New Treatment Alternative for High-risk Patients After Heart Attack
ORLANDO -- Two blood pressure-reducing drugs have shown equivalent survival benefits for patients at high risk after a heart attack, researchers announced today (Nov. 10 2003) at the 2003 Scientific Sessions of the American Heart Association. The results of the study were also published today in the New England Journal of Medicine.
"This knowledge should greatly improve the survival of the 40 percent of Americans who will have pump dysfunction after a myocardial infarction this year alone, up to half of whom receive neither drug tested in this study, " said cardiologist Robert M. Califf, M.D., director of the Duke Clinical Research Institute (DCRI), the study's coordinating center.
Under the direction of the coprincipal investigators, Marc Pfeffer, M.D., Brigham and Women's Hospital, Boston, and John McMurray, M.D., Western Infirmary in Glasgow, researchers analyzed 14,703 patients who had had a heart attack, or myocardial infarction (MI), within the previous ten days and who had signs of heart failure, pumping difficulty, or both.
The study is known as the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial.
Patients at 931 centers in 24 countries were evenly and randomly assigned to receive valsartan, an angiotensin II receptor blocker (ARB); captopril, an angiotensin-converting enzyme (ACE) inhibitor; or both. The doses of the drugs were to be gradually increased to their full strength over 90 days.
The primary outcome of the study was death from any cause over the follow-up period, which was to continue until at least 2,700 deaths had occurred. The primary comparisons of the trial tested valsartan vs. captopril and the combination of the two drugs versus captopril. If no treatment emerged as superior in these comparisons, then the researchers were to test the noninferiority of valsartan versus captopril.
Over the median follow-up period of 25 months, the mortality rates in the valsartan, captopril, and combination groups were 19.9 percent 19.5 percent, and 19.3 percent, respectively, none of which differed significantly from the others. The rates of a composite endpoint -- cardiovascular death, repeat heart attack, heart failure, resuscitation for cardiac arrest, or stroke -- also did not differ significantly, at 32.8 percent, 33.4 percent, and 32.3 percent, respectively. (For comparison, the rates with placebo in comparable trials have been about 25 percent for mortality and 42 oercent for the composite endpoint at two years.)
In the noninferiority analysis, the ARB valsartan was no less effective than captopril in reducing the risk of death in these patients, maintaining 99.6 percent of the benefit of the ACE inhibitor captopril. This pattern was repeated for the composite outcome and among subgroups of patients based on age, sex, and previous medical conditions and treatments.
"Although none of the treatments showed clear superiority, the newer agent, valsartan, did at least as well as captopril in benefiting these very high-risk patients," Califf said. "The study also shows that the doses chosen (160 mg of valsartan twice daily and 50 mg of captopril three times daily) are safe while providing these benefits."
The treatments were generally tolerated well. The highest rate of treatment discontinuation because of adverse events occurred in the combination-treatment group (9 percent), and the lowest, in the valsartan group (5.8 percent). The most frequent adverse events were low blood pressure and kidney impairment in the valsartan group and low blood pressure and cough in the two groups that received captopril. Overall, significantly more patients in the captopril group stopped treatment compared with the valsartan group.
"At the end of the day, this trial shows that we have a valuable alternative in the treatment of patients with pump dysfunction after MI," said Califf. "Further, it is only through large-scale, adequately powered collaborative trials such as VALIANT that we can make such statements with confidence."
The DCRI coordinated VALIANT, the largest study of heart attack survivors to date, and performed the data analysis.
The study was sponsored by Novartis Pharmaceuticals, East Hanover, NJ. In addition to Califf, Braunwald, and McMurray, the trial's Executive Committee included Aldo Maggioni, M.D., of ANMCO Research Center in Florence, Italy; Jean-Lucien Rouleau of the Montreal Heart Institute; Frans Van de Werf of the Leuven Coordinating Center in Leuven, Belgium; and Eric Velazquez, M.D., of the DCRI.
The DCRI is the largest academic research organization in the world. Affiliated with Duke University Medical Center, the DCRI's mission is to develop and share knowledge that improves the care of patients around the world through innovative clinical research. The DCRI combines the clinical expertise and academic leadership of a premier teaching hospital with the full-service operational capabilities of a major contract research organization.
The full results of the VALIANT study are being published simultaneously online by the New England Journal of Medicine, at http://www.nejm.org. Further information about the VALIANT study also is available online at http://www.dcri.org/research/presentations.jsp.