Angiotensin converting enzyme inhibitors (ACEI) have been shown to decrease morbidity and mortality in patients with congestive heart failure and post myocardial infarction. The beneficial effects of ACEI are attributed to a decrease in angiotensin II levels but also, possibly, to a decrease in the breakdown of bradykinins and thus to an increase in bradykinin levels. Elevated bradykinin levels may also be responsible for some of the adverse effects of ACEI, including cough and angioedema.
Blockade of the angiotensin II type 1 receptor can produce some of the effects of ACEI, without increasing bradykinin levels. Thus, these agents could be beneficial in CHF, without producing the ACEI side-effects related to elevated bradykinin levels, assuming the elevation of bradykinins is not the main mechanism behind the beneficial effects of ACEI in CHF.
This study was designed to look at the effect of an angiotensin II type 1 receptor antagonist, losartan, versus the ACEI captopril in the setting of CHF in an elderly patient population. The primary endpoint was the effect on renal function; secondary endpoints included mortality and worsening of CHF.
Multiple exclusion criteria. Primarily:
Patients were assessed weekly during the titration phase, then every
Other endpoints included all-cause mortality, hospitalization for worsening heart failure, the combination of these two endpoints (mortality and/or admission for CHF), drug withdrawal and side-effects (hypotension, cough, hyperkalemia), worsening CHF and admission for ischemic heart disease.
The study was designed with 90% power to detect a 40% reduction in renal events, assuming a rate of 30% in the captopril group. Patients were stratified according to age (under or over 70 years).
Baseline characteristics were well matched between the two groups. Some
characteristics include (numbers are for both groups pooled, unless otherwise
Total mortality was 4.8% in the losartan group, vs. 8.7% in the captopril group (p=0.035). Taking into account age stratification, the risk reduction was 0.46 (95% CI 0.05-0.69). This reduction was seen in all subgroups, except among women.
Hospital admissions for CHF were 5.7% in both groups. Improvement in
NYHA functional class was similar in the two groups; the number of patients
in class I or II increased from 66% to 80% in the losartan group, and from
64% to 81% in the captopril group.
The authors note that, although no significant difference was found between the two treatment groups in the primary endpoint (renal dysfunction), there was a significant decrease in all-cause mortality in the losartan group compared with the captopril group. The survival benefit for losartan occurred early and was consistent across all sub-groups except among women.
Although the discontinuation rate for captopril was much higher than for losartan, they argue that this was not the reason for the beneficial effect of losartan on mortality, since that effect was seen primarily in patients who remained on the study drugs.
As a result, two questions arise. First, how do these two agents compare as monotherapy for CHF? Second, is any advantage to be obtained by combining them? The current study sheds some light on the first question.
I have one methodological question about the data presented in this study. In the table which lists the primary reason for discontinuation of study medication before completion of the study, death is listed as a reason for 1 patient in the losartan group and for 5 patients in the captopril group. There were, however, 17 deaths in the losartan group and 32 in the captopril group. Why are most of these deaths not included here? There are two possible explanations for this, as far as I can tell. The first explanation is that most of the patients who died had already discontinued the drug for other reasons. The second explanation is that most of the deaths occurred after the study period had ended. Neither of these explanations is supported by the text of the study. The authors state that the difference in mortality was observed "predominantly in patients who remained on study therapy". Furthermore, the mortality data was presented as data during the study period, and it is noted that the survival benefit occurred early in the course of the study. Thus, this discrepancy remains unexplained as far as I can tell.
Assuming that this discrepancy does not represent a major problem, what are the practical implications of this study? Since mortality was not the primary endpoint of this study, and since there is much more data available on the efficacy of ACE inhibitors in the treatment of CHF and LV dysfunction, this study alone does not justify the use of angiotensin receptor antagonists as primary treatment for CHF; more studies of this question will be required. On the other hand, the results do suggest that, for patients with CHF who cannot tolerate ACE inhibitors because of cough or other side-effects, the use of a receptor antagonist may be an attractive alternative to the hydralazine/nitrates combination. It must be emphasized, however, that this is currently not an FDA-approved indication for losartan. Hopefully this issue will soon be clarified, given the fairly large number of patients with CHF who cannot tolerate ACE inhibitors.
Whether or not adding a receptor antagonist to an ACE inhibitor
will confer added benefit in patients with congestive heart failure is
another intriguing question, one which is being investigated in at least
one ongoing trial (1).
March 30, 1997
What are the current FDA indications for the drug and how much does
Date: Wed, 30 Apr 1997
From: Mario Ruiz <firstname.lastname@example.org>
An interesting finding that opens up interesting questions. Granted there are other mechanisms that contribute to the formation of Angiotensin I to II other than ACE. In fact, there is suggestion that a "chimase" enzyme actually produces 70% of the ANG II in the body whereas ACE contributes 30%. So there might be other mechanisms that we still don't understand that would allow an ANG II receptor blocker to affect something like "sudden death" that, based on our current understanding of the agent, it should not do. It really opens up the door to more research. Can an ANG II receptor blocker somehow stabilize the myocardium to make it less prone to sudden death?
On a second note, if you look at the Table 3 which lists endpoint measurements, you'll note that the Captopril group was admitted to the hospital significantly more for "any reason". Could this in fact mean that this population of patients was in fact different...i.e. they were sicker from other illnesses? It would be interesting as to what they were all admitted for. Maybe, these extra admissions provide a confounding bias as to a real difference between these two separate patient populations.
Also of interest is the fact that the women in the study did not reap the protective effects of the ANG II receptor blockers. Can anyone provide me with some logic to this finding? The future studies with ANG II receptor blockers should prove interesting....
-Mario Ruiz, M.D.
The effects of angiotensin converting enzyme inhibition and of angiotensin II receptor blockade are, as you point out, potentially quite different. I would not place too much emphasis on the specific cause of death (sudden vs. non-sudden), however, since these are often arbitrarily determined. I believe there is a general trend away from these sorts of classification and towards emphasizing all-cause mortality. There was an editorial on this topic in a recent Lancet (March 8, 1997), a propos the CAMIAT and EMIAT trials of amiodarone.
As you note, there were 20 hospital admissions for heart failure in the Losartan group vs. 21 in the captopril group, but there were 78 vs. 110 admissions "for any reason" (p=0.014). This is troubling and could imply a sicker patient population. Certainly, it would have been interesting to know more about these admissions.
The death rate among women was 9/118 in the Losartan group vs. 8/122 in the captopril group. No speculation was given about a cause for this result.
Date: Sun, 21 Dec 1997
From: Paul V Knight <email@example.com>
Could somebody tell me if there is any cross sensitivity between ACEI and Angiotensin II blockers? Specifically in relation to the generation of angio oedema. In other words if someone has had this reaction with an ACEI is it safe to give them Losartan?
Paul V Knight MB FRCP
Referring to the ELITE study. The doses of losartan & captopril were titrated. Does this mean the study was not blinded?
Dr. C. J. Martin
Laindon Health Centre,
Patients were randomized to either captopril (three times a day) plus losartan placebo or losartan plus captopril placebo (three times a day). This way, titration could be achieved in a blinded fashion. -- mj
Why would this drug-company sponsored trial use captopril as a comparison instead of enalapril or ramipril? Maybe because they wanted a "lesser" drug as a comparison to make their drug look better?
Terrace Bay, ON, Canada
Possibly, but I think it's more likely this drug was chosen because it's been most extensively studied in terms of mortality in CHF. Certainly, the target dose was adequate, and other ACE inhibitors, although easier to take, are probably not more effective. -- mj
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1. Pitt B, Chang P, Grossman W, Dunlay M, Timmermans P. Rationale, background, and design of the randomized angiotensin receptor antagonist--angiotensin-converting enzyme inhibitor study (RAAS). Am J Cardiol 1996; 78:1129-1131
References related to this article from the NLM's PubMed database.
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