In the REVEAL Trial, a single bolus of intravenous epoetin alfa in STEMI patients who underwent successful primary or rescue PCI failed to demonstrate a benefit, was associated with increased infarct size in older patients, and was associated with more cardiovascular adverse events, including stent thrombosis. Clinical interest in the use of erythropoietin as a cardioprotective agent emanated from a growing body of experimental evidence showing that erythropoietin’s non-erythropoietic effects include anti-inflammatory, anti-apoptotic, and angiogenic properties.10,22
In preclinical models, erythropoietin promotes neovascularization and induces mobilization of endothelial progenitor cells from bone marrow.23
In animal models of ischemic myocardial injury, erythropoietin was shown to reduce apoptotic cells,12,17
diminish cardiomyocyte loss,16
improve functional recovery,14
decrease infarct size16,17
and attenuate infarct expansion.17
Previous clinical studies evaluating the effects of erythropoietin on infarct size have yielded conflicting results. In four of these studies, infarct size was indirectly estimated from serial measurements of enzymatic markers of cardiac injury. In the HEBE III trial, a single dose of erythropoietin (60,000 U) within 3 hours of primary PCI in STEMI patients reduced enzymatic infarct size by 6.7% (P
=.06) but did not improve LVEF at 6 weeks.26
In a small pilot study, a single dose of erythropoietin (33,000 U) reduced enzymatic infarct size by 30%.27
However, in two other trials (one in non-STEMI patients and one in STEMI patients treated with fibrinolysis), a single dose of erythropoietin (40,000 U) did not reduce enzymatic infarct size.24,25
In the pilot study mentioned above,27
erythropoietin did not affect infarct size at 6 months as assessed by contrast-enhanced CMR, a powerful, validated tool that allows accurate and reproducible measurement of infarct size.28,29
Using CMR, the REVIVAL-3 study found that three daily doses of erythropoietin (33,000 U each) did not reduce infarct size at 5 days or 6 months30
; 6-month LVEF also remained unimproved.
Taken together with the REVEAL trial, these results indicate that no clinical study to date has shown any beneficial effect of erythropoietin on CMR-measured infarct size. Furthermore, the results in the subgroup of participants ≥70 years in REVEAL suggest that erythropoietin may adversely affect infarct size in this high-risk population. Although this concerning finding should be interpreted with caution due to the small number of older patients enrolled in REVEAL and the lack of multiplicity adjustment in the analyses, it suggests the need for added vigilance before enrolling older patients in any future trial evaluating erythropoietin in the setting of MI.
In the small (N
=30) pilot study that reported a 30% reduction in enzymatic infarct size with erythropoietin, the erythropoietin group had a greater decrease in LVESV than the placebo group, and a similar increase in LVEDV.27
Our larger study failed to replicate these observations. Instead, the epoetin alfa arm in REVEAL showed a smaller decrease in LVESVi and a larger increase in LVEDVi than the placebo group, suggesting a greater reliance on the Frank-Starling mechanism to augment stroke volume (data not shown). Thus, administration of erythropoietin may be associated with adverse LV remodeling at 3 months.
In REVEAL, we also found a significantly increased risk of death, recurrent MI, stroke, or stent thrombosis with erythropoietin, suggesting an increased thrombotic risk with erythropoietin in STEMI patients. This is consistent with other studies involving erythropoietin in non-cardiac populations.31–33
Chronic administration of erythropoietin can lead to increases in vasoconstriction, blood pressure, blood viscosity,34
and thrombotic risk.35
Some previous studies in patients with MI did not detect an increased risk of adverse events with erythropoietin,25,27,36
and the HEBE III trial even reported a lower risk of major adverse cardiovascular outcomes in patients receiving erythropoietin.24
On the other hand, the REVIVAL-3 observed an increased risk of death, recurrent MI, stroke, or target vessel revascularization in patients who received erythropoietin.30
Reconciling Animal and Clinical Studies
It is conceivable that the effects of erythropoietin differ across species. For example, although erythropoietin reduced infarct size in a rodent model of coronary occlusion,17
it failed to do so in a porcine model.37
Moreover, the average infarct size in REVEAL (approximately 15%–16%) was smaller than infarct sizes reported in animal studies. However, the average infarct size in the REVIVAL-3 study was approximately 27%–28%29
and erythropoietin still was not effective in reducing infarct size. In addition, the doses of erythropoietin used in animal studies (3000–5000 U/kg) were generally higher than those used in clinical studies. However, the cardioprotective effects of erythropoietin have been demonstrated at doses as low as 150 U/kg in rodents.38
Importantly, animal studies indicate that there is a therapeutic window of time beyond which the tissue-protective effects of erythropoietin are attenuated; further, the duration of this window is directly related to erythropoietin dose.31
For example, in a rodent model of coronary ligation, the benefits of erythropoietin at 3000 U/kg can still be observed when administration is delayed up to 12 (but not 24) hours after ischemic injury; whereas at 150 U/kg, these benefits are observed only when erythropoietin is administered within 4 (but not 8) hours of ischemic injury. Further, in a rodent model of ischemia (2 hours)-reperfusion (wherein infarct size is expected to be smaller than that achieved with permanent coronary ligation), an erythropoietin dose of 3000 U/kg was effective in reducing infarct size if administered at time of reperfusion, but not if infused 2 hours later (Talan M, unpublished data). In REVEAL, erythropoietin was infused, on average, >6 hours after symptom onset. Thus, we cannot exclude the possibility that administration of erythropoietin in our study occurred beyond the therapeutic window. We did not observe an association between infarct size and time from symptom onset to time of erythropoietin administration (data not shown). In addition, the REVIVAL-3 trial30
did not observe an effect on infarct size although erythropoietin was administered at time of PCI. Whether earlier administration of erythropoietin might reveal cardioprotective properties in humans remains to be determined.
In summary, a single bolus of 60,000 U of epoetin alfa in STEMI patients within 4 hours following successful PCI does not reduce infarct size and may increase infarct size among patients aged ≥70 years. Epoetin alfa was associated with unfavorable remodeling and higher risk of adverse clinical events. Whether very early administration of erythropoietin after symptom onset might reveal cardioprotective properties in humans remains to be determined.