The Lancet SEPTEMBER 06, 2003

Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial

Marc A. Pfeffer, Karl Swedberg, Christopher B. Granger, et al. on behalf of the CHARM Investigators and Committees

Bottom Line

In patients with symptomatic heart failure and reduced left ventricular ejection fraction who were intolerant to ACE inhibitors, the angiotensin receptor blocker candesartan significantly reduced the composite risk of cardiovascular death or heart failure hospitalization compared to placebo.

Key Findings

1. The primary composite endpoint of cardiovascular death or hospitalization for chronic heart failure occurred in 33% (334/1013) of the candesartan group compared to 40% (406/1015) in the placebo group (unadjusted hazard ratio 0.77, 95% CI 0.67-0.89, P=0.0004).

2. Candesartan significantly reduced the rate of heart failure hospitalizations (HR 0.68, P<0.0001), though the reduction in cardiovascular mortality alone did not reach statistical significance (HR 0.85, P=0.072).

3. Study-drug discontinuation rates were similar between the candesartan (30%) and placebo (29%) groups, indicating that candesartan was generally well tolerated in patients previously identified as ACE inhibitor-intolerant.

4. The most frequent causes of prior ACE inhibitor intolerance among participants were cough (72%), symptomatic hypotension (13%), and renal dysfunction (12%).

Study Design

Design

RCT

Double-Blind

Sample

2,028

Patients

Duration

33.7 mo

Median

Setting

Multicenter, International

Population Patients with symptomatic heart failure (NYHA class II-IV) and left ventricular ejection fraction ≤40% who were intolerant to ACE inhibitors.

Intervention Candesartan (titrated to a target dose of 32 mg once daily)

Comparator Matching placebo

Outcome Composite of cardiovascular death or hospital admission for chronic heart failure

Study Limitations

• The trial was conducted in a population defined by intolerance to ACE inhibitors, which may limit the generalizability to patients who have never been exposed to ACE inhibitors or those who might tolerate them at lower doses.

• The trial design did not specifically compare candesartan against other classes of medications that might have been alternatives for this population.

• The median follow-up of 33.7 months, while robust, captures a specific window of disease progression and may not reflect long-term outcomes beyond this period.

Clinical Significance

The CHARM-Alternative trial established the clinical utility of angiotensin receptor blockers as a critical therapeutic strategy for patients with heart failure with reduced ejection fraction who cannot tolerate ACE inhibitors, providing a clear evidence-based alternative to improve cardiovascular outcomes.

Historical Context

At the time of this trial, ACE inhibitors were the standard of care for heart failure with reduced ejection fraction; however, a significant percentage of patients could not tolerate them. This study provided essential evidence to support the use of ARBs as a viable therapeutic substitute, influencing subsequent clinical practice guidelines for heart failure management.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the primary pharmacological mechanism that causes the dry cough often leading to ACE inhibitor intolerance, and why does an ARB like candesartan avoid this side effect?

Key Response

ACE inhibitors prevent the breakdown of bradykinin and substance P in the lungs, leading to their accumulation and the stimulation of cough receptors. ARBs (Angiotensin II Receptor Blockers) specifically block the AT1 receptor and do not inhibit the Angiotensin Converting Enzyme, thus leaving the kinin degradation pathway unaffected.

Resident

A patient with HFrEF (LVEF 30%) developed symptomatic angioedema while taking Enalapril. Based on the findings and patient population of CHARM-Alternative, how should you approach the initiation of candesartan?

Key Response

While CHARM-Alternative included patients intolerant to ACE inhibitors, it specifically noted that only a small fraction (around 3.6%) had prior angioedema. Clinical guidelines and the trial context suggest that while ARBs are a viable alternative, there is a small risk of cross-reactivity (estimated <10%); therefore, initiation should be done with extreme caution or, in some cases of life-threatening reactions, avoided in favor of hydralazine/isosorbide dinitrate.

Fellow

In CHARM-Alternative, the reduction in the composite endpoint was significant, but the reduction in cardiovascular death alone did not reach nominal significance (p=0.072). How does this influence the interpretation of ARBs as a 'life-prolonging' therapy compared to the foundational ACE inhibitor trials like SOLVD-Treatment?

Key Response

Unlike the SOLVD-Treatment trial, which showed a clear mortality benefit for Enalapril, CHARM-Alternative’s primary success was driven largely by a 40% reduction in heart failure hospitalizations. However, when the entire CHARM program (Overall) was analyzed, the mortality benefit was clearer, leading to the clinical acceptance of ARBs as having comparable (though perhaps less robustly evidenced in isolation) survival benefits to ACE inhibitors in HFrEF.

Attending

The CHARM-Alternative trial was conducted before the widespread use of mineralocorticoid receptor antagonists (MRAs) and ARNI therapy. How does the 'intolerance' profile seen in 2003 (largely cough) compare to the modern challenge of managing 'intolerance' due to hyperkalemia and renal dysfunction in the era of quadruple therapy?

Key Response

In CHARM-Alternative, 72% of intolerances were due to cough. Today, 'intolerance' is more frequently defined by hyperkalemia or worsening renal function (WRF) because patients are on multiple RAAS inhibitors and SGLT2i. This trial reminds us that ARBs still carry similar risks for WRF and hyperkalemia as ACE inhibitors, meaning switching an ACE-intolerant patient to an ARB is effective for cough but often fails to solve 'intolerance' based on metabolic or renal parameters.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critically analyze the use of a 'non-standardized investigator-reported' definition of ACE intolerance in the trial's inclusion criteria. How might this selection bias impact the internal validity and the magnitude of the observed treatment effect?

Key Response

The lack of a standardized run-in phase to confirm ACE intolerance means the study population was heterogeneous. If investigators prematurely labeled patients as 'intolerant,' the cohort might include those who would have tolerated RAAS inhibition anyway, potentially diluting the perceived safety benefit. Conversely, it reflects 'real-world' clinical judgment, enhancing external validity but complicating the pharmacological purity of the 'intolerance' phenotype.

Journal Editor

Given that the CHARM-Alternative was one of three parallel trials (Alternative, Added, Preserved), what are the statistical implications of the 'multiple looks' at the data across the CHARM program, and did the authors adequately adjust the alpha for the Alternative component?

Key Response

A tough reviewer would flag the potential for type I error inflation across the three trials. However, the CHARM investigators pre-specified these as distinct populations (HFrEF-intolerant, HFrEF-added, and HFpEF), treating them as independent trials under one program umbrella. The editor would look for whether the primary endpoint was robust enough to survive the scrutiny of the hierarchical testing used for the overall CHARM program.

Guideline Committee

CHARM-Alternative is a cornerstone for the Class I recommendation of ARBs in HFrEF patients who cannot tolerate ACE inhibitors. How do these results compare to the 2022 AHA/ACC/HFSA guidelines regarding the use of ARNI as the preferred first-line agent over the ARB-only strategy established here?

Key Response

Current guidelines (AHA/ACC/HFSA 2022) now prefer ARNI (Sacubitril/Valsartan) as the first-line RAAS inhibitor (Class 1, LOE A). CHARM-Alternative remains the primary evidence base for using a pure ARB (like Candesartan) if an ARNI is not feasible (e.g., cost or history of angioedema), maintaining its status as a critical alternative for the 'ACE-intolerant' patient who cannot transition to ARNI.

Clinical Landscape

Noteworthy Related Trials

1987

CONSENSUS Trial

n = 253 · NEJM

Tested

Enalapril

Population

Patients with severe congestive heart failure

Comparator

Placebo

Endpoint

All-cause mortality

Key result: Enalapril significantly reduced mortality in patients with severe heart failure, establishing ACE inhibitors as a cornerstone therapy.

2001

Val-HeFT Trial

n = 5,010 · NEJM

Tested

Valsartan

Population

Patients with heart failure (NYHA class II–IV)

Comparator

Placebo

Endpoint

All-cause mortality and combined mortality-morbidity

Key result: Valsartan reduced the combined endpoint of mortality and morbidity, particularly in patients not receiving an ACE inhibitor.

2003

CHARM-Added Trial

n = 2,548 · Lancet

Tested

Candesartan

Population

Heart failure patients already receiving ACE inhibitors

Comparator

Placebo

Endpoint

Cardiovascular death or hospital admission for heart failure

Key result: Adding candesartan to an ACE inhibitor significantly reduced cardiovascular death and hospitalizations.

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