Heart Disease

Edited by: Nadia S. Halim B. Pitt, R. Segal, F.A. Martinez, G. Meurers, A.J. Cowley, I. Thomas, P.C. Deedwania, D.E. Ney, D.B. Snavely, P.I. Chang, "Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE)," The Lancet, 349:747-52, 1997. (Cited in more than 230 papers since publication) Comments by Bertram Pitt, professor of medicine, division of cardiology, University of Michigan, Ann Arbor, and Robert Segal, director of cardiovascular clinical research, Merck Research Laboratories, West Point, Pa. The Evaluation of Losartan in the Elderly (ELITE) study demonstrates how an unexpected finding generates research. ELITE started out as a safety and clinical outcome study comparing an angiotensin II receptor antagonist (AIIA), losartan, with an angiotensin-converting enzyme (ACE) inhibitor, captopril, in patients with heart failure. "We were all surprised to see a striking mortality benefit with losartan," says Bertram Pitt, principal investigator of the ELITE study. "ACE inhibitors have become our gold standards, so to speak, and if losartan [proves] better, it would mean a major change in health care." ACE inhibitors comprise the first orally available class of drugs to affect the renin-angiotensin system, which has an important role in the pathophysiology of hypertension and heart failure primarily via the vasoconstricting effects of angiotensin II. Angiotensin II mediates elevated blood pressure levels in hypertension and increases volume overload (fluid and salt retention) in chronic heart failure. Thus, blocking its formation or its effects has important clinical implications for treating cardiovascular diseases. Numerous clinical trials before ELITE clearly demonstrated the therapeutic benefits of suppressing angiotensin II formation by ACE inhibition. However, ACE inhibitors incompletely suppress ACE activity and angiotensin II formation. Also, angiotensin II production may occur independently of ACE via other pathways.1 Robert Segal AIIAs developed several years later introduced an alternative therapy to ACE inhibitors for the treatment of hypertension. AIIAs selectively block the effects of angiotensin II at the angiotensin II type 1 receptors.2 It was a logical next step to compare the two classes of drugs. "I suggested ... that we test the two classes of drugs in elderly patients. At that time, they had a very low use of ACE inhibitors,3 so it didn't pose an ethical problem. ... [T]his group of patients wasn't getting the benefits of the ACE inhibitors," says Pitt about his initial involvement. Despite the mortality and morbidity benefit provided by ACE inhibitors, these drugs are still underused,4 perhaps due to perceptions concerning tolerability. As expected, losartan, the AIIA, was generally better tolerated, with fewer patients discontinuing therapy. Common side effects of ACE inhibitors experienced by the captopril group included cough, rashes, and angio-oedema (swelling of lips, face, and/or throat). About tolerability findings, Robert Segal, clinical monitor, comments, "If patients are actually able to stay on therapy, they should theoretically continue to benefit from the drug." However, the ELITE trial did not show a difference in renal dysfunction, the primary drug characteristic being studied, between the two treatment groups. ACE inhibitors seem to decrease the number of progressive heart failure deaths. But losartan has the added benefit of decreasing the number of sudden cardiac deaths, which are the primary cause of death in captopril patients. Pitt comments that this is a landmark finding because it presented "the first clue that there may be some real differences in the effectiveness of these two classes of agents." The ELITE trial was not designed to compare mortality between ACE inhibitors and ARBs, and the numbers involved were small. The study followed 722 heart-failure patients 65 years old and over, for 48 weeks. "We are repeating almost identically the first trial now on a large scale with over 3,000 patients," says Pitt. The Losartan Heart Failure Survival Study (ELITE II), designed to determine if losartan is better than captopril in preventing mortality, will hopefully provide some concrete answers with statistically significant numbers. H.P. Brunner-La Rocca et al., "Recent insight into therapy of congestive heart failure: focus on ACE inhibition and angiotensin-II antagonism," Journal of the American College of Cardiology, 33:1163-73, April 1999. B. Pitt and M.A. Konstam, "Overview of angiotensin II-receptor antagonists," American Journal of Cardiology, 82:47S-49S, Nov. 19, 1998. N.L. Smith et al., "Temporal patterns in the medical treatment of congestive heart failure with angiotensin converting enzyme inhibitors in older adults, 1989 through 1995," Archives of Internal Medicine, 158:1074-80, May 25, 1998. R. Garg and S. Yusuf, "Overview of randomized trials of angiotensin-converting enzyme inhibitors on the mortality and morbidity in patients with heart failure," Journal of the American Medical Association, 18:1450-5, 1995.

Heart Disease

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