University of Minnesota, Minneapolis, MN, USA
Growing evidence that angiotensin II contributes to the structural abnormalities of the left ventricle and vasculature that characterize chronic heart failure has made it attractive to study the efficacy of angiotensin AT1-receptor blockade in this syndrome. The problem, however, has been in experimental design. Since most patients should be and are taking ACE inhibitors, and ACE inhibitors are thought to reduce angiotensin II formation, conventional wisdom suggested that angiotensin receptor blockers should be considered as alternatives to ACE inhibitors, not as supplemental therapy.Indeed, the earlier ELITE trial compared the efficacy of the two drug classes with inconclusiveresults.1
We elected to pursue a different strategy. Considerable data suggest that angiotensin II levels recover during chronic ACE inhibitor therapy2 and that ACE inhibitors may exhibit their effect at least in part through the bradykininnitric oxidecyclic GMP pathway.3 A pilot study carried out primarilyin Veterans Affairs Centers demonstrated that addition of the angiotensin receptor blocker (ARB) valsartan to chronic ACE inhibitor therapy inpatients with heart failure resulted in enhanced hemodynamic and neurohormonal effects.4
We therefore undertook the Valsartan Heart Failure Trial (Val-HeFT) to study the additive effect of valsartan in the dose shown to be haemodynamically and hormonally effective in the pilot study (160 mg b.i.d.) in patients receiving all prescribed background therapy for heart failure.5 Since our hypothesis was that the ARB would slow or even reverse the cardiac structural remodelling process, we selected patients who exhibited both a low ejection fraction (EF) (40%) and a dilated left ventricular chamber in diastole (LVIDD) (by echo >2.9 cm.m2BSA). Furthermore, since hormonal effects were thought to be critical we elected to perform baseline and follow-up hormonal assessments in all the patients except those in centres unable to process the blood properly.
Val-HeFT therefore randomized 5010 patients on four continents, over 80% of whom tolerated full doses of valsartan or double-blind placebo. Nearly all had sequential echocardiographic studies to document left ventricular structure and over 4300 had baseline and sequential measurements ofneurohormones. Overall, the population demonstrated no effect of valsartan on mortality but a highly significant 13.2% reduction in morbidity(including all-cause mortality, hospitalization for adjudicated worsening heart failure, sudden death episodes with resuscitation, and need for prolonged infusion of drugs on an outpatient basis for worsening heart failure).6 First hospitalizations for heart failure were reduced by 27.5% and there was a significant benefit on quality of life measured with the Minnesota Living with Heart Failure questionnaire. The benefit of valsartan on outcome was associated with a highly significant increase in EF, reduction in LVIDD, and a lower plasma norepinephrine and plasma B-type natriuretic peptide level than in the placebo group. Thus the predicted favourable effect of an ARB on structure, hormones and outcome in heart failure appears to have been corroborated. The absence of a mortality benefit could be ascribed to a modest effect too small to detect in this sample size.
The overall trial results, however, could not be allowed to mask what might be different effects in those on varying background hormone-inhibiting therapy. Thus subgroup analysis was necessary to explore possible differences in response in those taking ACE inhibitors, beta-blockers, both orneither. This analysis was most revealing. Theefficacy of valsartan in patients not taking an ACE inhibitor was striking on both mortality (reduced 33%) and morbidity (reduced 44%). Since this subgroup represented only 7% of the Val-HeFT population this favourable mortality effect did not have much impact on the overall results of the trial. Nonetheless, the fact that the benefit was less dramatic and of only modest significance inpatients taking an ACE inhibitor suggests that our initial hypothesisthat ARBs and ACE inhibitors work through independent mechanismswas only partially correct.
Furthermore, an ACE inhibitor dose-responseappeared to emerge. Those on low-dose ACE inhibitor exhibited a greater benefit of valsartan than those on high dose.
The only subgroup exhibiting a qualitatively different response was that of patients receiving both an ACE inhibitor and beta-blocker as background therapy. In that subgroup, mortality in the placebo group was very low, about 6% per year. The addition of valsartan in this group was associated with a higher mortality and a trend for a higher morbidity. Since neither the ventricular remodelling data nor the neurohormonal data revealed an adverse trend, and blood pressure did not fall on average any more than in the other subgroups, this apparent adverse effect of valsartan is likely to be a play of chance in a very low-risk population.
Val-HeFT has therefore provided a remarkable database that expands our insight into the patho-physiology of heart failure, strengthens our database demonstrating the efficacy of ACE inhibitors and beta-blockers, and confirms the efficacy of blockade of the AT1receptor. This pharmacologic approach can now be considered an effective and viable alternative to ACE inhibitors and is also an appropriate approach to reduce morbidity andimprove quality of life in patients on an ACE inhibitor. Use of valsartan in patients on full doses of ACE inhibitors plus beta-blockers is discouraged inpatients with heart failure because of apparent lack of efficacy and the as-yet unresolved possibility that an adverse effect could occur. It is possible that the lack of additional benefit of the three drugs together reflects a ceiling effect of neurohormonal inhibition. Perhaps, therefore, it is not surprising that additional sympathetic inhibition with a centrally acting drug and inhibition of endothelin and cytokines do not produce further reduction in morbidity and mortality.
The future of clinical trials also should beimpacted by Val-HeFT. The low mortality exhibited by patients treated for heart failure with ACEinhibitors or ARBs plus beta-blockers makes mortality an unlikely candidate end-point for future studies. Quality of life assessment, hospitalizations specifically for heart failure, left ventricular structure and BNP measurements appear to be useful markers for a favourable effect of therapy.These measurements should be incorporated in all future trials and might serve as components of a composite score to determine efficacy.
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