Review of the CHARM-Alternative trial

Candesartan in systolic heart failure in patients intolerant to ACEi

THE LANCET 2003;362:772-776

Background: Angiotensin converting enzyme inhibitors (ACEi) reduce mortality and morbidity in patients with systolic heart failure (see CONSENSUS and SOLVD trials). However, registry data showed that up to 20% of patients with systolic heart failure were not taking ACEi. One of the frequent causes for intolerance to ACEi is cough. Angiotensin converting enzyme inhibitors work by blocking the conversion of angiotensin I to angiotensin II, a key step in the renin–angiotensin–aldosterone system (RAAS). Angiotensin II receptor blockers were tolerated in patients with systolic heart failure who were intolerant to ACEi. However, data on long term effectives as an alternative to ACEi were lacking.

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

Patients: Eligible patients had left ventricular ejection fraction of 40% or less and NYHA class II, III or IV symptoms of at least 4 weeks duration. Patients had also to be intolerant to ACEi.

Exclusion criteria were not provided in the main manuscript.

Baseline characteristics: Patients were recruited from 618 centers in 26 countries. The trial randomized 2,028 patients – 1,013 randomized to receive candesartan and 1,015 to receive placebo.

The average age of patients was 67 years and 68% were men. The average left ventricular ejection fraction was 30%. Cardiomyopathy was ischemic in 68% of the patients. The NYHA class was II in 48% of the patients, III in 49% and IV in 4%.

Approximately 50% had hypertension, 27% had diabetes, 61% had prior myocardial infarction, 9% had stroke, 25% had atrial fibrillation and 14% were current smokers.

At the time of enrollment, 85% were taking a diuretic, 46% were taking digoxin, 55% were taking beta-blockers and 24% were taking spironolactone.

The most common reasons for ACEi intolerance were cough in 72% of the patients, hypotension in 13%, renal dysfunction in 12% and angioedema or anaphylaxis in 4%.

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 2,000 patients. The sample size calculation assumed 18% relative risk reduction in the primary outcome with candesartan assuming a 15% annual event rate in the placebo arm.

Results: The median follow up time was 34 months. The mean candesartan daily dose was 23mg at 6 months.

Candesartan reduced the primary endpoint of cardiovascular death or heart failure hospitalizations (33.0% vs 40.0%, adjusted HR: 0.70, 95% CI: 0.60 – 0.81; p< 0.001). Candesartan reduced the individual components of the primary outcome - (21.6% vs 24.8%; p= 0.02) for cardiovascular death and (20.4% vs 28.2%; p< 0.001) for heart failure hospitalizations. All-cause death was also lower with candesartan (26.2% vs 29.2%, adjusted HR: 0.83, 95% CI: 0.70–0.99; p= 0.033). The number of patients who had any hospitalization as well as the total number of hospitalizations were numerically but not statistically significantly lower with candesartan (60.2% with candesartan vs 63.3%; p= 0.16) and (1,718 vs 1,835; p= 0.06).

Candesartan was associated with more hypotension (3.7% vs 0.9%), more increase in creatinine (6.1% vs 2.7%) and more hyperkalemia (1.9% vs 0.3%). Angioedema occurred in three patients in the candesartan group and none in the placebo group. Cough occurred in two patients taking candesartan and four taking placebo.

Authors reported no significant subgroup interactions, however, a corresponding graph was not provided.

Conclusion: In patients with systolic heart failure who are intolerant to ACEi, candesartan reduced the primary composite outcome of cardiovascular death or heart failure hospitalizations with a number needed to treat of approximately of 14 patients over 34 months of follow up. Candesartan also reduced all-cause death with a number needed to treat of approximately 33 patients. Adverse events including hypotension, increase in creatinine and hyperkalemia were more common with candesartan.

The reduction in the primary endpoint with candesartan was significant and offers an alternative for patients who are unable to tolerate ACEi. Of note, 72% of the patients enrolled in the trial were intolerant to ACEi due to cough. This trial did not include a head-to-head comparison between ARBs and ACEi, and therefore does not address which agent should be preferred as first-line therapy. Only 24% of participants were receiving spironolactone. The combination of ARBs with spironolactone, may increase the risk of adverse events, particularly hyperkalemia and kidney injury.