Oral Inotrope Shown Safe, but Not Effective

STOCKHOLM — An oral inotropic drug was safe but not effective in a pair of studies that together enrolled more than 1,800 patients with advanced heart failure.

Although the Studies of Oral Enoximone Therapy in Advanced Heart Failure (ESSENTIAL) failed to show that enoximone could cut the incidence of death or cardiovascular hospitalization, the fact that the drug was safe means that it is eligible for further testing in very sick heart failure patients, Michael Bristow, M.D., said in an interview at the annual congress of the European Society of Cardiology.

“We have a lack of effective medications for very sick patients with decompensated heart failure,” especially those with recurrent episodes of acute decompensation, said Dr. Bristow, codirector of the Cardiovascular Institute at the University of Colorado in Denver. “Enoximone has now been [proved] safe, and we saw a signal of efficacy in the sickest patients.”

The studies enrolled 1,854 patients with New York Heart Association class III or IV heart failure at 211 centers in 16 countries. One study was done in North and South America; the other was done in Europe.

The patients also had a left ventricular ejection fraction (LVEF) of 30% or less and had had at least one hospitalization or two outpatient visits for worsening heart failure during the year before they entered the study. All were already on optimal treatment with both a β-blocker and an ACE inhibitor or an angiotensin-receptor blocker.

The patients were randomized either to placebo or to 25 mg enoximone t.i.d. After 2 weeks, the dosage was raised to 50 mg t.i.d for patients who weighed more than 50 kg and had no adverse effects from the lower dosage. These dosages were substantially lower than were those in previous enoximone studies.

After an average follow-up of 16.4 months, there was no significant difference between the two arms in either all-cause death, the major safety end point, or in all-cause death and cardiovascular hospitalizations, the major efficacy end point, said Marco Metra, M.D., professor of cardiology at the University of Brescia (Italy).

In the American but not the European study, treatment with enoximone was linked with a significant increase in a secondary end point measured by a 6-minute walk test done after 6 months of treatment. The two treatment arms showed no significant difference for the third efficacy end point of the study, patients' self-assessment of symptomatic improvement.

In a prespecified subgroup analysis that assessed efficacy responses in patients with an LVEF below the median for all patients (25%) and in those with an ejection fraction above the median, treatment with enoximone in patients with the worst left ventricular function was associated with a 10% reduction in both all-cause death and in deaths and cardiovascular hospitalizations, compared with placebo.

Enoximone treatment in the subgroup was also linked with a mean gain of 15 m in a 6-minute walk distance, compared with the placebo group. Further analyses of results in the sicker patients also showed enoximone treatment was especially effective for reducing deaths and hospitalizations after the first 16 months of treatment.

Enoximone is in the same inotropic class as milrinone. But enoximone is a pure phosphodiesterase inhibitor, which, along with its use in the setting of β-blocker treatment, may lead to its increased safety, said Dr. Bristow, who is also chief science and medical officer for Myogen, which sponsored ESSENTIAL and markets an intravenous formulation of enoximone (Perfan) in Europe, in an interview.

STOCKHOLM — An oral inotropic drug was safe but not effective in a pair of studies that together enrolled more than 1,800 patients with advanced heart failure.

Although the Studies of Oral Enoximone Therapy in Advanced Heart Failure (ESSENTIAL) failed to show that enoximone could cut the incidence of death or cardiovascular hospitalization, the fact that the drug was safe means that it is eligible for further testing in very sick heart failure patients, Michael Bristow, M.D., said in an interview at the annual congress of the European Society of Cardiology.

“We have a lack of effective medications for very sick patients with decompensated heart failure,” especially those with recurrent episodes of acute decompensation, said Dr. Bristow, codirector of the Cardiovascular Institute at the University of Colorado in Denver. “Enoximone has now been [proved] safe, and we saw a signal of efficacy in the sickest patients.”

The studies enrolled 1,854 patients with New York Heart Association class III or IV heart failure at 211 centers in 16 countries. One study was done in North and South America; the other was done in Europe.

The patients also had a left ventricular ejection fraction (LVEF) of 30% or less and had had at least one hospitalization or two outpatient visits for worsening heart failure during the year before they entered the study. All were already on optimal treatment with both a β-blocker and an ACE inhibitor or an angiotensin-receptor blocker.

The patients were randomized either to placebo or to 25 mg enoximone t.i.d. After 2 weeks, the dosage was raised to 50 mg t.i.d for patients who weighed more than 50 kg and had no adverse effects from the lower dosage. These dosages were substantially lower than were those in previous enoximone studies.

After an average follow-up of 16.4 months, there was no significant difference between the two arms in either all-cause death, the major safety end point, or in all-cause death and cardiovascular hospitalizations, the major efficacy end point, said Marco Metra, M.D., professor of cardiology at the University of Brescia (Italy).

In the American but not the European study, treatment with enoximone was linked with a significant increase in a secondary end point measured by a 6-minute walk test done after 6 months of treatment. The two treatment arms showed no significant difference for the third efficacy end point of the study, patients' self-assessment of symptomatic improvement.

In a prespecified subgroup analysis that assessed efficacy responses in patients with an LVEF below the median for all patients (25%) and in those with an ejection fraction above the median, treatment with enoximone in patients with the worst left ventricular function was associated with a 10% reduction in both all-cause death and in deaths and cardiovascular hospitalizations, compared with placebo.

Enoximone treatment in the subgroup was also linked with a mean gain of 15 m in a 6-minute walk distance, compared with the placebo group. Further analyses of results in the sicker patients also showed enoximone treatment was especially effective for reducing deaths and hospitalizations after the first 16 months of treatment.

Enoximone is in the same inotropic class as milrinone. But enoximone is a pure phosphodiesterase inhibitor, which, along with its use in the setting of β-blocker treatment, may lead to its increased safety, said Dr. Bristow, who is also chief science and medical officer for Myogen, which sponsored ESSENTIAL and markets an intravenous formulation of enoximone (Perfan) in Europe, in an interview.

STOCKHOLM — An oral inotropic drug was safe but not effective in a pair of studies that together enrolled more than 1,800 patients with advanced heart failure.

Although the Studies of Oral Enoximone Therapy in Advanced Heart Failure (ESSENTIAL) failed to show that enoximone could cut the incidence of death or cardiovascular hospitalization, the fact that the drug was safe means that it is eligible for further testing in very sick heart failure patients, Michael Bristow, M.D., said in an interview at the annual congress of the European Society of Cardiology.

“We have a lack of effective medications for very sick patients with decompensated heart failure,” especially those with recurrent episodes of acute decompensation, said Dr. Bristow, codirector of the Cardiovascular Institute at the University of Colorado in Denver. “Enoximone has now been [proved] safe, and we saw a signal of efficacy in the sickest patients.”

The studies enrolled 1,854 patients with New York Heart Association class III or IV heart failure at 211 centers in 16 countries. One study was done in North and South America; the other was done in Europe.

The patients also had a left ventricular ejection fraction (LVEF) of 30% or less and had had at least one hospitalization or two outpatient visits for worsening heart failure during the year before they entered the study. All were already on optimal treatment with both a β-blocker and an ACE inhibitor or an angiotensin-receptor blocker.

The patients were randomized either to placebo or to 25 mg enoximone t.i.d. After 2 weeks, the dosage was raised to 50 mg t.i.d for patients who weighed more than 50 kg and had no adverse effects from the lower dosage. These dosages were substantially lower than were those in previous enoximone studies.

After an average follow-up of 16.4 months, there was no significant difference between the two arms in either all-cause death, the major safety end point, or in all-cause death and cardiovascular hospitalizations, the major efficacy end point, said Marco Metra, M.D., professor of cardiology at the University of Brescia (Italy).

In the American but not the European study, treatment with enoximone was linked with a significant increase in a secondary end point measured by a 6-minute walk test done after 6 months of treatment. The two treatment arms showed no significant difference for the third efficacy end point of the study, patients' self-assessment of symptomatic improvement.

In a prespecified subgroup analysis that assessed efficacy responses in patients with an LVEF below the median for all patients (25%) and in those with an ejection fraction above the median, treatment with enoximone in patients with the worst left ventricular function was associated with a 10% reduction in both all-cause death and in deaths and cardiovascular hospitalizations, compared with placebo.

Enoximone treatment in the subgroup was also linked with a mean gain of 15 m in a 6-minute walk distance, compared with the placebo group. Further analyses of results in the sicker patients also showed enoximone treatment was especially effective for reducing deaths and hospitalizations after the first 16 months of treatment.

Enoximone is in the same inotropic class as milrinone. But enoximone is a pure phosphodiesterase inhibitor, which, along with its use in the setting of β-blocker treatment, may lead to its increased safety, said Dr. Bristow, who is also chief science and medical officer for Myogen, which sponsored ESSENTIAL and markets an intravenous formulation of enoximone (Perfan) in Europe, in an interview.