October 4th, 2013

A New Use for an Old Beta-Blocker?

CardioExchange’s Harlan Krumholz interviews Borja Ibañez, lead investigator of the METOCARD-CNIC trial, which assessed the effect of intravenous beta-blocker use before reperfusion in patients undergoing primary PCI.


Two hundred seventy patients with anterior STEMI and Killip class I or II undergoing PCI within 6 hours after symptom onset were randomized to receive intravenous metoprolol or not (control) before reperfusion. All patients without contraindications then received oral metoprolol within 24 hours.

Mean infarct size, according to MRI performed 5 to 7 days after STEMI in 220 patients, was significantly smaller in the intravenous metoprolol group than in the control group (25.6 vs. 32.0 g; P=0.012). Compared with controls, IV metoprolol recipients had a significantly higher post-PCI left ventricular ejection fraction (mean difference, 2.67%) and a nonsignificantly lower rate of the composite endpoint of death, malignant ventricular arrhythmia, cardiogenic shock, atrioventricular block, or reinfarction at 24 hours (7.1% vs. 12.3%; P=0.21).


Krumholz: What made you look to an older drug for a clinical trial? How did this trial get started?

Ibañez: The effect of beta-blockers on infarct size has been a matter of intense discussion with no clear answer. We started this program in 2006, when I was working at Mount Sinai Hospital in New York with Dr. Valentin Fuster and Dr. Juan Badimon. Using MRI, we showed that metoprolol could reduce infarct size and improve LVEF recovery in pigs. In a second study in the same pig model, we compared pre-reperfusion metoprolol versus oral post-reperfusion metoprolol (as clinical guidelines recommend) and observed that metoprolol reduced infarct size only when administered before reperfusion. We thought we generated enough evidence to merit a clinical trial in humans. Surprisingly, the effect of beta-blockers on infarct size had never been evaluated in the context of primary PCI. Given that this old, inexpensive drug is approved for STEMI, we believed that a trial like this one might have an impact in clinical practice.

Krumholz: Should a small, open-label study of infarct size, a surrogate outcome, be considered only as a rationale for a larger trial assessing outcomes, or should the findings be enough to change practice and guideline recommendations?

Ibañez: Ours was a PROBE trial rather than an open-label trial (all evaluations were done with blinding to treatment allocation). Given the clear effect of metoprolol on heart rate and blood pressure, double blinding would not eliminate this source of bias. The main endpoint is infarct size (a surrogate maker), but we must remember that intravenous metoprolol is allowed by clinical guidelines. We meticulously evaluated all side effects, and no excess was observed. All of these factors (infarct reduction, LVEF improvement, safety profile, and drug allowed by clinical guidelines) should be taken into consideration when revising the guidelines. Although a larger trial with hard endpoints is needed, the data from METOCARD-CNIC might be enough to reconsider the administration of pre-reperfusion metoprolol in patients with Killip I–II STEMI who present early (mainly due to the safety profile and potential benefit).

Krumholz: Will you now use intravenous beta-blockers as adjunctive therapy for selected patients with STEMI undergoing PCI?

Ibañez: I hope that soon we can embark on a large double-blind trial confirming these results with hard endpoints. I am convinced that this strategy will change outcomes for patients at a very low cost. While we await this trial, I will immediately start using intravenous metoprolol in patients with anterior Killip class I–II STEMI who undergo primary PCI. We know it is safe, reduces infarct size, and improves LVEF. This is too much to ignore for an already approved old drug. While we await data on mortality reduction, smaller infarcts are good news.

Krumholz: Some readers will remember the COMMIT trial. How do you see your study compared with the strategy and results of COMMIT?

Ibañez: Of course, COMMIT will be part of the discussion. Here are the main differences:

1. In COMMIT, all patients were revascularized by thrombolysis; in our trial, revascularization was by PCI.

2. In COMMIT, mean time from symptom onset to lytic initiation was 11 hours. This means that in half the population, even lytics would be questionable. After 11 hours of coronary occlusion, the amount of salvageable myocardium is negligible; therefore, the potential for infarct reduction is slim. In METOCARD-CNIC, all patients were revascularized within 6 hours, a much better time window for myocardial salvage.

3. COMMIT recruited patients with overt heart failure (Killip class III patients were included). This is a classical contraindication to IV beta-blockade, so the increase in shock was not surprising. In fact, in COMMIT’s subpopulation of Killip I–II patients, despite very late presentation, metoprolol was associated with a clear net benefit. Unfortunately, in the Killip III patients, metoprolol was unsurprisingly associated with a massive increase in shock. METOCARD-CNIC included only Killip I–II patients.

In summary, the COMMIT participants were not the kind of patients we treat every day, and the trial’s major effect on guidelines was, in my view, excessive. The lack of other available information was one major reason to conduct our trial. We still need the events trial, but I believe that the early-presenting population in our trial more closely represents daily practice. Thus, it might be prudent to consider pre-reperfusion metoprolol administration in Killip I–II STEMI patients. The strategy is safe and inexpensive.


What’s your view of using intravenous metoprolol in this clinical context, given the findings from the trial conducted by Dr. Ibañez and his colleagues?

2 Responses to “A New Use for an Old Beta-Blocker?”

  1. Saurav Chatterjee, MD says:

    We had actually looked at this (with Dr Ibanez as co-author)in the form of a large meta-analysis, which showed no increased risk of harms even if the patients given IV beta-blockers with Killip Class III HF were excluded from the overall analysis.Link below:

  2. Siqin Ye, MD says:

    I remember when I first learned about the COMMIT trial as a resident, when my attending gave his take on the potential benefit of beta blockers for Killip I-II patients with MI, similar to Dr. Krumholz and Ibanez’s discussion above. I’m glad to see that the results of METOCARD-CNIC support what probably many of us do in routine clinical practice, i.e., judicious early use of beta-blockers in appropriate patients.

    A similar issue also arose with the POISE trial (http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2808%2960601-7/abstract), where many thought that the harm observed with pre-op beta blocker use was due to the stringent dosing requirement leading to hypotension. For me, these considerations raise two broad questions: one, what approaches should we take to consider evidence that is imperfect (such as those from subgroup analyses or from trials with surrogate end points) during clinical decision making; and two, how can designs of clinical trials be made more pragmatic to reflect inherence nuances in clinical care, while preserving their ability to detect treatment effects?