CLINICAL RESEARCH: BETA-BLOCKERS IN MYOCARDIAL INFARCTION: EDITORIAL COMMENT
Beta-blocker therapy and primary angioplasty
What is the controversy?*
David P. Faxon, MD, FACC
,*
Section of Cardiology, Department of Medicine, University of Chicago, Chicago, Illinois, USA
* Reprint requests and correspondence: Dr. David P. Faxon, Chief, Section of Cardiology, The University of Chicago, 5841 South Maryland Avenue, MC 6080, Chicago, Illinois 60637, USA.
dfaxon{at}medicine.bsd.uchicago.edu
Beta-blocker therapy has long been recommended for the treatment of ST-elevation myocardial infarction (STEMI) and is listed as a class 1 indication in the American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for the treatment of acute myocardial infarction (MI) (1). Studies prior to the use of thrombolysis have demonstrated both short- and long-term benefits, and a meta-analysis of these trials showed a 25% reduction in mortality at one year (2). Likewise, a similar analysis of the studies in patients treated with thrombolysis showed an overall 23% reduction in mortality (3). Early intravenous beta-blocker therapy also has been shown to improve both short-term and long-term outcome in the Thrombolysis in Myocardial Infarction II-B trial (4). In the Carvedilol Post Infarction Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial, high-risk STEMI patients with reduced left ventricular (LV) function who were treated with the beta-blocker carvedilol realized a reduction in mortality of 23% over a 2.5-year period (5). With a wealth of information supporting the use of beta-blocker therapy, it is surprising and somewhat disappointing that 30% to 50% of patients with STEMI still failed to receive these agents (6). If the data for their use are so strong, what is the controversy? Although there seems to be little question that patients with STEMI, regardless of whether or not they receive thrombolysis, derive substantial benefits from both long- and short-term beta-blockade, there has been a surprising paucity of studies that support the use of beta-blockers after primary angioplasty in STEMI. Although it would seem logical to assume the same degree of benefit, many physicians have not been convinced of either short- or long-term benefit of beta-blockade after primary angioplasty, given the lack of evidence of benefit after percutaneous coronary intervention (PCI). The rationale for beta blockade in revascularized patients is unclear, particularly in those patients without any significant residual coronary obstructions and an uncomplicated hospital course (7). In this issue of the Journal, three separate articles (8–10) explore the question of beta-blocker therapy in primary angioplasty.
Only a few studies have examined the benefit of beta-blocker therapy in patients receiving primary angioplasty. A retrospective review of the Primary Angioplasty in Myocardial Infarction (PAMI) studies demonstrated improved outcome with beta-blocker use (11). In this study, 2,537 patients enrolled in four PAMI studies were pooled. Patients receiving pretreatment with beta-blockers before primary angioplasty were compared with those not receiving pretreatment. After adjustment for baseline differences between patient groups, a significantly lower incidence of in-hospital death with use of beta-blocker therapy was found (1.3% vs. 3.7% p = 0.0035). A strong trend toward a lower mortality at one year was also reported (p = 0.055). However, not all patients were receiving beta-blockers during the follow-up period (66% to 89%). When only those receiving beta-blockers during follow-up were included in the analysis, there was a significantly improved one-year mortality with its use (odds ratio [OR] = 0.43; p = 0.001). In this issue of the Journal, Kernis et al. (8) examined 2,442 patients with successful primary angioplasty that participated in four of the PAMI studies. This patient group was slightly different from the group in the previous report (two trials were the same, two were different from the previous publication); however, the findings were remarkably similar. In this study the authors evaluated only post-procedural beta-blocker use after PCI on six-month outcomes. Again, a significant reduction in mortality was observed (2.2 vs. 6.6; p > 0.001), and the multivariate analysis demonstrated an OR remarkably similar to the first study (OR = 0.43; p = 0.0016). Importantly, the authors showed a survival benefit in high-risk sub-groups such as those with ejection fractions <50% (OR = 0.34; p > 0.0001) and those with multivessel disease (OR = 0.26; p < 0.001).
Also, in this issue of the Journal, Halkin et al. (9) evaluated the effect of beta-blockers on 30-day mortality in the 2,082 patients undergoing primary PCI for STEMI as part of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications trial, a randomized trial of balloon angioplasty versus stenting with or without glycoprotein IIb/IIIa agent abciximab. The study demonstrated a lower 30-day mortality in the beta-blocker group (1.5% vs. 2.8%; p = 0.03). The improved survival was not realized at one year; although an absolute difference between groups (1.7%) was similar, suggesting the benefit was largely an early benefit. The lack of long-term benefit, however, might not have been realized owing to the high percentage of patients in both groups receiving beta-blockers during follow-up (86% for initial beta-blocker use vs. 70% for initial non-beta-blocker users). The benefit, however, was confined to those who were not receiving long-term beta-blocker therapy before hospital admission. This finding is surprising because a benefit has been observed previously in such patients (12). Together, these studies provide powerful support for the use of beta-blocker therapy in patients with STEMI undergoing primary angioplasty, and they support the ACC/AHA guideline recommendations (1). Pre-procedural administration resulted in a 50% to 65% reduction in hospital mortality. Likewise, long-term beta-blocker therapy had a favorable impact on long-term outcome by an equal degree.
The mechanism of benefit from beta-blocker therapy in STEMI is still unclear. It has been suggested that early beta-blocker treatment decreases myocardial oxygen consumption, favorably influences coronary blood flow, and reduces infarct size. The improvements in ejection fraction in a study by Halkin et al. (9) support a reduction in the infarct size as contributing. Another mechanism of benefit might be a reduction in procedural MI. In a recent retrospective study by Sharma et al. (13), 1,676 patients undergoing non-STEMI coronary interventions were reviewed. Previous beta-blocker therapy reduced the incidence of post-procedural creatine kinase-MB release and improved short-term mortality over a 15-month period (13). It remains controversial whether intravenous or intracoronary beta-blockers immediately before PCI reduce peri-procedural risk of MI after angioplasty (14,15). However, long-term therapy, particularly in high-risk patients undergoing PCI, has shown benefit (16). Another potential mechanism for benefit is a reduction in fatal ventricular arrhythmias. In a study from the PAMI group, Mehta et al. (10), in this issue of the Journal, demonstrated a reduced incidence of procedural ventricular tachycardia/ventricular fibrillation (VT/VF) in patients receiving beta-blocker therapy and undergoing primary angioplasty. Although VT/VF was rare (4.3%), it was a marker of poor outcome. Interestingly, this study failed to demonstrate a benefit with beta-blockers on post-procedural or late VT/VF. It has been postulated that the anti-ischemic effects of beta-blockers may contribute to the improved long-term outcome. However, in both the PAMI and Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications trials reported in this issue of the Journal, beta-blockade was not associated with the reduction in ischemic-driven target vessel revascularization or re-infarction.
Is the case closed on beta-blockers and STEMI undergoing primary angioplasty? Not quite yet. Although these studies are persuasive, we still have not had a single randomized trial of beta-blocker therapy in primary angioplasty. The potential selection bias that naturally occurs in non-randomized studies diminishes the powers of the observations reported in this issue of the Journal. It is also not clear whether all patients receiving primary angioplasty benefit from pre-procedural or long-term oral beta-blocker therapy. Kernis et al. (8) showed that in patients with either a normal ejection fraction or single-vessel disease and no in-hospital major adverse coronary events, long-term benefits of beta-blocker therapy could not be demonstrated. What should we do today based on the available data? It is clear that all patients without contraindication should receive beta-blockers before primary angioplasty and that those receiving long-term oral beta-blockers before admission should continue to receive beta-blockers. Patients who develop an in-hospital complication, have reduced LV function, or have multi-vessel disease derive the greatest benefit from long-term oral therapy. The question remains, however, whether a patient with normal ejection fraction and single-vessel disease who undergoes a successful angioplasty receives any benefit from either short- or long-term beta-blocker therapy. This question remains an unanswered one and will need to await further data from clinical trials to be resolved. In the absence of additional studies, the data would strongly support the current guidelines for the use of beta-blockers in all eligible patients, regardless of the revascularization strategy. In primary PCI, it is clear that pre-procedural beta-blocker therapy also is of significant benefit. Our major challenge in the future to ensure that all eligible patients with STEMI are treated with beta-blockers both before angioplasty and during long-term follow-up. The health implications of widespread use of beta-blockers after MI are enormous, given the magnitude of benefit reported in clinical trials. National efforts to improve compliance with guidelines, such as the AHA's "Get with the Guidelines" program, have already shown improvements in the use of beta-blockers and other secondary prevention treatments. Let's hope that the benefit now observed in patients with primary angioplasty will help further increase their use.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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- Ryan TJ, Antman EM, Brooks NH, et al. 1999 update: Acc/aha guidelines for the management of patients with acute myocardial infarction: executive summary and recommendations: a report of the american college of cardiology/american heart association task force on practice guidelines (committee on management of acute myocardial infarction). Circulation. 1999;100:1016–1030[Free Full Text]
- Yusuf S, Peto R, Lewis J. Beta blockade during and after myocardial infarction: An overview of the randomized trials. Prog Cariovasc Dis. 1985;27:335–371
- Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta-blockade after myocardial infarction: Systematic review and meta regression analysis. BMJ. 1999;318:1730–1737[Abstract/Free Full Text]
- Roberts R, Rogers WJ, Mueller HS, et al. Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of the Thrombolysis In Myocardial Infarction (TIMI) II-B study. Circulation. 1991;83:422–437[Abstract/Free Full Text]
- Dargie H, Colucci W, Ford I, et al. Effect of carvedilol on outcome after myocardial infarction in patients with left ventricular dysfunction: The capricorn randomized trial. Lancet. 2001;357:1385–1390[CrossRef][Medline]
- Burwen DR, Galusha DH, Lewis JM, et al. National and state trends in quality of care for acute myocardial infarction between 1994 to 1995 and 1998 to 1999; the Medicare health care quality improvement program. Arch Intern Med. 2003;163:1392–1393[Free Full Text]
- Pancu D, Lee DC. Beta-blocker use in the emergency department in patients with acute myocardial infarction undergoing primary angioplasty. J Emerg Med. 2003;24:379–382[Medline]
- Kernis SJ, Harjai KJ, Stone GW, et al. Does beta-blocker therapy improve clinical outcomes of acute myocardial infarction after successful primary angioplasty? J Am Coll Cardiol 2004;43:1773–9
- Halkin A, Grines CL, Cox DA, et al. Impact of intravenous beta-blockade before primary angioplasty on survival in patients undergoing mechanical reperfusion therapy for acute myocardial infarction. J Am Coll Cardiol 2004;43:1780–7
- Mehta RH, Harjai KJ, Grines L. Sustained ventricular tachycardia or fibrillation in cardiac catheterization laboratory among patients receiving primary percutaneous coronary intervention: incidence, predictors and outcomes. J Am Coll Cardiol 2004;43:1765–72
- Harjai KJ, Stone GW, Boura J, et al. Effects of prior beta-blocker therapy on clinical outcomes after primary coronary angioplasty for acute myocardial infarction. Am J Cardiol. 2003;91:655–660[CrossRef][Medline]
- Nidorf SM, Parsons RW, Thompson PL, Jarozik KD, Hobbs MS. Reduced risk of death at 28 days in patients taking a beta-blocker before admission to hospital with myocardial infarction. BMJ. 1990;300:71–74[Medline]
- Sharma SK, Annapoorna K, Marmur J, Fuster V. Cardioprotective effect of prior beta-blocker therapy in reducing creatine kinase-MB elevation after coronary intervention. Circulation. 2000;102:166–172[Abstract/Free Full Text]
- Wang FW, Osman A, Javier O, et al. Distal myocardial protection during percutaneous coronary intervention with an intracoronary beta-blocker. Circulation. 2003;107:2914–2919[Abstract/Free Full Text]
- Ellis SG, Brener SJ, Lincoff M, et al. Beta blockers before percutaneous coronary intervention do not attenuate postprocedural creatine kinase isoenzyme rise. Circulation. 2001;104:2685–2688[Abstract/Free Full Text]
- Chan AW, Quinn MJ, Bhatt DL, et al. Mortality benefit of beta-blockade after successful elective percutaneous coronary intervention. J Am Coll Cardiol. 2002;40:669–675[Abstract/Free Full Text]
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