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Addressing the Gap in the Management of Patients After Acute Myocardial Infarction: How Good Is the Evidence Supporting Current Treatment Guidelines?
Beta-adrenergic blocking drugs were thefirst agents shown in large clinical trials toimprove the outcomes of survivors of acutemyocardial infarction (MI). Lower mortalitywas observed in the group randomized toactive therapy, with a beta-adrenergic blockingdrug in most, but not all, of the trials.
Evidence Supporting Post-MI Use ofBeta-adrenergic Blockers
Table 1 shows the results in individual trialgroups according to the properties of the specificbeta-adrenergic blocking drug under evaluation.The Beta-Blocker Heart Attack Trial(BHAT),1 which randomized 3837 patients topropranolol or placebo, and the NorwegianMulticenter Timolol Study,2 with 1884 randomizedpatients convincingly demonstrated thattherapy with a nonselective beta-adrenergicblocking agent improved survival.
Conversely, trials with agents with significantintrinsic sympathomimetic activity (ISA) did notgenerally report positive results, with the exceptionof a small trial with acebutolol, an agentwith a low level of ISA. Similarly, results withagents with specificity for the beta1 adrenoceptorhave not consistently shown an improvementin mortality. Metoprolol, the shorter-actingtartrate salt, did not improve survival in the2395 patients included in the LopressorIntervention Trial (LIT).3 However, practolol,also a beta1-selective agent, did improve survivalin a trial of 3038 survivors of acute MI, althoughthe agent was subsequently withdrawn becauseof toxicity.4
All the original randomized clinical trialsthat provide support for the long-standing recommendationfor routine use of beta-blockingdrugs following acute MI were performed inthe 1970s and 1980s, which was a very differentera in the routine management of patientsduring and after acute MI and also in ourappreciation of the safety and benefit of beta-adrenergicblocking drugs in patients withheart failure (HF). The patients recruited intothese trials had not had the benefit of earlyacute thrombolysis or direct mechanical interventionto the infarct-related coronary occlusionby angioplasty. Aspirin use was notwidespread or was actually contraindicated inthe trial population to prevent a confoundingimpact on survival. Angiotensin-convertingenzyme (ACE) inhibitors had not yet beendeveloped, and other therapies, such asheparin, were not routinely used. On the otherhand, some other probably harmful therapies,such as lidocaine infusions, which are nolonger routinely used, were commonly used atthat time.
Although not every individual trial showeda survival benefit, the capability, demonstratedfor the first time, to improve long-time survivalfollowing acute MI resulted in a widespreadand general recommendation to use a beta-adrenergicblocking drug routinely in allpatients without a contraindication. Because atthat time beta-adrenergic blocking drugs wereconsidered to be contraindicated in HF andperhaps because it was thought that low-riskpatients did not require additional long-termtherapy, adoption of beta-adrenergic blockingdrugs fell short of expectations.
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Guidelines on post-MI management5 alsoadvocated widespread use of beta-adrenergicblocking agents based on their beneficialeffects on the risk of reinfarction. This effectwas demonstrated in the Norwegian trial, inwhich the nonselective beta-adrenergic blockertimolol reduced the risk of infarction by28% ( < .0006). Similarly, in the BHAT study,the nonselective beta-adrenergic blocker propranololreduced the risk of reinfarction by16% ( = NS).
Although all the trials of beta-adrenergicblocking drugs from this era excludedpatients with advanced HF, evidence fromsubgroup analyses provided a tantalizing prediction,which was confirmed more than adecade later, that beta-adrenergic blockadewould be especially beneficial in patientswith HF. In the BHAT study, a subgroup ofpatients with mild HF following the index MIhad a higher subsequent mortality rate andthe greatest benefit from randomization topropranolol. Similarly, in the Norwegian study,a subgroup of patients with cardiomegaly onchest radiograph was especially likely to benefitfrom timolol. Although atenolol and metoprolol(tartrate or succinate salt) are currentlythe beta-adrenergic blockers most commonlyprescribed following acute MI, neither ofthese agents has been demonstrated in alarge-scale randomized trial to improve eithersurvival or the risk of reinfarction.
How Effective Are Other Post-MITherapies?
Not all agents that have been evaluatedfor post-MI therapy are effective. Drugs, suchas diuretics, nitrates, and calcium channelblockers, that do not directly counter theabnormal neurohormonal environment inthis patient population have not been shownto be effective.6,7 Despite lowering bloodpressure and reducing myocardial ischemia,calcium channel blocking drugs do notimprove survival and are actually detrimentalin patients with HF.
Only neurohormonal antagonists have beenshown to attenuate or reverse the progressiveleft ventricular (LV) remodeling that occursafter MI, especially in patients whose LV ejectionfraction is reduced to ≤ 40%. For example,in the Survival and Ventricular Enlargement(SAVE) trial, ACE inhibitors improved survivaland attenuated the LV remodeling process inpatients with LV dysfunction after acute MI.8
CAPRICORN Trial of Beta BlockersPost-MI
The Carvedilol Post Infarct SurvivalControl in LV Dysfunction (CAPRICORN)study9 is the only trial to date to evaluate therole of beta-adrenergic blocking drugs inpatients with significant post-MI LV dysfunctionas an entry criterion. Patients also had tohave been treated with ACE inhibitors for atleast 48 hours prior to randomization (unlessthere were contraindications). The trial comparedcarvedilol with placebo in patientswho had had an acute MI within the previous21 days and who had an LV ejection fractionof ≤ 40%. HF was present in approximatelyhalf of the patients studied.
CAPRICORN is also the only study of beta-adrenergicblocking drugs undertaken inpatients who had the benefit of contemporarymanagement of acute MI. Therapies routinelyapplied to the study population that areknown to improve survival included thrombolytictherapy or direct angioplasty whenindicated, ACE inhibition (use of which wasan actual inclusion criteria), aspirin, andstatins. Table 2 shows the percentage ofpatients in the CAPRICORN study whoreceived these agents.
The CAPRICORN trial enrolled 1959patients, 975 randomized to carvedilol and 984to placebo, who were followed for an averageof 1.3 years. The dose of the study medicationwas uptitrated from 6.25 mg twice daily to amaximum of 25 mg twice daily.
The trial was initially designed and poweredto detect a favorable impact of carvedilol onsurvival. Subsequently, on the advice of anindependent end points committee, the primaryend point was altered to an analysis of deathfrom any cause or hospitalization for a cardiovascularcause. When the results were analyzed,it was found that carvedilol hadimproved survival by 23% (Figure), whereasthere was no statistically significant differencebetween the carvedilol and placebo groups inthe combined end point of death or cardiovascularhospitalization.
The impact of carvedilol on reinfarctionwas substantial and was the greatest reductionin reinfarction reported in any large trialof beta blockers following acute MI.Carvedilol also had a favorable influence onthe risk of supraventricular or ventriculararrhythmias.10
Carvedilol was well tolerated, and theresults are especially remarkable because"drop-in" patients—given open-label beta-adrenergicblocking drugs—would have tendedto reduce the observed favorable influenceof carvedilol. Patients who received optimaltherapy for acute MI, including revascularizationby angioplasty or thrombolysis, were noless likely to benefit than the other patients.Approximately half the patients in the trial didnot have HF, but they obtained a similar benefitto the group with HF.
Class Effect or Drug-specific Effect?
Meta-analyses suggest that all beta-adrenergicblocking drugs that do not have ISAimprove survival following MI. Most meta-analysesand the latest study that includedthe current data with carvedilol suggest thatimportant and clinically relevant differencesmay exist between the benefit obtained frombeta1 selective agents and nonselectivedrugs, such as carvedilol. Meta-analyses of the26 580 patients in placebo-controlled trialsfollowing acute MI and the 15905 patientsevaluated in HF trials do show an average ≥13% reduction in mortality with the nonselectiveagents in both clinical scenarios.11
The suggestion that nonselective beta-adrenergicblocker agents may produce agreater clinical benefit after acute MI is wellsupported on a mechanistic basis, althoughmost of the studies, including the Carvedilol orMetoprolol European Trial (COMET),12 thatconfirmed the superiority of a nonselectiveagent (carvedilol) over a selective agent (short-actingmetoprolol),were conducted in patientswith HF.
Following acute MI, many of the pathophysiologicalfeatures that influence disease progressionand outcomes are the same as those in HF.Norepinephrine exerts an important influenceon the risk of reinfarction, the risk of supraventricularand ventricular arrhythmias, and theadverse remodeling process that develops, particularlyin survivors of MI.
Conclusion
Beta-adrenergic blocking drugs have beenconvincingly demonstrated in large clinical trialsto improve the natural history followingacute MI. Improved survival and reduced riskof reinfarction have been shown in large-scalerandomized trials. Much of the evidence supportingthe routine use of beta-adrenergicblocking drugs for the long-term therapy ofpatients without contraindications comes fromtrials of nonselective agents. In the modern eraof acute MI management, when many successfultherapies are combined to improve post-MIoutcomes, only carvedilol has been shown notonly to improve survival and reduce reinfarctionbut also to attenuate the remodelingprocess.
Moreover, carvedilol has been shown tobenefit a patient population selected on thebasis of high risk and treated because of thishigh risk with concomitant ACE inhibitors.TheCAPRICORN study found that far from beingsurpassed by more modern agents and approachesto the management of acute MI, betaadrenergicblocking drugs, specificallycarvedilol, are highly effective and importanttherapy for post-MI patients.
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