Lack of Benefit, Potential Harm REVEALed with EPO in STEMI Patients

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Despite showing earlier promise, high-dose erythropoietin (EPO) alfa failed to reduce infarct size as an adjunct to percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) while showing signs of causing harm in the elderly, according to a study in the May 11, 2011, issue of the Journal of the American Medical Association.

For the phase 2 REVEAL (Reduction of Infarct Expansion and Ventricular Remodeling with Erythropoietin After Large Myocardial Infarction) trial, researchers led by Samer S. Najjar, MD, of the Washington Hospital Center (Washington, DC), randomized 222 STEMI patients in 2 phases after successful primary or rescue PCI at 22 US sites. In the dose-finding phase (n = 84), patients received 1 of 3 doses of EPO as a single IV bolus (15,000 U, 30,000 U, or 60,000 U) or placebo. In the efficacy phase, 138 patients were randomized to 60,000 U of EPO or placebo. EPO was given within 4 hours of PCI and at a median of 6 hours after symptom onset. All patients received cardiac MRI to assess infarct size and LV parameters at 2 to 6 days and 12 weeks.

The results of REVEAL were first presented in November 2010 at the American Heart Association Scientific Sessions in Chicago, IL.

No Benefit, Possible Harm

In the efficacy cohort, the primary endpoint of infarct size (percentage of LV mass) was equivalent between the EPO and placebo groups on the first cardiac MRI scan (15.8% vs. 15.0%; P = 0.67). This held true at 12 weeks on the second scan (10.6% vs. 10.4%; P = 0.89). LVEF was also similar between the EPO and placebo groups at 2 to 6 days (48.2% vs. 48.9%; P = 0.67) and 12 weeks (52.5% vs. 52.0%; P = 0.76). Measures of infarct mass and LV volume indexed to body surface area were also equivalent between groups.

The only value that showed a difference was LV mass indexed to body surface area, showing an increase in the EPO group at 2 to 6 days (74.2 g/m² vs. 69.2 g/m²; P = 0.04) and 12 weeks (67.3 g/m² vs. 61.8 g/m²; P = 0.04).

On subgroup analysis, infarct size was 41.2% larger among patients aged 70 years or older in the EPO group than in the placebo group at the first cardiac MRI scan (19.9% vs. 11.7%; P = 0.03). Infarct size remained 40% larger in elderly patients receiving EPO on the second scan (15.0% vs. 9.0%; P = 0.12), although the difference was not statistically significant at the latter time point.

In a safety analysis that combined the efficacy and dose-finding cohorts, EPO was associated with a higher rate of adverse events, serious adverse events, and the composite of death, MI, stroke, or stent thrombosis in the overall study population (table 1).

Table 1. Safety Outcomes

There were no clinically meaningful differences between groups in hemoglobin levels, reticulocyte counts, or blood pressure.

“In the REVEAL trial, a single bolus of intravenous [EPO] in patients with STEMI who underwent successful primary or rescue PCI failed to demonstrate a reduction in infarct size,” Dr. Najjar and colleagues write. “There was a significant increase in infarct size in prespecified analyses among older patients. There was also a significant increase in the composite of cardiovascular adverse events that included stent thrombosis.”

Previous animal studies had shown EPO to exert a cardioprotective effect in reducing infarct size and improving LV function, presumably due to the agent’s antiapoptotic and angiogenic properties. Clinical trials, meanwhile, have demonstrated more mixed results, with some showing benefit and others not. Some studies, like REVIVAL-3, have demonstrated an increase in adverse events with EPO.

“Due to these conflicting safety findings, temporary withholding of [EPO] in patents who are receiving this medication for labeled indications and who sustain an MI merits further study,” the researchers write.

Not Worth Further Study?

In an editorial accompanying the study, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), theorized along similar lines, noting that the “totality of evidence strongly suggests that this class of medication has cardiovascular risk, most likely to manifest in higher-risk individuals.”

As such, “a phase 2 trial [such as REVEAL] that finds no reduction on infarct size may not be worth taking into phase 3 trials, and certainly an agent or device that potentially increases infarct size would not be moved forward to phase 3 testing,” he writes.

A Question of Timing

Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), though, was not so sure. If it were possible to give EPO earlier, such a trial might be worthwhile, he told TCTMD in a telephone interview.

“In REVEAL, they had to wait until angioplasty was successful,” he said. “You could envision a clinical trial where you would give the drug in the emergency department when the ECG demonstrates ST-elevation MI, and we’re sure that the patient is going to the cath lab for a procedure, just like we do with other medications.”

In a telephone interview with TCTMD, Thomas D. Stuckey, MD, of the LeBauer Cardiovascular Research Foundation (Greensboro, NC), agreed. “Myocardial salvage is something that occurs early,” he said, explaining that REVEAL accepted patients presenting with STEMI during a time window that was too large to show an effect on reperfusion. “Intravenous EPO is not unlike pexelizumab, it’s not unlike aspiration thrombectomy, it’s not unlike the multitude of devices that we’ve tried to reduce infarct size, the earlier the better.”

Harmful Effects Discounted

Both Drs. Brener and Stuckey did not place much value on the clinical results. “The numbers are so small that I wouldn’t make anything of it,” Dr. Brener said, adding that the larger infarct size in elderly patients “is concerning to a certain extent.”

Nevertheless, “I would doubt that EPO is detrimental,” he noted. “If you take this together with [previous research], it appears that it is probably not beneficial, but not deleterious.”

Dr. Stuckey did not even place much credence in the elderly data. “Once you start parsing data with subset analysis, even if it’s prespecified, you’re dealing only with potentially hypothesis-generating findings,” he said. “But once again—for a therapy that’s delivered late, that probably won’t have any impact because of its late delivery—if this were repeated in a very large clinical trial, I would be surprised if there would be much difference in outcome, even in the over-age-70 group.”

Dr. Brener chalked up REVEAL to merely another promising therapy that fails to pan out. “This paper always reminds us why it’s important to do appropriately sized and controlled trials,” he said. “This is not the first time we are disappointed by the results of an intervention that looked very promising in preclinical and animal studies or that held a theoretical advantage, and I’m sure it will not be the last time. It’s a good example of the fact that what seems to make sense doesn’t always work.”

 

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Sources:
1. Najjar SS, Rao SV, Melloni C, et al. Intravenous erythropoietin in patients with ST-segment elevation myocardial infarction. REVEAL: A randomized controlled trial. JAMA. 2011;305:1863-1872.

2. Bhatt DL. Evaluation of agents to reduce infarct size: It can be quite REVEALing. JAMA. 2011;305:1908-1909.

 

 

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