Valsartan

The angiotensin receptor blocker (ARB) valsartan can be considered a clinically effective alternative to the ACE inhibitor captopril following myocardial infarction (MI) complicated by left ventricular dysfunction and/or signs and symptoms of heart failure. Adding valsartan to captopril under these circumstances does not further improve outcomes but increases the rate of adverse events compared with either monotherapy.

These were the main outcomes of a trial known as VALIANT (Valsartan in Acute Myocardial Infarction), the results of which were presented by Marc A. Pfeffer, MD, PhD, during the 2003 annual scientific sessions of the American Heart Association in Orlando.

"Valsartan in the dose we used should be considered as effective as the ACE inhibitor captopril in a proven dose in reducing the risk of death, cardiovascular death, the development of heart failure, and the development of subsequent MI," said Dr. Pfeffer, professor of medicine, Harvard Medical School, Boston.

VALIANT included 14,703 patients (mean age: 65 years) with acute MI complicated by a reduced left ventricular ejection fraction ([less than or equal] 35%), signs and symptoms of acute pulmonary congestion, or both. They were randomized beginning 12 hours to 10 days following their MI to receive captopril, valsartan, or the combination. Captopril monotherapy was titrated up to 50 mg three times daily, a dosage proven to reduce the risk of death and nonfatal cardiovascular events in clinical trials. Valsartan monotherapy was titrated to 160 mg twice daily. The group assigned to combination therapy was titrated up to 80 mg twice daily of valsartan and 50 mg three times daily of captopril.

Captopril was chosen as the comparator because it is the most extensively studied of the ACE inhibitors in the post-infarct period, said Dr. Pfeffer.

The study was designed to test whether valsartan alone or in combination with captopril offered a clinical advantage compared with captopril monotherapy. VALIANT was also designed with a noninferiority aspect to test whether valsartan alone can be considered as effective as the proven ACE inhibitor regimen.

At a median follow-up of 24.7 months, the mortality rates were 19.9% in the patients assigned to valsartan, 19.5% in those randomized to captopril, and 19.3% in those assigned to the combination. The intent-to-treat analysis showed no difference between valsartan and captopril monotherapy with respect to the primary outcome of all-cause mortality (hazard ratio: 1.00), and also no difference between combination therapy and captopril monotherapy in all-cause mortality (hazard ratio: 0.98). The incidence of the combined endpoint of cardiovascular death, reinfarction, or heart failure hospitalization also occurred with equal frequency among the three treatment groups.

"The noninferiority test showed that valsartan preserved 99.6% of the benefits of captopril," said Dr. Pfeffer. "This efficacy extended to all patient subgroups."

The need for dose reduction was similar in the captopril and valsartan monotherapy arms (43.0% vs. 43.1%, respectively), although the adverse drug profile was different in each group. As expected, patients randomized to captopril experienced side effects such as cough, rash, and taste disturbance significantly more often than patients randomized to valsartan, who experienced hypotension and renal dysfunction more often than the group treated with captopril.

"Patients receiving both drugs had the combination of these adverse events," said Dr. Pfeffer. "In the combination group, the rate of overall adverse events was greater, and more patients in the combination group discontinued the study medication."

By showing that valsartan is as effective as a proven regimen, "we're giving physicians and patients yet another tool to expand life-saving benefits for larger groups of patients," he said. "For those patients who have trouble taking ACE inhibitors, this is the perfect opportunity (to use valsartan), and then it becomes a matter of choice when there are equal alternatives." The choice between agents will depend on cumulative clinical experience, tolerability, safety, convenience, and cost.

Caution should be used in extrapolating the data from VALIANT to other ARBs and ACE inhibitors, said Bertram Pitt, MD, professor of internal medicine, University of Michigan, Ann Arbor. He noted that the doses of ACE inhibitors and ARBs are critical in achieving optimal outcomes in patients with acute MI and left ventricular dysfunction.

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