CHARM-Preserved
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Clinical Question
In patients with HFpEF, does candesartan reduce the rate of death or HF hospitalizations when compared to placebo?
Bottom Line
In patients with HFpEF and NYHA class II-IV symptoms, the addition of candesartan modestly reduced the rate of HF-related hospitalizations, but had no effect on CV mortality.
Major Points
Heart failure with preserved ejection fraction (HFpEF) remains difficult to treat, with limited data to suggest optimal treatment strategies. By comparison, multiple landmark studies in patients with heart failure with reduced ejection fraction (HFrEF) have demonstrated improved survival when ACE inhibitors and ARBs have been used to block the renin-angiotensin system. Examples of these studies include CONSENSUS (1987), SOLVD (1991), and CHARM-Alternative (2003). Whether the benefit of ARBs extended to patients with HFpEF has been unclear. Two main studies, CHARM-Preserved and I-PRESERVE, addressed this question.
CHARM-Preserved enrolled 3,025 patients with HFpEF, defined as HF with LVEF >40% with NYHA functional class II-IV, and a history of hospitalization for a cardiac reason. The majority of patients had either ischemic (56%) or hypertensive (22%) cardiomyopathy and at baseline received concurrent HF therapy with an ACE inhibitor (20%), beta-blocker (56%), diuretic (75%), digoxin (29%), or spironolactone (11%). Patients were randomized to either candesartan, starting at 4-8 mg/d and titrating up to a dose of 32 mg/d, or to matching placebo. Patients were seen every 2 weeks initially, and then every 4 months. At a median follow-up of about 3 years, there was no difference in the primary outcome of CV death or HF hospitalization between the candesartan and placebo groups (22% vs. 24%). There was no difference in CV mortality between groups (11.2% vs. 11.3%), although there was a modest reduction in the rate of HF hospitalizations (15.9% vs. 18.3%).
It is important to clarify the magnitude and statistical significance of the difference in outcomes between groups. Specifically, the difference in the primary outcome was modest (absolute difference 2%) and was not statistically significant on initial analysis (P=0.118). Similarly, the reduction in HF hospitalizations was not statistically significant (P=0.072). These only reached borderline statistical significance (P=0.051 and P=0.047, respectively) after adjusting for covariates.
If one accepts that a modest benefit was observed with candesartan, several questions emerge. Are the potential benefits of ARBs driven by neurohormonal blockade, or simply by improving blood pressure control? Confounding this issue is the fact that only about 20% of patients in CHARM-Preserved were receiving ACE inhibitor therapy at baseline. It is unknown whether candesartan's benefits would have been seen if candesartan had been compared to an ACE inhibitor rather than placebo. Regarding blood pressure control, it is well known that hypertension management is an important component of overall HF therapy, particularly among patients with HFpEF. The candesartan group of CHARM-Preserved achieved better control of hypertension compared to the placebo control group, and this may have conferred a significant proportion of any potential ARB benefit.
Similar results were seen with the 2008 study I-PRESERVE, in which patients with HFpEF were randomized to the ARB irbesartan or placebo.[1]
Cumulatively, there is modest benefit to suggest that candesartan reduces HF admission rate among patients with HFpEF, but does not impact CV mortality. Consequently, ARBs should be considered for the control of hypertension, and may be considered to help reduce HF hospitalizations in this patient population.
Guidelines
AHA/ACCF Heart Failure Guidelines (2013, adapted)[2]
- The use of beta-blocking agents, ACE inhibitors, and ARBs in patients with hypertension is reasonable to control blood pressure in patients with HFpEF (class IIa, level C)
- The use of ARBs might be considered to decrease hospitalizations for patients with HFpEF (class IIb, level B)
Design
- Multicenter, double-blind, randomized, controlled trial
- N=3,023
- Candesartan (n=1,514)
- Placebo (n=1,509)
- Setting: 618 centers in 26 countries
- Enrollment: 1999-2000
- Mean follow-up: 3.1 years
- Analysis: Intention-to-treat
- Primary outcome: Cardiovascular death or HF admission
Population
Inclusion Criteria
- LVEF >40%
- NYHA class II-IV symptoms for at least 4 weeks
- History of at least one cardiac hospitalization
Exclusion Criteria
- LVEF less than or equal to 40%
Baseline Characteristics
From the candesartan group.
- Demographics: Mean age 67 years, 61% male, 91% European in origin
- Heart failure characteristics
- NYHA Class
- II: 61%
- III: 37%
- IV: 2%
- Mean LVEF
- 41-49%: 35%
- 50-59%: 36%
- >= 60%: 29%
- Mean SBP: 136 mmHg
- Ischemic CM: 56%
- NYHA Class
- Comorbidities: Hospital admission for HF 69%, T2DM 29%, MI 45%, CVA 9%, HTN 65%, AF 29%, cancer 9%, smoker 15%, PCI 15%, CABG 21%
- Medical treatment: ACE inhibitor 20%, beta blocker 56%, diuretic 75%, spironolactone 11%, digoxin 28%, oral anticoagulant 25%, aspirin 58%, lipid-lowering drug 41%
Interventions
- Randomized to candesartan or placebo in 1:1 fashion
- Treatment group started at 4-8mg daily and doubled every 2 weeks as tolerated until 32mg
- After randomization, patients seen at 2, 4, and 6 weeks, at 6 months, and every 4 months thereafter
- All other cardiac medications at discretion of treating physician
- All outcomes adjudicated by committee unaware of treatment assignment
Outcomes
Comparisons are candesartan vs. placebo.
Primary Outcomes
- Cardiovascular death or HF admission
- 22.0% vs. 24.3% (adjusted HR 0.86; 95% CI 0.74-1.00; P=0.051)
Secondary Outcomes
- Cardiovascular death
- 11.2% vs. 11.3% (adjusted HR 0.95; 95% CI 0.76-1.18; P=0.635)
- Hospital admission for HF
- 15.9% vs. 18.3% (adjusted HR 0.84; 95% CI 0.70-1.00; P=0.047)
- Cardiovascular death, hospital admission for HF, or MI
- 24.1% vs. 26.4% (adjusted HR 0.87; 95% CI 0.75-1.00; P=0.051)
- Cardiovascular death, hospital admission for HF, MI, or stroke
- 25.6% vs. 28.4% (adjusted HR 0.86; 95% CI 0.75-0.99; P=0.037)
- Cardiovascular death, hospital admission for HF, MI, stroke, or coronary revascularization procedure
- 30.4% vs. 32.9% (adjusted HR 0.91; 95% CI 0.80-1.03; P=0.130)
Adverse Events
Adverse events requiring drug discontinuation.
- Hypotension
- 2.4% vs. 1.1% (P=0.009)
- Increase in creatinine
- 4.8% vs. 2.4% (P=0.0005)
- Hyperkalemia
- 1.5% vs. 0.6% (P=0.029)
- Any AE or laboratory abnormality
- 17.8% vs. 13.5% (P=0.001)
Criticisms
- Primary endpoint driven exclusively by a modest reduction in hospitalization for heart failure which was marginally statistically significant only after pre-specified adjustment for baseline covariates (adjusted P=0.051; unadjusted P=0.118).
- Results not replicated in later I-PRESERVE study[1] study, although the latter included patients with more severe symptoms, greater baseline ACE inhibitor use, and greater baseline LVEF (60% vs. 55% in CHARM-Preserved).
Funding
- Funded by AstraZeneca with multiple authors disclosing consultant honoraria and/or research funding