Surprising Benefit of Losartan in Congestive Heart Failure
ABSTRACT & COMMENTARY
Synopsis: This trial, while small and not definitive, clearly suggests that the concept of angiotensin II receptor blockade may be more promising than had initially been thought by many.
Source: Pitt B, et al. Lancet 1997;349:747-752.
At the march 1997 american college of cardiology Scientific Sessions, the ELITE study was presented, raising considerable interest regarding the positive findings with losartan in elderly patients with heart failure. This multicenter trial randomized more than 700 patients not on an ACE inhibitor with a history of heart failure to either losartan or captopril with a follow-up of 48 weeks. Losartan, an angiotensin II receptor antagonist, was titrated to a dose of 50 mg daily; captopril was titrated to 50 mg tid in this double-blind protocol. Inclusion criteria were age over 65, history of congestive heart failure (NYHA Class II-IV), and no previous ACE inhibitor therapy. The majority of the patients were on a diuretic; 55% were using digitalis. More than one-third were on non-ACE inhibitor vasodilators (either nitrate or calcium channel blocker). The primary end point was worsening of renal function (i.e., a sustained rise of creatinine of ³ 0.3 mg/dL from baseline). A variety of secondary end points were assessed, including combined death and/or heart failure admission, total mortality, and hospitalization for heart failure. The composite end point was added at the completion of the study. Adverse symptoms, such as hypertension, increased potassium, and cough, were tertiary end points. Patients were randomized to 48 weeks of active therapy after a two-week placebo run-in with careful dose titration. Creatinine was measured two weeks after drug initiation, as well as during continuous treatment.
The results indicated worsening of renal function by both drugs to a comparable degree (10.5%, considerably less than projected for captopril). All secondary end points except total mortality were not different between losartan and captopril, although there was a trend in favor of the combined end point of death and/or heart failure admission, with a 32% risk reduction for losartan vs. captopril (P = 0.075). Frequency of hospitalization was not different, but total or all-cause mortality was substantially decreased in the losartan cohort, reaching 4.8% at 48 weeks vs. 8.7% in the captopril patients, representing a risk reduction of 46% (confidence intervals, 5-69%; P = 0.035). Although the total number of deaths were few (17 vs 32), it appeared that the decrease in total mortality in the losartan patients was due to a reduction in sudden cardiac death, as adjudicated by an independent end point committee. Worsening of or admission for heart failure was very uncommon and equivalent in both groups. Adverse events were substantially less in the losartan cohort for cough, worsening heart failure, hypercreatininemia, taste/appetite disturbances, rash, and angioedema.
Pitt et al conclude that these results cannot be extrapolated to patients younger than 65 or those who do not have systolic left ventricular dysfunction (mean ejection fraction at entry, approximately 30%).
COMMENT BY JONATHAN ABRAMS, MD
The ELITE study was somewhat of a surprise when announced at the recent annual meeting of the American College of Cardiology. It is the first comparative trial between an angiotensin II receptor antagonist and an ACE inhibitor in heart failure. A number of studies are underway adding an angiotensin II blocker to an ACE inhibitor vs. placebo, but the ELITE trial compared the two drugs head-on, with the rationale that protection against the adverse effects of angiotensin II would be provided by both classes of agents. This trial, while small and not definitive, clearly suggests that the concept of angiotensin II receptor blockade may be more promising than had initially been thought by many. These drugs have been available for the treatment of hypertension but have shown no major advantage over ACE inhibitors. The unexpected finding of a decrease in all-cause mortality in the losartan patients could be due to the play of chance; scrutiny of the baseline characteristics of the two cohorts does not identify any obvious difference in risk factors or co-morbidity. Nevertheless, these data need to be amplified by future studies. There was no difference between the two agents with respect to improvement in symptoms, and both were effective in this regard, improving NYHA functional class significantly. Hospitalization for congestive heart failure was no different, and renal function effects were similar. The side effect profile of losartan clearly was better than captopril, with a reduction in many of the classic ACE inhibitor adverse reactions, particularly less cough, taste disturbance, and angioedema. Overall adverse events were 12.2% in the losartan patients vs. 20.8% in the captopril group; these numbers were not affected by the deaths during the trial.
The question of increased levels of kinins caused by ACE inhibitor therapy has remained an important focus of speculation and attention. The ELITE trial suggests that decreased kinin degradation, common to ACE inhibitors, may not be particularly beneficial compared to more effective angiotensin II blockade. The angiotensin II type 1 receptor blockers provide a more complete suppression of circulating angiotensin II. It is now recognized that there are non-converting enzyme pathways for the production of angiotensin II. Furthermore, there may be some loss of control or incomplete suppression of angiotensin II by ACE inhibitors. Many believe that bradykinin or other kinins are responsible for the cough and other side effects related to ACE inhibition, and the ELITE trial would appear to bear that out. It has been speculated that stimulation of angiotensin II type 2 receptors by the elevated levels of angiotensin II that follow type 1 receptor blockade may be beneficial. Little is known about the type 2 receptor, but preliminary evidence suggests that it may produce vasodilation and a number of other physiologic actions opposite to stimulation of type 1 receptors. Thus, unopposed stimulation of the angiotensin II type 2 receptors may be advantageous. This is clearly speculative.
In conclusion, the ELITE trial is encouraging in several ways. It clearly suggests that substitution of an ACE inhibitor with an angiotensin II receptor blocker may not only be safe, but is as effective as ACE inhibitor therapy for heart failure patients. The substantial decrease in all-cause mortality is not well explained and could be a quirk of the data. The authors point out that in two previous three-month studies enrolling approximately 350 patients, there was an unexpected reduction in mortality. Physicians should not substitute losartan for ACE inhibitors in patients who are doing well. However, the rather common problem of cough with the older class of drugs should be clinically tested with a trial of an angiotensin II blocker. Valsartan is also on the market, and other companies have angiotensin II receptor blockers in the pipeline. It is conceivable that, in the future, patients will be treated with a combination of both an ACE inhibitor and an angiotensin II blocker. I would not predict that the receptor blockers will turn out to be of greater benefit than the ACE inhibitors, but only time will tell. The ELITE trial certainly represents good news to patients with heart failure and their physicians but needs confirmation in far more subjects, including those less than 65 years of age.