Author + information
- Peter J. Kudenchuk, MD∗ ()
- Department of Medicine, Division of Cardiology/Arrhythmia Services and King County Emergency Medical Services, Seattle, Washington
- ↵∗Reprint requests and correspondence:
Dr. Peter J. Kudenchuk, Department of Medicine, Division of Cardiology/Arrhythmia Services, University of Washington, Box 356422, 1959 NE Pacific Street, Seattle, Washington 98195.
Cardiac arrest results in devastating injuries, particularly to the heart and brain. These are the most common causes of hospital death following an initially successful resuscitation from out-of-hospital cardiac arrest (OHCA). Brain and/or heart-related complications kill, on average, 2 of every 3 patients admitted to the hospital after OHCA, for which no pharmacological cardioprotective or neuroprotective agent has yet proven to be beneficial (1–3). Some of these effects are directly attributable to the ischemic injury from the arrest itself, whereas others are attributable to the series of adverse events that accompany issue reperfusion upon return of spontaneous circulation (ROSC), likened to the opening of a Pandora’s box.
Erythropoietin (Epo) is a growth hormone, best known for its regulation of circulating red blood cell mass (4). As such, it is not a drug that immediately leaps to mind as a possible therapy for cardiac arrest. Although an increase in erythrocyte number and the resulting enhanced oxygen delivery might be theoretically beneficial in cardiac arrest, these effects are usually delayed by days after receipt of the drug, and are unlikely to be of help in the acute arrest setting. Rather, Epo is believed to have nonhormonal properties that may confer more immediate myocardial protection and neuroprotection, making it a potentially useful agent in OHCA. These include a variety of pleiotropic effects that result from its binding to receptors in the heart and brain, activating signaling pathways that condition cells against ischemic injury and promote recovery of function (5,6).
A narrow temporal relationship likely exists between Epo administration and its cardioprotective effects. In experimental studies of cardiac arrest, pre- and post-ischemic conditioning with Epo improved the likelihood of ROSC and preserved post-resuscitation myocardial function under conditions in which time-to-treatment was brief. Benefits were seen when the drug was administered within a few minutes of cardiac arrest onset or as a pre-conditioning dose beforehand, with a rapid decline in benefit thereafter (6–9). In a small clinical study, Epo was associated with higher rates of successful resuscitation and hospital survival after OHCA when administered at or very proximal to resuscitation onset (10). Preventing neurological injury may afford a longer therapeutic time window (11). In a small, matched-comparison study by the current investigators (12) (which served as the basis for the current trial), treatment with Epo in conjunction with targeted temperature management within 75 min of OHCA was associated with a nonsignificant trend toward improved survival and neurological outcome.
However, although efficacy studies have signaled potential benefit from Epo, larger effectiveness trials have not. Epo-treated patients were found to have an unexpectedly higher death rate in a large, randomized clinical trial of ischemic stroke (13), a higher incidence of adverse cardiovascular events, including stent thrombosis in acute myocardial infarction (AMI) (14), and a significant increase in thrombotic events among randomized critically ill patients (15).
In this issue of the Journal and on the basis of their previous work, Cariou et al. (16) explored the possibility of a neuroprotective benefit from Epo in patients with OHCA of cardiac cause. They report findings from a randomized, multicenter, single-blind effectiveness trial of 435 patients who remained comatose after ROSC and were randomized to Epo treatment for the ensuing 48 h, along with standard post-cardiac arrest hospital care. The investigators were careful to ensure that targeted temperature management was coupled with Epo in both the treatment and control groups. The trial’s primary and secondary outcomes were survival with minimal neurological deficit at 60 days and total mortality, respectively.
The investigators are to be congratulated for orchestrating such a trial and, in particular, for achieving virtually complete neurological follow-up at 60 days—an extraordinary feat in itself! What is disappointing is that no differences were found in either survival or in neurological outcome between the treatment groups. Of greater concern was that the frequency of adverse events, particularly thrombotic complications, was higher with Epo treatment (a signal seen in their earlier study), raising concerns over the safety of this intervention and any future prospect for Epo in OHCA.
As designed, the trial potentially gave optimal opportunity for Epo to demonstrate its worth. Potential recipients were highly selected to represent those most likely to survive the event and benefit from therapy, composed of patients with witnessed OHCA of strictly cardiac origin and a limited period of circulatory arrest before ROSC. Patient selection and treatment were initiated before hospital arrival, with targeted temperature management and acute coronary interventions, if required, upon hospitalization. Care providers were not blinded to treatment assignment, which arguably could have served in favor of the intervention, were there bias toward Epo’s efficacy.
Even in this idealized context, Epo showed no benefit and conferred possible harm. Arguably, a variety of factors might have worked against seeing a benefit from the drug. Optimal dosing, for example, may have been an issue. Receipt of Epo was also surprisingly late for a pre-hospital trial, a median of 1.43 h from ROSC, raising the question as to what advantage there might have been in conducting the investigation outside the hospital?
Virtually all interventions for acute cardiovascular conditions have time-dependent outcomes, whether that be the interval from collapse to the first defibrillation shock in OHCA, the first medical contact to an acute coronary intervention in AMI, or the period from “last seen normal” to thrombolysis for stroke. Late treatment can even be hazardous. For example, thrombolytic agents are not only ineffective when administered late, but expose patients to unnecessary dangers from bleeding risks that are not balanced by any benefit when their administration is delayed. Similarly, experimental findings with Epo have suggested a benefit from early treatment, whereas clinical studies have raised safety concerns when the drug was administered later in the course of acute illnesses.
As administered in the present trial, Epo failed to deliver either neuroprotection or improved survival from OHCA. Moreover, as in previous clinical trials, at higher doses and with more extended therapy, Epo was capable of mischief in promoting unwanted thrombotic events, to which critically ill patients may be uniquely susceptible. These findings exemplify how experimental and efficacy studies, although important, are insufficient to establish an intervention’s actual effectiveness. Rather, true effectiveness must be achievable in the actual clinical environment and within the spectrum of time, place, persons, and practices encountered there. With its acknowledged limitations, this trial exemplifies what might be expected from the use of Epo in the “typical” setting of OHCA. Whether explained by administering too little, too much, too late, or being administered at all, these findings, added to those reported from stroke and AMI trials, should give pause to using the growth hormone in acute cardiovascular emergencies. Indeed, perhaps the time has come for this once budding relationship to grow apart.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Kudenchuk has reported that he has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Chalkias A.,
- Xanthos T.
- Fisher J.W.
- Ehrenreich H.,
- Weissenborn K.,
- Prange H.,
- et al.,
- EPO Stroke Trial Group
- Cariou A.,
- Deye N.,
- Vivien B.,
- et al.