Background: The effect of beta-blockers on infarct size when used in conjunction with primary PCI is unknown. We hypothesize that metoprolol reduces infarct size when administered early (intravenously before reperfusion).
Methods and results: Patients with Killip class II or less anterior STEMI undergoing PCI within 6 h of symptoms onset were randomized to receive intravenous metoprolol (n = 131) or not (control, n = 139) before reperfusion. All patients without contraindications received oral metoprolol within 24 h. The predefined primary end point was infarct size on MRI performed 5–7 days after STEMI. MRI was performed in 220 patients (81%). Mean ± SD infarct size by MRI was smaller after intravenous metoprolol compared with control (25.6 ± 15.3 vs 32.0 ± 22.2 g; adjusted difference, −6.52; 95% confidence interval, −11.39 to −1.78; p = 0.012). In patients with pre-PCI TIMI grade 0 to 1 flow, the adjusted treatment difference in infarct size was −8.13 (95% confidence interval, −13.10 to −3.16; p = 0.0024). Infarct size estimated by peak and area under the curve CK release was measured in all study populations and was significantly reduced by intravenous metoprolol. LVEF was higher in the intravenous metoprolol group (adjusted difference, 2.67%; 95% confidence interval, 0.09–5.21; p = 0.045). The composite of death, malignant ventricular arrhythmia, cardiogenic shock, AV block and re-infarction at 24 h in the intravenous metoprolol and control groups was 7.1% and 12.3%, respectively (p = 0.21).
Conclusions: In patients with anterior Killip class II or less STEMI undergoing primary PCI, early intravenous metoprolol before reperfusion reduced infarct size and LVEF with no excess of adverse events during the first 24 h after STEMI.
1. Perspective
1.1. Early intravenous metoprolol in acute STEMI before timely primary PCI–A stitch in time saves nine?
The benefit of oral beta-blockers in STEMI patient is well known and is recommended in all STEMI patients within 24 h unless contraindicated. Beta-blockers have pleiotropic effects on ischemic myocardium and its cardioprotective effect primarily stems from reduction of ischemia reperfusion injury. The literature on acute IV beta-blocker (BB) therapy in STEMI patients before mechanical reperfusion is limited and reveals conflicting results. Hence there is no clear-cut guideline advocating routine use of early intravenous BB (EIVBB) therapy in all STEMI patients.
METOCARD-CNIC is the largest prospective randomized study in the era of mechanical reperfusion clearly showing infarct limiting potential of EIVBB in STE AWMI patients resulting in improved LVEF as compared to control arm. This study forms a landmark because it attempts in a better way in demystifying the fact that EIVBB in STEMI patients is harmful and takes an extra step in proving significant 20% reduction in infarct size above that achieved with mechanical reperfusion with a trend towards reduction in adverse clinical events.
In the era when fibrinolytic therapy was not widely used, trials on IV beta-blockers had shown mixed results. Goteborg metoprolol trial revealed a 17% reduction in infarct size and 36% reduction in mortality with IV metoprolol when it was administered within 7 h of symptom onset.1 MIAMI trial did show a statistically insignificant 13% reduction in mortality with IV metoprolol in acute MI patients administered within 12 h of symptom onset. ISIS-1 trial on 16,027 patients of suspected myocardial infarction had shown a 15% reduction with IV atenolol therapy. But a meta-regression analysis in the pre-reperfusion era had demonstrated no extra mortality benefit with IV beta-blockers.2
In the fibrinolytic reperfusion era, two major trials failed to show any difference in mortality, LVEF or infarct size with EIVBB therapy in STEMI patients reperfused with alteplase. Both GUSTO and COMMIT trials had shown increased rates of CHF and cardiogenic shock with EIVBB in STEMI patients.3, 4 The COMMIT trial also had shown that EIVBB therapy in STEMI patients in Killip class III increased mortality hence nullifying the benefits like reduced reinfarction rates and ventricular fibrillation.4 Learning lessons from COMMIT trial, the use of EIVBB was restricted to class I and II patients in the present study.
In the mechanical reperfusion era, again results were mixed on EIVBB. Conflicting reports exist on cardioprotective effect of beta-blocker therapy and post PCI procedural enzyme release. CADILLAC investigators had shown that EIVBB improved 30-day mortality (1.5% vs 2.8%) and LVEF only in those patients who had not received prior beta blocker therapy (3.8% vs 1.3%).5 Valle et al showed that pre-primary PCI beta blocker use was associated with reduced arrhythmia and mortality without increased rates of cardiogenic shock and congestive cardiac failure.6
Majority of the strategies attempting to improve cardioprotection like thrombectomy devices, distal embolization devices, glucose insulin potassium infusion, adenosine, endovascular cooling etc., have yielded equivocal results because of delayed time to reperfusion. In the present study mechanical reperfusion was established within 6 h of symptom onset, hence ensuring reasonable reperfusion window period.
In our opinion this is an important landmark study showing potential cardioprotective benefit of EIVBB in STEMI patients undergoing primary PCI within 6 h and having no contraindications for BB and it may play a vital role in the future in shifting the guideline for IV beta-blocker from class IIa to class I, especially in acute anterior wall MI with sympathetic stimulation and Killip class ≤ II. The 20% greater reduction in infarct size above that was achieved by mechanical reperfusion offers great hope. Hence EIVBB can be regarded as an asset with certainty for cardioprotection. Well-designed RCTs aiming to achieve improvement in hard clinical outcomes with EIVBB in STEMI patients is the need of the hour.
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