Reactions 630 - 7 Dec 1996 Important lessons from disappointing trial of vesnarinone in CHF The Vesnarinone Evaluation of Survival Trial (VEST) has shown that vesnarinone increases the risk of mortality, compared with placebo, in patients with congestive heart failure (CHF). In addition to adding to the growing list of failed agents in this indication, the trial has implications for drug approval processes, due to the huge discrepancy between the results of VEST and those of a previous randomised, placebo-controlled, double-blind study of the effect of vesnarinone on mortality. The results of VEST were presented at the 69th Scientific Sessions of the American Heart Association [New Orleans, US; November 1996], and the impact of the trial was discussed by Dr Jay Cohn from the Minnesota University School of Medicine, Minneapolis, US. In 1993, the results of a mortality study involving 730 patients with heart failure who were treated with oral vesnarinone were published in the NEJM.1 The trial was conducted by the Vesnarinone Study Group. The data from the study showed that vesnarinone 60 mg/day was associated with a 62% reduction in mortality, compared with placebo, over a 6-month follow-up period [see table 1]. This was considered to be a ‘remarkable effect on survival’, that was far greater than that seen with conventional treatments for heart failure, said Dr Cohn. However, a higher dose of vesnarinone (120 mg/day) was associated with a 2-fold increase in mortality risk, leading to the discontinuation of this arm of the trial. At present in many countries, it is common for drug treatments to be approved after just 1 randomised, placebo-controlled, long-term mortality study. However, the data from this trial were considered to be inadequate due to the discrepancy between the results achieved with the 2 doses of vesnarinone, and the modest number of patients in the study. Thus, the US FDA requested a second mortality study involving the treatment of a larger number of patients with low-dose vesnarinone over a longer period of time.

Contrasting results in second study Vesnarinone’s manufacturer Otsuka complied with the FDA request and initiated a trial that was exceptionally well designed and controlled, according to Dr Cohn. In the trial, 3833 patients with New York Heart Association (NYHA) class III or IV heart failure were randomised to receive oral vesnarinone 60 or 30 mg/day, or placebo. All patients were maintained on background therapy of diuretics, digoxin and ACE inhibitors. The study was initiated in January 1995 and terminated in July 1996 after the predetermined endpoint of 232 deaths in the placebo arm. In contrast to the earlier study, treatment with low-dose vesnarinone was found to increase mortality, compared with placebo. Vesnarinone 30 and 60 mg/day were associated with increases in mortality of 12 and 23%, respectively, compared with placebo. The difference between vesnarinone 60mg and placebo was highly significant. The increased mortality was attributed to an increased risk of sudden death, probably as a result of arrhythmia,

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as the incidence of this event increased in a dosedependent manner. The rates of mortality due to worsening heart failure were equivalent in the 3 treatment groups. Further data analyses failed to single out any subgroups that benefitted from treatment with vesnarinone. Similarly, no subgroups were shown to have a more adverse response to treatment, compared with other subgroups.

Loyalty to drug Despite knowledge of this increased mortality risk, many patients and physicians with experience of vesnarinone have agreed to continue receiving vesnarinone therapy. A number of patients claim that the drug improves their quality of life (QOL) and they are ‘convinced that it is helping them’, said Dr Cohn. The VEST researchers assessed QOL in their study using the Minnesota Living with Heart Failure questionnaire. A significant improvement in QOL was seen in the first 3 months of treatment with vesnarinone 60 mg/day, compared with placebo. However, the benefits were no longer apparent at a 6-month followup. Due to the drug’s status as an investigational new drug (IND), some patients in the US have been allowed to continue treatment.

Big in Japan The drug is already marketed in Japan, where it is used by physicians to treat patients with heart failure. Dr Cohn said that it was not clear how the results of the study would affect the use of the drug in that country. However, it is highly likely that certain drug labelling changes will be required. The future of the drug may be influenced by investigations into the differences between the 2 trials of vesnarinone in heart failure. However, as yet, no significant discrepancies in design or patient characteristics have been identified between the 2 studies.

Impact on approval processes The impact on the FDA has been dramatic. In view of the findings of the 2 studies, the agency may decide to revise its approval procedure. Such changes would obviously affect other drugs that currently have IND status for heart failure in the US. This would include carvedilol, a β-blocker that has only one long-term, placebo-controlled mortality study to support its proposed benefits. Although the drug has already received approval in many countries,* regulatory agencies in the US and the UK are not yet convinced that carvedilol has a positive impact on survival. The recent findings relating to vesnarinone are likely to reinforce any concerns. However, carvedilol has a number of factors in its favour. The positive results of the large mortality trial involving this drug are supported by the results of a number of smaller trials of carvedilol. Also, data from studies involving the use of other β-blockers provide further insight into the role of this class of agents in heart failure. In addition, carvedilol has a favourable effect on a number of surrogate markers of cardiovascular function, such as heart rate and left ventricular mass. Data on these markers provide additional support for its use in this indication.

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Reactions 7 Dec 1996 No. 630

Single Article

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Lack of supporting data with vesnarinone This is not the case with vesnarinone. There are no apparent surrogate markers for this agent, and its mechanism of action is unclear. It does not appear to influence any of the established mechanisms of disease progression, said Dr Cohn. Vesnarinone is described as a phosphodiesterase inhibitor that has mild inotropic activity. Although other phosphodiesterase inhibitors have been developed, vesnarinone appears to have unique characteristics, said Dr Cohn. Phosphodiesterase inhibitors in general have been notorious for their detrimental effects in patients with heart failure. A meta-analysis conducted by researchers in France indicated that the use of these agents was associated with an increase in mortality in this indication.2 The data came from 13 placebo-controlled trials involving 2808 patients with CHF. Interestingly, the increase was nonsignificant when data from all phosphodiesterase inhibitors were included, but became significant when data were included from all trials except those involving vesnarinone (the study was conducted prior to the VEST trial). The negative data associated with the use of these agents in heart failure appears to have influenced drug manufacturers as many have discontinued the development of their phosphodiesterase inhibitors in this indication. In spite of this, investigations continue for a handful of agents in this class. A couple of these have already been launched, received approval or are in phase III trials [see table 2]. The greatest interest in the agents is in Japan. Table 1. Positive and negative effects of vesnarinone on mortality in patients with CHF Trial

Vesnarinone Study Group

Total no. of patients in study

Vesnarinone dose

Effect on mortality compared with placebo

730

60 mg/day

30 mg/day

62% reduction > 100% increase 12% increase

60 mg/day

23% increase

120 mg/day Vesnarinone Evaluation of Survival Trial

3800

Reactions 7 Dec 1996 No. 630

Table 2. Phosphodiesterase inhibitors that are in the late stages of development or have been launched Agent

Company

Status

Comment

Vesnarinone

Otsuka

Launched in Japan; submitted for approval in the US

Pimobendan

Thomae; Boehringer Ingelheim

Launched in Japan

Doubt cast on future of the agent due to increased mortality compared with placebo in the Vesnarinone Evaluation of Survival Trial Calcium sensitising activity; doubt cast on future of the agent due to increased mortality compared with placebo in the Pimobendan in Congestive Heart Failure trial

Toborinone

Otsuka

Phase III in Japan and the US Registered in Japan

Loprinone

Levosimendan

Eisai

Orion

Phase III in Finland Germany Sweden and the US

Exerts positive inotropic and vasodilatory activity Coronary vasodilatory activity

* Carvedilol has been launched for the treatment of heart failure in Mexico and Denmark. It has been approved for this indication in Canada, Spain, Sweden, Norway and Israel. 1. Feldman AM, et al. Effects of vesnarinone on morbidity and mortality in patients with heart failure. New England Journal of Medicine 329: 149-155, 15 Jul 1993. 2. Nony P, et al. Evaluation of the effect of phosphodiesterase inhibitors on mortality in chronic heart failure patients. A meta-analysis. European Journal of Clinical Pharmacology 46: 191-196, No. 3, 1994. 800458272

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