Favorable effects of intravenous beta blockers in ST elevation myocardial infarct

Introduction A wealth of data in the literature support the long-term use of beta blockers after ST elevation myocardial infarct (STEMI). The use of these drugs intravenously in the early phase after the infarct or before reperfusion, though, is not supported by much evidence. In fact, despite the solid mechanistic hypothesis (reduction of the heart rate, contractility, oxygen consumption, and the modulation of the reperfusion damage signaling, Fig. 1),1–3 proven in animal models (decreased infarct size), the scientific evidence for their efficacy in clinical practice has been difficult to come by. Accordingly, present guidelines4 recommend intravenous beta blockers as potentially useful, in the acute phase after myocardial infarct, in hemodynamically stable patients without contraindication to the treatment (class IIa, level of evidence B).Fig. 1: Beta-blockers mechanisms of cardio-protection in the acute phase after myocardial infarction.Background In a historic study, Rasmussen et al.5 demonstrated, in an animal model, that a pretreatment with propranolol decreased the infarct area after coronary artery occlusion. These findings were confirmed by Braunwald et al.6 in 1984, by showing that timolol significantly reduced the necrotic area after left anterior descending coronary artery ligature. During the same year,7 a study on patients after myocardial infarction (MI) demonstrated a decrease in the infarct area in patients treated with timolol vs. placebo. During the 1980s, two important studies showed a reduction of short-term mortality after intravenous beta blockers. The International Study of Infarct Survival-18 multicentric study compared intravenous atenolol vs. placebo in 16 027 patients with acute myocardial infarct showing a benefit in reducing cardiovascular deaths in the treatment group. The treatment protocol included a 10 mg intravenous atenolol at admission, followed by a 100-mg daily dose for the following 7 days or until discharge. In the beta-blockers group, cardiovascular mortality decreased by 15% during treatment mainly, though, during the first 24 h. The inference from the study was that for every 1000 patients receiving atenolol, there were five deaths and five reinfarcts prevented. Similarly, a double-blind study by the Goteborg group9 in 1981 tested the effects of 15 mg of intravenous metoprolol at admission, followed by 100-mg b.i.d. (bis in die), vs. placebo. After 90 days, there was a 36% reduction of all-cause mortality for the treatment group. Opposite results were reached by the Multicenter Investigation of the Limitation of Infarct Size Trial,10 in which 269 patients with acute MI were randomized to intravenous propranolol vs. placebo: the study did not reveal any differences as far as infarct extension was concerned among the two groups. The introduction of pharmacologic reperfusion refurbished the interest in this topic, and several trials were set up to test the efficacy of intravenous beta blockers in patients after fibrinolysis: the results have not been as encouraging as they were in the prereperfusion era. In the thrombolysis in myocardial infarction (TIMI)-IIb,11 1434 patients were randomized to intravenous metoprolol within 2 h from fibrinolysis or oral metoprolol from the 6th post infarct day. The study demonstrated a lower incidence of reinfarction (2.7 vs. 5.1%, P = 0.02) and angina (18.8 vs. 24.1%, P < 0.02) in the early treatment group. Nonetheless, there were no advantages as far as mortality or left ventricular (LV) function were concerned. In the study by Van de Werf et al.,12 a total of 292 patients, 5 h within the onset of acute myocardial infarct, were randomized to atenolol (5–10 mg intravenously followed by 25 or 50 mg per os every 12 h) – 100 patients, 98 patients to alinidin (20 or 40 mg intravenously followed by 20 or 40 mg per os every 8 h), and 94 to placebo. All patients received fibrinolysis with alteplase. The study did not show differences as far as reperfusion rates, ejection fraction, or segmental wall motion at 10–14 days. Similar were also the extension of the infarct area (peak of the enzymes and scintiscan) and the incidence of arrhythmias during the first 24 h. On the other hand, the atenolol group had a higher incidence of nonfatal pulmonary edema (6 vs. 1% in alinidin group and 0% for placebo, P = 0.021). A prespecified analysis of the randomized study13 Global Utilization of t-PA and STreptokinase for Occluded Coronary Arteries-I allowed a comparison, albeit with the limitations of a post-hoc analysis, of the outcomes in different groups of patients after fibrinolysis: patients not receiving atenolol (n = 10 073), patients whichever way treated with atenolol (n = 30 771), patients on intravenous atenolol (n = 18 200), patients on oral atenolol (n = 12 545), and patients on both (n = 16 406). The conditions of patients on atenolol were less severe, bias due to the researchers’ discretion in using beta blockers. The adjusted 30-day mortality was lower for the patients on atenolol, but for the group receiving both intravenous and oral atenolol the risk of death was higher [odds ratio, 1.3; confidence interval (CI) 99% 1.0–1.5; P = 0.02]. The various subgroups had a similar rate of stroke, intracranial hemorrhage and reinfarction, but patients on intravenous atenolol had a higher risk of heart failure, cardiogenic shock, recurrent ischemia, and need for pacemaker than patients receiving the drug orally. In summary, this study confirmed the benefit of beta blockers after reperfusion but raised doubts about the usefulness of intravenous beta blockers, highlighting their potential risks and suggesting that starting the drug orally, after clinical stabilization, could be a better strategy. ClOpidogrel and Metoprolol in Myocardial Infarction Trial At the beginning of the 2000s, the use of intravenous beta blockers in patients after fibrinolysis for acute myocardial infarction (AMI) was reevaluated in the double-blind COMMIT Trial (ClOpidogrel and Metoprolol in Myocardial Infarction Trial).14 The study enrolled 45 852 patients admitted to 1250 hospitals within 24 h from the onset of AMI (Table 1). Patients were randomized to metoprolol (up to 15 mg intravenously followed by 200 mg/die orally; n = 22 929) or placebo (n = 22 923). Ninety-three percent of the patients at admission had ST elevation or left bundle branch block, and 7% had ST depression on ECG. The treatment was continued for 4 weeks or until discharge. The two coprimary endpoints were as follows: first, composite of death, reinfarction, or cardiac arrest; second, all-cause mortality during treatment. The data did not reveal any favorable effect of the treatment on the two endpoints. Nonetheless, the metoprolol group had a significantly less incidence of reinfarction [464 (2.0%) vs. 568 (2.5%); P = 0.001] and ventricular fibrillation [581 (2.5%) vs. 698 (3.0%); P = 0.001]. These positive effects were offset by 29% increased risk of cardiogenic shock [1141 (5.0%) vs. 885 (3.9%); P < 0.00001]. It is important to notice that in the COMMIT Trial, moderate heart failure (Killip class II and III) was not an exclusion criterion, at variance from previous trial on beta blockers in the acute settings. In particular, in the COMMIT Trial the intravenous use of metoprolol in patients in Killip class III was associated with a 58% increased risk of cardiogenic shock; similarly, the risk was increased in patients with initial SBP less than 120 mmHg. The risk of cardiogenic shock occurred in the first 24 h of treatment, whether the reduction of reinfarction and ventricular fibrillation occurred after the first day. It is also important to point out that the mean time from the symptoms onset to fibrinolysis was rather long: 10.3 h. Furthermore, data on the infarct size were not collected.Table 1: Randomized trials with intravenous beta blockers in patients with acute myocardial infarctionEffect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction Trial The METOCARD-CNIC (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction)15 Trial was published in 2013 and has been the first randomized study to analyze the effect of intravenous beta blockers in the primary Percutaneous Transluminal Coronary Angioplasty era. In this open-blinded study, patients with STEMI in Killip class II or less, undergoing mechanical reperfusion, were randomized to receive intravenously metoprolol (n = 131) or not (n = 139) before reperfusion (Table 1). All patients were given oral metoprolol within 24 h. Primary endpoint was the extent of the infarct area as documented by cardiac MRI within 5–7 days after the acute event. The infarct size was smaller in patients treated with intravenous metoprolol (25.6 ± 15.3 vs. 32.0 ± 22.2 g; adjusted difference − 6.52 g; P = 0.012). In patients with TIMI flow grade 0 or 1 of the culprit vessel after reperfusion the treatment difference in infarct size was more evident (−8.13 g; P = 0.0024). The peak and area under the curve creatine-kinase release was significantly reduced by intravenous metoprolol. LV ejection fraction, consequently, was higher in the intravenous metoprolol group (adjusted difference 2.67%; P = 0.045). The composite of death, malignant ventricular arrhythmia, cardiogenic shock, atrioventricular block, and reinfarction at 24 h was trending in favor of the intravenously metoprolol group (7.1 vs. 12.3%, P = 0.21). It should be pointed out as follows: first, patients with inferior MI were excluded from this trial, and accordingly, the negative effect of beta blockers on bradyarrhythmias could not be fully evaluated; second, for the subgroup with culprit vessel initial TIMI flow 2–3, there was no advantage for metoprolol over placebo; third, patients with Killip class III or IV at admission were excluded from the study: these patients have a large area of myocardium at risk and could have particularly benefitted from the cardio-protective effects of metoprolol; their exclusion from the study could have undercut the advantage of early beta-blockers treatment. Finally, it should be kept in mind that the METOCARD Trial was not blinded. A recent post-hoc analysis16 of the trial divided the study population according to the time interval between metoprolol administration and reperfusion; treated patients were divided into short-interval (mean 35 min) and long-interval (mean 79 min) groups. Patients with longer metoprolol exposure had smaller infarcts (22.9 vs. 28.1 g; P = 0.06) and higher LV ejection fraction (48.3 vs. 43.9%; P = 0.019) on day 5 of cardiac MRI, despite the shorter mean total ischemic time of the short group: 160 vs. 214 min (P < 0.001). Early Beta-blocker Administration before primary PCI in patients with ST-elevation Myocardial Infarction Trial The EARLY-BAMI (Early Beta-blocker Administration before primary PCI in patients with ST-elevation Myocardial Infarction)17 study enrolled STEMI patients presenting less than 12 h from symptom onset in Killip class I to II, to be randomized to IV metoprolol (2 × 5-mg bolus) or matched placebo before reperfusion with primary angioplasty (Table 1). Primary endpoint was myocardial infarct size as assessed by cardiac MRI on day 30. Secondary endpoints were enzymatic infarct size and incidence of ventricular arrhythmias. Safety endpoints included symptomatic bradycardia, symptomatic hypotension, and cardiogenic shock. A total of 683 patients (mean age 62 ± 12 years; 75% men) were randomized to metoprolol (n = 336) or placebo (n = 346) and 342 patients (54.8% of the total) were studied with cardiac MRI. Infarct size 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 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 vs. 6.9% in placebo (P = 0.050). The incidence of adverse events was not different between groups. The study showed that in a STEMI population, early intravenous metoprolol before primary percutaneous coronary intervention was not associated with a reduction in infarct size. Metoprolol reduced the incidence of malignant arrhythmias and was not associated with an increase in adverse events. The results of the EARLY-BAMI were at variance from the METOCARD Trial; the different population analyzed by the studies could be a good reason: the latter trial included only patients with anterior MI, so, as a consequence the mean infarct area as assessed by cardiac MRI differed significantly among the two studies (21.2% METROCARD vs. 15.3%). In other words, it could be said that the smaller the infarct, the lesser is the benefit of beta blockers after mechanical reperfusion. Furthermore, the second metoprolol dose in the EARLY-BAMY Trial (to reach the 10 mg target) was administered just before PCI, so that the time for action of the full dose was rather short. This could explain the neutral results of this trial, on the basis of the observations of the post-hoc analysis of the METROCARD Trial.16 Finally, it is of significance that the arterial blood pressure after the first 5-mg dose of intravenous metoprolol did not differ from the placebo group, indicating a suboptimal beta blocking. Discussion and clinical perspectives Reperfusion, at first with fibrinolysis and then with primary angioplasty, represented a key moment in the history of medicine. Could the short-term benefit of reperfusion be enhanced by concurrent pharmacologic therapy? The prereperfusion intravenous beta-blockers therapy has met with contrasting results. A large randomized trial could fill this gap in knowledge. Recently has been published an interesting study conducted in 55 patients with STEMI, using landilol, a new highly cardio-selective beta blocker, with a short half-life; in this study, the use of landilol before reperfusion provided for a better ST-resolution and myocardial blush, as compared with historic control (n = 60), even though the study was not randomized and lacked a control group. The mid-term and long-term follow-up data of the METROCARD Trial supported its initial positive data. The beneficial effect on the LV ejection fraction, as assessed by cardiac MRI, persisted after 6 months (48.7 ± 9.9 vs. 45.0 ± 11.7% control group; adjusted effect of the treatment 3.49%; P = 0.025). The percentage of patients with significant reduction of the LV ejection fraction (≤35%) after 6 months was lower in the intravenous metoprolol group (11 vs. 27%, P = 0.006). The number of patients qualifying for class I indication to implantable cardioverter defibrillator was lower for intravenous metoprolol (7 vs. 20%, P = 0.012). At a median follow-up of 2 years, the composite endpoint of death, admission for heart failure, reinfarction, and malignant ventricular arrhythmias was 10.8% in the intravenous metoprolol group and 18.3% in the control (hazard ratio 0.55; CI 95%: 0.26–1.04; P = 0.065). New hospital admissions for heart failure were also lower in the intravenous metoprolol group (P = 0.046). Following are some convincing points: Intravenous beta blockers are well tolerated as long as patients at high risk for complications are excluded (admission heart failure). The reduction of malignant arrhythmias in the acute phase is an established effect of intravenous beta blockers. There is a cardio-protective effect of beta blockers suggesting their administration as soon as possible. This effect is consistent with the cardio-protective effect mechanism in reperfusion injury. Beta blockers with short half-life should be preferred. In conclusion, intravenous beta-blockers treatment is a tool the cardiologist could use in patients with STEMI, aiming at improving short-term and mid-term prognosis by saving myocardial tissue. LV ejection fraction, in fact, is the main determinant of long-term survival in these patients. Caution, experience, and clinical intuition should guide the cardiologist in selecting the best candidate for early intravenous beta-blockers treatment. For these patients, without a doubt, time is survival. Acknowledgements Conflicts of interest There are no conflicts of interest.