Stockholm, Sweden - Daily oral therapy with the inotropic drug enoximone, a selective inhibitor of phosphodiesterase-3 (PDE-3), failed to alter clinical and functional outcomes in patients with NYHA class 3-4 systolic heart failure in a large international trial, investigators reported here at the European Society of Cardiology Congress 2005. But in a prospectively planned subgroup analysis, the drug did appear to improve submaximal exercise tolerance in patients with extremely low ejection fractions and also appeared safe throughout the study.

Oral enoximone had been previously shown to provide limited benefit to low-LVEF patients hospitalized with HF, inspiring hopes that it could be used chronically in a broader heart-failure population.

Dr Marco Metra

In two parallel investigations conducted on both sides of the Atlantic according to identical protocols, called the Studies of Oral Enoximone Therapy in Advanced Heart Failure (the ESSENTIAL trials), 1854 patients in 16 countries were randomized to enoximone—starting at 25 mg three times-daily—or placebo on top of standard medications. The patients were required to have an LVEF <30% and echocardiographic signs of LV dilatation. Nearly 90% were on beta blockers, and virtually all were on either ACE inhibitors or angiotensin-receptor blockers (ARBs), reported Dr Marco Metra (Universita di Brescia, Italy),

Over a mean follow-up of 16.3 months, actively treated patients showed no significant advantages in the three primary end points: time to all-cause mortality or CV hospitalization, six-month change in six-minute-walk distance, and patient self-assessment of overall well-being at six months. Nor did they show significantly longer times to all-cause mortality, a secondary safety end point.

Six-month clinical outcomes

End point	Enoximone (n=926)	Placebo (n=928)	p
All-cause mortality/CV hospitalization (n)	458	465	0.71
All-cause mortality (%)	21.7	22.6	0.73

On the other hand, a post hoc analysis pointed to a significant interaction between baseline LVEF and six-minute-walk distance, driven by North and South American results as opposed to those from Europe, among patients who entered the trial with an ejection fraction lower than the average of 25%. Those who were on enoximone for longer than 16 months also showed a significant survival benefit, Metra said.

Median change in six-minute-walk distance (m) from baseline over six months, all patients

LVEF	Enoximone	Placebo
<25%	+15.0*	0.0
>25%	+13.5	+15

Median change in six-minute-walk distance (m) by geographic region

End point	Enoximone	Placebo	p
North/South America	+10	0	0.025
East/West Europe	+16.5	+15	0.82

That the drug appeared to benefit some patients with very low ejection fractions is consistent with the results of a prior randomized, placebo-controlled trial called Oral Enoximone in Intravenous Inotrope-Dependent Subjects (EMOTE), according to Metra. As previously reported by heartwire, the thrice-daily EMOTE dosing regimen, similar to what was used in ESSENTIAL, made it significantly more likely that patients with an LVEF <25% hospitalized with acute HF could be weaned off IV inotrope support.

Dr Markku S Nieminen (Helsinki University Central Hospital, Finland), the assigned discussant for the ESSENTIAL presentation, observed, "There was an astonishingly [small] excess of adverse events in the enoximone-treated group." The most common of these were palpitations and diarrhea. But given the lack of clinical or functional benefit in the overall population, enoximone cannot be recommended for patients like those entered into the trial, he said. "Some patients may benefit in quality of life [based on] the six-minute-walk test results, but that would require further testing in prespecified groups."

The ESSENTIAL trial contained some clues as to what patient groups might benefit from enoximone more. Nieminen observed that patients in the North and South American cohort were more likely to be on carvedilol and digitalis and to have dilated cardiomyopathy as well as to have lower ejection fractions, six-minute-walk distances, and systolic pressures. "In general, they were worse off than the European group of patients."