Late-Breaking Trials from the American Heart Association Annual Scientific Sessions

VALIANT

In the Valsartan in Acute Myocardial Infarction Trial (VALIANT) the angiotensin II receptor blocker (ARB) valsartan (V) was evaluated in 14,703 high-risk acute MI patients to determine its efficacy and safety profile compared to the ACE inhibitor captopril (C).

Subjects had to have clinical or radiographic evidence of heart failure (HF) or depressed LV systolic function, (EF < 35%); enrollment was on days 1-10 after admission. Target drug dosage was C 50 mg t.i.d. or V 160 mg b.i.d. Three study cohorts were established, each with 4900 patients: C alone, C + V, and V alone. The trial was event driven and lasted a mean of 24.7 months. The primary end point was all-cause mortality; secondary end points included cardiovascular death, recurrent MI, and HF hospitalization.

This was a multinational, multicenter trial, headed by Mark Pfeffer of Harvard Medical School and John McMurray from Glasgow, UK. VALIANT was carried out in 24 countries and 931 sites. The study population averaged 65 years of age; two-thirds were males, 75% were New York Heart Association classes II or III, and the mean ejection fraction was 35%. Two-thirds had a Q-wave MI; lytic therapy or primary percutaneous intervention (PCI) were performed in half of all subjects. Baseline prerandomization therapy included aspirin (91%), beta blockers (70%), and statins (34%). ACEI and ARB were stopped before enrollment.

Results

The C vs V and C + V comparisons were equivalent, with a 19% cumulative mortality and comparable hazard ratios. One-year mortality was 12-13% in each group (P = NS). Cardiovascular death, recurrent MI, and HF hospitalization were also equal in all 3 groups. There was a slight superiority of C + V and V alone vs C alone for recurrent MI or HF admission (P = .005).

V was considered to be noninferior (and nonsuperior) to C for all end points. Nineteen percent of C + V subjects were off the study drug at one year vs C (16.8%) and V (15.3%) alone (P = .007). Target dose was achieved in 56% of C patients, 47% of C + V patients, and 50% of V alone patients (P = NS); all were considerably lower than the trial goals. Concomitant beta-blocker therapy was tolerated well in both C groups. Hypotension resulting in dose reduction or discontinuation was more common in C + V (18%) vs C (12%) or V (15%) alone. The 2 C groups had a 5-7% rate of significant cough. Conversely, renal problems were greater in the 2 V groups at 6% each.

Pfeffer and associates concluded that V is safe and demonstrates equivalent efficacy to captopril alone. In the just-published VALIANT manuscript,1 they conclude that V " . . . should be considered a clinically effective alternative" to C.

Comment by Jonathan Abrams, MD

This is an important contribution to the ACEI/ARB battle and the heart failure randomized trial database. Of note, it strongly supports equivalent efficacy between V (an ARB) and C (an ACEI) for heart failure patients.

Several Caveats

The target doses were quite robust and unlikely to be widely used. Furthermore, only 55% of all subjects reached their target dosing. It seems (in my opinion) that ACEI are often underdosed in HF patients. It thus behooves physicians to strive to reach RCT doses in clinical practice. Furthermore, the equivalency and efficacy of other ACEI or ARB remain unclear.

The mean LV ejection fraction in the entire population of almost 15,000 subjects was 35%, higher than in SAVE and SOLVD. Thus, many VALIANT subjects must have had diastolic heart failure. VALIANT does not conclusively confirm that V would be as effective in patients with poor LV systolic function (eg, LVEF < 30%). Nevertheless, the recent CHARM studies are concordant with ARB efficacy over a wide range of LV function.

Adverse effects were not rare and clearly related to the mechanisms of action of the 2 drugs; careful monitoring of BP, renal function, and potassium seems appropriate if both drug classes are used.

The data appear to refute the unexpected finding in ValHEFT that triple therapy (ACEI, ARB, beta blocker) may be hazardous in the treatment of heart failure (however, LV function was worse in ValHeft). The take-home message is that V in an appropriate alternative to an ACEI (high dose) in post-MI heart failure. It is likely, but not proven, that different ACEI and ARBS would produce similar outcomes.

Reference

1. Pfeffer MA, et al. N Engl J Med. 2003;349:1893-1906.

Dr. Abrams, Professor of Medicine in the Division of Cardiology at the University of New Mexico in Albuquerque, is on the Editorial Board of Clinical Cardiology Alert.