Lancet September 06, 2003

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

John J V McMurray, Jan Ostergren, Karl Swedberg, Christopher B Granger, Peter Held, Eric L Michelson, Bertil Olofsson, Salim Yusuf, Marc A Pfeffer

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Bottom Line

In patients with chronic heart failure and a reduced left ventricular ejection fraction who were already receiving an ACE inhibitor, the addition of the angiotensin receptor blocker candesartan significantly reduced cardiovascular mortality and heart failure hospitalizations.

Key Findings

1. The primary composite outcome (cardiovascular death or hospital admission for heart failure) occurred in 38% (483 of 1,276) of patients in the candesartan group compared to 42% (538 of 1,272) in the placebo group (unadjusted HR 0.85, 95% CI 0.75-0.96, p=0.011).

2. Candesartan significantly reduced both individual components of the primary outcome: cardiovascular death and the total number of hospital admissions for chronic heart failure.

3. The clinical benefits of candesartan were consistent across all predefined subgroups, notably including patients who were concurrently receiving baseline beta-blocker therapy.

4. Study drug discontinuation due to adverse effects, specifically hyperkalemia and elevated serum creatinine, was more frequent in the candesartan group compared to placebo.

Study Design

Design

Randomized Controlled Trial

Double-Blind

Sample

2,548

Patients

Duration

41 months

Median

Setting

Multicenter, 26 countries

Population Adults with symptomatic chronic heart failure (NYHA class II-IV) for at least 4 weeks, left ventricular ejection fraction ≤ 40%, currently treated with an ACE inhibitor.

Intervention Candesartan (initiated at 4 or 8 mg and titrated to a target dose of 32 mg once daily) added to baseline ACE inhibitor therapy.

Comparator Matching placebo added to baseline ACE inhibitor therapy.

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

Study Limitations

• Combining an ARB with an ACE inhibitor increased the incidence of adverse events, particularly renal dysfunction and hyperkalemia.

• The background medical therapy does not reflect contemporary heart failure management, lacking modern guideline-directed medical therapies such as SGLT2 inhibitors and ARNIs, with lower utilization of mineralocorticoid receptor antagonists than is standard today.

• While efficacious, the strategy of dual RAAS blockade (ACE inhibitor plus ARB) has since fallen out of favor in clinical guidelines due to the combined adverse effect profile seen here and in subsequent trials across broader populations.

Clinical Significance

The CHARM-Added trial was a landmark study proving that intensifying renin-angiotensin-aldosterone system (RAAS) blockade by adding an ARB to an ACE inhibitor provides incremental morbidity and mortality benefits in HFrEF. However, because of safety concerns regarding hyperkalemia and renal dysfunction, routine dual ACEi/ARB therapy was ultimately superseded in clinical practice by the introduction of neprilysin inhibitors (ARNIs) and the broader use of mineralocorticoid receptor antagonists.

Historical Context

Prior to the CHARM program, ACE inhibitors were the firmly established cornerstone of HFrEF therapy. The earlier Val-HeFT trial had investigated adding the ARB valsartan to standard therapy but raised alarms about a potentially harmful interaction when ACE inhibitors, ARBs, and beta-blockers were used together. CHARM-Added resolved this controversy by demonstrating clear cardiovascular benefits of adding candesartan to an ACE inhibitor regardless of concurrent beta-blocker use, establishing the physiological value of maximal RAAS suppression.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Physiologically, why might a patient with heart failure benefit from the addition of an angiotensin receptor blocker (ARB) when they are already taking an angiotensin-converting-enzyme (ACE) inhibitor?

Key Response

ACE inhibitors do not completely block angiotensin II production due to alternative enzymatic pathways like chymase. Adding an ARB blocks the AT1 receptor directly, theoretically providing more complete suppression of the detrimental effects of angiotensin II in heart failure, a concept known as overcoming angiotensin escape.

Resident

When adding candesartan to a patient already on an ACE inhibitor for HFrEF, what specific adverse events must be closely monitored, and how does this dual therapy compare to the safety profile of monotherapy?

Key Response

Dual RAAS blockade significantly increases the risk of hyperkalemia, symptomatic hypotension, and worsening renal function. Residents must know to closely monitor basic metabolic panels, specifically potassium and creatinine, and blood pressure shortly after initiation and titration, as the side effect profile is significantly worse than monotherapy.

Fellow

Given the findings of CHARM-Added demonstrating improved outcomes with dual ACE inhibitor and ARB therapy, why is this combination rarely prescribed in contemporary HFrEF management, and what therapies have replaced it?

Key Response

While CHARM-Added showed a reduction in cardiovascular death and HF hospitalizations, the absolute benefit was modest, and subsequent data highlighted significant overlapping risks of hyperkalemia and renal failure. Contemporary practice relies on ARNIs (sacubitril/valsartan) and the addition of MRAs (spironolactone) rather than ACEi plus ARB, as these newer agents provide superior mortality benefits without the same degree of overlapping toxicity.

Attending

In the modern era of guideline-directed medical therapy, including ARNIs, SGLT2 inhibitors, and MRAs, is there still any clinical scenario where you would consider the CHARM-Added strategy of combining an ACE inhibitor with an ARB for a patient with HFrEF?

Key Response

The combination is virtually obsolete and currently considered harmful. Guidelines explicitly recommend against combining ACE inhibitors, ARBs, and/or ARNIs due to unacceptable risks of renal dysfunction and hyperkalemia. Attending physicians must emphasize that historical trials like CHARM-Added reflect the evolution of knowledge, but evidence integration from newer trials supersedes this historical approach.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

How does the heterogeneity in baseline ACE inhibitor dosing among the CHARM-Added study population impact the interpretation of the trial finding that candesartan provides an additive efficacy effect?

Key Response

If patients in the trial were on sub-target doses of ACE inhibitors, the benefit of adding candesartan might simply reflect the achievement of adequate overall RAAS blockade rather than a true synergistic or additive effect of dual-mechanism blockade. Analyzing subgroup data based on baseline ACE inhibitor dose intensity is critical to validating the mechanistic claims of the study.

Journal Editor

As a peer reviewer analyzing the CHARM-Added manuscript, how would you critically evaluate the reporting of the trial secondary safety endpoints versus its primary efficacy endpoints to determine the true net clinical benefit?

Key Response

A rigorous reviewer would flag the higher rates of study drug discontinuation due to adverse events, such as hyperkalemia and elevated creatinine, in the candesartan arm. Evaluating whether the statistical significance of the primary composite efficacy endpoint outweighs the real-world clinical burden of these adverse events is essential for determining editorial significance and clinical applicability.

Guideline Committee

How did the findings of the CHARM-Added trial initially influence heart failure guidelines, and why do current ACC/AHA guidelines now explicitly assign a Class 3 recommendation against the routine use of combined ACE inhibitor and ARB therapy?

Key Response

Initially, guidelines gave a weak recommendation for adding an ARB to an ACEi in persistently symptomatic HFrEF patients based on CHARM-Added. However, subsequent trials like ONTARGET in higher-risk populations demonstrated harm, and the advent of ARNIs and MRAs shifted the risk-benefit calculus. Current ACC/AHA guidelines give a Class 3 (Harm) recommendation against combining these agents due to increased risks of renal dysfunction and hyperkalemia without sufficient offsetting benefit compared to newer optimal combinations.

Clinical Landscape

Noteworthy Related Trials

1999

RALES Trial

n = 1,663 · NEJM

Tested

Spironolactone 25 mg daily

Population

Patients with severe heart failure (NYHA class III-IV) and reduced LVEF

Comparator

Placebo

Endpoint

All-cause mortality

Key result: Adding spironolactone to standard therapy (including an ACE inhibitor) significantly reduced the risk of morbidity and all-cause mortality by 30 percent.

2001

Val-HeFT Trial

n = 5,010 · NEJM

Tested

Valsartan 160 mg twice daily

Population

Patients with heart failure (NYHA class II-IV)

Comparator

Placebo

Endpoint

Composite of mortality and heart failure morbidity

Key result: Valsartan significantly reduced the combined endpoint of mortality and morbidity, primarily driven by fewer heart failure hospitalizations.

2014

PARADIGM-HF Trial

n = 8,399 · NEJM

Tested

Sacubitril/valsartan 200 mg twice daily

Population

Patients with HFrEF (LVEF 40% or less)

Comparator

Enalapril 10 mg twice daily

Endpoint

Composite of cardiovascular death or heart failure hospitalization

Key result: Sacubitril/valsartan was superior to enalapril in reducing both the risk of cardiovascular death and the risk of hospitalization for heart failure.

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