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When given prior to percutaneous coronary intervention (PCI) in patients who present within 6 hours of onset of ST-segment elevation myocardial infarction (STEMI), the beta blocker metoprolol reduces infarct size and increases left ventricular ejection fraction (LVEF), according to a multicenter, randomized trial published online September 3, 2013, ahead of print in Circulation.
For the METOCARD-CNIC (METOprolol in CARDioproteCtioN during an acute myocardial InfarCtion) trial, investigators led by Borja Ibanez, MD, PhD, of Centro Nacional de Investigaciones Cardiovasculares Carlos III (Madrid, Spain), randomized 220 patients with anterior STEMI (Killip class ≤ II) to receive intravenous (IV) beta-blocker therapy with metoprolol (n = 106) or no beta blocker (n = 114) prior to primary PCI.
Infarct size was evaluated by magnetic resonance imaging (MRI) performed at 5 to 7 days after STEMI and by creatine kinase levels.
Reduced Infarct Size, No Increased CV Events
Mean infarct size, the primary endpoint, was reduced with metoprolol while mean LVEF increased. In addition, infarct size was reduced to an even greater extent in the prespecified subgroup of patients with an occluded artery (TIMI flow grade 0/1) before PCI (table 1).
Table 1. Endpoints
Metoprolol(n = 106)
Control(n = 114)
Adjusted Treatment Effect
Infarct Size, gOverallTIMI 0/1 Subgroup
Incidence of MACE within 24 hours after STEMI, the prespecified safety endpoint, was similar in metoprolol-treated patients and controls (7.1% vs. 12.3%; P = 0.21).
Dr. Ibanez and colleagues point out that current guidelines from the American Heart Association Foundation, American College of Cardiology, and the European Society of Cardiology all recommend oral beta-blockade within 24 hours after STEMI but do not emphasize early IV initiation before intervention. This position, they add, stems mainly from the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT), which showed significantly reduced rates of reinfarction and ventricular fibrillation—but an excess of cardiogenic shock—in response to early IV metoprolol in STEMI patients. However, the study was conducted in the era of thrombolysis, prior to primary PCI becoming the treatment of choice for STEMI.
According to the study authors, metoprolol represents an inexpensive medication already approved for STEMI that “can significantly reduce infarct size simply by being administered before reperfusion. Further evidence is needed to assess potential longer-term clinical benefits in a larger clinical trial.”
Not Convincing Enough to Change Practice
In an editorial accompanying the study, Gjin Ndrepepa, MD, and Adnan Kastrati, MD, both of Deutsches Herzzentrum (Munich, Germany), say beta blockers also may have a direct protective effect against reperfusion injury, scavenging free radicals by binding to hydrophobic sites in the cellular membranes and exerting an antioxidant effect.
They also note that while infarct size is an important predictor of outcomes, the surrogate endpoint is a poor substitute for hard clinical endpoints such as mortality. Overall, they say, use of beta blockers in the acute setting in patients with STEMI “may be summarized as predominantly beneficial in the pre-reperfusion era, controversial in the thrombolytic era, and poorly investigated in the primary PCI era.”
Although Drs. Ndrepepa and Kastrati agree that the results are encouraging, they do not believe METOCARD-CNIC alone is strong enough to warrant a change in clinical practice.
“Instead, these data provide a solid basis for further investigation of intravenous beta blockers and should stimulate the performance of dedicated randomized trials powered for hard clinical endpoints so that we may more fully know the role of an old therapy in the contemporary era of reperfusion with primary PCI,” they write.
Patients randomized to metoprolol received at least 1 5-mg IV bolus (82% and 67% received 2 and 3 5-mg boluses, respectively). All patients, except for those who developed contraindications, received oral metoprolol between 12 and 24 hours post-infarction in line with clinical guidelines.
2. Ndrepepa G, Kastrati A. Intravenous beta blockers in primary PCI: New hope for an old therapy [editorial]. Circulation. 2013;Epub ahead of print.