CHARM-Alternative

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Granger CB, et al. "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". The Lancet. 2003. 362(9386):772-776.
PubMedFull text

Clinical Question

In patients with heart failure with reduced ejection fraction (HFrEF) with LVEF ≤ 40%, NYHA class II-IV symptoms and intolerance to ACE inhibitors, do angiotensin receptor blockers (ARBs) reduce CHF-related mortality or hospitalization with an acceptable side effect profile when compared to placebo?

Bottom Line

Use of the ARB candesartan in symptomatic HFrEF patients intolerant to ACE inhibitors was well tolerated and resulted in a 20% reduction in cardiovascular mortality as well as a 40% reduction in hospitalization for heart failure.

Major Points

Multiple landmark studies in patients with heart failure with reduced ejection fraction (HFrEF) have demonstrated improved survival when ACE inhibitors are used to suppress the renin-angiotensin system. Examples of these studies include CONSENSUS (1987) and SOLVD (1991). However, ACE inhibitor intolerance is common, with the most frequent side effect being a persistent dry cough that affects up to 10% of patients.[1] Several side effects associated with ACE inhibitors including ACE inhibitor-related cough are mediated by increases in bradykinin levels. By inhibiting the angiotensin-II receptor directly, angiotensin receptor blockers (ARBs) can suppress the renin-angiotensin system without increasing bradykinin levels. As a result, for HFrEF patients who have failed to tolerate an ACE inhibitor, ARB use may provide similar protective effects with a better side effect profile.

The 2003 Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) - Alternative study demonstrated that use of the ARB candesartan in patients with HFrEF and LVEF ≤ 40% who had previously failed an ACE inhibitor was associated with a 20% reduction cardiovascular mortality and a 40% reduction in heart failure hospitalization over 3 years of follow up. These benefits rivaled those of the ACE inhibitor enalapril in the earlier SOLVD trial. Candesartan was tolerated well despite previous ACE inhibitor intolerance, with similar discontinuation rates to placebo. Notably, only about half of the population were on beta blocker therapy and only a quarter were receiving spironolactone. Nevertheless, due to the convincing results of CHARM-Alternative, ARBs are considered standard of care agents for neurohormonal blockade in patients with HFrEF and intolerance to ACE inhibitors. They are also considered reasonable first-line agents among patients without ACE inhibitor intolerance in cases of physician or patient preference. Furthermore, the later CHARM-Added study suggested that combination therapy with ACE inhibitors and ARBs may be beneficial. However, this approach is seldom utilized due to tolerability issues and questions regarding whether the results of CHARM-Added still apply in the era of aldosterone antagonists.

Guidelines

AHA/ACCF Heart Failure Guidelines (2013, adapted)[2]

  • ACE inhibitors in patients with HFrEF with present or former symptoms unless contraindicated (class I, level A)
  • ARBs for above if ACE inhibitor intolerant unless contraindicated (class I, level A)
  • ARBs are reasonable as first-line agents for HFrEF (class IIa, level A)
  • ARBs can be added to ACE inhibitor and beta blocker for those in which an aldosterone antagonist is not indicated or is poorly tolerated (class IIb, level A)
  • Routine combined ACE inhibitor and ARB use is potentially harmful in HFrEF (class III, level C)

Design

  • Multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=2028
    • Candesartan (n=1013)
    • Placebo (n=1015)
  • Setting: 618 centers in 26 countries
  • Enrollment: March 1999 to March 2001
  • Median follow-up: 33.7 months
  • Analysis: Intention-to-treat
  • Primary outcome: Cardiovascular death or hospitalization for CHF
  • Secondary outcomes: Cardiovascular death, hospitalization for CHF, nonfatal MI, nonfatal stroke, coronary revascularization, all-cause death, all-cause hospitalization, all-cause death or hospitalization for CHF, development of new diabetes

Population

Inclusion Criteria

  • Age >= 18
  • LVEF <= 40%
  • NYHA class II-IV symptoms
  • Previous documented intolerance to ACE inhibitors

Exclusion Criteria

  • NYHA class I

Baseline Characteristics

From the placebo group

  • Demographics: Mean age 66.8 years, 68% male, 89% white
  • Heart failure characteristics:
    • NYHA class: II (47.2%), III (49.2%), IV (3.6%)
    • Mean LVEF: 30.0%
    • Etiology: 67% ischemic, 20.3% idiopathic, 7.2% hypertensive
  • Cardiac history: CHF hospitalization 66.3%, MI 60.9%, angina 22.5%, stroke 8.9%, PCI 16.7%, CABG 24.0%, AF 25.7%
  • Other PMH: HTN 50.7%, DM 26.6%, smoker 12.5%, cancer 7.1%
  • Medical treatment: diuretic 85.6%, beta blocker 54.5%, spironolactone 23.0%, digoxin 46.2%, oral anticoagulant 29.5%, aspirin 58.6%, lipid-lower drug 40.3%
  • ACE inhibitor intolerance: cough 74.0%, hypotension 11.7%, renal dysfunction 9.9%, angioedema 4.3%, other 10.7%

Interventions

  • Double-blind randomization to candesartan or matching placebo
  • Candesartan starting dose was 4mg or 8mg daily and was doubled as tolerated every 2 weeks to a target dose of 32mg daily
  • Patients seen at 2, 4, and 6 weeks, at 6 months, and every 4 months thereafter until the trial ended
  • In a subset of patients, routine laboratory assessments done at baseline, 6 weeks and 14, 26, and 38 months for safety monitoring

Outcomes

Comparisons are candesartan vs. placebo.

Primary Outcomes

All hazard ratios and p-values reflect adjusted analyses

Cardiovascular death or hospitalization for CHF
33% vs. 40% (HR=0.70 [0.60-0.81]; p<0.0001)

Secondary Outcomes

Cardiovascular death
21.6% vs. 24.8% (HR=0.80 [0.66-0.96]; p=0.02)
Hospitalization for CHF
20.4% vs. 28.2% (HR=0.61 [0.51-0.73]; p<0.0001)
Cardiovascular death, hospitalization for CHF, MI, stroke, or coronary revacularization
39.1% vs. 44.9% (HR=0.76 [0.66-0.87]; p<0.0001)

Subgroup Analysis

Effects of candesartan therapy on cardiovascular death or hospitalization for CHF were similar across all prespecified subgroups.

Adverse Events

All listed adverse events required study drug discontinuation

Hypotension
3.7% vs. 0.9% (p<0.0001)
Increase in creatinine
6.1% vs. 2.7% (p<0.0001)
Hyperkalemia
1.9% vs. 0.3% (p=0.0005)
Cough
0.2% vs. 0.4% (p=0.69)
Angioedema
0.1% vs. 0% (p=0.50)
Any adverse event or laboratory abnormality
21.5% vs. 19.3% (p=0.23)

Criticisms

  • Relatively low proportion of patients receiving other standard of care agents such as beta blockers (50%) and aldosterone antagonists (25%).
  • Does not address the role of ARBs versus ACE inhibitors in patients without a history of ACE inhibitor intolerance.

Funding

  • Study sponsor managed the data and its representatives were involved in the data analysis and interpretation.

Further Reading

  1. Angiotensin-coverting enzyme inhibitor associated cough: deceptive information from the Physician's Desk Reference Am J Med 2010;123(11):1016-30
  2. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.