Evaluation of Losartan in the Elderly (ELITE) Trial: clinical implications.

The Evaluation of Losartan in the Elderly (ELITE) Trial'^ is the first relatively long term (48 weeks) trial to compare an angiotensin converting enzyme (ACE) inhibitor with proven benefit in heart failure, captopril, to an angiotensin II type 1 receptor antagonist, losartan in patients with heart failure due to systolic left ventricular dysfunction (<40%). In brief, patients >65 years of age with New York Heart Association Class II-IV heart failure who were ACE inhibitor naive were randomized to captopril (n = 370) or losartan (n = 352) while maintained on their baseline therapy, including diuretics and/or digoxin and followed for 48 weeks. The dosing strategy for patients randomized to captopril was to start therapy at 6-25 mg three times a day and to up-titrate slowly to a target dose of 50 mg three times daily as tolerated, which is the same target dose used in SAVE. The strategy for losartan was to begin at a dose of 12-5 mg daily and then up-titrate slowly to 50 mg daily as tolerated. Over 80% of the patients achieved their target dose with both treatments and over 70% were maintained on their target dose for the duration of the trial. The mean dose of captopril was approximately 123 mg and for losartan 43 mg a day. The primary endpoint of the study was the incidence of the development of persistent renal dysfunction defined as an increase in serum creatinine >03 mg . dl~' on at least two occasions. The secondary endpoint was the incidence of heart failure hospitalizations and/or total mortality. Tertiary endpoints included the incidence of cough, hypotension, and persistent increases in serum potassium (>0-5 mEq . 1~ ') on at least two occasions. Patients randomized to losartan were found to have a similar incidence of persistent renal dysfunction (10-5%) to those randomized to captopril, and less than 2% of patients discontinued for this reason. Persistent increases in serum potassium occurred in 18-8% of patients randomized to losartan vs 22% of patients randomized to captopril. Less than 2% of patients discontinued in either group due to hyperkalaemia. There was also a similar incidence of symptoms of hypotension and less than 2% of patients experienced first dose hypotension. However, significantly more patients withdrew from captopril therapy than losartan (21% vs 12%, P=0002), mainly due to ACE inhibitor and/or captopril-related side effects such as cough, angioedema, rash, and/or taste disturbances. Patients randomized to losartan had a significant improvement in New York Heart Association Class from baseline to 48 weeks. This improvement was, however, similar to that observed in the captopril-treated patients. There was also a similar incidence of hospitalizations for heart failure (57%). Of particular interest was the finding that patients randomized to losartan had a 46% reduction in all-cause mortality in comparison to captopril-treated patients (95% confidence limits, 5-69%, />=0035) which was primarily due to a decrease in sudden cardiac deaths in the losartan group. This benefit of losartan on all-cause mortality could not be attributed to the greater withdrawal rate of patients randomized to captopril, since there was an even greater benefit (57% reduction in all cause mortality) in those patients who remained on their study drug. It is noteworthy that an improvement in survival was also observed in two earlier placebo-controlled 12 week exercise studies with approximately 350 patients with symptomatic heart failure in each'. There are a number of implications of this study that are potentially important for clinical practice a few of which will be described below. It was important to find that >80% of this population of elderly patients with heart failure could achieve the target dose of captopril or losartan and that this dose could be satisfactorily maintained over the study duration in >70% of patients. Secondly, the incidence of renal dysfunction and hypotension was relatively low. Only 0-9% of patients discontinued therapy for renal dysfunction with captopril and 11% with losartan; only 1% discontinued therapy for symptomatic hypotension with captopril and 06% with losartan. This relatively low rate of discontinuation because of renal dysfunction or hypotension is further evidence of the relatively good tolerability of either strategy in elderly patients with heart failure.