Interruption of the Renin-Angiotensin Access
Abstract & commentary
Synopsis: Combination therapy with candesartan and enalapril was the most effective approach with respect to remodeling and neurohormones.
Source: McKelvie RS, et al. Circulation 1999;100: 1056-1064.
The randomized evaluation of strategies for Left Ventricular Dysfunction (RESOLVD) Trial pilot study was reported at the annual American Heart Association meeting one year ago and has finally been published. This controversial study assessed the effects of an angiotensin II receptor blocker (ARB) (candesartan) and an angiotensin converting enzyme (ACE) inhibitor, enalapril, and their combination in almost 800 individuals with heart failure. RESOLVD was a relatively short-term study of 43 weeks duration that was not powered to look at major morbidity and mortality results. It was a multicenter, double-blind, randomized parallel trial of 768 patients with an ejection fraction of less than 40%, NYHA class II-IV; most were in functional class II. They were evaluated by serial six-minute walk test, echocardiographic left ventricular function and volume data, neurohormones, and quality of life/functional class assessment at weeks 17 and 43. Patients had to terminate a six-minute walk distance in less than 500 meters. All individuals were submitted to a run-in period with enalapril, candesartan, and the combination. Three groups were studied: candesartan, 327 subjects; enalapril, 109 subjects; and the combination, 332 subjects. There was no placebo group. In addition, candesartan patients were individually randomized to three dosing strategies—4, 8, and 16 mg daily; the enalapril group received 10 mg bid; and combination patients received enalapril, 10 mg bid plus candesartan 4 or 8 mg.
The external safety and efficacy monitoring committee stopped the trial early because of a differential mortality in the candesartan group vs. enalapril. The enalapril patients had a mortality of 3.7%, the candesartan patients 6%, and the combination group 8.7%. Congestive heart failure (CHF) hospitalizations included 10.7% for candesartan, 3.7% for enalapril, and 7.2% for the combination. The combination of death plus CHF hospitalization was roughly 2.5 times higher for the combination group than for enalapril alone (15.1% vs 6.4%). No available data in the literature or from other ARB trials have suggested an adverse result with an ARB, but the study was terminated against the wishes of the investigators. Nevertheless, this occurred only six weeks prior to the scheduled trial termination, and 90% of the entire cohort had completed all visits at the time of termination; approximately 9% of patients had a shortened follow-up by a mean of 16 days. The results of the trial indicated no differences among the groups for the six-minute walk distance, with no improvement over baseline. Left ventricular function showed a trend toward an increase in ejection fraction for the combination patients at the highest dose of candesartan plus enalapril. LV volumes increased with candesartan and enalapril, although there was no significant change for the combination patients at 43 weeks. Neuro-hormonal levels demonstrated a rise in renin in all groups; ANG II increased markedly with candesartan alone and less with combination therapy. Aldosterone declined in all groups, as did norepinephrine and epinephrine levels. Pro-ANP and BNP levels showed declines. There were no significant differences among the three groups for NYHA, functional class, or quality-of-life scores at 18 or 43 weeks. There were no significant differences in mortality or morbidity among the three groups.
McKelvie and colleagues conclude that candesartan has a similar effect to enalapril on the walk test, ventricular function, and clinical status. Of interest, only the combination group demonstrated prevention of left ventricular remodeling and the most effective suppression of aldosterone and BNP. Few adverse effects were noted and were not different among the treatment groups. McKelvie et al concluded that combination therapy was the most effective approach with respect to remodeling and neurohormones. In no group was there a significant increase in neurohormonal activation. Aldosterone declined the most and renin increased the most with combination therapy; this suggests that "more complete blockade of the renin-angiotensin-aldosterone system was achieved." Furthermore, the 8 mg dose of candesartan was shown to be the most effective.
There is a problem with the major clinical event differences among the groups. The enalapril group was only 109 patients and the mortality was much lower than would be expected in a cohort of similar heart failure patients. McKelvie et al conclude that "the RESOLVD study should not be viewed as being reliable in estimating the effects of candesartan or candesartan plus enalapril vs. enalapril alone on clinical outcomes." They also conclude that candesartan was as effective, safe, and tolerable as enalapril, and that the combination may be more beneficial than either drug alone in preventing LV remodeling and suppressing neuro-hormones. In an accompanying editorial, Barry Greenberg, MD, goes through the physiologic rationale of ACE inhibitors and ARBs, which underlines the hypothesis that combination therapy with both classes of drugs might be better than either alone. Greenberg concludes that one cannot make any definite assumptions regarding the RESOLVD study, partly because of the relatively small numbers of patients in this pilot study and because of the multiple treatment regimens that make intergroup comparisons hazardous. In addition, some individuals were randomized to a beta blocker after 19 weeks of therapy; data were not provided. Greenberg suggests that the beneficial effects of combination therapy on remodeling may be due to a greater blood pressure lowering effect of both candesartan and enalapril together, and that the differences in LV volumes could reflect "acute unloading effects of combined therapy." He points out that many other data sets have indicated the prevention of remodeling with an ACE inhibitor, unlike the findings of RESOLVD.
Comment by Jonathan Abrams, MD
This study is confusing with respect to the divergence of hard clinical end points due to the failure of the ARB or the ACE inhibitor to prevent left ventricular cavity expansion, but it does suggest that combination therapy may be particularly beneficial in heart failure patients. The construct that more complete suppression of angiotensin II will be beneficial is not new. This would result in lower aldosterone levels as well; the recent RALES Trial strongly supports the clinical benefits of aldosterone lowering in heart failure patients. The prevention of LV remodeling in the RESOLVD Trial has been shown in larger trials with ACE inhibitors alone (SAVE, SOLVD) but in this study was seen only in the combination group.
Large trials, including VAL-HEFT and CHARM, are currently assessing the role of combination therapy with an ARB and an ACE inhibitor in heart failure patients. The results are eagerly anticipated. Furthermore, other studies, including ELITE-2, are asking the question as to whether an ARB or an ACE inhibitor is more beneficial in the therapy of heart failure. It is unfortunate that RESOLVD was terminated early, as it has cast a cloud of controversy over this trial. However, it is doubtful that the results were significantly altered, in that at trial cessation, only 10% of individuals had incomplete data and only for a short period.
It is clear that the RESOLVD study design contributed to the messiness of the data with multiple groups (three candesartan dose arms in the ARB cohort and two in the combination cohort). The failure to have a placebo arm also contributes to the uncertainty of the various data sets. The marked differences in clinical events are unexpected and in contradistinction to the recently published ELITE Trial comparing losartan to captopril, which favored the ARB. For reasons already stated, the reliability of the data is somewhat suspect because of multiple groups and the small number of individuals taking enalapril alone, as well as the short duration of the study (less than 12 months).
What is the clinician to do? It would appear that RESOLVD does support the safety of the combination of an ARB and an ACE inhibitor. For patients with heart failure who are not doing well on an ACE inhibitor alone, it may be reasonable to add an ARB to attempt to achieve a greater ANG II and aldosterone suppression and perhaps more blunting of LV cavity expansion. There are no solid clinical data as yet to support this suggestion, however. Nevertheless, no obvious adverse effects were found in RESOLVD with combination therapy, so that careful clinical and laboratory monitoring would appear to allow such a strategy to be used without serious risk. We must await the results of VAL-HEFT and other trials to answer the hotly contested question of whether an ARB or an ACE inhibitor is better, or whether combination therapy is the best of all.
The efficacy of ACE inhibitors has been well shown in heart failure, asymptomatical LV dysfunction, hypertension, and diabetes. The recently released HOPE Trial, assessing more than 9000 patients who were treated with ramapril or placebo, represents a major advance in understanding the benefits of ACE inhibitors. There was a 20-25% reduction in all major clinical end points with ACE inhibitor therapy. Subjects enrolled in the study had to have coronary or peripheral vascular disease or were diabetics with one or more other risk factors. HOPE was not a hypertension or heart failure trial, but asked the question whether an ACE inhibitor would be beneficial in patients with established vascular disease and/or who are at high risk for cardiovascular problems.
In conclusion, an ACE inhibitor remains the mainstay for patients with LV systolic dysfunction, whether symptomatic or not. HOPE suggests that these drugs might be appropriate for all individuals with vascular disease, irrespective of LV function and hypertension. Clearly, diabetics should be considered for an ACE inhibitor if they have a significant vascular disease risk factor profile. The ARB story is promising but less well supported by clinical trial data.
Angiotensin receptor blockers are clearly indicated for:
a. heart failure.
b. post-myocardial infarction.
c. diabetic nephropathy.
d. hypertension.
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