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CURRENTOPINION Should b-blockers still be routine after myocardialinfarction?

Peter L. Thompsona,b

Purpose of review

This review will assess whether the 25-year-old evidence base to support routine prescribing ofb-blockersafter 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 near-finalized in the mid-1980s. Whereas the use of intravenous b-blockers is waning, the routine use of oralb-blockers after MI is still regarded as evidence based. In the past 25 years, the introduction of coronaryreperfusion 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 patientswho bear little resemblance to todays MI patients is questioned. Recent analyses have shown that there isno convincing evidence for the use ofb-blockers as first-line therapy in hypertension or in patients withstable coronary heart disease. In contrast, the evidence base for the use of b-blockers in heart failure isstrong and contemporary.

Summary

A rational recommendation for the modern treatment of MI would be to limit the use of b-blockers in thepost-MI patient to higher-risk patients with evidence of ongoing ischemia, heart failure, or left ventriculardysfunction. 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 ofb-blockersafter myocardial infarction (MI) is over 25 years old.This review will assess whether this evidence is stillrelevant to the modern management of patientswith MI and will challenge the current recommen-dation that most postinfarction patients should beconsidered for b-blockers.

INTRAVENOUS b-BLOCKERS

Although both the ISIS (International Study ofInfarct Survival) [1] and MIAMI (Metoprolol inAcute Myocardial Infarction) [2] trials of the1980s commenced b-blockade via the intravenous(i.v.) route, the evidence to support the early i.v. useofb-blockers in the modern era is weak. Guidelineshave recognized this and have progressively backedaway from earlier recommendations for their rou-tine use in MI. The evidence base for i.v. b-blockersin patients receiving reperfusion therapy is evenmore limited. With thrombolytic therapy, a singlesmall trial within a larger trial in patients treated

with alteplase compared i.v. and oral with oralb-blockers and showed an apparent benefit of com-mencing treatment with i.v. [3]. Two other relativelysmall randomized trials of i.v.b-blockade [4,5] and apost-hoc analysis of the use of atenolol in theGUSTO-I [Global Utilization of Streptokinase andTPA (alteplase) for Occluded Coronary Arteries] trial[6] all failed to provide any evidence to support theroutine use of i.v. b-blockers with thrombolysis.There have been no trials of the use of i.v.b-blockersin the percutaneous coronary intervention (PCI)

era of treatment of ST elevation myocardial infarc-tion (STEMI), although such a trial is planned [7].When the available data were examined in a 1999

aHeart 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: [email protected]

Curr Opin Cardiol 2013, 28:399404

DOI:10.1097/HCO.0b013e328361e97a

0268-4705 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-cardiology.com

REVIEW
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systematic review of 54 234 patients with STEMI,there was no significant reduction in mortality withthe i.v. use ofb-blockers [8]. More recent data raiseserious concerns about the i.v. use ofb-blockers. Therecent large Chinese COMMIT (Clopidogrel andMetoprolol in Myocardial Infarction Trial) trial ofi.v. followed by oral b-blocker in STEMI with limited

use of reperfusion therapy (just over half receivedurokinase) [9] showed some benefits on re-infarc-tion and ventricular fibrillation, but a 30% increasein cardiogenic shock. An updated meta-analysis ofthe clinical trials including the COMMIT trial con-firmed the lack of efficacy for early b-blockers [10

&

].The 2012 update of the American College of Cardio-logy/American Heart Association (ACC/AHA) guide-lines for the treatment of STEMI concludes that theevidence for i.v. b-blockers is only of evidence levelB and makes a class IIa recommendation for theiruse, that is, reasonable, but not strongly recom-mended [11

&

], with the recommendation limitedto patients who are hypertensive or with ongoingischemia. The latest European guidelines for STEMIreach a similar conclusion [12].

LONG-TERM ORAL b-BLOCKERS AFTERMYOCARDIAL INFARCTION

Although support for i.v. b-blockers has waned inrecent years, practice guidelines still recommend theuse of oral b-blockers. All international guidelinesrecommend that b-blockers should be commencedas soon as possible after the onset of MI, and

continued indefinitely or at least for several years[11

&

,12,13&

]. Although the guidelines generallyacknowledge that the data were collected over25 years ago, the lack of relevant modern evidencehas not prevented adherence to these guidelinesbeing championed as the standard of care in moderncardiology practice. Programs to encourage guide-

line adherence have been launched irrespective ofwhether the evidence base is sufficiently robust inthe modern era. The Get With The Guidelines(GWITG) programs of the AHA [14] and the Guide-lines Applied in Practice (GAP) program of the ACC[15] have promoted high levels of b-blocker pre-scribing as quality measures for patients with acuteMI, and some hospital reimbursement programspenalize hospitals which do not achieve adequatelevels of adherence to b-blocker prescribing on dis-charge [16].

ORAL b-BLOCKERSThe collection of evidence from randomized clinicaltrials of oral b-blockade after MI commenced in thelate 1970s, reached a peak in the mid-1980s, and wasessentially complete by the early 1990s (Fig. 1).

Since 1985, there have been major changes inMI and its management. We have seen the reper-fusion era introduced into coronary care, initiallywith thrombolysis as a result of the ISIS-2 [17] andGUSTO trials [18], later with primary PCI [19,20],the near universal use of aspirin [21], high-dosestatins [22], and dual antiplatelet therapy [23,24].

Although there is no doubt that the evidencecollected in the mid-1980s was relevant to the treat-ment of patients at that time, there are four import-ant reasons to question the relevance of the oldb-blocker evidence to modern cardiology practice.

First, most patients in the modern era receivereperfusion therapy. Early reperfusion changes thepathophysiology of MI [25] with the net result beingfar less and sometimes no damage to the myo-cardium, in contrast to persistent ischemia resultingin extensive myocardial necrosis, scarring, andadverse remodeling. The uptake of reperfusion

therapies, initially with thrombolytic therapy andlater with PCI, was rapid during the late 1980s andhas accelerated into the modern reperfusion era forthe treatment of STEMI. The clinical judgment andavailability of resources determine use of lytictherapy or PCI in almost all patients. In the PerthMONICA (Multinational Monitoring of Trends andDeterminants in Cardiovascular Disease) study con-ducted from the mid-1980s to the early 1990s, theuse of thrombolysis increased from 12 to 49% andcoronary revascularization therapy in the year post-infarction increased from 2 to 38% [26

&

]. These

KEY POINTS

The evidence base to support the routine use of oralb-blockers after MI is 25 years out of date.

The widespread uptake of reperfusion therapy forSTEMI, introduction of effective nonreperfusiontherapies, subsequent dramatic improvements in the

outcomes of MI, and changes in the definition of MIhave changed the clinical profile of MI so substantiallythat evidence from the mid-1980s is not relevant to themodern management of MI.

Recent observations have challenged the rationale forthe use ofb-blockers in hypertension and stablecoronary heart disease, weakening the assumption thatall post-MI patients should be on oral b-blockers.

In contrast, the evidence base to support b-blockers incardiac failure and left ventricular dysfunction is strongand contemporary.

The routine use ofb-blockers after MI should be

reconsidered and limited to high-risk post-MI patients(cardiac failure, left ventricular dysfunction, or ongoingmyocardial ischemia).

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trends have accelerated since. The US NationalRegistry of Myocardial Infarction (NRMI) docu-mented the patterns of care in over 2.5 millionpatients with MI in 2157 hospitals in the UnitedStates between 1990 and 2006 and showed that

the use of revascularization procedures with PCIincreased from 37 to 73% for STEMI and 25 to44% for non-STEMI [27

&

].Second, other highly effective nonreperfusion

therapies have been introduced into practice on thebasis of evidence accumulated in the past 20 years.The use of antiplatelet therapies and statins nowapproaches 100 and 90%, respectively [28].

Third, there is evidence that the abovemen-tioned changes in therapy, with efficacy proven inRCTs, have been effective when applied in practiceand have contributed to an improved natural

history and better outcomes for patients with MI.Patients with MI have fewer complications andbetter outcomes in 2012 compared with themid-1980s when the b-blocker clinical trials wereconducted. Within coronary care units, the inci-dence of cardiogenic shock and heart failure duringMI has declined significantly [29

&

,30], and, in aunique long-term study of the trends in mortalityin patients treated in a coronary care unit, the30-day mortality reduced by two-thirds and the5-year mortality reduced by half from 1985 to2008 [31]. Community-wide studies have also

confirmed declines in mortality from MI. In Perth,the adjusted odds ratio for acute myocardial infarc-tion (AMI) mortality declined by 36% in the decadefrom the mid-1980s to the mid-1990s, with similartrends observed in 12-year mortality in 1-year sur-

vivors [26&

]. Nationwide studies show the samepattern. In the United States, STEMI and non-STelevation myocardial infarction (NSTEMI) mortalityrates have declined dramatically from the 1980sto the 2000s. In over 1.3 million patients withSTEMI, total mortality rates declined from 15 to10% and age-adjusted rates nearly halved from406 to 286 per 100 000 between 1988 and 2004[32

&

]. In 1.4 million patients with NSTEMI, totalmortality rates decreased from 29.6% in 1988 to11.3% in 2004 and age-adjusted mortality morethan halved from 727 to 305 per 100 000 [33]. These

trends have accelerated into the 2000s with a 24%decline between 1999 and 2008 [34

&

]. In patientsrepresented in large clinical trials of MI, earlymortality rates over the period mid-1980s to mid-2000s have declined by up to 70% [35

&

].Finally, the definition of myocardial has changed

dramatically since the mid-1980s. At that time, theclinical trials used a variety of definitions to includepatients in the b-blocker trials. The most commondefinition was the WHO definition, which requiredthe development of Q waves or serial ECG changes,and an increase in creatine kinase level to twice the

1400

1200

1000

800

600

400

200

0

Number

of deaths

Long-term post-AMI

Beta blockers vs. placebo trials

Cumulative deaths

1975 1980 1985 1990 1995 2000 2005 2010

Number

oftrials

0

5

10

15

Thrombolysis

Primary PCI

High dose statins

Aspirin

Dual antiplatelet therapy

Placebo

Treatment

FIGURE 1. Cumulative evidence for mortality benefit of postmyocardial infarction (MI) b-blockers in randomized controlled

trials (RCTs) from the 1970s to the present. The bars show the number of trials (scale on right) and the curves show the numberof deaths with 95% confidence intervals (scale on left) in each 5-year period in the RCTs, which compared b-blockers withplacebo. The evidence for superiority ofb-blockers was evident by the late 1980s with minimal additional evidence sincethen. The horizontal bars below show the significant changes in therapy that have been introduced since then. The evidencefor the timing of introduction of new therapies is based on [17,18] (thrombolysis), [17,21] (aspirin), [19,20] (primary PCI),[23,24] (dual anti-platelet therapy) and [22] (high dose statins).

b-Blockers and myocardial infarction Thompson

0268-4705 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-cardiology.com 401



upper limit of normal [36]. The latest Universal Defi-nition allows the diagnosis of AMI when the high-sensitivity troponin level shows a rise and fall outsidethe normal range [37

&&

], significantly increasing thesensitivity of the diagnostic criteria. Patients beingdiagnosed with MI today include many patients withlower risk than in previous definitions [38

&

].

In brief, the introduction of reperfusion therapyfor STEMI has changed the pathophysiology of thecondition for the better, nonreperfusion therapieshave been introduced on the basis of proven efficacyin large randomized controlled trials (RCTs), thenatural history has consequently changed to fewercomplications and deaths, and changes in thedefinition of MI have widened the diagnosis toinclude patients with lower risk. Patients with MIwho were being treated in the mid-1980s were sodifferent in their pathophysiology, treatment pro-file, and natural history and definition that theb-blocker trials conducted at that time bear littlerelevance to those being treated for AMI in themodern era of coronary care. This raises the questionof whether there is any relevant modern evidence tosupport the widespread prescribing of b-blockersafter MI.

EVIDENCE FROM THE MODERN ERA ON

THE EFFECTIVENESS OF b-BLOCKERS

As there are no RCTs examining the effect ofb-blockers after AMI in the modern era, indirectevidence must be examined to decide whether the

old evidence is relevant. Only guarded conclusionscan be drawn from observational studies and RCTsin related conditions, but there is no clear supportfor the unrestricted use ofb-blockers after MI.

LACK OF EFFICACY OF THE b-BLOCKERSIN THE HYPERTENSION TRIALS

Although the role ofb-blockers as standard therapyafter MI has been accepted with only minimal chal-lenge, there has been a re-appraisal of the role ofb-blockers as first-line treatment in hypertension.

When the effect of b-blockers, primarily atenolol,was compared with other first-line antihyperten-sives, the effects on outcomes were less impressivefor the b-blockers [39]. This led to a re-appraisal ofthe overall efficacy of b-blockers in all the hyper-tension trials, leading to disconcerting findings intheir effect on coronary heart disease (CHD) events.In 13 RCTs with 91 561 participants with hyperten-sion, the risk of all-cause mortality was not differentbetween b-blockers used as first-line therapy andplacebo [relative risk (RR) 0.99, 95% confidenceinterval (CI) 0.881.11]. Although the risk of total

cardiovascular disease (CVD) was 12% lower forfirst-line b-blockers compared with placebo, thiswas primarily due to a significant 20% decrease instroke and there was no difference in CHD outcomes[40]. The latest update of this evidence confirmsthese findings, with the additional finding thatb-blockers are less effective in reducing CHD end-

points than calcium channel blockers and conclud-ing that the evidence is generally weak, with thepotential for bias [41

&&

].

LIMITED EVIDENCE IN STABLE

CORONARY HEART DISEASE PATIENTS

A study of patients who have undergone PCI duringtheir hospital treatment for STEMI showed nobenefit for the use of postdischarge b-blockers inpatients free of heart failure after adjustment forclinical and demographic factors [42

&&

].A report on follow-up from the REACH

(Reduction of Atherothrombosis for ContinuedHealth) study on data collected in the early 1990son 44708 patients whose CHD was stable included atotal of over 14 000 with known prior MI. A propen-sity-matched analysis failed to show any survivalbenefit for patients taking b-blockers [43

&&

].

STRONG EVIDENCE OF BENEFIT OF

b-BLOCKERS IN HEART FAILURE

In contrast to the old evidence for post-MIb-blockers, and limited convincing evidence for

their use in hypertension and stable CHD, the evi-dence for a benefit of b-blockers in heart failure isstrong, relatively free of publication bias, and con-temporary [44]. Multiple trials and meta-analyseshave confirmed this conclusion, the latest indicat-ing a likely reduction of 30% in 1-year mortalityin patients with heart failure or left ventriculardysfunction treated with b-blockers [45

&&

]. Onemeta-analysis concluded that the probability thatb-blocker therapy reduced total mortality and hos-pitalizations for congestive heart failure was almost100% and that these benefits are clinically signifi-

cant is 99% [46].

CONCLUSION

The following conclusions can be drawn:

(1) The use of i.v.b-blockers in MI has little supportand has been progressively downgraded inguidelines.

(2) The data for long-term oral post-AMI b-blockers,collected in the 1980s in a different era, with adifferent pathophysiology, different treatment

Clinical trials




profile, different natural history, and differentdefinition of the condition, can no longer beused as a basis for current evidence-based prac-tice.

(3) There is lack of evidence that b-blockers asfirst-line therapy in hypertension or use inpatients with stable CHD can reduce coronary

events.(4) The data for the benefits ofb-blockers in heartfailure or left ventricular systolic dysfunctionare persuasive.

(5) This review of the available evidence does notsupport routine prescribing ofb-blockers for allpatients with acute coronary syndromes andsupports even less the use of adherence to highb-blocker target prescribing rates as a qualitymeasure.

(6) An alternative interpretation of the availableevidence is that the use of b-blockers in post-MI patients should be restricted to patients athigh risk, especially those who have ongoingevidence of myocardial ischemia, proven heartfailure, or left ventricular dysfunction. The datato support b-blockers in low-risk patients in themodern era are lacking.

Acknowledgements

None.

Conflicts of interest

There are no conflicts of interest.

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&&

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&&

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A Bayesian meta-analysis. Ann Intern Med 2001; 134:550560.

Clinical trials


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