Drug Criteria & Outcomes
Angiotensin II type 1 receptor blockers
Review and role in congestive heart failure therapy
By Minhduc Pham, PharmD
College of Pharmacy
The University of Texas at Austin
Angiotensin-converting enzyme inhibitors (ACEIs) decrease the synthesis of angiotensin II and also reduce bradykinin degradation. However, angiotensin II can be formed in a number of tissues, including the heart, through non-angiotensin-converting-enzyme (ACE)-dependent pathways.1,2 Therefore, blockade of the chronic detrimental effects of angiotensin II by ACE inhibition in congestive heart failure (CHF) patients is thought to be incomplete. The angiotensin II receptor blockers (ARBs) block the angiotensin II receptor subtype, AT1, reducing the effects of angiotensin II, regardless of origin. Thus, these agents offer a theoretical advantage for the treatment of heart failure over ACEIs through a more complete blockade of angiotensin II activity.
Whether ARBs are superior to ACE inhibitors — or if more complete blockade of angiotensin II actions in combination therapy with ACE inhibitors could further decrease morbidity and mortality — currently is being investigated.
Review of clinical trials
Although the ARBs are approved only for the treatment of hypertension, significant interest exists in the potential role of these agents in heart failure. Presently, only three randomized clinical trials are available investigating the effects of ARBs in long-term morbidity and mortality in chronic heart failure patients.
The purpose of the ELITE (Evaluation of Losartan in the Elderly) trial was to determine whether specific angiotensin II receptor blockade with losartan (Cozaar) offered safety and efficacy advantages in the treatment of heart failure over ACE inhibition with captopril (Capoten).
Methods. This double-blind, randomized, controlled trial examined 722 ACE-inhibitor naïve patients ages 65 years or older with New York Heart Association (NYHA) class II-IV heart failure and ejection fraction of 40% or less. Patients were assigned randomly to losartan (n = 352) titrated to 50 mg once daily or captopril (n = 370) titrated to 50 mg three times daily. The primary endpoint was measurement of persistent increases in serum creatinine of 26.5 mg/L or more (greater than or equal to 0.3 mg/dL) in patients on therapy. The secondary endpoint was the composite of death and/or hospital admission for heart failure. Other efficacy measures were total mortality, admission for heart failure, NYHA class, and admission for myocardial infarction or unstable angina.
Results. Duration of therapy was 48 weeks. All-cause mortality was reduced significantly in the losartan group (8.7%) vs. the captopril group (4.8%). Risk reduction was 46% (95% confidence interval [CI] 5-69%); P = 0.035. Death and/or hospital admission for heart failure was recorded in 9.4% of the losartan and 13.2% of the captopril patients. Risk reduction was 32% (95% CI -4% to +55%); P = 0.075. Although there was no difference in renal dysfunction, losartan generally was better tolerated than captopril, and fewer patients discontinued losartan therapy. No losartan-treated patients experienced cough or angioedema.
ELITE II 4
The initial ELITE study showed an association between angiotensin II receptor blocker losartan (Cozaar) utilization and an unexpected survival benefit in elderly heart failure patients, compared to captopril (Capoten). As a result, the ELITE trial investigators initiated the ELITE II Losartan Heart Failure Survival Study to determine whether losartan was superior to captopril in improving survival. Tolerability was another endpoint.
Methods. This double-blind, randomized, controlled trial assessed 3,152 patients age 60 or older with NYHA class II-IV heart failure and ejection fraction of 40% or less. Patients, stratified for beta-blocker use, were assigned randomly to losartan (n = 1,578) titrated to 50 mg once daily or captopril (n = 1,574) titrated to 50 mg three times daily. The primary and secondary endpoints were all-cause mortality and sudden death or resuscitated arrest. Safety and tolerability were assessed.
Results. The median follow-up was 555 days. No statistically significant differences were observed in all-cause mortality between the losartan group (11.7%) and the captopril group (10.4%) in average annual mortality rate, sudden death, or resuscitated arrests (9% on losartan vs. 7.3% on captopril). Significantly fewer patients in the losartan group (excluding those who died) discontinued study treatment because of adverse effects (9.7% vs. 14.7%, P < 0.001), including cough (0.3% vs. 2.7%).
Val-HeFT (Valsartan and Heart Failure Trial) was a large multinational study involving 16 countries and more than 5,000 patients to evaluate the effects of valsartan (Diovan) on long-term mortality and morbidity in heart failure patients. The following are preliminary, unpublished data presented at a recent American Heart Association meeting.
Methods. This double-blind, randomized, controlled trial evaluated 5,010 patients age 18 or older with NYHA class II-IV heart failure and ejection fraction of 40% or less. Patients received "background" therapy throughout the duration of the study: ACE inhibitors (n = 4,614), diuretics (n = 4,300), digoxin (n = 3,374), and beta-blockers (n = 1,784). Patients were assigned randomly to valsartan 40 mg bid titrated to 160 mg bid or placebo. The primary endpoints were all-cause mortality and combined all-cause mortality and morbidity.
Results. The study was discontinued when a total of 906 deaths were reported in both placebo and valsartan groups. No difference in all-cause mortality between valsartan and placebo (19.7% on valsartan vs. 19.4% on placebo; P = 0.8) was noted. Hospitalization admission for heart failure was reduced significantly in the valsartan group (13.9%) vs. placebo (18.5%). Risk reduction was 27.5% (P < 0.001). Valsartan significantly reduced combined mortality and morbidity by 13.3% (28.8% on valsartan vs. 32.1% on placebo; P = 0.009). This risk reduction was mostly contributed by the risk reduction in the hospitalization incidence.
Subgroup analysis indicated:
1) the benefits of valsartan on combined mortality and morbidity were prominent in patients receiving one or no neurohormonal inhibitor (i.e., a beta-blocker or an ACE inhibitor);
2) significant improvements in signs and symptoms of heart failure, NYHA heart class, and quality of life as measured by the Minnesota Living with Heart Failure Scale and ejection fraction; however,
3) a subgroup of patients who were taking an ACE inhibitor, beta-blocker, and valsartan together showed an unfavorable trend on the endpoints.
Until more definitive evidence supporting the use of ARBs as first-line therapy in CHF is available, these agents may be considered in patients intolerant to ACE inhibitor therapy because of:
- severe cough;
- persistent heart failure symptoms; or
- persistent hypertension despite maximal ACE inhibitor doses.
1. Goodfriend TL, Elliott ME, Catt KJ. Angiotensin receptors and their antagonists. N Engl J Med 1996; 334:1649-1654.
2. Messerli FH, Weber MA, Brunner HR. Angiotensin II receptor inhibition. A new therapeutic principle. Arch Intern Med 1996; 156:1957-1965.
3. Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan vs. captopril in patients over 65 with heart failure. Lancet 1997; 349:747-752.
4. 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.
5. Data on file. Basel, Switzerland: Novartis; 2000.