Valsartan

Q Are angiotensin-receptor blockers (ARBs) equivalent to or better than angiotensin-converting enzyme (ACE) inhibitors in the treatment of heart failure?

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A Juanita Reigle, RN, MSN, ACNP, replies:

ACE inhibitors reduce mortality and morbidity in patients with chronic heart failure and left ventricular systolic dysfunction. (1,2) The evidence is so compelling that for patients with left ventricular systolic dysfunction, the prescription of an ACE inhibitor at hospital discharge is used by various regulatory agencies as a quality indicator.

The mechanism of these benefits is likely due to the inhibition of angiotensin II production and a decrease in the breakdown of bradykinin. Angiotensin II is a potent vasoconstrictor that has deleterious effects on the failing heart by increasing oxidative demands, promoting cell growth, stimulating vascular and left ventricular remodeling, and triggering proteinuria. (3) Bradykinin stimulates the release of nitric oxide and prostacyclin, both potent vasodilators that may account for the beneficial hemodynamic effects of ACE inhibitors. However, bradykinin has been implicated in some of the adverse reactions of ACE inhibitors, including cough, renal dysfunction, and angioedema. (4)

ARBs block the angiotensin II type 1 receptor and thus inhibit the effects of angiotensin II by both ACE-dependent and non-ACE-dependent pathways. (5) Moreover, ARBs block the receptor without increasing bradykinin levels, which is likely the reason there is less cough with this group of medications. Thus, some clinicians argue that ARBs may be better tolerated and more beneficial than ACE inhibitors.

The use of ARBs in heart failure first gained favor in the Evaluation of Losartan In The Elderly (ELITE) study. (6) In this study, 722 elderly patients with heart failure were randomized to receive either losartan or captopril. The primary endpoint was to assess tolerability by evaluating increases in serum creatinine. Although the increases in serum creatinine were similar in both groups, the authors reported an unexpected lower, although not statistically significant, mortality in the losartan group.

The mortality finding in the ELITE study prompted the ELITE II study that was designed to compare all-cause mortality benefits between losartan and captopril. (7) In this study of 3152 patients age 60 or older, losartan was not superior to captopril as there was no significant difference in the primary and secondary endpoints between the 2 groups. The authors concluded that ACE inhibitors should remain the initial treatment for heart failure, but that ARBs may be a suitable alternative in patients who are ACE-inhibitor intolerant. The Valsartan Heart Failure Trial (Val-HeFT) reported a similar finding with the ARB, valsartan, in the comparable subset of patients. (8) In the ARB trials to this point, only ELITE II and Val-HeFT were powered to evaluate the mortality effect of ARBs as a primary outcome in heart failure.

The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) study (9) was designed to compare the ARB, candesartan, to placebo in 3 distinct populations. One arm of the study, CHARM-Alternative, was designed to compare candesartan to a placebo in ACE intolerant patients with reduced left ventricular function. (10) The most common reasons that patients were unable to tolerate an ACE inhibitor before the study were cough (72%), symptomatic hypotension (13%), and renal dysfunction (13%). The results of the study demonstrated that patients who received candesartan had significant reductions in cardiovascular mortality and hospital admissions for heart failure compared to the placebo group. This positive effect continued throughout the 3 years of the study. Because some patients with heart failure are unable to tolerate ACE inhibitors, the CHARM--Alternate trial demonstrated that the addition of the ARB candesartan offers additional clinical benefits over placebo to this population.

The CHARM-Added limb investigated the effect of adding candesartan to patients with an ejection fraction <0.40 who were currently taking ACE inhibitors. (11) The investigators reported that 96% of the patients were taking optimum doses of ACE inhibitors at randomization. In addition, 55% of the patients at baseline were taking a [beta]-blocker and 17% were taking spironolactone. The results of the study showed that the addition of candesartan to an ACE inhibitor significantly reduced cardiovascular morbidity and mortality. However, at the conclusion of the study, 25% of patients in the candesartan group were no longer taking the medication. The primary reasons for discontinuing the drug were elevated serum creatinine, hyperkalemia, and symptomatic hypotension. The Val-HeFT study, which added valsartan to an ACE inhibitor, also showed similar results. (8)

Finally, the third group in the CHARM study were patients with heart failure symptoms and preserved systolic function who were randomized to receive candesartan or placebo. (12) There have been few studies that have evaluated treatment outcomes in this population and the results were eagerly anticipated. Unfortunately, there was no significant difference in clinical outcomes between candesartan and placebo.

ACE inhibitors remain the cornerstone of heart failure therapy for patients with reduced systolic function. Clinicians should carefully evaluate intolerance to ACE inhibitors as often the effects of rising creatinine or hypotension are transient and do not persist with continued treatment. However, if patients are unable to take ACE inhibitors, the results of the studies discussed above suggest that some ARBs are an appropriate alternative for patients with left ventricular systolic dysfunction.

The addition of an ARB to heart failure patients taking ACE inhibitors and [beta]-blockers should be individualized. The CHARM-Added trial suggests that an ARB may provide additional benefit but this should be interpreted with caution. Certainly patients should be on optimal doses of ACE inhibitors and [beta]-blockers before addition of an ARB. Patients with New York Heart Association (NYHA) Class III or IV symptoms will derive morbidity and mortality benefits from the addition of an aldosterone antagonist such as spironolactone and other medications such as digoxin and diuretics have important symptomatic and quality of life benefits. (2,13,14) The addition of an ARB to this course of therapy may be a challenge but should be considered.

References

1. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA. 1995;273:1450-1456.

2. Hunt SA, Baker DW. Chin MH, et al. ACC/AHA practice guidelines for evaluation and management of chronic heart failure in the adult. J Am Coll Cardiol. 2001;38:2101-113.

3. MacLellan WR. Advances in the molecular mechanisms of heart failure. Curr Opin Cardiol. 2000;15:128-135.

4. Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy: a review of the literature and pathophysiology. Ann Intern Med. 1992;117:234-242.

5. Maggioni AP, Anand I, Gottlieb SO, et al. Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors. J Am Coll Cardiol. 2002;40:1414-1421.

6. Pitt B. Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997;349:747-752.

7. Pitt B. Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial--the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355:1582-1587.

8. Cohn JN, Tognoni G. The effect of angiotensin receptor blocker valsartan on morbidity and mortality in heart failure. N Engl J Med. 2001;345:1667-1675.

9. Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362:759-766.

10. Granger CB, McMurray JJV, Yusuf S, 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. Lancet. 2003;362:772-776.

11. McMurray JJV, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:767-771.

12. Yusuf S, Pfeffer MA. Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777-781.

13. Pitt B, Zannad F, Remme WJ. et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709-717.

14. Garg R, Gorlin R, Smith T, Yusuf S. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525-533.

Author

Juanita Reigle is a nurse practitioner in the Heart Failure and Cardiac Transplantation Program at the University of Virginia Health Sciences Center, Charlottesville, Va.

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