Author + information
- L. Kristin Newby, MD, MHS∗ ()
- Division of Cardiology, Department of Medicine and Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina
- ↵∗Reprint requests and correspondence:
Dr. L. Kristin Newby, Division of Cardiology, Department of Medicine and Duke Clinical Research Institute, Duke University Medical Center, P.O. Box 17969, Durham, North Carolina 27715-7969.
The quest to identify therapeutic strategies for cardioprotection in the setting of reperfusion therapy for acute myocardial infarction (AMI) has been long and arduous. Despite solid mechanistic hypotheses and favorable results on infarct size in animal models, translation to humans has been difficult. Even among agents that have shown favorable effects on infarct size or left ventricular function in humans, for a variety of postulated reasons, none have translated to improved outcomes (1). Early use of intravenous β-blockers before reperfusion to modulate ischemia-reperfusion injury in AMI has mechanistic (reductions in heart rate, contractility, and myocardial oxygen demand; mediation of signaling pathways of reperfusion injury) and practical (readily available, inexpensive) appeal, as well as supporting animal model data on infarct size (2,3). Yet, a large clinical outcomes trial of pre-reperfusion intravenous β-blockade among patients with ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytic therapy showed no benefit on mortality and potential for harm, particularly among patients with Killip class III at presentation (4).
There have been no large outcomes trials of pre-reperfusion intravenous β-blockade among STEMI patients undergoing primary percutaneous coronary intervention (PPCI). However, in 2013, the METOCARD-CNIC (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction) randomized trial of early intravenous metoprolol revealed promising results on reduction in infarct size and improved left ventricular function among patients with anterior STEMI undergoing reperfusion with PPCI (5). In this issue of the Journal, Roolvink et al. (6) report the results of the EARLY-BAMI (Early β-blocker Administration before primary PCI in STEMI) trial, providing an additional perspective on these prior observations.
In contrast to the METOCARD-CNIC trial, which randomized only patients with anterior STEMI, the EARLY-BAMI investigators randomized patients in the field with any STEMI to blinded, double-bolus 5-mg metoprolol or matching placebo. The first dose was administered in the ambulance, and the second dose, in the catheterization laboratory before PPCI if systolic blood pressure was >100 mm Hg and heart rate was >60 beats/min (6). Of 683 patients randomized, only 342 (55%) had the primary endpoint assessment of infarct size by cardiac magnetic resonance imaging (CMR) at 30 days. Among these patients, investigators found no effect of pre-PPCI intravenous metoprolol on infarct size (15.3% vs. 14.9%; p = 0.616). However, patients who did not undergo CMR were different (older, more often women, and had fewer first contacts at a referring hospital or PCI center) from those who did, which may have resulted in bias in the primary endpoint assessment. Infarct size was also estimated enzymatically during hospitalization for the index event in all randomized patients using a variety of necrosis markers. There were no differences in infarct size by any of these acute measures of myonecrosis in either the population assessed for the primary CMR endpoint or those who did not have CMR, providing some reassurance of the validity of the CMR results.
In considering the neutral results of the EARLY-BAMI trial, it is important to note that infarct size as determined by CMR was much smaller (15%) than estimated for the placebo arm (28%) or than that observed in the METOCARD-CNIC trial (21%, metoprolol group; 25%, control group) (5,6). Thus, the EARLY-BAMI trial was substantially underpowered to detect differences between treatment arms, but the smaller infarct size overall also may have rendered incremental improvement due to cardioprotection difficult to attain compared with the larger anterior STEMIs treated in the METOCARD-CNIC trial. The low overall 30-day clinical event rates also suggest that the population randomized may not have been representative of the broader population of STEMI patients, even excluding those with Killip class III at initial assessment. However, there was no apparent heterogeneity of treatment effect among subgroups, including by location of infarction (anterior vs. other) or timing of administration of the first bolus of metoprolol.
Although the EARLY-BAMI trial failed to provide clarity on the role of intravenous β-blockade as an adjunctive therapy for cardioprotection with PPCI, and leaves many questions unanswered, it did address some of the open questions raised by the METOCARD-CNIC trial (7). Specifically, by enrolling only anterior STEMI patients, the METOCARD-CNIC trial could not address the potential for bradycardia that may be of greater concern in treating inferior STEMI. The EARLY-BAMI trial found no significant difference in safety endpoints, including symptomatic severe bradycardia between the metoprolol (1.6%) and placebo (0.6%) groups. Further, in the METOCARD-CNIC trial, patients with initial Thrombolysis In Myocardial Infarction (TIMI) flow grade 0/1 responded more favorably than those with TIMI flow grade 2/3, which could not be readily explained. In the EARLY-BAMI trial, Roolvink et al. (6) found no evidence for similar heterogeneity in treatment effect. An important secondary finding from the EARLY-BAMI trial, though only nominally significant, was a reduction in ventricular arrhythmias requiring defibrillation (12 [3.6%] with intravenous metoprolol vs. 24 [6.9%] with placebo; p = 0.05) (6). Finally, the METOCARD-CNIC trial used a metoprolol 5 mg × 3 dosing regimen compared with 5 mg × 2 in the EARLY-BAMI trial, selected for safety concerns (5,6). However, dosing regimen alone is unlikely to explain the lack of treatment effect given that infarct size overall was much lower than expected in both groups.
Finally, the EARLY-BAMI trial highlighted important perspectives on health care delivery that are worth considering. First, in the EARLY-BAMI trial, the vast majority of patients received the first bolus of study medication (as well as other routine early STEMI treatment) in the ambulance. Although this is a model system, this feature of the EARLY-BAMI trial highlights the importance of considering regional variations in practice in designing, interpreting, and generalizing trial results as they may not be replicable in all health care delivery systems; in this case, the emergency response systems in the United States. Also, it is noted that angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and β-blockers were used in only 68% and 73%, respectively, of EARLY-BAMI patients at discharge. Although this use was not significantly different by treatment arm and was unlikely to explain the observed absence of treatment effect, it highlights the need to optimize the use of therapies demonstrated to improve outcomes after STEMI.
In summary, despite 2 randomized trials (the METOCARD-CNIC trial and now the EARLY-BAMI trial), each with their methodological strengths and weaknesses, controversy remains with regard to the benefits of pre-reperfusion intravenous β-blockade in the setting of PPCI for STEMI. It is unlikely that additional trials using infarct size as a surrogate marker of treatment effect will resolve these issues given the challenges experienced by the EARLY-BAMI and METOCARD-CNIC trials (e.g., slow enrollment, expense, substantial proportions of recruited patients not undergoing the CMR primary endpoint assessment, and subselected populations). Further, such trials would likely be insufficient to affect change in practice, even if consistent results on infarct size reduction were to be achieved in additional trials.
Given the apparent safety of intravenous metoprolol when administered to patients who are Killip class I/II at presentation, and potentially beneficial effects on ventricular arrhythmias, a more reasonable approach may be to conduct a definitive trial stratified by STEMI location and adequately powered for clinical outcomes, including death, recurrent myocardial infarction, and heart failure events. Although this will undoubtedly require a larger sample size and greater costs, if successful, it could result in an inexpensive advance in treating patients with STEMI undergoing reperfusion with PPCI. In the meantime, given strong evidence that they reduce morbidity and mortality and prevent adverse remodeling after AMI, every effort should be made to improve the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and β-blockers, both early after reperfusion and at discharge.
↵∗ 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. Newby has reported that she has no relationships relevant to the contents of this paper to disclose. Christopher Granger, MD, served as Guest Editor for this paper.
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