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Therapeutics

Vesnarinone for congestive heart failure

ACP J Club. 1994 Jan-Feb;120:2. doi:10.7326/ACPJC-1994-120-1-002


Source Citation

Feldman AM, Bristow MR, Parmley WW, et al. Effects of vesnarinone on morbidity and mortality in patients with heart failure. N Engl J Med. 1993 Jul 15;329:149-55.


Abstract

Objective

To investigate the effect of vesnarinone, an oral inotropic agent, on mortality, morbidity, and quality of life in patients with congestive heart failure (CHF).

Design

Randomized, double-blind, placebo-controlled trial with 6-month follow-up and interim analyses.

Setting

22 hospitals in the United States.

Patients

Patients were enrolled if they were > 18 years old, had evidence of left ventricular dysfunction despite conventional therapy, and had an ejection fraction of ≤ 0.30 as determined by radionuclide scanning (mean ejection fraction, 0.20). Exclusion criteria were postpartum cardiomyopathy, myocardial infarction, cardiac surgery, history of cardiac arrest, presence of an implantable defibrillator, serum digoxin > 1.8 g/L, serum creatinine > 212 mmol/L, or predisposition to neutropenia. Follow-up was 93%. 70% of patients were New York Heart Association class III.

Intervention

Patients initially received vesnarinone, 60 or 120 mg/d, or placebo. Interim analysis showed higher early mortality in patients taking high-dose vesnarinone, and these patients were removed from the study. 239 patients were assigned to receive vesnarinone, 60 mg/d, and 238 patients were assigned to receive placebo.

Main Outcome Measures

All-cause mortality and major cardiovascular events (cardiac death or hospitalization for worsening CHF that required intravenous inotropic therapy). Quality of life was measured by the Sickness Impact Profile at baseline and at week 12.

Main Results

Using intention-to-treat analysis, patients taking vesnarinone, 60 mg/d, compared with those taking placebo, had less all-cause mortality (13 [5%] vs, 33 [13%] deaths {95% CI for 8% difference 3% to 14%}*, P = 0.002), had fewer major cardiovascular events (26 [11%] vs, 50 [21%] {CI for 10% difference 4% to 17%}*, P = 0.003), and had greater improvement in quality-of-life scores (P = 0.008). A committee judged that 9 patients (4%) discontinued vesnarinone because of drug-related adverse events (6 because of reversible neutropenia); no patient receiving placebo had such events ({CI for the 4% difference, 1% to 6%}*, P < 0.01).

Conclusion

Although vesnarinone, 120 mg/d, significantly increased mortality, 60 mg/d decreased all-cause mortality and major cardiovascular events and increased quality of life in patients with congestive heart failure.

Source of funding: Otsuka America Pharmaceutical.

For article reprint: Dr. A.M. Feldman, Peter Belfer Cardiac Laboratories, Department of Medicine, Johns Hopkins University School of Medicine, Richard S. Ross Research Building, Room 835, 720 Rutland Avenue, Baltimore, MD 21205. FAX 410-955-7953.

*Numbers calculated from data in article.


Commentary

Inotropic agents can provide substantial symptomatic relief in patients with severe CHF. With the possible exception of digoxin (currently being examined in the National Heart, Lung, and Blood Institute digoxin trial), however, all previous inotropic agents investigated increased mortality (1, 2).

Although the mechanism for increased mortality is not clear, the results seem uniform. Even the agent currently reported, vesnarinone, had an early and potent 2-fold increase in mortality at the higher dosage range, similar to flosequinan, which was recently withdrawn from the market in the United States. It may be that past failures with other inotropic agents represent a lack of recognition of a narrow therapeutic range. Vesnarinone does have some pharmacologic differences from other inotropic agents, but the clinical relevance of these remain undetermined.

An important adverse effect of vesnarinone has been leukopenia. This appears to occur in a small number of patients from 4 to 16 weeks after initiation of therapy and appears to be reversible. Careful monitoring during this time frame may minimize the seriousness of this side effect.

What then is the potential role for vesnarinone in heart failure therapy? Angiotensin-converting-enzyme (ACE) inhibitors and, to a lesser extent, the combination of hydralazine and nitrates remain the primary agents for mortality reduction in CHF. Patients who remain severely symptomatic despite appropriate doses of the triple regimen of ACE inhibitors, diuretics, and digoxin might be candidates for vesnarinone. Although the present results are encouraging, further study and experience will tell whether vesnarinone is truly better than previous inotropic agents that also looked promising initially.

Dalane W. Kitzman, MD
Bowman Gray School of Medicine of Wake Forest University Winston-Salem, North Carolina, USA