Abstract & Commentary
Metoprolol Prior to Primary PCI: An Old Drug Gets Some New Data
Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco, Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
Source: Pizarro G, et al. Long term benefit of early pre-reperfusion metoprolol administration in patients with acute myocardial infarction: Results from the METOCARD-CNIC trial. J Am Coll Cardiol 2014; Mar 24. doi: 10.1016/j.jacc.2014.03.014. [Epub ahead of print.]
Beta-blockers have long been considered a cornerstone of therapy for patients with acute myocardial infarction (MI). The optimal timing of beta-blocker administration has been a question, however, and the most recent American College of Cardiology Foundation/American Heart Association guidelines give a class I indication only to the use of oral beta-blockers in the first 24 hours in ST-segment elevation myocardial infarction (STEMI) patients who do not have contraindications. The Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD) trial was a multicenter, randomized trial of early intravenous metoprolol administration in hemodynamically stable anterior STEMI patients who were going for primary percutaneous coronary intervention (PCI). Patients assigned to the metoprolol arm received the drug prior to reperfusion. This was based on the hypothesis that early beta-blocker therapy would attenuate reperfusion injury. During the trial, 270 patients were randomized to pre-PCI metoprolol (139 patients) or to no metoprolol (131 patients). All patients without exclusions subsequently received oral metoprolol within 24 hours. The primary endpoint of the trial was infarct size, measured by MRI at 5-7 days. In the initial publication of the trial results, the authors reported that the mean infarct size by MRI was lower in the metoprolol group as compared with controls, and that the left ventricular ejection fraction (LVEF) was higher.1 Interestingly, this effect was shown primarily in patients who had a completely occluded artery prior to intervention (26.7 ± 15.0 g in metoprolol patients vs 34.4 ± 20.0 g in the control group, adjusted difference, −8.13; 95% confidence interval [CI], −13.10 to −3.16; P = 0.0024), while no significant effect was revealed in patients with an already open infarct artery at the time of initial angiography (20.7 ± 16.4 g in the metoprolol group vs 22.2 ± 28.3 g in the control group, P = 0.6).
The authors now report on the longer-term results of the study, with some intriguing findings. All patients had at least 12 months of clinical follow-up. In addition, 101 patients per group had follow-up MRI at 6 months post-MI. At the 6-month time point, fewer patients in the early metoprolol group had severely depressed LVEF (≤ 35%) compared with the control group (11% vs 27%, P = 0.006). With a median follow-up of 2 years, the prespecified endpoint of a composite of death, heart failure admission, reinfarction, and malignant arrhythmia occurred less often in the IV metoprolol group compared with controls (10.8% vs 18.3%; adjusted hazard ratio [HR], 0.55; 95% CI, 0.26-1.04, P = 0.065). Heart failure readmission was significantly reduced in the treatment group (2.2% in IV metoprolol vs 6.9% in controls; HR, 0.32; 95% CI, 0.015-0.95; P = 0.046). In addition, fewer patients in the intervention group had a class I indication for implantable cardioverter-defibrillator (ICD) at 6 months, compared with controls. The number needed to treat to avoid one ICD indication was 8 (95% CI, 4.5-31; P = 0.015). In patients undergoing primary PCI for STEMI, pre-procedure IV metoprolol resulted in higher long-term LVEF, less major adverse effects, fewer readmissions for heart failure, and reduced indications for ICD placement.
The METOCARD trial was a relatively modest-sized trial, powered to look primarily at a surrogate endpoint — infarct size by MRI. That the long-term secondary clinical endpoints also showed a significant effect is remarkable, especially given that the study was not powered for clinical endpoints. The hypothesized chain of effects here is simple and elegant: Pre-PCI metoprolol reduces reperfusion injury, resulting in decreased in infarct size, which translates downstream into less ventricular remodeling, higher LVEF, and a reduction in clinical events.
It is worth commenting on the differences between this study population and that of prior trials. Much of the tempered enthusiasm for early IV beta-blocker in STEMI comes from the 2005 COMMIT/CCS2 trial, which studied early IV followed by oral metoprolol in a population of 45,852 patients with acute MI.2 In that trial, the effect of metoprolol on the combined endpoint of death, recurrent MI, or cardiac arrest was neutral. Although recurrent MI and VT were lower in the treated group, this was counterbalanced by a significant increase in the occurrence of early cardiogenic shock. Thus, the class IIa recommendation: "It is reasonable to administer intravenous beta blockers at the time of presentation to patients with STEMI and no contraindications to their use who are hypertensive or have ongoing ischemia." The METOCARD trial was comparatively selective in enrolling patients with anterior MI, who were likely to have a large region of myocardium affected, but excluded patients with SBP < 120 mmHg, AV block, or heart rate < 60, as well as patients with prior infarction. Notably, in the COMMIT trial, certain subgroups were more likely to develop cardiogenic shock, including patients of advanced age, systolic BP < 120 mmHg, presenting heart rate > 110 beats per minute, or increased time since onset of symptoms. With the addition of the METOCARD data to the knowledge base, pre-reperfusion IV beta-blocker appears worth considering for patients who do not fit into these high-risk subgroups.
1. Ibanez B, et al. Effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: The Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial. Circulation 2013;128:1495-1503.
2. Chen ZM, et al. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: Randomised placebo-controlled trial. Lancet 2005;366: 1622-1632.