10.1586/ERC.13.15 293ISSN 1477-9072© 2013 Expert Reviews Ltdwww.expert-reviews.com

Key Paper Evaluation

Statistical data presented by the American Heart Association indicated that an estimated 788,000 Americans have a new heart attack while approx-imately 470,000 individuals experience a recur-rent attack [1]. Recurrent heart attacks remain relatively high and are a significant predictor of mortality [2]. Therefore, any measure that would reduce events associated with heart attacks and subsequent death is a welcome intervention. One postsecondary measure is appropriate pharmaco-therapy. The use of a polypill that includes aspi-rin, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), β-blockers (BBs) and statins has been discussed [3]. Furthermore, the usefulness of BBs has been the subject of greater scrutiny in recent years in order to determine whether they are relevant and useful in an era where thrombolytic and/or revascularization and reperfusion are more com-monly utilized.

Based on meta-analysis, BBs reduce mortal-ity, and data from smaller clinical studies have confirmed what has been shown by larger studies [4]. BBs reduce mortality by approximately 40% in patients with acute myocardial infarction (AMI). Moreover, this was observed not only for patients in low-risk category but also those in high risk (i.e., elderly, blacks, low ejection fraction, Type-I diabetics, patients with chronic

obstructive pulmonary disease) [5]. There is always ongoing discussion as to the effective-ness of BBs in individuals with cardiovascular disorders by the virtue of the fact that this class of drugs have antiarrhythmic, anti-ischemic and antiadrenergic actions, and a recent study by Zuckerman et al. (2012) is adding further thoughts to this debate.

Methods & resultsThe effectiveness of four cardiovascular drugs (statins, ACEIs/ARBs, BBs and clopidogrel) on outcome from a cohort composed of 5% random sample on Medicare beneficiaries that were diagnosed with AMI over a 33-month period and survived at least 30 days after dis-charge from hospital between 2006 and 2008 were evaluated. The total sample for the study was 9583 with 83.6% Caucasian, 10.5% black, 64.7% female and 56.7% 75 years of age or older. Comorbidities in the population stud-ied were hypertension: 86.9%, ischemic heart disease: 78.9%, hyperlipidemia: 66.6%, con-gestive heart failure: 53.3% and diabetes mel-litus: 47.4%. Two end points were the subject of measurements: composite outcome consisting of hospitalization for transient ischemic attacks, recurrent AMI, stroke, congestive heart failure or all-cause death and mortality alone. Measure

Reza TabrizchiFaculty of Medicine, Division of Biomedical Sciences, Memorial University, St. John’s, NL, A1B 3V6, CanadaTel.: +1 709 7777 6864 Fax: +1 709 777 7010 rtabrizc@mun.ca

Evaluation of: Zuckerman IH, Yin X, Rattinger GB et al. Effect of exposure to evidence-based pharmacotherapy on outcomes after acute myocardial infarction in older adults. J. Am. Geriatr. Soc. 60(10), 1854–1861 (2012).

The number of myocardial infarctions (MIs) in population remains high and this event is a significant predictor of mortality. Information in literature points to a reduction in mortality, reinfarction and sudden death in first year, especially in patients with high risk, if β-blockers (BBs) are used after MI. In a perspective study, Zuckerman et al. have determined outcome following pharmacotherapy after acute MI in older adults. It is apparent that a number of matters require consideration in evaluation of the effectiveness of BBs. It seems that not all patients benefit equally from treatment with BBs but such an intervention reduces mortality. It is also important to recognize that the beneficial effects of BBs should not be considered in isolation since the biological system is too complex to manipulate with the use of a single class of drugs.

β-blocker therapy after acute myocardial infarctionExpert Rev. Cardiovasc. Ther. 11(3), 293–296 (2013)

Expert Review of Cardiovascular Therapy

© 2013 Expert Reviews Ltd

10.1586/ERC.13.15

1477-9072

1744-8344

Key Paper Evaluation

Keywords: β-blockers • compliance • mortality • myocardial infarction • polymorphism • risk

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of drug exposure as monthly proportion of drug covered from January 2006 through to death or the end of the study was the primary independent variable.

A period of 18 months was the median follow-up, while 33% of the sample died. The proportion of drug covered pat-tern was comparable for all four classes with the statins (0.5) as the highest followed by ACEIs/ARBs (0.48), BBs (0.42) and clopidogrel (0.37). A comparison of each four for composite outcome revealed a significantly lowered outcome with great-est exposure to drugs with adjusted hazard ratios (aHRs) for statins (0.64; 95% CI: 0.59–0.7), ACEIs/ARBs (0.74; 95% CI: 0.68–0.80), clopidogrel (0.75; 95% CI: 0.68–0.82) and BBs (0.83; 95% CI: 0.76–0.90). Evidently, BBs seem to have the smallest effects in reducing the hazard of the composite out-come. A comparison involving all groups together showed that HR remained significantly lower following greatest exposure for the three classes expect BBs. In parallel, in assessment of mortal-ity, HR was lowest with greatest exposure period, ACEIs/ARBs (0.56; 95% CI: 0.51–0.62), BBs (0.66; 95% CI: 0.6–0.73) and clopidogrel (0.6; 95% CI: 0.54–0.68). Statins displayed age dif-ferences for HRs being most effective in ages 65–74 (0.38; 95% CI: 0.3–0.47). Simultaneous analysis of all four drugs revealed significantly lower hazard of mortality with greatest exposure.

Discussion & conclusionThe benefit of BBs in reducing composite outcome was nullified when all four classes of medication were analyzed simultaneously suggesting dependence of this treatment with others. By contrast, survival benefit following greatest level of exposure to BBs was independent of the other three agents. Lower rate of exposure to medication clearly seemed to have detrimental effects on both composite outcome and mortality. This suggests that reduced exposure can lead to higher rate of hospitalization and/or death.

Expert commentaryA shadow hanging over BB therapy is their overall usefulness in patients with AMI in a post-thrombolytic and -antiplatelet age. In 1999, Freemantle et al. carried out a comprehensive meta-analysis with the working hypothesis that thrombolytic and antiplatelet intervention reduces the beneficial effects of BBs [6]. The anti-platelet analysis revealed that 10.1% of patients with AMI died. BBs were noted to reduce all-cause mortality, and while intrave-nous treatment did not produce additional benefits, continua-tion of treatment with BBs did. Long-term treatment with BBs (6–48 months) was found to result in a reduction of 1.2 deaths in 100, and most of the evidence was for propranolol, timolol and metoprolol. While agents with intrinsic activity may have reduced benefits, cardioselectivity does not seem to be a factor for their beneficial effects [6]. The antiplatelet investigation does seem to provide evidence in support of the effectiveness of BBs in patients who have been treated with thrombolytic and/or anti-platelet agents but the overall beneficial effects of BBs in patient undergoing successful recanalization and reperfusions remains to be determined. Simpson et al. [7] have reported that 44.4% patients die within 5 years following AMI with 27.1% in less

than 30 days and 23.7% longer than 30 days. While it is evident that percutaneous transluminal coronary angioplasty is associ-ated with significant reduction in mortality so is pharmaco logical intervention with the use of BBs (aHR: 0.58; 95% CI: 0.46–0.74) and statins (aHR: 0.60; 95% CI: 0.47–0.77). In addition, a retro-spective analysis of the additive effects of BBs to ACEIs in patients who had undergone percutaneous coronary intervention revealed that survival and cardiac event-free rate was lower in cohort that had not received BBs [8]. The analysis by Zuckerman et al. further supports the view that treatment with BBs reduces mortality [9].

More recent evidence seem to imply that low-risk patients benefit the least from using BBs after AMI but there is clear evidence of reduction in total mortality, reinfarction and sudden cardiac death in the first year with use of these drugs especially in patients in a high risk category [10]. However, there is also the view that very modest lowering of the central aortic pressure by BBs leads to less than ideal cardiovascular protection by this class of drugs [11], especially in the elderly with their retardation in overall vascular elasticity. Here, this may speak to the lack of significant reduction in the composite outcome by BBs when all four classes of medications were analyzed simultaneously in the report by Zuckerman et al. Nonetheless, an issue that still needs consideration is patients who may or may not respond favorably to treatment with a BB. One aspect of this may relate to poly-morphism of the β-adrenoceptors. It seems that polymorphism of β-adrenoceptors has an impact of outcome following treatment with BBs. For example, patients with Glu27Glu homozygous for β-2-adrenoceptors have been noted to have higher chance of increase in progression of end-systolic volume and largest pro-gression of diastolic volume and decreased left ventricular ejec-tion fraction [12]. It has also been reported that polymorphism of β-adrenoceptors could determine outcome in patients with acute coronary syndrome [13]. Long-term prognosis in the use of BBs should perhaps be determined by gene analysis and this naturally leads to the subject of ‘personalized medicine’. The beneficial role of BB therapy should not be isolated in patients with AMI. The biological system is too complex to manipulate with use of only a single class of drugs that would produce the appropriate benefit. Optimal pharmacotherapy therapy should be considered with multiple drugs if necessary [14] and while baseline factors, comor-bidity and inherent intrinsic features should play an important role in choosing the optimal treatment in a patient with AMI. The fact that composite outcome did not remain significantly lower for BBs in the analysis by Zuckerman et al., thus, may be due to other factors such as adherence and/or responsiveness to BBs.

Five-year viewDiscontinuation of BBs in patients who have experienced an AMI leads to increased mortality. Ho et al. reported that patients’ discontinuation of BBs was associated with significant reduction in survival within the first year following AMI [15]. Long-term adherence to drug therapy after AMI has been reported to be approximately 94.0% within the first 30 days, and about 82, 76 and 53% within 6, 12 and 24 months, respectively, for BBs with a comparable pattern of drop-off for ACEIs/ARBs and with no

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observable plateauing of the decline for either class [16]. Among the factors that contribute to poor compliance are certainly cost of medication but also in certain cases, poor cognitive function and complicated drug regimens. However, a more important factor that seems to play a role in adherence is limited under-standing of the drug treatment benefits by patients. Clearly, it is vital to put in place a mechanism of counseling by health-care professionals, either the physician and/or the pharmacist, to educate the patients and provide positive reinforcement as to the health benefits of pharmacotherapy. This issue is a critical ingredient in achieving favorable outcome and is best conveyed by the healthcare professionals where trust is a vital part of the equation.

Simulation analysis suggests that the use of BBs in patients with MI would result in gains in health and potentially provide

cost savings [17]. Secondary prevention using a combination of drugs (i.e., BBs, ACEIs/ARBs and statins) saves both lives and money in patients with AMI [18]. It is logical to assume that both epidemiological and economical impact of BB use in patients with AMI have to be contenders when considering the use of this class of drugs in future.

Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial con-flict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Based on statistical data 788,000 Americans have a new heart attach and approximately 470,000 individuals experience a recurrent attacks per year.

• Any intervention that would reduce events associated with heart attacks and subsequent death is a welcome measure, and postsecondary intervention by appropriate pharmacotherapy is a logical option.

• β-blockers (BBs) have been shown to reduce mortality by approximately 40% in patients with acute myocardial infarction (MI).

• An issue that needs consideration is the individual patient that may or may not respond favorably to treatment with BBs, and this may, in part, be related to baseline conditions and/or polymorphism of β-adrenoceptors.

• Discontinuation of BB therapy has been noted with significant reduction in survival within the first year following acute MI.

• Poor compliance is an important issue, and factors that contribute to it include cost of medication, poor cognitive function and complicated drug regimens but a more critical factor seems to be limited patient understanding of the benefits of drug treatment.

• It is vital to have a mechanism of counseling by healthcare professionals to educate the patient and provide positive reinforcement as to the health benefits of pharmacotherapy.

• Secondary prevention using a combination of drugs (BBs, angiotensin-converting enzyme inhibitor/angiotensin receptor blockers and statins) save both life and money in patients with acute MI.

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