Author + information
- Received March 17, 2016
- Revision received March 24, 2016
- Accepted March 24, 2016
- Published online June 14, 2016.
- Vincent Roolvink, MDa,
- Borja Ibáñez, MD, PhDb,c,
- Jan Paul Ottervanger, MD, PhDa,
- Gonzalo Pizarro, MDb,d,
- Niels van Royen, MD, PhDe,
- Alonso Mateos, MDf,
- Jan-Henk E. Dambrink, MD, PhDa,
- Noemi Escalera, BPTb,
- Erik Lipsic, MD, PhDg,
- Agustín Albarran, MD, PhDh,i,
- Antonio Fernández-Ortiz, MD, PhDh,j,
- Francisco Fernández-Avilés, MD, PhDh,k,
- Javier Goicolea, MD, PhDh,l,
- Javier Botas, MD, PhDh,m,
- Wouter Remkes, MDa,
- Victoria Hernandez-Jaras, PharmDf,
- Elvin Kedhi, MD, PhDa,
- José L. Zamorano, MD, PhDh,n,
- Felipe Navarro, MD, PhDc,h,
- Fernando Alfonso, MD, PhDh,o,
- Alberto García-Lledó, MD, PhDh,p,
- Joaquin Alonso, MD, PhDh,q,
- Maarten van Leeuwen, MDe,
- Robin Nijveldt, MD, PhDe,
- Sonja Postma, PhDr,
- Evelien Kolkman, MScr,
- Marcel Gosselink, MD, PhDa,
- Bart de Smet, MD, PhDs,
- Saman Rasoul, MD, PhDt,
- Jan J. Piek, MD, PhDu,
- Valentin Fuster, MD, PhDb,v,
- Arnoud W.J. van 't Hof, MD, PhDa,∗ (, )
- EARLY-BAMI Investigators
- aDepartment of Cardiology, Isala Hospital, Zwolle, the Netherlands
- bDepartment of Cardiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
- cDepartment of Cardiology, IIS-Fundacion Jimenez Díaz Hospital, Madrid, Spain
- dDepartment of Cardiology, Hospital Universitario Quirón, Universidad Europea de Madrid & Hospital Ruber-Quirónsalud, Madrid, Spain
- eDepartment of Cardiology, VU University Medical Center, Amsterdam, the Netherlands
- fDepartment of Cardiology, Servicio de Urgencia Medica de Madrid (SUMMA 112), Madrid, Spain
- gDepartment of Cardiology, University Medical Center Groningen, Groningen, the Netherlands
- hDepartment of Cardiology, Codigo Infarto, Madrid, Spain
- iDepartment of Cardiology, Hospital 12 de Octubre, Madrid, Spain
- jDepartment of Cardiology, Hospital Clínico San Carlos, Madrid, Spain
- kDepartment of Cardiology, Hospital Gregorio Marañón, Madrid, Spain
- lDepartment of Cardiology, Hospital Puerta de Hierro, Madrid, Spain
- mDepartment of Cardiology, Hospital Fundación Alcorcón, Madrid, Spain
- nDepartment of Cardiology, Hospital Ramón y Cajal, Madrid, Spain
- oDepartment of Cardiology, Hospital de La Princesa, Madrid, Spain
- pDepartment of Cardiology, Hospital Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
- qDepartment of Cardiology, Hospital de Getafe, Madrid, Spain
- rDiagram, Diagnostic Research and Management, Zwolle, the Netherlands
- sDepartment of Cardiology, Meander Medisch Centrum, Amersfoort, the Netherlands
- tDepartment of Cardiology, Maastricht University Medical Center, Maastricht, the Netherlands
- uDepartment of Cardiology, Academic Medical Center, Amsterdam, the Netherlands
- vThe Zena and Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- ↵∗Reprint requests and correspondence:
Dr. Arnoud W.J. van 't Hof, Department of Cardiology, Isala Hospital, Dr. van Heesweg 2, 8025 AB, Zwolle, the Netherlands.
Background The impact of intravenous (IV) beta-blockers before primary percutaneous coronary intervention (PPCI) on infarct size and clinical outcomes is not well established.
Objectives This study sought to conduct the first double-blind, placebo-controlled international multicenter study testing the effect of early IV beta-blockers before PPCI in a general ST-segment elevation myocardial infarction (STEMI) population.
Methods STEMI patients presenting <12 h from symptom onset in Killip class I to II without atrioventricular block were randomized 1:1 to IV metoprolol (2 × 5-mg bolus) or matched placebo before PPCI. Primary endpoint was myocardial infarct size as assessed by cardiac magnetic resonance imaging (CMR) at 30 days. Secondary endpoints were enzymatic infarct size and incidence of ventricular arrhythmias. Safety endpoints included symptomatic bradycardia, symptomatic hypotension, and cardiogenic shock.
Results A total of 683 patients (mean age 62 ± 12 years; 75% male) were randomized to metoprolol (n = 336) or placebo (n = 346). CMR was performed in 342 patients (54.8%). Infarct size (percent of left ventricle [LV]) by CMR did not differ between the metoprolol (15.3 ± 11.0%) and placebo groups (14.9 ± 11.5%; p = 0.616). Peak and area under the creatine kinase curve did not differ between both groups. LV ejection fraction by CMR was 51.0 ± 10.9% in the metoprolol group and 51.6 ± 10.8% in the placebo group (p = 0.68). The incidence of malignant arrhythmias was 3.6% in the metoprolol group versus 6.9% in placebo (p = 0.050). The incidence of adverse events was not different between groups.
Conclusions In a nonrestricted STEMI population, early intravenous metoprolol before PPCI was not associated with a reduction in infarct size. Metoprolol reduced the incidence of malignant arrhythmias in the acute phase and was not associated with an increase in adverse events. (Early-Beta blocker Administration before reperfusion primary PCI in patients with ST-elevation Myocardial Infarction [EARLY-BAMI]; EudraCT no: 2010-023394-19)
Despite advances in the care for patients with ST-segment elevation myocardial infarction (STEMI), mortality in these patients remains relatively high, especially in an all-comer population (1). Although early diagnosis and treatment have improved outcome of these patients, additional interventions early after onset of ischemia might further enhance outcomes. The clinical guidelines recommend treatment with beta-blockers for STEMI patients (2), although evidence of mortality reduction with beta-blockers after reperfusion therapy is limited (2–4).
Whether administration before reperfusion improves clinical outcome or reduces myocardial infarct size is less clear. Experimental studies presented conflicting results as to whether beta-blockers decrease extent of myocardial necrosis (4–6). In clinical studies in STEMI, the effect of early β-blockade was mostly studied in the pre-reperfusion era, with inconclusive results (7–10). In the era of thrombolysis, 2 randomized controlled trials testing the effect of beta-blockers in STEMI showed no reduction in mortality with β-blockade (11,12). In patients treated by primary percutaneous coronary intervention (PPCI), only 2 randomized controlled trials studied the effect of early beta-blocker treatment. In 1 small study (N = 96), Hanada et al. (13) observed that continuous intravenous (IV) landiolol immediately after PPCI was associated with improved left ventricular (LV) function. The METOCARD-CNIC (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction) trial (N = 220) showed that IV metoprolol administered before PPCI reduced infarct size and preserved LV function (14–16). In the latter trial, however, only patients with an anterior STEMI were included, and the trial was neither blinded nor placebo controlled.
We present the results of the EARLY-BAMI (Early Beta-blocker Administration before primary PCI in patients with ST-elevation Myocardial Infarction) trial, the first double-blinded, placebo-controlled multicenter international study assessing the effect of early IV beta-blocker therapy before PPCI in a less restricted STEMI population (17).
The primary objective of the EARLY-BAMI trial was to assess the effect of early, pre-hospital, pre-reperfusion administration of IV metoprolol on myocardial infarct size in patients with STEMI eligible for PPCI. The study design has previously been published (17). The EARLY-BAMI trial was a double-blind, placebo-controlled randomized clinical trial involving a total of 5 PCI centers and 3 ambulance services in the Netherlands, and 9 PCI centers and 1 ambulance service in Spain. All centers had longstanding experience in the pre-hospital diagnosis, triage, and treatment of STEMI patients in the ambulance and were part of a STEMI network. The study was approved by the medical ethical committees of the participating hospitals. Trial funding came from a research grant of the Dutch Heart Foundation (Utrecht, the Netherlands, no. 2010B125) and an unrestricted grant by Medtronic Inc. (Heerlen, the Netherlands), which was used for additional analyses.
Patients >18 years of age with symptoms of acute STEMI for >30 min but <12 h, plus ST-segment elevation >1 mV in 2 adjacent electrocardiogram leads or new left bundle branch block were eligible for enrollment. The diagnosis of STEMI was made by the ambulance medical personnel. Electrocardiogram transmission to a physician at the PCI center was allowed to confirm the diagnosis. After the in-ambulance diagnosis of STEMI, medical treatment proceeded per current guidelines: administration of 500 mg of IV aspirin, 600 mg of clopidogrel or 180 mg of ticagrelor orally, and 5,000 international units of IV unfractionated heparin. Exclusion criteria were Killip class III and IV, systolic blood pressure (BP) <100 mm Hg, heart rate <60 beats/min, type II and III atrioventricular block, history of previous myocardial infarction (MI), known asthma bronchiale, pacemaker or implanted cardioverter-defibrillator (no cardiac magnetic resonance imaging [CMR] possible), pregnancy or breastfeeding, or inability to provide informed consent. If patients fulfilled the inclusion/exclusion criteria, verbal informed consent was obtained.
The trained ambulance paramedic completed the administration/enrollment procedure. After informed consent, a blinded study medication box was opened. This box contained 2 vials of metoprolol 5 mg or matching placebo and labeled with a number that corresponded with the randomization list. Randomization took place without stratification and in blocks of 4. The first bolus of study medication was given in the ambulance, the second bolus was given at the catheterization laboratory pre-PCI but only if systolic BP was >100 mm Hg and heart rate >60 beats/min. Given that the COMMIT CC2 study (Clopidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study) (12) showed that 15 mg of metoprolol administered in a short interval was associated with a slight increase in cardiogenic shock (although this was restricted to Killip III patients), the reference ethics committee suggested reducing the dose to 10 mg separated into two 5-mg boluses: the first 5-mg bolus during ambulance transit and the second 5-mg bolus on arrival at the catheterization laboratory (i.e., immediately before initiating PCI). The METOCARD-CNIC trial results (using 15 mg of metoprolol) were not known at the time of the study design. Patients participating in the trial were treated during hospital admission and thereafter according to current guidelines. During PCI, the use of thrombus aspiration and glycoprotein IIb/IIIa inhibitors was left to operator discretion. Stenting was performed with a second-generation drug-eluting stent. After PCI, patients received detailed written study information detailing the protocol and the CMR follow-up, whereafter written informed consent was obtained. Plans were for all patients to receive oral metoprolol within 12 h post-PCI, according to current guidelines, during hospitalization. At discharge, all patients received oral metoprolol at a dose recommended by their treating physician. Follow-up included outpatient clinic visits to obtain follow-up data.
The primary endpoint was myocardial infarct size (percent infarcted myocardium, percentage of LV) as measured by CMR at 30 days (±10 days). The secondary efficacy endpoints were peak creatine kinase (CK), peak CK-MB, troponin at 24 h, the CK and CK-MB area under the curve during the first 24 h, residual ST-segment deviation 1 h after PCI/coronary angiogram, ventricular arrhythmias requiring defibrillation during transportation and hospitalization, and major adverse cardiac event (MACE) rate, defined as cardiac death, nonfatal reinfarction, or target vessel revascularization at 30 days. The secondary safety endpoints included symptomatic bradycardia, symptomatic hypotension, and cardiogenic shock. The following subgroups were prespecified for analysis: anterior versus nonanterior infarctions, patients presenting <6 h after symptom onset versus patients presenting ≥6 h, and occluded (Thrombolysis In Myocardial Infarction [TIMI] flow grade 0 and 1) infarct-related vessel at time of PCI versus open (TIMI flow grade 2 and 3) infarct-related vessel.
Initially, the study was designed and initiated with enzymatic infarct size as the primary endpoint. However, after inclusion of 164 patients, the primary endpoint was changed into a CMR-based endpoint (at July 3, 2013), which was approved by the steering committee and the medical ethics committee. The original primary outcome measure was enzymatic infarct size assessed by cardiac troponin T, and required 770 patients, based on the assumption that pre-hospital administration of 2 × 5-mg metoprolol IV would give a relative 20% reduction in infarct size (alpha = 0.05; power: 80%; mean troponin T: 3.34 ng/l; SD = ±3.30). This original primary outcome became a secondary outcome after the protocol change. This change in primary outcome was mostly made to reduce the necessary sample size and accommodate a time limitation on funding. Also, infarct size could be studied more precisely with CMR. The change occurred while the investigators were still entirely blinded to trial results and without any interim analysis performed. The sample size was than determined for the revised primary endpoint by a power analysis with reasonable clinical and statistical assumptions. With an expected infarct size of 28% (18) in a population under standard treatment (no beta-blocker pre-PCI), we considered a reduction in infarct size from 28% to 23.5% clinically relevant. Assuming an SD of the MI size measured by CMR equal to 10% (19), the power analysis indicated a total sample size of 326 patients (163 subjects in each group) was needed to achieve 80% power with significance level of 0.05 to detect a difference in infarct size.
Patients who died after completing the CMR study were included in the primary outcome analysis. Patients who died before performance of the CMR were not included in the primary outcome analysis; however, they were included in the secondary outcome analysis because death within 1 year is a secondary endpoint. Statistical analysis was performed with SAS, version 9.3 (SAS Institute, Cary, North Carolina) and SPSS Statistics for Windows, version 22.0 (IBM Corp, Armonk, New York). Continuous data were expressed as mean ± SD, and categorical data as percentage, unless otherwise denoted. The analysis of variance and the chi-square tests were appropriately used for continuous and categorical variables, respectively. For quantitative variables, data were expressed as mean ± SD, and median with first and third quartiles. Non-normal data were compared by nonparametric methods (Wilcoxon rank sum test) and normal data by parametric methods. Categorical data were expressed as percentages and compared by chi-square test (or Fisher exact test when appropriate). For all analyses, statistical significance was assumed when the 2-tailed p < 0.05.
All CMR studies were performed blinded to treatment allocation and according to a centralized protocol. Dedicated sequences evaluating cardiac function, myocardial edema, myocardial perfusion, and myocardial necrosis/fibrosis were performed. All CMR studies were stored and further analyzed in a central core laboratory at the Centro Nacional de Intervestigaciones Cardiovasculares Carlos III in Madrid, Spain. CMR study analyses were performed in a random manner by expert observers blinded to treatment allocation. Quantification was performed on a separate workstation using a dedicated software package (QMass MR 7.6, Medis, Leiden, the Netherlands). In all CMR studies, the following information was determined: LV volumes, LV function, and myocardial delayed enhancement. Myocardial necrosis was defined by the extent of abnormal delayed enhancement. All measurements were expressed as percentage of the total LV myocardial volume; the absolute MI size was also quantified in grams. All results were given in absolute numbers and indexed by patients’ body surface. Differences between the 2 groups were estimated by multivariable linear regression adjusted for the participating hospital center and the stratification variables.
Between February 2012 and November 2015, 684 patients were enrolled in 14 participating hospitals and 4 ambulance services in the Netherlands and Spain. In 1 case, the box with the study medication was lost during transportation, and this patient was excluded from the analysis. The remaining 683 patients were randomized to metoprolol (n = 336) or placebo (n = 347) before PPCI (Figure 1). Mean age was 62 ± 12 years, and 75% were male (Table 1 presents baseline characteristics). Although time from onset of complaints until first medical contact was comparable between the 2 groups, early presenters (<6 h after complaint onset) were more often present in the metoprolol group. At inclusion (before randomization), mean BP on admission was comparable between the 2 groups, whereas mean heart rate was not significantly lower in the metoprolol group (78.6 beats/min vs. 80.5 beats/min; p = 0.09). A total of 20 patients (2.9%) were enrolled at the emergency department of the PCI center, mainly because patient transport to the PCI center was very short. In these patients, the first study bolus was given as soon as possible at the emergency department with the second bolus at catheterization laboratory arrival.
Of the 336 patients allocated to pre-reperfusion metoprolol, 81.1% also received the second bolus compared with 86% in the placebo group (p = 0.08). BP before the second bolus (administered at the catheterization laboratory) was not different between groups, whereas heart rate was lower in the metoprolol group. Approximately 99% of patients in both groups underwent coronary angiography. One-vessel disease was observed in 53% of the metoprolol group compared with 59% of the placebo group (p = 0.06). Similar rates of initial TIMI flow grade 0 or 1 were demonstrated in the metoprolol group versus the placebo group (62% vs. 60%; p = 0.61) and PPCI performed in (93% vs. 92%; p = 0.66); the latter was successful in 97% in both groups (p = 0.70). Oral metoprolol was initiated within 24 h in 78% of the metoprolol group and 73% of the placebo group (p = 0.13).
CMR was performed in 342 of the 520 patients (66%) who were included after the change of the primary endpoint (67% in each group; p = 0.77) (Online Appendix). In the 342 patients who had CMR performed, no major differences in baseline characteristics between the treatment groups were present. In the CMR sample size calculation, we accounted for a 20% dropout rate, but the actual dropout rate was higher (34%). So, to meet the needed CMR number, patient recruitment was continued until 326 analyzed CMRs were reached. The main reasons given for not performing CMR included claustrophobia, planning out of the time window of 1 month ± 10 days, and patient refusal due to transfer to a different hospital (Figure 1).
The primary endpoint, mean infarct size (percent delayed enhancement of LV), was 15.29 ± 10.97% in the metropolol group versus 14.91 ± 11.52% in the placebo group (p = 0.616) (Table 2). Pre-reperfusion administration of IV metoprolol did not improve LV ejection fraction (LVEF) on CMR (50.97 ± 10.93% vs. 51.65 ± 10.83% in the placebo group).
The peak CK, CK-MB, and troponin levels at 24 h were available in 591 (86.4%) patients (Table 3). Peak CK was 2,102 ± 2,029 U/l in the metoprolol group versus 2,072 ± 2,018 U/l in the placebo group (p = 0.88). Mean single troponin T measured at 24 h of hospitalization was 3,711 ± 3,587 ng/l in the metoprolol group versus 3,166 ± 3,998 ng/l in the placebo group (p = 0.1). Results of enzymatic infarct size are summarized in Figure 2 (area under the curve).
MACE rates at 30 days were 6.2% (n = 19) in the metoprolol group versus 6.9% (n = 22) in the placebo group (p = 0.72) (Table 4).
Pre-reperfusion administration of IV metoprolol did not change the incidence of the prespecified secondary safety endpoints. There were 16 (4.8%) safety events in the metoprolol group versus 11 (3.2%) in the placebo group (p = 0.271). Bradycardia was observed in more metoprolol patients, but the difference was not significant (4.2% vs. 2.6%; p = 0.25) (Table 5). There was, however, a borderline significant reduction in the occurrence of malignant arrhythmias in the acute phase in the metoprolol group, 12 patients (3.6%) versus 24 patients (6.9%; p = 0.050).
Prespecified subgroup analysis
Infarct size 1 month post-STEMI did not differ in patients presenting with an anterior infarction between the metoprolol (18.8 ± 12.2%) and placebo groups (19.3 ± 12.7%; p = 0.33) (Figure 3). Similarly, there were no significant differences seen between patients in the metoprolol and placebo groups in regard to infarct size in patients with a nonanterior infarction, early or late presentation after symptom onset, or infarct size in patients with an occluded vessel (TIMI flow grade 0/1) at time of coronary angiography (Figure 3).
In this double-blind, randomized controlled trial of patients with STEMI undergoing PPCI, pre-reperfusion administration of up to 10 mg of IV metoprolol was safe, but had no effect on infarct size or LVEF.
Beta-blockers have multiple actions on the heart. Blockade of β1 receptors results in slowing of heart rate, reduction in myocardial contractility, and lowering of systemic BP. In the context of acute MI, which represents a state of reduced oxygen supply to the affected portion of the heart, these effects may be beneficial, because they result in reduced myocardial workload and oxygen demand. Furthermore, beta-blocker therapy decreases the incidence of life-threatening arrhythmias, reinfarction, and recurrent ischemia, preventing LV remodeling (11,13–15,18–21). These agents have been shown to be beneficial, resulting in mortality reductions in patients with reduced LV function and when administered post-MI. However, there is debate whether pre-reperfusion administration of IV beta-blockers may reduce reperfusion injury compared with post-reperfusion administration (22).
The MIAMI (Metoprolol in Acute Myocardial Infarction) trial tested the effect of pre-reperfusion metoprolol (3 × 5 mg IV) versus placebo in STEMI patients (N = 5,778) treated by thrombolysis and demonstrated no effect of metoprolol (11). In the COMMIT CC2 trial with 45,825 patients, IV metoprolol 3 × 5 mg followed by oral administration up to 4 weeks did not improve survival in STEMI patients (12). However, this was mainly caused by a higher incidence of cardiogenic shock in patients treated by early beta-blocker therapy, possibly due to inclusion of patients with heart failure. In the current era of PPCI, the METOCARD-CNIC trial showed reduced infarct size and increased LVEF in STEMI patients without signs of heart failure treated with early IV metoprolol (14,23). However, this study had a relatively small sample size (N = 270), was not blinded or placebo controlled, and included a select patient group (anterior STEMI presenting <6 h from symptom onset).
Our study included all patients with STEMI, with a double-blinded, placebo-controlled design. Our results do not confirm the effect observed in the METOCARD-CNIC trial. One possible explanation could be that the METOCARD-CNIC trial included only anterior infarctions, and the average infarct size (infarcted myocardium, percent LV) in the METOCARD-CNIC trial was 21.2% in patients treated with IV metoprolol compared with 15.3% in our study. These differences might support this theory: the smaller the infarction, the less likely an additional treatment effect could be demonstrated. However, the subgroup with anterior infarction also had no benefit of early β-blockade. In the METOCARD-CNIC trial, the dose of metoprolol was higher, up to 3 times 5 mg (15-mg target dose), whereas in our trial only 2 times 5 mg (10-mg target dose) was given.
Another explanation might be that 18.8% of patients in our trial were on long-term beta-blocker treatment before admission; this, however, was an exclusion criteria in the METOCARD-CNIC trial. Also, CMR timing can be an influence. In the METOCARD trial, CMRs were performed at 5 to 7 days and at 6 months. Data from the first CMR showed an improvement in LVEF in the metoprolol group and a significant reduction in infarct size. Follow-up CMR data at 6 months showed an even more significant difference in LVEF favoring metoprolol, but with no remaining significant difference in infarct size. In the metoprolol groups, the CMR infarct size as percent of LV was 15.7 ± 9.6% in the METOCARD-CNIC trial at 6 months versus 15.3 ± 11.0% in the EARLY-BAMI trial at 1 month. Another potential reason for the different effect observed between these trials pertains to when metoprolol was administered. A recent METOCARD-CNIC subanalysis showed that the timing of metoprolol administration was a critical factor accounting for its infarct-limiting effect: only patients receiving IV metoprolol long before reperfusion had a reduction in infarct size (24). Similar to control patients, METOCARD-CNIC trial patients receiving IV metoprolol close to PPCI had significantly larger infarctions than those receiving IV metoprolol long before reperfusion. In the present trial, the second 5-mg bolus (to complete the 10-mg target dose) was administered per protocol immediately before catheterization (median time from bolus and reperfusion: 14 min). The first 5 mg of IV metoprolol might be insufficient to attain cardioprotection; in fact, BP after the first bolus of medication (i.e., before the second bolus) was no different between metoprolol and placebo arms in this trial, supporting the low-dosing hypothesis.
Based on these data, and the conflicting results with the METOCARD-CNIC trial, additional randomized trials are needed to clarify whether early beta-blocker treatment has any effect in these patients. We advocate that future studies test the cardioprotective effects of IV metoprolol in STEMI patients using a target dose of 15 mg and administer medication immediately after STEMI diagnosis to allow a maximum “on-board” metoprolol time before reperfusion. Given the reduced observed infarct size with a trial of our sample size, the reduction in infarct size by metoprolol should be at least 3.5% to demonstrate a significant difference between the groups. The safety profile, low cost, and the reduction of acute malignant arrhythmias seen in this trial encourage the performance of additional larger trials.
In most randomized trials, in which infarct size or LVEF was measured with CMR, CMR was performed at 1 month (25,26). This was the main reason why we chose 1 month in our trial. All participating PCI centers and ambulance services had a longstanding experience in pre-hospital triage and treatment of STEMI patients. Regional differences in systems of care in which prehospital drug administration in the ambulance differ (Europe vs. United States) can lead to different application of these study results to daily practice.
During the course of the trial, the primary endpoint was changed from enzymatic infarct size to infarct size measured by CMR, to reduce the necessary sample size and because infarct size could be studied more precisely with CMR. The results from enzymatic infarct size analysis, however, were completely in line with the results from the primary CMR endpoint.
The trial was powered with a reduction of infarct size from 28% to 23.5%. The smaller-than-estimated infarct size in this trial (15.1%) could affect the neutral effect seen (the smaller the infarct size, the less probability a difference could be found). However, in the larger anterior infarctions, there was no observed effect. Also, patients who died before CMR was performed, meaning they probably had larger infarctions, may have caused a selection of patients with smaller infarctions undergoing CMR.
Although we defined several subanalyses, these analyses should be interpreted with caution, since the included number of patients in several subgroups were small. Also, we could not blind physicians and nurses to heart rate and BP; however, CMR analyses (primary endpoint) were blinded for both heart rate and study medication.
Early pre-reperfusion administration of IV metoprolol, at a dose of 10 mg (2 × 5 mg), had no beneficial effect on infarct size in patients with STEMI treated by PPCI (Central Illustration).
COMPETENCY IN PATIENT CARE: In patients with acute STEMI symptoms of <12 h duration given intravenous metoprolol before primary angioplasty, infarct size measured by CMR was not significantly different than in those given a placebo.
TRANSLATIONAL OUTLOOK: The conflicting results of available studies require additional large randomized trials to clarify whether intravenous beta-blocker treatment before angioplasty is beneficial for patients with STEMI.
The authors are grateful for the commitment of all the ambulance personnel in the Netherlands (RAV IJsselland, Witte kruis, UMCG ambulancezorg) and in Spain at SUMMA 112. The recruitment of patients in Spain was performed within the “Codigo Infarto” Network. Dr. Ibáñez, Dr. Pizarro, Ms. Escalera, and Dr. Fernández-Avilés are members of the Red de Investigación Cardiovascular-RIC (RETIC# RD12/0042/0054, RETIC#RD12/0042). All coinvestigators in the different hospitals have been capital for the rigorous conduct of this trial.
The Early-BAMI trial was an investigator-initiated, noncommercial trial. The trial was funded by a research grant from the Dutch Heart Foundation (Utrecht, the Netherlands) (no. 2010B125) and an unrestricted grant of Medtronic Inc. (Heerlen, the Netherlands). QMass software version MR 7.6 was partially supported by a scientific collaboration between CNIC and Medis. Dr. Botas has been a consultant for Terumo. Dr. van 't Hof has received speakers fees from AstraZeneca, Iroko, and Daiichi-Sankyo; has received nonpersonal grants from Medtronic and Daiichi-Sankyo to his research institution. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Christopher Granger, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- blood pressure
- creatine kinase
- cardiac magnetic resonance imaging
- left ventricular
- left ventricular ejection fraction
- major adverse cardiac events
- myocardial infarction
- primary percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- Thrombolysis In Myocardial Infarction
- Received March 17, 2016.
- Revision received March 24, 2016.
- Accepted March 24, 2016.
- American College of Cardiology Foundation
- Fokkema M.L.,
- James S.K.,
- Albertsson P.,
- et al.
- Van de Werf F.,
- Bax J.,
- Betriu A.,
- et al.
- Hammerman H.,
- Kloner R.A.,
- Briggs L.L.,
- Braunwald E.
- Rasmussen M.M.,
- Reimer K.A.,
- Kloner R.A.,
- Jennings R.B.
- Peter T.,
- Heng M.K.,
- Singh B.N.,
- et al.
- The MIAMI Trial Research Group
- Herlitz J.,
- Waagstein F.,
- Lindqvist J.,
- Swedberg K.,
- Hjalmarson A.
- Ibanez B.,
- Macaya C.,
- Sanchez-Brunete V.,
- et al.
- Ibanez B.,
- Fuster V.,
- Macaya C.,
- et al.
- Roolvink V.,
- Rasoul S.,
- Ottervanger J.P.,
- et al.
- Wu E.,
- Ortiz J.T.,
- Tejedor P.,
- et al.
- Atar D.,
- Petzelbauer P.,
- Schwitter J.,
- et al.
- Ibanez B.,
- Heusch G.,
- Ovize M.,
- Van de Werf F.
- Pizarro G.,
- Fernandez-Friera L.,
- Fuster V.,
- et al.
- García-Ruiz J.M.,
- Fernández-Jiménez R.,
- García-Alvarez A.,
- et al.
- Eppinga R.N.,
- Hartman M.H.,
- van Veldhuisen D.J.,
- et al.