VALIANT Results Suggest ARBs as Effective as ACE Inhibitors Post-MI

Peggy Peck

November 10, 2003

Nov. 10, 2003 (Orlando) -- Valsartan is as effective as captopril in reducing mortality and morbidity after myocardial infarction (MI), but combining the two drugs does not improve outcome and increases the risk of adverse events, according to results of the 14,808-patient Valsartan in Acute Myocardial Infarction Trial (VALIANT).

Results of the study were presented here today at a late-breaking clinical trials session at the American Heart Association Scientific Sessions and simultaneously published by the New England Journal of Medicine ( NEJM).

Principal investigator Marc A. Pfeffer, MD, PhD, professor of medicine at Harvard Medical School in Boston, Massachusetts, told Medscape that the results represent the first time that an angiotensin receptor blocker (ARB) "has demonstrated that it is as good an ACE inhibitor in this high-risk population. Moreover, it demonstrated equivalence against a clinically proven dose of captopril, 6.25 mg. This means that we now have two ways to save lives."

Just as important, he said, is the finding that "combining the drugs does not increase benefit. This is an important observation since in daily practice physicians are routinely prescribing this combination."

Dr. Pfeffer emphasized that at every endpoint -- mortality, repeat MI, or development of congestive heart failure -- valsartan was as effective as captopril.

Raymond Gibbons, MD, chairman of the AHA program committee and professor of medicine at Mayo Medical School, Mayo Clinic and Foundation, in Rochester, Minnesota, said that Dr. Pfeffer "nicely summarized the scientific importance of this study.... Until now the evidence indicated that an ACE inhibitor was the preferred agent post-MI. Now we have evidence that ARBs also work in this population. I think in time this will change clinical practice and in time it will also be reflected in practice guidelines.

Rodman D. Starke, MD, former scientific director of the AHA, told Medscape that "the statistical evidence is there, so the agents do appear to be equivalent. I agree that this will probably be reflected in clinical practice."

Within 0.5 to 10 days of acute MI, patients were randomized in a 1:1:1 ratio to receive valsartan monotherapy (4,909 patients), valsartan plus captopril (4,885 patients) or captopril monotherapy (4,909 patients). All patients also had either clinical or radiological signs of heart failure, left ventricular ejection fraction of less that 35%, or both.

Doses were increased while patients were hospitalized until patients reached the dose of 80 mg of valsartan twice a day, 40 mg of valsartan twice a day plus 25 mg of captopril three times a day, or 25 mg of captopril three times a day. After discharge, dose was increased to 160 mg valsartan twice daily, 80 mg of valsartan twice daily and 50 mg of captopril three times a day, or 50 mg of captopril three times a day. Patients were enrolled from December 1998 through June 2001 and followed for a median of 24.7 months.

There were 979 deaths in the valsartan group (19.9%), 958 deaths in the captopril group (19.5%), and 941 deaths in the combined therapy group (19.3%).

But while valsartan demonstrated clinical efficacy, it is nonetheless significantly more expensive than captopril, according to an editorial that accompanies the study in NEJM. "Given that ACE inhibitors have been shown to reduce the risk of death and nonfatal events after acute MI in 100,000 patients, whereas the clinical experience with angiotensin-receptor blockers has been more limited," write Douglas L. Mann, MD, and Anita Deswal, MD, MPH, "and given that, in the United States, the cost of using valsartan at the doses in the study by Pfeffer et al. is approximately four to six times as high as the cost of using generic captopril at the doses used in this study, ACE inhibitors remain the logical first-line therapy for high risk patients after acute myocardial infarction."

In an interview, Dr. Pfeffer countered by pointing out that ACE inhibitors are often not well tolerated by patients. "It is not only a question of which drug, but of which drug will the patient really use and continue to use for the rest of his or her life," he said. In practice, he suggested that valsartan is a good option "first for patients who don't achieve the desired response with an ACE inhibitor and second for those patients who stop taking their ACE inhibitor because they can no longer tolerate the drug." In addition, he noted that in the real world of clinical practice many physicians are not prescribing generic captopril, but rather newer — and more expensive — ACE inhibitors such as ramapril.

Novartis, the maker of valsartan, funded the study.

AHA 2003 Scientific Sessions: Late-breaking clinical trials. Presented Nov. 10, 2003.

N Engl J Med. Published online Nov. 10, 2003.

Reviewed by Gary D. Vogin, MD