Role of Intravenous β-Blockers in the Treatment of ST-Elevation Myocardial Infarction
Of Mice (Dogs, Pigs) and Men
But Mouse, thou are not alone,
In proving foresight may be in vain:
The best laid schemes of mice and men,
Often go awry,
And leave us nought but grief and pain,
For promised joy!
— —Robert Burns, “To a Mouse” (1785)
Reimer et al1 have been widely acclaimed for helping to usher in the reperfusion era in the treatment of ST-elevation myocardial infarction (STEMI). Using a dog model of proximal circumflex artery ligation for different periods of time, they demonstrated that a “wave of cell death” develops first in subendocardial myocardium and progressively spreads to midepicardial and subepicardial myocardium over hours. Transmural infarct size was 38% after 40 minutes, 57% after 3 hours, 71% after 6 hours, and 85% after 24 hours of ischemic injury. The presence of a subepicardial zone of ischemic but viable myocardium that might be salvaged by early reperfusion established the anatomic justification for fibrinolytic therapy and primary percutaneous coronary intervention to modify infarct size in patients with STEMI.
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Interestingly, the article that immediately followed the Reimer et al article in the November 1977 issue of Circulation was by the same group and was entitled “Infarct Size Reduction by Propranolol Before and After Coronary Ligation in Dogs.”2 Using the same animal model, they randomized dogs to intravenous propranolol before coronary occlusion, intravenous propranolol 3 hours after coronary occlusion, or saline infusion and euthanized the dogs at 24 hours without restoring reperfusion. Pretreatment with propranolol decreased transmural infarct size from 85% to 52%, whereas delayed treatment was about half as effective, decreasing infarct size to 71%.
Whether other pharmacological or mechanical interventions added to reperfusion therapy can further reduce myocardial infarct size has been a major area of preclinical and clinical investigation for 3 decades.3 There have been dozens of preclinical studies investigating the effect of intravenous β-adrenergic receptor blocking agents (β-blockers) on infarct size and left ventricular remodeling in ischemia-reperfusion models with rats, rabbits, dogs, and pigs. Benefit has been inconsistent, influenced by drug, dose, timing of initiation, ischemic time, measurement technique, and other variables.
In this issue of Circulation, Ibanez and colleagues4 subjected 12 Yorkshire pigs to balloon occlusion of the left anterior descending artery for 90 minutes followed by reperfusion. Compared with placebo, intravenous metoprolol administered 15 minutes after the onset of ischemia resulted in a 27% reduction in infarct size and was associated with improved regional and global left ventricular function as measured by high-resolution cardiac magnetic resonance imaging. Two of the placebo-treated pigs died before completing the protocol.
The use of cardiac magnetic resonance imaging to measure infarct size is an exciting research application of a new imaging modality, as illustrated by this elegant study. However, the clinical relevance of infarct size reduction with intravenous β-blocker therapy seen in this study is less obvious, especially when one considers that treatment was initiated only 15 minutes after interruption of coronary blood flow and total ischemic time was only 90 minutes. Moreover, abrupt ligation of a normal dog artery or balloon occlusion of a normal pig artery is different from thrombotic occlusion of an inflamed atherosclerotic human artery with distal embolization after reperfusion. In addition, human infarct size is modulated by preconditioning, intermittent or persistent infarct artery occlusion, collateral circulation, oxygen demand, and completeness of reperfusion. It has been known since the beginning of the fibrinolytic era that reperfusion must be accomplished within 3 hours of symptom onset to achieve human enzymatic infarct size reduction.5,6 Unfortunately, delays in time to treatment often prevent achievement of that goal. The major explanation for the failure of new interventions (drugs, thrombectomy devices, distal protection devices, cooling) to reduce infarct size in recent clinical trials has been that treatment usually was initiated within a later time frame.
Guideline Recommendations and Performance Measures
The 2004 European Society of Cardiology expert consensus document on β-blockers7 states that “intravenous administration should be considered in patients with ischemic pain resistant to opiates, recurrent ischemia, and for the control of hypertension, tachycardia, and arrhythmias” (class I indication). Intravenous β-blockers to limit infarct size have a class II recommendation. The 2004 American College of Cardiology/American Heart Association STEMI guidelines8 state that “it is reasonable to administer intravenous β-blockers promptly to STEMI patients without contraindications, especially if a tachyarrhythmia or hypertension is present” (class IIa recommendation). Furthermore, “β-blockers should not be administered to patients with frank cardiac failure evidenced by pulmonary congestion or signs of a low-output state” (class III recommendation). For the past 5 years, one of the Joint Commission core measures for STEMI has been the percentage of patients without contraindications who receive a β-blocker within 24 hours after hospital arrival (http://www.coreoptions.com/new_site/jcahocore.html). Contraindications include β-blocker allergy, bradycardia (heart rate <60 bpm), heart failure, shock, and second- or third-degree atrioventricular block.
The evidence base for these guideline recommendations was heavily influenced by 3 trials from the early 1980s in which intravenous followed by oral β-blockers were used as monotherapy for STEMI.9–11 For instance, fibrinolytic therapy was not given in the First International Study of Infarct Survival (ISIS-1) trial, and only 5% of patients were discharged on an antiplatelet agent.11 Patients treated within 12 hours of symptom onset had a 17% reduction in enzymatic infarct size in the Goteborg Metoprolol Trial,12 whereas enzymatic infarct size was lower in patients treated within 7 hours of symptom onset in the Metoprolol in Acute Myocardial Infarction (MIAMI) trial.10 A meta-analysis of 28 trials suggested that treatment of 1000 patients with β-blockers would lead to the avoidance of 6 deaths, 6 reinfarctions, and 4 cardiac arrests.11 A later meta-regression analysis found no mortality benefit with intravenous initiation of β-blocker therapy.13
In the reperfusion era, it has been difficult to prove any added benefit of intravenous β-blocker therapy. Van de Werf and coworkers14 randomized 292 patients receiving alteplase within 5 hours of STEMI onset to early intravenous and continued oral atenolol, alindine (a bradycardic agent lacking negative inotropism), or placebo. No differences could be observed in enzymatic or scintigraphic infarct size, left ventricular ejection fraction, or regional wall motion. Clinical events were similar except for a greater incidence of nonfatal pulmonary edema in the atenolol group (6% versus 1% in the alindine group and 0% in the placebo group; P=0.02). In the Thrombolysis in Myocardial Infarction II-B (TIMI-IIB) study,15 1434 patients treated with alteplase within 6 hours of STEMI onset were randomized to immediate (within 2 hours of initiating lytic therapy) intravenous followed by oral metoprolol or deferred (day 6) oral metoprolol. No differences were detected in left ventricular ejection fraction or regional wall motion at hospital discharge. Mortality was not different at 6 weeks, but a lower incidence existed of reinfarction (2.7% versus 5.1%; P=0.02) and recurrent chest pain (18.8% versus 24.1%; P<0.02) at 6 days in the immediate intravenous group. This study was done in an era before routine treatment with enoxaparin, clopidogrel, and coronary stent implantation, interventions that also have been shown to reduce postreperfusion ischemic events.
In a post hoc analysis of the Global Utilization of Streptokinase and TPA for Occluded Arteries (GUSTO-1) trial,16 early intravenous atenolol was associated with more death, heart failure, shock, recurrent ischemia, and pacemaker use than early oral use, despite the exclusion of patients with preexisting hypotension, bradycardia, or signs of heart failure. In the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT),17 45 852 patients within 24 hours of suspected STEMI were randomized to intravenous and continued oral metoprolol or placebo. For every 1000 patients on treatment (mean, 15 days), metoprolol was associated with 1 less death (7.7% versus 7.8%; P=0.69), 5 fewer reinfarctions (2.0% versus 2.5%; P=0.001), and 5 fewer episodes of ventricular fibrillation (2.5% versus 3.0%; P=0.001). In contrast, 11 more patients had cardiogenic shock (5.0% versus 3.9%; P<0.0001), occurring mainly during the first 24 hours. Rates of cardiogenic shock were greater for those ≥70 years of age, with systolic blood pressure <120 mm Hg, with a heart rate >110 bpm, or with Killip class >1. In addition, an excess of 14 patients experienced heart failure requiring treatment (14.1% versus 12.7%; P<0.0001), 31, persistent hypotension (6.0% versus 2.9%; P<0.0001), and 32, bradycardia (5.4% versus 2.2%; P<0.0001). The conclusion from both of these studies was that early intravenous β-blocker therapy had limited value and that later initiation of oral β-blocker therapy in stable patients was more prudent.
Robert Burns, the Scottish poet, earned his living by farming. His sadness and despair at destroying a field mouse nest while plowing his fields, at a time (December) when it was impossible to rebuild, led to his poem “To a Mouse.” The famous lines quoted above and often by others in different human experiences serve as a metaphor 30 years after the seminal observations by Reimer et al for the mostly unsuccessful clinical attempts at further reducing myocardial infarct size with several agents, despite best intentions and great promise in preclinical studies and even phase II clinical trials. Similarly, one could conclude that frustration has been associated with a variety of cell therapy attempts in clinical trials to rebuild myocardial scar with functioning myocytes, despite preclinical promise, although it is hoped that goal will not be impossible to achieve.
Intravenous β-blockers have inconsistently reduced infarct size in animal models and have not reduced mortality rates in recent clinical trials. They also have been associated with some harm in those trials. It has been >2 years, after presentation of the COMMIT trial results, that the American College of Cardiology/American Heart Association/Agency for Healthcare Research and Quality/Centers for Medicare and Medicaid Services/Joint Commission on Accreditation of Healthcare Organizations Practice Advisory was issued on the use of intravenous then oral β-blockers in the early stages of STEMI (http://www.ahrq.gov/clinic/commitadvisory.htm). No final statement on performance measures has been released. It may be time to remove routine intravenous β-blocker therapy from our acute treatment protocols for STEMI and instead focus on initiating oral β-blocker (and angiotensin-converting enzyme inhibitor) therapy the next day when hemodynamic stability has been established. This technique would remove the early risk associated with β-blockers while retaining their hospital benefit on reinfarction and ventricular fibrillation rates. Unfortunately, despite the best laid schemes of mice (dogs, pigs) and men with regard to intravenous β-blocker therapy, early reperfusion therapy remains the best (and maybe only) strategy for limiting myocardial infarct size in patients with STEMI.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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