We appreciate the interest of and comments by Drs Argulian and

Defining inclusion and exclusion criteria, along with dose selection of the administered pharmacological therapy, is critical in the early stages of a clinical trial design. The scientific method strongly recommends performing a profound bibliographic research in this regard, and for this purpose, we carefully reviewed previously conducted trials on the use of β-blockers in the setting of ST-segment–elevation acute myocardial infarction, taking note of the strengths and weaknesses of each of them. Thus, for the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial, we randomized anterior myocardial infarctions revascularized by primary angioplasty in <6 hours from symptom onset because this is the population that most benefits from any cardioprotective intervention. More important, and for safety reasons, we designed a trial to recruit patients with no obvious contraindications for the administration of intravenous metoprolol. Because β-blockers are clearly contraindicated in the acute phase of severe heart failure, patients in Killip-Kimball classes III and IV were strictly excluded from randomization, 2 fulfilling the primum non nocere principle. Patients randomized to intravenous metoprolol received up to three 5-mg boluses of metoprolol tartrate 2 minutes apart, following the same scheme as that in the Thrombolysis in Myocardial Infarction (TIMI) II-B trial, 3 closely checking for the presence of contraindications—heart rhythm and rate, PR-interval duration, blood pressure, and clinical examination—before the administration of every single bolus. Similarly, the dose and timing for oral metoprolol after reperfusion were selected according to current recommendations. 4 Thus, an initial low dose of 25 mg metoprolol twice a day was initiated in the vast majority of the patients included in the trial within the first 24 hours of admission and was carefully titrated according to clinical judgment. The increase in mortality observed in patients with initial systolic blood pressure <120 mm Hg or Killip-Kimball class III in the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) trial 5 is one of the main reasons why clinical practice guidelines do not emphasize early intravenous β-blocker initiation in ST-segment– elevation myocardial infarction. These patients were systematically excluded from our trial; consequently, prereperfusion administration of intravenous metoprolol did not increase the incidence of major adverse cardiac events in our study. This reinforces the contraindications for intravenous β-blocker therapy in patients with overt heart failure but supports its use in the population that can potentially benefit most from this inexpensive, safe, and effective intervention. Although there are other important differences between the METOCARD-CNIC trial and previously conducted studies evaluating the effect of β-blockers in the setting of ST-segment–elevation acute myocardial infarction, we totally agree with Drs Argulian and Messerli that a careful design of the dose and timing of any given intervention can make a huge difference in the outcomes of a trial.