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REVIEW

URRENT C OPINION

Should b-blockers still be routine after myocardial infarction?
Peter L. Thompson a,b

Purpose of review This review will assess whether the 25-year-old evidence base to support routine prescribing of b-blockers after myocardial infarction (MI) is relevant to modern management. Recent findings The evidence base to support the recommendation for the widespread use of b-blockers after MI was nearfinalized in the mid-1980s. Whereas the use of intravenous b-blockers is waning, the routine use of oral b-blockers after MI is still regarded as evidence based. In the past 25 years, the introduction of coronary reperfusion and of effective nonreperfusion therapies has changed the natural history of MI and there have been substantial changes in the definition of MI. The relevance of old clinical trial data collected in patients who bear little resemblance to today’s MI patients is questioned. Recent analyses have shown that there is no convincing evidence for the use of b-blockers as first-line therapy in hypertension or in patients with stable coronary heart disease. In contrast, the evidence base for the use of b-blockers in heart failure is strong and contemporary. Summary A rational recommendation for the modern treatment of MI would be to limit the use of b-blockers in the post-MI patient to higher-risk patients with evidence of ongoing ischemia, heart failure, or left ventricular dysfunction. There is no evidence to support the routine use of oral b-blockers in low-risk MI patients. Keywords b-blockers, myocardial infarction, outcomes, prognosis

INTRODUCTION
The evidence base to support the use of b-blockers after myocardial infarction (MI) is over 25 years old. This review will assess whether this evidence is still relevant to the modern management of patients with MI and will challenge the current recommendation that most postinfarction patients should be considered for b-blockers.

INTRAVENOUS b-BLOCKERS
Although both the ISIS (International Study of Infarct Survival) [1] and MIAMI (Metoprolol in Acute Myocardial Infarction) [2] trials of the 1980s commenced b-blockade via the intravenous (i.v.) route, the evidence to support the early i.v. use of b-blockers in the modern era is weak. Guidelines have recognized this and have progressively backed away from earlier recommendations for their routine use in MI. The evidence base for i.v. b-blockers in patients receiving reperfusion therapy is even more limited. With thrombolytic therapy, a single small trial within a larger trial in patients treated

with alteplase compared i.v. and oral with oral b-blockers and showed an apparent benefit of commencing treatment with i.v. [3]. Two other relatively small randomized trials of i.v. b-blockade [4,5] and a post-hoc analysis of the use of atenolol in the GUSTO-I [Global Utilization of Streptokinase and TPA (alteplase) for Occluded Coronary Arteries] trial [6] all failed to provide any evidence to support the routine use of i.v. b-blockers with thrombolysis. There have been no trials of the use of i.v. b-blockers in the percutaneous coronary intervention (PCI) era of treatment of ST elevation myocardial infarction (STEMI), although such a trial is planned [7]. When the available data were examined in a 1999

Heart Research Institute, Sir Charles Gairdner Hospital and bUniversity of Western Australia, Perth, Western Australia, Australia Correspondence to Professor Peter L. Thompson, Director, Heart Research Institute, R Block, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. E-mail: peterlthompson@bigpond.com Curr Opin Cardiol 2013, 28:399–404 DOI:10.1097/HCO.0b013e328361e97a

a

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We have seen the ‘reperfusion era’ introduced into coronary care. practice guidelines still recommend the use of oral b-blockers. continued indefinitely or at least for several years [11 . the evidence base to support b-blockers in cardiac failure and left ventricular dysfunction is strong and contemporary.v. the lack of relevant modern evidence has not prevented adherence to these guidelines being championed as the standard of care in modern cardiology practice. More recent data raise serious concerns about the i. In the Perth MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease) study conducted from the mid-1980s to the early 1990s. left ventricular dysfunction. followed by oral b-blocker in STEMI with limited use of reperfusion therapy (just over half received urokinase) [9] showed some benefits on re-infarction and ventricular fibrillation. The uptake of reperfusion therapies. Although the guidelines generally acknowledge that the data were collected over 25 years ago. the near universal use of aspirin [21]. and adverse remodeling. The Get With The Guidelines (GWITG) programs of the AHA [14] and the Guidelines Applied in Practice (GAP) program of the ACC [15] have promoted high levels of b-blocker prescribing as quality measures for patients with acute MI. The latest European guidelines for STEMI reach a similar conclusion [12]. b-blockers has waned in recent years. there was no significant reduction in mortality with the i. most patients in the modern era receive reperfusion therapy. Programs to encourage guideline adherence have been launched irrespective of whether the evidence base is sufficiently robust in the modern era.com Volume 28  Number 4  July 2013 Copyright © Lippincott Williams & Wilkins. Early reperfusion changes the pathophysiology of MI [25] with the net result being far less and sometimes no damage to the myocardium.13 ]. All international guidelines recommend that b-blockers should be commenced as soon as possible after the onset of MI. initially with thrombolytic therapy and later with PCI.  The routine use of b-blockers after MI should be reconsidered and limited to high-risk post-MI patients (cardiac failure.  The widespread uptake of reperfusion therapy for STEMI. but a 30% increase in cardiogenic shock. there have been major changes in MI and its management. the use of thrombolysis increased from 12 to 49% and coronary revascularization therapy in the year postinfarction increased from 2 to 38% [26 ]. or ongoing myocardial ischemia). in contrast to persistent ischemia resulting in extensive myocardial necrosis. reasonable. Since 1985. with the recommendation limited to patients who are hypertensive or with ongoing ischemia. initially with thrombolysis as a result of the ISIS-2 [17] and GUSTO trials [18].co-cardiology. The recent large Chinese COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) trial of i.12. & & ORAL b-BLOCKERS The collection of evidence from randomized clinical trials of oral b-blockade after MI commenced in the late 1970s. and 400 www. use of b-blockers [8]. later with primary PCI [19. high-dose statins [22]. Unauthorized reproduction of this article is prohibited. b-blockers is only of evidence level B and makes a class IIa recommendation for their use. 1). and changes in the definition of MI have changed the clinical profile of MI so substantially that evidence from the mid-1980s is not relevant to the modern management of MI. that is. subsequent dramatic improvements in the outcomes of MI.v. weakening the assumption that all post-MI patients should be on oral b-blockers.20]. The clinical judgment and availability of resources determine use of lytic therapy or PCI in almost all patients.24].v. reached a peak in the mid-1980s. and dual antiplatelet therapy [23. An updated meta-analysis of the clinical trials including the COMMIT trial confirmed the lack of efficacy for early b-blockers [10 ].v. The 2012 update of the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the treatment of STEMI concludes that the evidence for i. and was essentially complete by the early 1990s (Fig. scarring. introduction of effective nonreperfusion therapies. but not strongly recommended [11 ]. use of b-blockers. Although there is no doubt that the evidence collected in the mid-1980s was relevant to the treatment of patients at that time.  In contrast. . was rapid during the late 1980s and has accelerated into the modern ‘reperfusion era’ for the treatment of STEMI. First.  Recent observations have challenged the rationale for the use of b-blockers in hypertension and stable coronary heart disease. These & systematic review of 54 234 patients with STEMI.Clinical trials KEY POINTS  The evidence base to support the routine use of oral b-blockers after MI is 25 years out of date. & & LONG-TERM ORAL b-BLOCKERS AFTER MYOCARDIAL INFARCTION Although support for i.v. and some hospital reimbursement programs penalize hospitals which do not achieve adequate levels of adherence to b-blocker prescribing on discharge [16]. there are four important reasons to question the relevance of the old b-blocker evidence to modern cardiology practice.

and. These trends have accelerated into the 2000s with a 24% decline between 1999 and 2008 [34 ]. total mortality rates declined from 15 to 10% and age-adjusted rates nearly halved from 406 to 286 per 100 000 between 1988 and 2004 [32 ]. the clinical trials used a variety of definitions to include patients in the b-blocker trials. Nationwide studies show the same pattern. The evidence for the timing of introduction of new therapies is based on [17. Third.20] (primary PCI). Within coronary care units. which required the development of Q waves or serial ECG changes. the definition of myocardial has changed dramatically since the mid-1980s. The most common definition was the WHO definition. The use of antiplatelet therapies and statins now approaches 100 and 90%.3% in 2004 and age-adjusted mortality more than halved from 727 to 305 per 100 000 [33]. respectively [28]. Finally.co-cardiology. STEMI and non-ST elevation myocardial infarction (NSTEMI) mortality rates have declined dramatically from the 1980s to the 2000s. In 1. other highly effective nonreperfusion therapies have been introduced into practice on the basis of evidence accumulated in the past 20 years.3 million patients with STEMI. [23. [17. the adjusted odds ratio for acute myocardial infarction (AMI) mortality declined by 36% in the decade from the mid-1980s to the mid-1990s. with similar trends observed in 12-year mortality in 1-year survivors [26 ]. and an increase in creatine kinase level to twice the & & & & 0268-4705 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.24] (dual anti-platelet therapy) and [22] (high dose statins). there is evidence that the abovementioned changes in therapy. Patients with MI have fewer complications and better outcomes in 2012 compared with the mid-1980s when the b-blocker clinical trials were conducted. placebo trials Cumulative deaths Number of deaths 1400 1200 1000 800 600 400 200 0 1975 1980 1985 1990 1995 2000 2005 2010 Placebo Treatment 15 10 5 0 Thrombolysis Aspirin Primary PCI Dual antiplatelet therapy High dose statins FIGURE 1. the incidence of cardiogenic shock and heart failure during MI has declined significantly [29 . The evidence for superiority of b-blockers was evident by the late 1980s with minimal additional evidence since then. The US National Registry of Myocardial Infarction (NRMI) documented the patterns of care in over 2. Unauthorized reproduction of this article is prohibited. . the 30-day mortality reduced by two-thirds and the 5-year mortality reduced by half from 1985 to 2008 [31]. In Perth. trends have accelerated since. The bars show the number of trials (scale on right) and the curves show the number of deaths with 95% confidence intervals (scale on left) in each 5-year period in the RCTs.5 million patients with MI in 2157 hospitals in the United States between 1990 and 2006 and showed that the use of revascularization procedures with PCI increased from 37 to 73% for STEMI and 25 to 44% for non-STEMI [27 ]. which compared b-blockers with placebo. [19. At that time.b-Blockers and myocardial infarction Thompson Long-term post-AMI Beta blockers vs.4 million patients with NSTEMI.21] (aspirin). Community-wide studies have also & & confirmed declines in mortality from MI.com Number of trials 401 Copyright © Lippincott Williams & Wilkins. with efficacy proven in RCTs. In over 1.6% in 1988 to 11. Cumulative evidence for mortality benefit of postmyocardial infarction (MI) b-blockers in randomized controlled trials (RCTs) from the 1970s to the present. early mortality rates over the period mid-1980s to mid2000s have declined by up to 70% [35 ].30]. in a unique long-term study of the trends in mortality in patients treated in a coronary care unit. have been effective when applied in practice and have contributed to an improved natural history and better outcomes for patients with MI. Second. The horizontal bars below show the significant changes in therapy that have been introduced since then. In patients represented in large clinical trials of MI. In the United States. total mortality rates decreased from 29.18] (thrombolysis).

treatment profile. with the additional finding that b-blockers are less effective in reducing CHD endpoints than calcium channel blockers and concluding that the evidence is generally weak. the natural history has consequently changed to fewer complications and deaths. A report on follow-up from the REACH (Reduction of Atherothrombosis for Continued Health) study on data collected in the early 1990s on 44 708 patients whose CHD was stable included a total of over 14 000 with known prior MI. && LIMITED EVIDENCE IN STABLE CORONARY HEART DISEASE PATIENTS A study of patients who have undergone PCI during their hospital treatment for STEMI showed no benefit for the use of postdischarge b-blockers in patients free of heart failure after adjustment for clinical and demographic factors [42 ]. 95% confidence interval (CI) 0.11]. One meta-analysis concluded that the probability that b-blocker therapy reduced total mortality and hospitalizations for congestive heart failure was almost 100% and that these benefits are clinically significant is 99% [46]. and limited convincing evidence for their use in hypertension and stable CHD. with a different pathophysiology. The latest Universal Definition allows the diagnosis of AMI when the highsensitivity troponin level shows a rise and fall outside the normal range [37 ]. the risk of all-cause mortality was not different between b-blockers used as first-line therapy and placebo [relative risk (RR) 0. and natural history and definition that the b-blocker trials conducted at that time bear little relevance to those being treated for AMI in the modern era of coronary care. The latest update of this evidence confirms these findings. Patients being diagnosed with MI today include many patients with lower risk than in previous definitions [38 ].co-cardiology. indirect evidence must be examined to decide whether the old evidence is relevant. different treatment Volume 28  Number 4  July 2013 Copyright © Lippincott Williams & Wilkins. the latest indicating a likely reduction of 30% in 1-year mortality in patients with heart failure or left ventricular dysfunction treated with b-blockers [45 ]. and changes in the definition of MI have widened the diagnosis to include patients with lower risk. the introduction of reperfusion therapy for STEMI has changed the pathophysiology of the condition for the better. with the potential for bias [41 ]. was compared with other first-line antihypertensives. This led to a re-appraisal of the overall efficacy of b-blockers in all the hypertension trials. this was primarily due to a significant 20% decrease in stroke and there was no difference in CHD outcomes [40]. && LACK OF EFFICACY OF THE b-BLOCKERS IN THE HYPERTENSION TRIALS Although the role of b-blockers as standard therapy after MI has been accepted with only minimal challenge. Patients with MI who were being treated in the mid-1980s were so different in their pathophysiology. significantly increasing the sensitivity of the diagnostic criteria. STRONG EVIDENCE OF BENEFIT OF b-BLOCKERS IN HEART FAILURE In contrast to the old evidence for post-MI b-blockers. relatively free of publication bias. the evidence for a benefit of b-blockers in heart failure is strong. A propensity-matched analysis failed to show any survival benefit for patients taking b-blockers [43 ]. leading to disconcerting findings in their effect on coronary heart disease (CHD) events. and contemporary [44].99. Although the risk of total 402 www. Unauthorized reproduction of this article is prohibited. b-blockers in MI has little support and has been progressively downgraded in guidelines. but there is no clear support for the unrestricted use of b-blockers after MI.v. collected in the 1980s in a different era. Multiple trials and meta-analyses have confirmed this conclusion.com CONCLUSION The following conclusions can be drawn: (1) The use of i. && & cardiovascular disease (CVD) was 12% lower for first-line b-blockers compared with placebo. Only guarded conclusions can be drawn from observational studies and RCTs in related conditions. In 13 RCTs with 91 561 participants with hypertension. && && EVIDENCE FROM THE MODERN ERA ON THE EFFECTIVENESS OF b-BLOCKERS As there are no RCTs examining the effect of b-blockers after AMI in the modern era. there has been a re-appraisal of the role of b-blockers as first-line treatment in hypertension.88–1. nonreperfusion therapies have been introduced on the basis of proven efficacy in large randomized controlled trials (RCTs). When the effect of b-blockers. primarily atenolol.Clinical trials upper limit of normal [36]. In brief. . (2) The data for long-term oral post-AMI b-blockers. the effects on outcomes were less impressive for the b-blockers [39]. This raises the question of whether there is any relevant modern evidence to support the widespread prescribing of b-blockers after MI.

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