Correspondence

Vesnarinone for Heart Failure

N Engl J Med 1994; 330:64-66January 6, 1994

Article

To the Editor:

In the report by Feldman et al. (July 15 issue)1 we are concerned about the lack of agreement between the results of the two doses used in the trial. When the study was designed, it seemed plausible that the 120-mg dose would be more effective than the 60-mg dose. However, the opposite was found. We think it is important to combine the mortality data for the 87 patients receiving the higher dose of vesnarinone with those for the 239 patients receiving the lower dose, in addition to the analyses presented in the article. When this is done, it turns out that there were 33 deaths among the 238 patients in the placebo group (13.9 percent) and 29 deaths among the 326 patients in the two vesnarinone groups combined (9.9 percent; P = 0.085; relative risk, 0.79; 95 percent confidence interval, 0.60 to 1.04). In the article, it is mentioned that the time of death in the 120-mg group differed from that in the other two groups. We would also like to see life-table curves for the placebo group and all treated patients.

The authors must believe that the high dose of vesnarinone is deleterious, and the low dose beneficial. We do not think this is plausible.

Karl Swedberg, M.D., Ph.D.
Ostra Hospital, S-416 85 Goteborg, Sweden

Hans Wedel, Ph.D.
Nordic School of Public Health, S-402 42 Goteborg, Sweden

1 References

1. 1

   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;329:149-155
   Full Text | Web of Science | Medline

To the Editor:

The marked dichotomy between the results of 60 mg and the results of 120 mg of vesnarinone is fascinating. A more detailed description of the group of patients who received 120 mg would help us decide whether this drug is safe or not. Were all the excess deaths attributed to cardiac causes? Did they all involve arrhythmia? Were there any distinguishing features of the patients in the 120-mg group who died early?

David Neely, M.D.
Northwestern Medical Faculty Foundation, Chicago, IL 60611

To the Editor:

Packer's assertion in his editorial1 that vesnarinone “produces no hemodynamic effect whatsoever,” which is based on one pilot study of 17 patients (reference 7 in his editorial), contradicts the reported evidence from several trials. A substantial improvement in hemodynamics and contractile function has been reported in seven clinical trials involving patients with depressed cardiac function (references 21 through 25 and 42 in the article by Feldman et al. and reference 7 in Packer's editorial). Most of the studies used the 60-mg daily dose. In addition, in a study involving 34 patients with New York Heart Association class II to IV heart failure, vesnarinone at a dose of 30 or 60 mg per day increased the ejection fraction and decreased the left ventricular end-systolic volume2. In another study, vesnarinone at a dose of 60 mg per day caused a displacement of the end-systolic pressure-dimension relation to the left with a steeper slope, indicating a clear enhancement of contractile function3.

Although the positive inotropic activity of vesnarinone is minimal, these data provide unequivocal clinical evidence of such activity. More important, perhaps, are the inferences to be drawn from the presence or degree of positive inotropic activity with regard to the treatment of chronic heart failure. Irrespective of positive inotropic activity, phosphodiesterase inhibitors in general appear to be inappropriate for the treatment of chronic heart failure. On the other hand, the usefulness of digitalis and the relation of its efficacy to its positive inotropic activity have been amply demonstrated in countless cases over more than two centuries and reaffirmed by vigorous recent investigation4-6.

Surely it is time to counterbalance the phobia about positive inotropic agents exhibited by some physicians. Biases related to drug classification, like the bias suggested by the statement by Packer et al. that “the ideal `positive inotropic agent' may be one that exerts no positive inotropic effect at all,” may not be relevant once the data establishing the clinical efficacy of a drug are available. All drugs, but particularly drugs affecting cardiac performance, are aided by mechanisms other than those suggested by their official classification; digitalis is no exception, nor is vesnarinone.

Arnold Schwartz, M.D.
University of Cincinnati Medical Center, Cincinnati, OH 45267

6 References

1. 1

   Packer M. The search for the ideal positive inotropic agent. N Engl J Med 1993;329:201-202
   Full Text | Web of Science | Medline

2. 2

   Inoue M, Hori M, Yasuda H, et al. A multicenter study of a new inotropic agent, piperanometozine (OPC-8212) in congestive heart failure: clinical improvement during short-term treatment. Cardiovasc Drugs Ther 1987;1:169-175
   CrossRef | Medline

3. 3

   Asanoi H, Sasayama S, Kameyama T, Ishizaka S, Iuchi K. Sustained ionotropic effects of a new cardiotonic agent: OPC-8212 in patients with chronic heart failure. Clin Cardiol 1989;12:133-138
   CrossRef | Web of Science | Medline

4. 4

   Moss AJ, Davis HT, Conard DL, DeCamilla JJ, Odoroff CL. Digitalis-associated cardiac mortality after myocardial infarction. Circulation 1981;64:1150-1156
   CrossRef | Web of Science | Medline

5. 5

   Smith TW. Digoxin in heart failure. N Engl J Med 1993;329:51-53
   Full Text | Web of Science | Medline

6. 6

   Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. N Engl J Med 1993;329:1-7
   Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: In response to the assertion of Drs. Swedberg and Wedel regarding expectations for the 120-mg dose of vesnarinone: we did not expect 120 mg to be more effective than 60 mg. We had no prospective information that a 120-mg dose of vesnarinone was effective. Indeed, compelling evidence from studies of other inotropic agents1-3 suggested that higher doses might be deleterious. Therefore, after considerable debate, we designed our study to identify the upper limits of both safety and efficacy. However, we remained alert to the potential adverse effects at the higher dose, conducting close surveillance and promptly discontinuing the higher dose when adverse effects were observed.

We strongly disagree with Swedberg and Wedel's suggestion that the mortality data for the two treatment groups be combined. The protocol required pairwise group comparisons, and it was this comparison of 120-mg vesnarinone with placebo that led to the discontinuation of the high dose. Since the 120-mg dose of vesnarinone resulted in treatment failure, the study was modified to provide a valid comparison of only 60 mg of vesnarinone with placebo. Therefore, it would not be statistically valid to combine the two original treatment groups retrospectively.

It is surprising that Swedberg and Wedel do not find the disparity between the 120-mg and 60-mg doses plausible, since virtually all pharmacologic agents have a narrow range of therapeutic efficacy in patients with heart failure: doubling the dose of warfarin sodium, diuretics, digoxin, or angiotensin-converting-enzyme inhibitors results in untoward responses in most cases. We therefore believe that high-dose vesnarinone is harmful, just as high doses of milrinone,1 enoximone,2 pimobendan,3 and flosequinan are harmful.

In reply to Dr. Neely: base-line characteristics of the 120-mg group were indistinguishable from those of the other groups. However, all 8 of the 16 patients in the 120-mg group who died within the first six weeks of therapy died suddenly, as compared with only 50 percent of those who died after six weeks of therapy. These results have led us to hypothesize that the higher-than-expected death rate with 120-mg vesnarinone may be due to proarrhythmic effects at high doses.

Arthur M. Feldman, M.D., Ph.D.
Johns Hopkins University School of Medicine, Baltimore, MD 21205

Michael R. Bristow, M.D., Ph.D.
University of Colorado Health Sciences Center, Denver, CO 80462

William W. Parmley, M.D.
University of California, San Francisco, San Francisco, CA 94122

3 References

1. 1

   Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 1991;325:1468-1475
   Full Text | Web of Science | Medline

2. 2

   Uretsky BF, Jessup M, Konstam MA, et al. Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure: lack of benefit compared with placebo. Circulation 1990;82:774-780
   CrossRef | Web of Science | Medline

3. 3

   Kubo SH, Gollub S, Bourge R, et al. Beneficial effects of pimobendan on exercise tolerance and quality of life in patients with heart failure: results of a multicenter trial. Circulation 1992;85:942-949
   Web of Science | Medline

Author/Editor Response

The studies cited by Dr. Schwartz to support his contention that vesnarinone acts as a positive inotropic agent in patients with heart failure evaluated only short-term treatment with high doses of the drug or measured its effects with noninvasive techniques, which are limited in their ability to assess changes in cardiac performance accurately. In contrast, the two studies that have evaluated the long-term effects of low doses of vesnarinone (60 mg daily) with invasive techniques have shown no improvement in ventricular function in patients treated with the drug. Only one of these studies1 was cited in my editorial. The other -- a recently completed, placebo-controlled study performed as part of the trial by Feldman et al. -- could not show any beneficial hemodynamic effect of vesnarinone (Gilbert EM: personal communication), although the drug reduced mortality in the main trial.

Despite these findings, low doses of vesnarinone might still exert a small positive inotropic effect, but even if this were so, the resulting hemodynamic improvement would clearly be less than that produced by vasodilator drugs or angiotensin-converting-enzyme inhibitors. Yet the reduction in mortality associated with low doses of vesnarinone appears to be much greater than that associated with vasodilators or angiotensin-converting-enzyme inhibitors2,3. Thus, the improvement in survival with vesnarinone cannot be explained solely by its hemodynamic actions but must be related to another pharmacologic effect of the drug.

Although he recognizes the importance of this noninotropic effect, Schwartz still refers to vesnarinone as a positive inotropic agent. Such a classification may be convenient, but it does not serve a useful purpose if it fails to provide insight into how the drug actually works in the treatment of heart failure. The problem is not academic, and it is not confined to vesnarinone. For example, in considering the therapeutic effect of aspirin in cardiovascular medicine, is it appropriate to classify the drug as an analgesic agent (which it is at high doses) if its ability to relieve pain cannot explain its ability to reduce the risk of myocardial infarction (which occurs at low doses)? Such a misclassification carries two risks. In the case of aspirin, it may lead physicians to believe that other analgesic agents are useful in the treatment of ischemic heart disease, but more important, it may inhibit the vigorous search for the specific property (its antiplatelet effect) that is responsible for the cardiovascular benefits of the drug. Such a search is especially important with respect to vesnarinone. If the mechanism responsible for its effect on mortality can be identified and addressed selectively, it may be possible to develop a new drug that offers the source benefits without the narrow toxic-therapeutic ratio or risk of leukopenia associated with vesnarinone.

Milton Packer, M.D.
Columbia University College of Physicians and Surgeons, New York, NY 10032

3 References

1. 1

   Kubo SH, Rector TS, Strobeck JE, Cohn JN. OPC-8212 in the treatment of congestive heart failure: results of a pilot study. Cardiovasc Drugs Ther 1988;2:653-660
   CrossRef | Web of Science | Medline

2. 2

   The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-1435
   Full Text | Web of Science | Medline

3. 3

   Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-1552
   Full Text | Web of Science | Medline

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