironolactone, hyperkalemia occurred in 4% of the patients taking candesartan compared to 1% of the patients taking placebo.

There were two cases of angioedema in the candesartan group and three in the placebo group. All patients were taking an ACEi.

There were no significant subgroup interactions, including in patients taking both beta-blockers and ACEi at baseline.

Conclusion: In patients with systolic heart failure, adding candesartan to an ACEi reduced the primary composite outcome of cardiovascular death or heart failure hospitalizations with a number needed to treat of approximately of 23 patients over 41 months of follow up. The total number of all-cause hospitalizations was reduced by 336 with candesartan. All-cause death was not significantly reduced with candesartan.

While the results of the trial appear impressive, the high number of adverse outcomes with candesartan in patients taking spironolactone is concerning. Spironolactone led to significant reduction in all-cause mortality in patients with systolic heart failure, as seen in the RALES trial, and should be prioritized over adding candesartan. Notably, fewer than 20% of patients in the trial were on spironolactone at baseline; if more had been, the incremental benefit of candesartan would likely have been reduced due to an increased risk of adverse effects from triple neurohormonal blockade (ACEi, ARBs, and mineralocorticoid receptor antagonists). Furthermore, spironolactone acts by blocking the aldosterone receptor, which is downstream in the renin–angiotensin–aldosterone system. Since candesartan blocks angiotensin II upstream in the same pathway, simultaneous inhibition at multiple points may lead to diminishing benefit.

Finally, the differences observed in the subgroup of patients on beta-blockers between this trial and Val-HeFT remain unclear and may simply reflect the play of chance. As we previously discussed, patients receiving both an ACEi and beta-blockers had worse outcomes with valsartan in the Val-HeFT trial.

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