HEBE III: EPO een no-go in post-MI patiënten

Presentation slides

Stockholm, Sweden - Following a successful PCI, a single dose of erythropoietin (EPO) failed to improve left ventricular ejection fraction (LVEF) in acute-MI patients who received the investigational treatment, a new study shows. While the trial missed its primary end point, investigators report that EPO did reduce major adverse cardiovascular end points, a reduction driven primarily by a lower incidence of heart failure.

Published concurrently in the European Heart Journal, the results of the HEBE III study were presented here today at the European Society of Cardiology 2010 Congress by lead investigator Dr Adriaan Voors (University Medical Center Groningen, the Netherlands), who noted that EPO is traditionally given to patients with renal anemia. Animal data, however, have suggested it might also be cardioprotective, with these studies consistently showing reductions in infarct size and improved contractility and hemodynamics with EPO-based therapy.

In moving from animal models to humans, the group performed a large phase 2 investigational study of EPO in 529 patients with a first ST-segment-elevation MI. In this prospective, multicenter, open-label trial, patients were randomized to 60 000 IU of epoetin alfa (Epogen, Amgen; Procrit, Amgen, distributed by Ortho Biotech) or usual care. As noted, after six weeks, treatment with EPO failed to improve the LVEF of treated patients but did reduce major adverse cardiovascular events, a benefit driven primarily by reductions in heart failure.

HEBE III: Primary and secondary end points

End point	Erythropoietin (n=263)	Control (n=266)	p
Primary end point: Left ventricular ejection fraction (%)	0.53	0.52	0.41
Secondary end point: Major adverse cardiovascular events (n)	8	19	0.032
Cardiovascular death	1	2	NS
Emergency PCI for in-stent thrombosis/reinfarction/unstable angina	5	9	NS
Stroke	1	1	NS
Heart failure	1	7	0.034

"The first question is whether we should do a phase 3 clinical trial, and if I had to personally invest my money in it, the number of events we see here are rather small, so it would be rather risky," he said, adding, "To be very honest with you, it took me a long time to get this study funded."

Fails to confirm EPO's rescue-mission role

Commenting on the results of the study, Dr Piotr Ponikowski (Wroclaw Medical University, Poland), who discussed the results during the late-breaking clinical-trials session and who wrote an editorial with Dr Ewa Jankowska (Wroclaw Medical University) accompanying the paper [2], said the secondary findings are "promising" but reiterated the conclusions of Voors, that the study failed to confirm EPO's "rescue-mission" role in post-MI. He questioned whether LVEF is a sensitive enough marker and whether the six-week study was long enough to detect subtle beneficial effects of EPO.

Despite the difficulties in getting this investigator-initiated study off the ground, Voors said the secondary findings are intriguing enough to warrant a larger, longer look at EPO in post-MI or heart-failure patients. He also noted that other studies are coming. A study of erythropoietin will likely be presented at the American Heart Association Scientific Sessions in November, and if pooled results from the different studies suggest a larger benefit, a phase 3 study might be justified, he said.

One future option, said Voors, would be to focus on patients with impaired LVEF—patients in HEBE III had an average LVEF of 53%—to see whether these sicker patients would benefit more from EPO. Ponikowski, who agrees with this assessment, added that the large, one-time dose of EPO did not unfavorably alter the hematopoietic profile, pointing out that hematocrit and platelet activity were not significantly increased, nor were there increases in blood pressure or reported cases of seizure or deep vein thrombosis.