John J.V. McMurray, MB, MD; James B. Young, MD; Mark E. Dunlap, MD; Christopher B. Granger, MD; James Hainer, MD; Eric L. Michelson, MD; Steven Earle, PhD; Bertil Olofsson, PhD; Jan Östergren, MD; Salim Yusuf, MD, DPhil; Karl Swedberg, MD, PhD; Marc A. Pfeffer, MD, PhD 

Am Heart J.  2006;151(5):985-991.  ?2006 Mosby, Inc.

Abstract and Introduction

Abstract

Background: Whether an angiotensin receptor blocker is of benefit when added to a full dose of angiotensin-converting enzyme (ACE) inhibitor in heart failure (HF) is uncertain.
Methods: The effect of candesartan, compared with placebo, in 2548 patients randomized in the CHARM-Added trial was analyzed according to (i) ACE inhibitor dose at baseline, (ii) ACE inhibitor dose during follow-up, and (iii) combination treatment with ACE inhibitor and β-blocker at baseline. The main outcome was the composite of cardiovascular death or HF hospitalization.
Results: The benefit of candesartan was not modified by the dose of ACE inhibitor. In all patients (n = 2548), the candesartan/placebo hazard ratio (HR) for the primary outcome was 0.85 (95% CI 0.75-0.96). In patients taking a guideline recommended dose of ACE inhibitor at baseline (n = 1291), this HR was 0.79 (95% CI 0.67-0.95; interaction P value .26). In patients taking a Food and Drug Administration?designated maximum dose of ACE inhibitor (n = 529), this HR was 0.75 (95% CI 0.57-0.98; interaction P value .29). The benefit of candesartan was preserved in patients taking β-blockers in addition to a higher dose of ACE inhibitor and in patients maintaining a high dose of ACE inhibitor throughout follow-up.
Conclusions: These clinical findings support the pharmacologic evidence that ACE inhibitors and angiotensin receptor blockers have distinct mechanisms of action and show that their combined use improves outcomes in patients with HF more than an evidence-based dose of ACE inhibitor alone.

Introduction

The theoretical reasons for combining an angiotensin-converting enzyme (ACE) inhibitor and angiotensin II type 1 receptor blocker (ARB) in heart failure (HF) are well known.^[1] However, for this strategy to be valuable, clinically, it must offer benefits incremental to those obtained with an optimal dose of an ACE inhibitor. We present evidence that this is so, based upon analyses of the CHARM-Added trial, which were carried out during the approval process for candesartan as a treatment of heart failure by the US Food and Drug Administration (FDA).

Methods

Patients and Procedures

The inclusion criteria for CHARM-Added were New York Heart Association (NYHA) functional class II to IV, left ventricular ejection fraction ≤40%, and a constant dose of ACE inhibitor for ≥30 days.^[2] Investigators were given the target and mean achieved doses ACE inhibitors shown to be of benefit in randomized trials in HF and after myocardial infarction and asked to individually optimize ACE inhibitor treatment accordingly, that is, to aim for an evidence-based target dose or, failing that, the maximum tolerated dose of ACE inhibitor. The study had ethical approval at all centers, and each patient gave written informed consent.

Randomization, Follow-up, and Outcomes

Randomized treatment with candesartan or matching placebo was usually started at a dose of 4 mg once daily, and the dose was doubled at 2 weekly intervals, as tolerated, according to a forced titration protocol with recommended monitoring of blood pressure, serum creatinine, and potassium. The target dose was 32 mg once daily from 6 to 8 weeks onward (Figure 1).

Figure 1. 

Dosing and visit schedule in the CHARM-Added trial. Mean daily dose (in milligrams) for the 5 most commonly used ACE inhibitors at baseline (visit 1) and during the trial. ACEi, ACE inhibitor.

     

The primary outcome in CHARM-Added was cardiovascular (CV) death or HF hospitalization. Other prespecified outcomes included death or HF hospitalization and all-cause mortality.

Subgroups

The 2 prespecified subgroup analyses divided patients into those taking (1) the recommended dose or more, or less than the recommended dose, of ACE inhibitor (based on the European Society of Cardiology guidelines, Table I ) and (2) β-blocker or no β-blocker at baseline.^[2]

Post hoc subgroup analyses were carried out according to

Statistical Methods

Hazard ratios (HRs) and corresponding 95% CIs for candesartan versus placebo analyses within ACE inhibitor dose groups were derived from Cox proportional hazard models with only treatment in the model. The analyses were repeated adjusting for 32 prospectively defined potential confounding variables, as previously reported, with the exclusion of ACE inhibitor use as a covariate.^[2] Tests for heterogeneity across subgroups were also conducted.

Results

The baseline characteristics of patients taking or not taking a maximum dose of ACE inhibitor (FDA recommendation, January 2005) are shown in Table II . Overall, there was little difference between patients in these 2 groups, though patients taking a higher dose of ACE inhibitor were more likely to have a history of hypertension.

Enalapril, lisinopril, captopril, ramipril, and trandolapril accounted for 80% of all ACE inhibitors used ( Table II ). The mean daily doses were 16.8, 17.7, 82.2, 6.8, and 2.5 mg in the candesartan group and 17.2, 17.7, 82.7, 7.3, and 2.4 mg in the placebo group. In the opinion of the site investigators, 96% of the patients were on an optimum individualized dose of ACE inhibitor. The dose was maintained during follow-up (Figure 1). A recommended dose of ACE inhibitor or more was used in 51% of the patients at baseline and maintained in 47% of the candesartan group and 50% of the placebo group at the 6 months' visit (after completion of the study drug titration).

Other treatments used at baseline (end of study) included β-blocker 55% (64% candesartan and 68% placebo) and spironolactone 17% (20% candesartan and 25% placebo).

Primary Outcome in Overall Study and Prespecified Subgroups

Four hundred eighty-three (37.9%) patients in the candesartan and 538 (42.3%) in the placebo group experienced CV death or HF hospitalization (HR 0.85; 95% CI 0.75-0.96, P = .011 unadjusted, P = .010 covariate adjusted) (Figure 2). Candesartan reduced this risk in the 2 predefined subgroups with no evidence of heterogeneity of treatment effect.

Figure 2. 

Primary outcome of CV death or HF hospitalization for patients in CHARM-Added at recommended or higher dose of ACE inhibitor or maximum dose of ACE inhibitor as defined by the US FDA in the communication of December 2004 and as revised in January 2005. Also presented are the results for CHARM-Alternative (no ACEi) and the pooled results for these 2 trials in patients with low LVEF. ACEi, ACE inhibitor.

     

Post Hoc Subgroups

The results of the analyses, using the 2 higher ACE inhibitor dose thresholds suggested by the FDA, are shown in Figures 2 and 3. Baseline dose of ACE inhibitor did not modify the effect of candesartan on any clinical outcome.

Figure 3. 

Outcome analyses based on recommended or higher ACE inhibitor dose at baseline, and maximum or higher (as defined by FDA in January 2005) ACE inhibitor dose at baseline.

     

Similarly, maintenance of a maximum ACE inhibitor dose during study follow-up (Figure 4) or baseline treatment with a combination of both a maximum dose of ACE inhibitor and β-blocker did not modify the effect of candesartan (Figure 5).

Figure 4. 

Outcome analyses in a subgroup of patients maintained at recommended or higher ACE inhibitor (ACEi) dose during the trial, and maximum or higher (as defined by FDA in January 2005) ACE inhibitor dose during the CHARM-Added trial.

     

     

Components of Primary Outcome

The HR for CV death was 0.864 (95% CI 0.727-1.027) in those not taking a maximum dose and 0.764 (95% CI 0.543-1.075) in those taking a maximum dose of ACE inhibitor. The HR for heart failure hospitalization was 0.865 (95% CI 0.728-1.029) in those not taking a maximum dose and 0.698 (95% CI 0.507-0.961) in those taking a maximum dose. In other words, the background ACE inhibitor dose did not modify the effect of candesartan on either component of the primary outcome.

Tolerability

In CHARM-Added, the rates of study drug discontinuation in the candesartan and placebo groups were creatinine increase (7.8% vs 4.1%), hypotension (4.5% vs 3.1%), and hyperkalemia (3.4% vs 0.7%). These rates in the subgroup taking a maximum dose of ACE inhibitor (second definition) were 7.4% versus 8.1%, 4.5% versus 3.1%, and 4.1% versus 1.5%, respectively.

Discussion

The CHARM investigators used evidence-based doses of ACE inhibitors, and there was a clinical benefit of adding candesartan irrespective of ACE inhibitor dose.

The most studied ACE inhibitor in HF (and most commonly used in CHARM-Added) is enalapril.^[3-7] The target and mean achieved daily doses in the 5 large trials that used forced titration were CONSENSUS (target 20 mg BID, mean achieved daily dose 18.4 mg), SOLVD-Treatment (T) (10 mg BID, 16.6 mg), V-HeFT II (10 mg BID, 15.0 mg), OVERTURE (10 mg BID, 17.7 mg), and CARMEN (10 mg BID, 16.8 mg, and 14.9 mg in the group receiving active treatment with the β-blocker carvedilol).^[3-7] In CHARM-Added, the mean daily dose was 17.0 mg. The doses of ACE inhibitor used in CHARM-Added exceed those in other recent add-on trials in HF (eg, daily enalapril dose of 15 mg in RALES and 14 mg in MERIT-HF) and greatly exceed those used in clinical practice (weighted mean daily dose of enalapril from 13,764 patients in 7 community and hospital studies 13.8 mg).^[8-10] The dose of ACE inhibitor was maintained during follow-up in the candesartan group in CHARM-Added. Despite all of these, there was a benefit from adding candesartan.

Could the same benefit have been obtained by increasing the dose of ACE inhibitor, above those shown to be effective in prior trials? This hypothetical question has 2 parts. First, would patients tolerate higher doses? Other than the data from the large randomized trials such as SOLVD-T in which 51% of the patients could not be titrated up to 10 mg of enalapril twice daily (despite an active run-in period), there is very little other information on this subject.^[4] The mean achieved daily dose of enalapril (18.4 mg) in CONSENSUS where the target dose was 20 mg BID was only slightly higher than in SOLVD-T (16.6 mg)^[3], and only 22% of patients reached the target dose. Some patients can tolerate larger doses, but how representative these are of all patients with HF is unknown. Of greater importance is the second part of the question; that is, even if patients can be titrated to higher than evidence-based doses of ACE inhibitors, will this lead to greater clinical benefit? Only one trial compared an evidence-based dose to a higher dose, randomizing 248 patients with symptomatic HF and left ventricular ejection fraction (LVEF) ≤35% to enalapril 20 or 60 mg daily.^[11] The mean doses achieved were 17.9 and 42.5 mg daily, respectively (72.5% and 32.5%, respectively, reached the target dose by 3 months). After 12 months, there was no difference in mortality or morbidity between the 2 treatment groups, although the number of events was small. There was also no statistically significant or clinically meaningful difference in blood pressure, heart rate, left ventricular ejection fraction, or NYHA functional class.

Overall, therefore, the effect of candesartan was similar in patients taking no ACE inhibitor (CHARM-Alternative), a moderate dose of ACE inhibitor (all patients in CHARM-Added), or a high dose of ACE inhibitor (maximum dose subgroup analysis of CHARM-Added). These findings support the pharmacologic evidence that ACE inhibitors and ARBs have distinct mechanisms of action and that, clinically, these 2 classes of drug can complement each other in a way that improves outcomes in patients with HF. A more stringent test of this hypothesis, however, would be a prospective randomized comparison of the effect of adding either additional ACE inhibitor or an ARB on clinical outcomes in patients with HF.

In summary, candesartan is beneficial in patients with HF receiving conventional treatment, including a β-blocker, irrespective of background dose of ACE inhibitor. Moreover, the addition of the ARB candesartan improves outcomes beyond those achievable with even an optimal or maximum dose of ACE inhibitor.