Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Losartan compared with captopril reduced mortality but not renal function in heart failure

ACP J Club. 1997 Sep-Oct;127:29. doi:10.7326/ACPJC-1997-127-2-029


Source Citation

Pitt B, Segal R, Martinez FA, et al., on behalf of ELITE Study Investigators. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997 Mar 15;349:747-52.


Abstract

Objective

To compare the safety and efficacy of losartan and captopril in older adults with symptomatic heart failure (HF).

Deszign

Randomized, double-blind, captopril-controlled trial with 48-week follow-up.

Setting

125 centers in the United States, Europe, and South America.

Patients

722 patients aged ≥ 65 years (mean age 73.5 y, 67% men, 89% white) with HF, left ventricular ejection fraction ≤ 40%, and no history of angiotensin-converting enzyme (ACE) inhibitor therapy. Exclusion criteria were systolic blood pressure < 90 mm Hg, uncontrolled hypertension or diabetes, obstructive valvular disease, risk for recent cardiac procedure or event or anticipated cardiac surgery, or recent stroke or transient ischemic attack.

Intervention

After a 2-week placebo run-in period, 352 patients were allocated to losartan (12.5 mg titrated to 50 mg once daily) and 370 to captopril (6.25 mg titrated to 50 mg 3 times daily).

Main outcome measures

The primary outcome was renal dysfunction (increase in serum creatinine ≥ 26.5 µmol/L from baseline). The secondary outcome was the composite of death or hospitalization or both for HF. All-cause mortality was a prespecified end point.

Main results

No difference between losartan and captopril was found for renal dysfunction (P = 0.63) (Table). All-cause mortality and hospitalization for any reason were lower for losartan than for captopril (P = 0.035 and P = 0.014, respectively) (Table).

Conclusion

Compared with captopril, losartan was associated with a similar rate of renal dysfunction and reduced all-cause mortality in older patients with symptomatic heart failure.

Source of funding: Merck Research Laboratories.

For article reprint: Dr. B. Pitt, Division of Cardiology, University Hospital, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0366, USA. FAX 313-936-5256.


Table. Losartan vs captopril*

Outcomes at 48 weeks Losartan EER Captopril CER RRR (95% CI) ARR |EER-CER| NNT (CI)
Renal dysfunction 10.5% 10.5% 0.3% (-52 to 35) 0% (CI, -45 to 4.6) NS
All-cause mortality 4.8% 8.7% 46% (5 to 69) 3.9% 26 (13 to 740)
Hospitalization (any reason) 22.2% 29.7% 26% (5 to 43) 7.5% 14 (7 to 91)

*NS = not significant. Other abbreviations defined in Glossary; RRR, ARR, NNT, and CI calculated from data in article.


Commentary

The renin-angiotensin system plays a central role in the pathophysiology of HF. ACE inhibitors improve symptoms and reduce mortality in HF, and it is believed that these benefits can be attributed to decreased angiotensin II formation as well as to bradykinin potentiation and resultant vasodilatory and endothelial protective actions.

The Evaluation of Losartan in the Elderly (ELITE) trial is a long-term, moderately sized trial. In this trial, a trend existed toward a reduction in death or hospitalization (or both) for patients with HF receiving losartan. Patients receiving losartan also had fewer adverse effects that required drug discontinuation; primarily, these patients had a lower incidence of cough. These data and another preliminary report of improved survival with losartan compared with placebo suggest a role for angiotensin-receptor blockers in HF and bring into question the mechanism by which ACE inhibitors effect clinical improvements (1). Alternate pathways of angiotensin II formation independent of ACE have been found, and more complete inhibition of angiotensin II effects are attained through direct angiotensin-receptor blockers. However, these blockers do not affect the kallikrein-bradykinin system, which experimentally seems to be important in mediating the benefits of ACE inhibitors.

It is important to view this study, which had relatively few hard end points (17 deaths in the losartan group vs 32 for captopril) in a selected group of patients, in the context of more robust data for ACE inhibitors. A recent review of 32 randomized trials of ACE inhibitors in patients with HF noted > 1300 deaths in 7105 patients but showed a reduction in mortality of 23% (2); similar benefits were found in recent studies of patients with left ventricular dysfunction after myocardial infarction (3). It thus may be premature to conclude that angiotensin-receptor blockers are superior to ACE inhibitors or that they should be widely recommended for HF. The ELITE study emphasizes the need for larger trials, which are currently under way, to further evaluate angiotensin-receptor blockers. Until these trials are completed, it remains mandatory to use ACE inhibitors in all patients with HF who can tolerate this therapy. For those with adverse reactions, angiotensin-receptor blockers offer an alternative.

Eva M. Lonn, MD
Hamilton General HospitalHamilton, Ontario, Canada


References

1. Klinger G, Jaramillo N, Ikram H, et al. J Am Coll Cardiol. 1997;29(Suppl):205A.

2. Garg R, Yusuf S. JAMA. 1995;273:1450-6.

3. Pfeffer MA, Braunwald E, Moye LA, et al. N Engl J Med. 1992;327:669-77.