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Background Inotropic therapy, other than with digitalis glycosides, has had limited success in patients with chronic congestive heart failure. We investigated whether vesnarinone, a new positive inotropic agent, reduces morbidity and mortality and improves the quality of life of patients with symptomatic heart failure.
Methods Patients receiving concomitant therapy with digoxin (87 percent) and an angiotensin-converting-enzyme inhibitor (90 percent) who had ejection fractions of 30 percent or less were randomly assigned to receive double-blinded therapy with 60 mg of vesnarinone per day, 120 mg of vesnarinone per day, or placebo. After 253 patients had been enrolled, randomization to the 120-mg vesnarinone group had to be stopped because of a significant increase in early mortality in this group. Thereafter, patients were randomly assigned only to 60 mg of vesnarinone per day (a total of 239 patients) or placebo (a total of 238 patients).
Results Significantly fewer patients in the group receiving 60 mg of vesnarinone than in the group receiving placebo (26 vs. 50 patients; P = 0.003) died or had worsening heart failure during the six-month study period. The reduction in risk was 50 percent (95 percent confidence interval, 20 to 69 percent). Similarly, there was a 62 percent reduction (95 percent confidence interval, 28 to 80 percent) in the risk of dying from any cause among the patients receiving vesnarinone. Furthermore, quality of life improved to a greater extent in the vesnarinone group than in the placebo group over 12 weeks (P = 0.008). The principal side effect associated with vesnarinone was reversible neutropenia, which occurred in 2.5 percent of the patients.
Conclusions Six months of therapy with 60 mg of vesnarinone per day resulted in lower morbidity and mortality and improved the quality of life of patients with congestive heart failure. However, a higher dose of vesnarinone (120 mg per day) increased mortality, suggesting that this drug has a narrow therapeutic range; the long-term effects of vesnarinone are unknown.
Vesnarinone (OPC-8212; 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone), a quinolinone derivative, is an oral inotropic agent that augments myocardial contractility in model systems, with little effect on the heart rate or myocardial oxygen consumption15. The mechanisms of action associated with the inotropic properties of vesnarinone in animals include a decrease in the delayed outward and inward rectifying potassium currents16; an increase in intracellular sodium caused by the prolonged opening of sodium channels17; and an increase in the inward calcium current attributable to the mild inhibition of phosphodiesterase18,19. In contrast to agents that act exclusively by increasing the levels of cyclic AMP, vesnarinone slows the heart rate, prolongs the action potential, and suppresses the delayed outward potassium current16,20.
In studies without concomitant placebo groups, vesnarinone improved hemodynamic indexes and exercise capacity21,22,23. Moreover, two randomized, placebo-controlled trials suggested that vesnarinone improves both the quality of life and the combined end point of mortality and major cardiovascular morbidity in patients with heart failure24,25. Although the results of these studies were encouraging, they involved relatively small patient populations, and the use of vesnarinone was associated with reversible neutropenia. We therefore designed the present study to clarify the risks and benefits of vesnarinone in a larger population.
Methods
Organization of the Study
The study was a randomized, double-blind, placebo-controlled trial involving 22 study centers. The study was directed by an executive committee responsible for documenting all the major end points. Data were analyzed by the coordinating center at the George Washington University Biostatistics Center. The coordinating center held the treatment codes of the randomly assigned patients and presented four interim analyses to the data and safety monitoring committee using a protocol-defined monitoring procedure. The coordinating center and the data and safety monitoring committee functioned independently of the study sponsor. The protocol was approved by the institutional review board of each participating center, and all the patients gave informed consent.
Patient Eligibility
Patients over the age of 18 years were eligible for enrollment if they had symptoms of left ventricular dysfunction despite conventional therapy and an ejection fraction of 30 percent or less as determined by radionuclide scanning. The criteria for exclusion have been reported previously25. In addition, patients were excluded from the study if they met any of the following criteria: a diagnosis of postpartum cardiomyopathy, a myocardial infarction, or cardiac surgery within the previous three months; a history of cardiac arrest; the presence of an implantable defibrillator; a serum digoxin level of more than 1.8 µg per liter; and a serum creatinine level of more than 2.4 mg per deciliter (212 µmol per liter). Because of the risk of neutropenia associated with vesnarinone,23 additional exclusion criteria included factors associated with drug-induced hematotoxicity: a history of lupus erythematosus or other lupus-like syndromes, treatment with the antiarrhythmic agent tocainide, a history of drug-induced neutropenia, an influenza vaccination within the previous three months, and an absolute neutrophil count of less than 2000 per cubic millimeter.
Study Design
Before randomization, the patients entered a two-week stabilization period during which they underwent three physical examinations, standard electrocardiography, 48-hour ambulatory electrocardiography, echocardiography, and radionuclide scanning. At least two upright-bicycle exercise tests were performed during the stabilization period. Patients were excluded from the study if the total exercise times in two successive tests differed by more than 20 percent or if exercise was accompanied by depression of more than 2 mm in the ST segment.
Using a permuted-block design,26 we randomly assigned eligible patients to receive 60 mg of vesnarinone per day, 120 mg of vesnarinone per day, or placebo for six months. The randomization was stratified according to clinic, and within clinics according to whether the patient was receiving digoxin. After 253 patients had entered the trial, randomization to 120 mg of vesnarinone per day was discontinued, and the patients receiving 120 mg per day were withdrawn from the trial. Patients continued to be assigned to placebo or 60 mg of vesnarinone per day until the goal for sample size had been reached. The trial then continued until all the patients had completed six months of follow-up.
Clinical evaluations were performed monthly, electrocardiography was performed at each of the first three monthly visits, and radionuclide scanning was repeated at week 12. Blood-chemistry profiles were obtained every two weeks, and hematologic profiles were obtained weekly. Determinations of New York Heart Association (NYHA) classifications were made by the study coordinators. Quality of life was assessed with the Sickness Impact Profile27 at base line and at week 12 by means of a telephone interview. Values are presented as changes in the base-line scores after 12 weeks of therapy; lower scores indicate an improved quality of life.
Follow-up and Outcomes Analysis
The prospectively defined primary outcome variable was the combined end point of major cardiovascular morbidity or mortality from any cause. For this analysis, major cardiovascular morbidity was prospectively defined as admission to a hospital for the treatment of worsening congestive heart failure requiring therapeutic doses of an intravenous inotropic agent for at least four hours. Analysis of the secondary end point of mortality from any cause included all patients and ignored events (e.g., morbidity) before death. Information about outcomes at six months was obtained from all the patients who withdrew from the study. After an initial classification of deaths by the individual principal investigators, all deaths were reviewed blindly by the executive committee and reclassified if necessary28.
Statistical Analysis
The study was originally designed to assign 150 patients to each of the three treatment groups. After the 120-mg group, to which 87 patients had been assigned, was discontinued, the study design was modified to involve a total of 450 patients (225 patients per group) on the basis of a standard determination of sample size29.
Data analysis was performed at the Biostatistics Center of George Washington University with use of SAS30 and StatXact31 software. Dichotomous and polychotomous base-line characteristics of the randomized groups were compared by Fisher's exact test32. Ordinal and continuous base-line characteristics and the distribution of the changes in quality of life, ejection fraction, and NYHA classification were compared by a Wilcoxon rank-sum test33. Patients who died before week 12 were assigned the worst possible score. For the time-to-event end points, product-limit life-table distributions were compared by the protocol-specified Peto-Peto-Prentice Wilcoxon test34. The proportional-hazards regression model was used to estimate the percentage reduction in the occurrence of the primary end points within and across strata of subgroups. The analysis included all the patients who received 60 mg of vesnarinone or placebo, all in their randomly assigned groups regardless of adherence to the assigned treatment regimen (intention-to-treat principle). However, data on 19 patients who received heart transplants during the 26-week treatment period were censored from the date of transplantation. To protect against increasing the rate of a type I error because of interim analyses, we used the Lan-DeMets procedure,35 with adjustment for continuous monitoring. We computed the Lan-DeMets boundaries at each interim analysis, using a spending function with an overall type I error rate of 0.05 (two-sided). Because interim analyses were performed, we considered a value of P<0.025 (two-sided) to indicate significance at the end of the study, rather than the usual P<0.05.
Results
Discontinuation of the 120-mg Study Arm
As required by the study protocol, the morbidity and mortality data from the ongoing study were reviewed by the independent data and safety monitoring committee. During the enrollment of the first 253 patients, 3 patients receiving 60 mg of vesnarinone per day and 6 patients receiving placebo died; however, 16 patients receiving 120 mg of vesnarinone per day died during the same period. Furthermore, half the deaths in the 120-mg group occurred within the first six weeks of therapy, whereas none of the deaths in either the 60-mg group or the placebo group occurred during that period. Protocol-mandated pairwise comparison of the three treatment groups with respect to mortality from any cause indicated a significant (x2 = 6.55, P = 0.01) difference between event rates in the 120-mg and placebo groups. Although the higher mortality rate did not reach the protocol-mandated level of significance for termination of the study arm (P = 0.0001), the data and safety monitoring committee unanimously agreed that the more than twofold increase in mortality warranted the discontinuation of the 120-mg study arm to protect the safety of the patients. The study code was therefore broken, and all the patients randomly assigned to 120 mg of vesnarinone and taking the coded medication were offered treatment with open-label vesnarinone in a dose of 60 mg per day.
60-mg and Placebo Groups
Between April 24, 1990, and February 27, 1992, a total of 477 patients were randomly assigned to receive either 60 mg of vesnarinone per day or placebo. The clinical characteristics of the two study groups were similar, except that more patients in the placebo group were receiving antiarrhythmic therapy (Table 1). Fifty-two percent of the patients had ischemic heart disease, the mean ejection fraction was 20 percent, most patients were in NYHA class III, and nearly 90 percent of the patients were receiving an angiotensin-converting-enzyme inhibitor and digoxin.
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Seventy-six patients died or required intravenous inotropic support during the six-month study period. Of the patients who reached this combined end point, 26 were receiving vesnarinone, and 50 were receiving placebo (P = 0.003) (Figure 1 and Table 2). The use of vesnarinone was associated with a reduction in risk of 50 percent (95 percent confidence interval, 20 to 69 percent). Five patients reached a morbidity or mortality end point after withdrawal from the study but before the six-month follow-up ended. No patients were lost to follow-up during the study.
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Quality of life, as assessed by the Sickness Impact Profile, improved in both the placebo and vesnarinone groups (Table 4). The improvement was greater, however, in the vesnarinone group (median change in score, -4.2; lowest quartile, -10.5; highest quartile, -0.5) than in the placebo group (median, -2.5; lowest quartile, -6.5; highest quartile, +1.1) (P = 0.008). The greater improvement in quality of life in the vesnarinone group was not attributable to a single factor, since the difference in both physical scores (P = 0.017) and psychosocial scores (P = 0.006) was consistent with the overall Sickness Impact Profile score. This improvement in quality of life was not associated with a change in either the ejection fraction or the NYHA class.
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There were 13 deaths from any cause in the vesnarinone group and 33 deaths in the placebo group during the six-month study period (P = 0.002) (Figure 2 and Table 2). The reduction in the risk of death from any cause in the vesnarinone group was 62 percent (95 percent confidence interval, 28 to 80 percent). Five of the patients who died in the vesnarinone group and four of those who died in the placebo group had withdrawn from the study before they died. The deaths of 5 of the patients in the vesnarinone group and 16 of the patients in the placebo group were preceded by morbid events. Of the total number of deaths in the vesnarinone group, 38 percent were sudden and 54 percent were due to worsening heart failure (Table 2). Similarly, in the placebo group, 45 percent of the deaths were sudden and 54 percent were attributable to worsening heart failure.
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Withdrawals from the study were prospectively divided by the executive committee into three subgroups: those potentially attributable to the study medication (adverse events), those thought to be unrelated to drug use, and those related to the patient's preference (Table 3). Six patients in the vesnarinone group withdrew because neutropenia developed (incidence, 2.5 percent). The neutropenia was reversible in all cases; one patient, however, subsequently died of cardiac failure in the hospital. All the cases of neutropenia occurred between weeks 4 and 16 of treatment. Twelve patients had myocardial infarctions during the study before the occurrence of an event: six patients in each of the study groups. Among the 87 patients who received 120 mg of vesnarinone per day, 2 withdrew because of neutropenia, 1 because of a reversible abnormality of liver function, and 1 because of ventricular dysrhythmia. Two patients in this group had myocardial infarctions.
Discussion
Our results demonstrate that in patients with symptomatic congestive heart failure refractory to routine therapy, 60 mg of vesnarinone per day (as compared with placebo) led to a 50 percent decrease in the risk of death from any cause or worsening heart failure and a 62 percent reduction in the risk of death during the six-month study period. In marked contrast, 120 mg of vesnarinone per day was associated with increased mortality, requiring discontinuation of this arm of the study. Since improved functional ability and comfort are also important therapeutic end points,36 it is noteworthy that the study patients reported an improvement in the quality of life during 12 weeks of therapy with vesnarinone. These beneficial effects occurred despite concomitant therapy with angiotensin-converting-enzyme inhibitors, agents known to improve survival in heart failure, in both groups3,4. Although the patients were stratified according to whether they received digoxin therapy, the small number of patients who were not taking digoxin precluded analysis of the effects of vesnarinone in this group.
The results of the present study are consistent with those of two previous, smaller investigations24,25. Our results differ, however, from those of recent clinical trials in which several different inotropic agents were associated with reduced survival7,9,10,37. Differences between the study populations are unlikely to account for this disparity. With the exception of the mean ejection fraction, which was lower in our patients (20 percent) than in the patients in previous trials, base-line demographic and clinical characteristics were similar to those in other studies8,9,10,12. The event rate in the placebo group (21 percent) was also consistent with that in other heart-failure trials,10,12 whereas the withdrawal rate (4.2 percent) was lower. However, the mortality rate in the placebo group was higher than in the recent Studies of Left Ventricular Dysfunction trial,3 perhaps owing to more advanced heart failure in our patients.
The unique mechanisms of action of vesnarinone provide possible explanations for its beneficial effects. In contrast to other inotropic agents, vesnarinone affects both ion channels and the phosphodiesterase enzyme. This dual activity has several potential benefits. Like phosphodiesterase inhibitors, vesnarinone appears to be mildly vasodilative,15,22 a property that has been associated with beneficial effects in patients with heart failure28. In contrast to phosphodiesterase inhibitors, however, vesnarinone prolongs the action potential and slows the heart rate16,20. The prolongation of the action potential may have antiarrhythmic effects, but it may also contribute to improved contractility38. The effects of vesnarinone on the potassium channel may also be associated with antiarrhythmic properties, and indeed, electrophysiologic studies suggest that vesnarinone resembles class III antiarrhythmic drugs39. It is unlikely, however, that the beneficial effects of vesnarinone are attributable solely to its antiarrhythmic properties, since there was a substantial reduction in the worsening of heart failure in the vesnarinone group and since the proportion of mortality attributable to cardiac failure or sudden death was the same in the two groups. Furthermore, no antiarrhythmic agent has been found to improve survival in patients with congestive heart failure. Finally, we cannot exclude the possibility that vesnarinone has as yet unrecognized lusitropic effects (improving diastolic function), since diastolic dysfunction may play an important part in heart failure40.
Studies in animal models have clearly identified the positive inotropic properties of vesnarinone41. In addition, the long-term administration of vesnarinone in patients with heart failure moves the end-systolic pressure-dimension relation to the left, with a steeper slope, indicating that the drug enhances the contractile state42. Our inability to demonstrate an increase in the ejection fraction in the patients receiving vesnarinone does not preclude the existence of a positive inotropic effect, since drugs that increase cardiac contractility do not necessarily increase ejection fraction8,43,44. The beneficial effects of vesnarinone may thus be attributable to vasodilatation, antiarrhythmic action, increased contractility, or, most probably, a combination of these effects.
It is also possible that the beneficial effects of vesnarinone can be attributed to the use of relatively low doses. Our study design did not allow an end-point analysis comparing the low-dose and high-dose vesnarinone groups, since the 120-mg arm was discontinued. However, the more than twofold increase in mortality in the 120-mg group provides substantive evidence that high doses are deleterious and that the drug has a narrow therapeutic range. This hypothesis is supported by the results of several previous trials involving other inotropic agents7,37,44,45.
The principal adverse effect associated with the use of vesnarinone in a dose of 60 mg per day was a 2.5 percent incidence of neutropenia. This incidence was comparable to that reported in several small studies in the United States,23,25 but greater than that reported in Japan24. Although the neutropenia was reversible in all cases, one patient died of cardiac failure after the drug was discontinued. All cases of neutropenia occurred between weeks 4 and 16 of treatment, suggesting that only a relatively short period of weekly monitoring may be necessary to follow patients receiving vesnarinone.
In summary, 60 mg of vesnarinone per day reduced the six-month risk of a morbid event or death by 50 percent and the risk of death by 62 percent in patients with symptoms of NYHA class III disease. However, 120 mg of vesnarinone per day was associated with an increase in mortality, suggesting that the drug has a narrow therapeutic range. Furthermore, in 2.5 percent of patients, the use of vesnarinone was complicated by reversible neutropenia, a potentially serious adverse effect. In considering the long-term use of vesnarinone for congestive heart failure, physicians must therefore take into account the risk-benefit ratio for each patient.
Supported by a grant from Otsuka America Pharmaceutical, which did not have access to unblinded information.
Source Information
The members of the Vesnarinone Study Group are listed in the Appendix.
Address reprint requests to Dr. Feldman at the Peter Belfer Cardiac Laboratories, Department of Medicine, Johns Hopkins University School of Medicine, Richard S. Ross Research Bldg., Rm. 835, 720 Rutland Ave., Baltimore, MD 21205.
References
The members of the Vesnarinone Study Group were as follows: Johns Hopkins Hospital, Baltimore -- A.M. Feldman, K.L. Baughman, P.D. Kessler, K. Carnivale, K. Kiernan-Pownall, and E.G. Van Anden; University of Florida and Veterans Affairs Medical Center, Gainesville -- C.J. Pepine, H. Chen, J.B. Conti, J.R. Green, Jr., M.C. Limacher, T.J. Wargovich, K.L. Citta, E.M. Handberg, and T. Norred; University of Utah, Salt Lake City -- M.R. Bristow, E.M. Gilbert, J.B. O'Connell, D.G. Renlund, D. Ferguson, P. Mealey, L. Reynolds, and A.K. Volkman; Veterans Affairs Medical Center, Washington, D.
-- P.E. Carson and M. Smith; Fairfax Hospital, Falls Church, Va. -- J.T. O'Brien, P.E. Carson, L.A. Miller, and M. Obeid; Valley Hospital, Ridgewood, N.J. -- J.E. Strobeck, W.K. Lee, R. Bauerle, C. Pecararo, and J. Rowland; Medical University of South Carolina, Charleston -- G.H. Hendrix, J.N. Evans, and M. Schulz; University of Virginia, Charlottesville -- E.R. Powers, J.D. Bergin, M.D. Feldman, C. McCarter, C. McDaniel, and C. Tedesco; Duke University Medical Center, Durham, N. -- M.B. Higginbotham, C.M. O'Connor, S.E. Kasprzak, B.B. Kuzil, R.D. Page, and P. Shaw; Presbyterian University Hospital, Pittsburgh -- B.F. Uretsky, S. Murali, A. Betshert, Y. Cannon, S. Loftus, and T. Tokarczyk; San Diego Cardiac Center, San Diego, Calif. -- B.E. Jaski, R.H. Miller, L. Brewster, S.A. Hawley, I.H. Lamb, and B. Tulley; Oregon Health Sciences University, Portland -- J.D. Hosenpud, B.H. Greenberg, R.E. Hershberger, M. Guillotte, and D. Nauman; Philadelphia Heart Institute, Philadelphia -- J.D. Ogilby, M.J. Jessup, D. DiMarzio, and B. Paugh; Emory University School of Medicine, Atlanta -- R.C. Schlant, R.W. Alexander, D. Arsenberg, S. Ballou, V.D. Jeffries, and B. Brackney; Francis Scott Key Medical Center, Baltimore -- S.H. Gottlieb and M. Gunn; Massachusetts General Hospital, Boston -- G.W. Dec, M.A. Fifer, and D. Cocca-Spofford; Veterans Affairs Medical Center, Fresno, Calif. -- P.C. Deedwania, R. Kanefield, and E. Murphy; Brigham and Women's Hospital, Boston -- W.S. Colucci, M.A. Creager, L.H. Hartley, J.S. Landzberg, E. Loh, G.H. Mudge, J.D. Parker, and D.F. Gauthier; Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y. -- T.H. LeJemtel, M. Galvao, and P. Levato; Pacific Heart Institute, Santa Monica, Calif. -- R.F. Wright, D. Boylan, C. Cook, P. Rosenberg, and S.M. Talken; Wadsworth Veterans Affairs Medical Center, Los Angeles -- B.N. Singh, M. Luu, and A. Fast; University of California, San Francisco -- K. Chatterjee, T. DeMarco, C. Klinski, and D. Lau; Administrative Coordinators, Otsuka America Pharmaceutical, Maryland Office of Clinical Research, Rockville, Md. -- B.G. White, T.D. Cowart, M.Q. Huffert, A.T. Lwin, C. Mulligan, and M.C. Riggs; Clinical Reference Laboratory -- Met Path, Teterboro, N.J.; Coordinating Center and Statistics, Biostatistics Center, George Washington University, Rockville, Md. -- R.P. Bain, W.F. Rosenberger, and C.M. Rowland; Data and Safety Monitoring Committee -- J. Borer, J. Lachin III (ex officio), E. Sonnenblick, and N. Young; and Executive Committee -- R. Bain, M.R. Bristow, A.M. Feldman, W. Parmley, B. Scoville (deceased), and B.G. White.
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Related Letters:
Vesnarinone for Heart Failure
Swedberg K., Wedel H., Neely D., Schwartz A., Feldman A. M., Bristow M. R., Parmley W. W., Packer M.
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Full Text
N Engl J Med 1994;
330:64-66, Jan 6, 1994.
Correspondence
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