Late-Breaking Trials: American Heart Association
December 1, 1999 6 minutes read
Late-Breaking Trials: American Heart Association
Conference coverage
Source: American Heart Association Annual Scientific Sessions, November 7-10, 1999, Atlanta, GA.
THE HOPE STUDY
The heart outcomes prevention evaluation (hope) trial randomized 9541 high-risk patients to the angiotensin-converting enzyme (ACE) inhibitor ramipril (10 mg/d) or placebo and vitamin E (400 IU/d) or placebo for a mean follow-up period of 4.5 years. This international study was carried out in 267 hospitals and 19 countries, with the majority of patients coming from the United States. The ramipril arm was stopped in early 1999 because of a favorable outcome for the ACE inhibitor; the vitamin E arm has continued. The study population consisted of individuals with documented coronary artery disease (CAD), cerebrovascular, or peripheral vascular disease. In addition, diabetics without vascular disease with at least one additional CAD risk factor were enrolled. All individuals were older than 55 years of age. Patients had no history of heart failure; hypertensives could be enrolled if blood pressure was controlled (46% had hypertension). Thirty-eight percent had diabetes, 11% had a previous stroke, 43% had peripheral vascular disease, and two-thirds had an elevated cholesterol level. Eighty-one percent of all patients had CAD, half with a prior myocardial infarction (MI). The results were striking, with a robust 20-25% reduction in relative risk favoring ramipril for all vascular end points. (See Table.) There was a 22% reduction in the primary end point of cardiac death, stroke, or nonfatal MI (17.7% vs 14.1%). There was a major decrease in stroke and in new heart failure as well as for revascularization. Of interest, new onset diabetes was decreased by 32% (P = 0.002). New renal dysfunction/dialysis or microalbuminuria was also decreased by ramipril. An echo substudy of approximately half the entire cohort (mean ejection fraction of 60%) demonstrated comparable risk reductions for all end points as the entire cohort. Higher risk patients had a greater reduction in events than those at lower risk. It was concluded that lowering of blood pressure only accounted for a small proportion of the decrease of MI and other end points; individuals in the highest quartile of baseline systolic blood pressure had the greatest risk reduction. The hypertensive and nonhypertensive patients had no difference in benefit from ramipril. Vitamin E had no effect on total mortality, cardiovascular deaths, or other end points.
Comment by Jonathan Abrams, MD
These data have already achieved considerable attention and were formally announced at the European Cardiac Society Meeting at the end of August. The benefits of the ACE inhibitor in individuals who ordinarily would not be treated with such a drug are impressive and concordant with a large amount of vascular biology research, endothelial function studies, and mechanistic hypotheses regarding prevention or slowing progression of vascular disease. These data raise the question as to whether all individuals who meet the HOPE criteria should be treated with an ACE inhibitor. Given that the entire cohort had an event rate of cardiac death, stroke, or MI of greater than 3% per year, it seems reasonable that for patients with documented vascular disease, representing the majority of the HOPE cohort, or individuals at high risk for future events (e.g., diabetics with risk factors or those with multiple CAD risk factors), ACE inhibitor therapy should be considered. There is considerable disappointment regarding the antioxidant hypothesis because of the null effects of vitamin E. Earlier data this year from the GISSI-3 trial were also negative in a large population given vitamin E. Some believe that the combination of vitamin E and vitamin C, or the use of different antioxidants, will be necessary to really test the oxidation hypothesis. Certainly, HOPE and GISSI-3 deflate the present enthusiasm for routine use of antioxidant vitamins.
| Table | ||||
| HOPE | End Points (Ramipril vs Placebo) | |||
| RAM (%) | PLAC (%) | P Value | RR | |
| CV death, MI, or stroke | 14.1 | 17.7 | 0.001 | 0.78 |
| All MI | 9.8 | 12.0 | 0.0005 | 0.80 |
| CV death | 6.0 | 8.0 | 0.0002 | 0.75 |
| NMFI | 5.9 | 7.5 | 0.0002 | 0.78 |
| Revascularization | 16.0 | 18.6 | 0.001 | 0.85 |
| All death | 10.3 | 12.2 | 0.003 | 0.83 |
| Stroke | 3.4 | 4.9 | 0.0002 | 0.68 |
| Nondiabetes | 3.7 | 5.3 | 0.002 | 0.68 |
| CHF | 9.2 | 11.7 | 0.002 | 0.77 |
| Note: The New England Journal of Medicine has taken the unusual step of premature electronic publication of this trial on its electronic website: (http://www.nejm.org/content/yusuf/1.asp). | ||||
BEST
Many knew something was amiss when the BEST report was canceled at the March 1999 American College of Cardiology meeting. When finally reported at the American Heart Association meeting, the problem was clear—the results were strikingly negative. BEST is a heart failure survival trial using the beta-blocker bucindolol. The study randomized 2708 mainly class III (92%) and class IV (8%) heart failure patients on standard therapy including ACE inhibitors to the nonselective beta-blocker or placebo and followed the patients for a mean of two years. Although bucindolol reduced deaths by 10% overall, this was not statistically significant and those with more advanced disease in particular did not benefit. Also, subgroup analyses showed that African-American patients did not benefit from bucindolol therapy (23% of the study population).
Carvedilol and metoprolol studies have been clearly positive. What went wrong with BEST? Discussion at the meeting focused on several issues. First, most of the other beta-blocker trials focused on class II patients, with some class IIIs and a few class IVs. In fact, carvedilol is not recommended in class IV or unstable patients even with lesser symptoms. Thus, beta-blocker therapy should perhaps be applied early rather than later in the course of heart failure. Second, bucindolol is nonselective like carvedilol, but bucindolol does not have much alpha-blocking properties like carvedilol does. Thus, perhaps the wrong beta-blocker was chosen for the trial. Third, the relative lack of effect in the African-American patients who comprised about a quarter of the patients may have reduced the results of an otherwise positive trial. Clearly, the Scandinavian metoprolol trials and the carvedilol studies done in southeastern Asia included few black patients. —mhc
ELITE II
ELITE I was a study of the effect of the angiotensin receptor blocker (ARB) losartan on renal function in elderly patients with heart failure, which surprisingly showed reduced mortality in the losartan group. Accordingly, an international, multicentered, randomized trial of losartan vs. captopril therapy in 3152 severe heart failure patients was undertaken (ELITE II). The results presented at the AHA meeting showed no difference in all-cause mortality between the two groups. Since these two therapies seem roughly equivalent, losartan could be used if the patient was intolerant to ACE inhibitor therapy, but ACE inhibitors remain the treatment of choice. Trials with other ARBs are under way, so we should have more data soon.
Clearly, this is a disappointment for the proponents of ARB therapy, which now has no primary indications. Their sole role seems to be a substitute for ACE inhibition when adverse effects preclude its use. Despite the theoretic advantage of blocking more of angiotensin’s effects on the body, in practice it seems to make little difference. Of interest were some early reports at this meeting of a new class of drugs called vasopeptidase inhibitors, which block ACE, bradykinin degradation, and atrial naturetic factor (ANF) metabolism, thus decreasing angiotensin II and increasing bradykinin and ANF. These drugs have a solid theoretic basis and look promising in initial studies, but again large clinical trials will be needed to establish their role, if any, in the treatment of hypertension, heart failure, and other circulatory diseases. —mhc
Which is most correct concerning late-breaking trials at the AHA meeting?
a. ACE inhibitors are beneficial in a wide range of vascular disease patients.
b. Beta blockers continue to show benefit in heart failure patients.
c. Angiotensin receptor blockers reduce mortality in heart failure patients.
d. All of the above
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