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EDITORIAL COMMENT

Beta-Blockers in AsymptomaticCoronary Artery DiseaseNo Benefit or No Evidence?*

Philippe Gabriel Steg, MD,yzx Ranil De Silva, PHDxjj

SEE PAGE 247

T he benefit of beta-blockers in the manage-ment of patients with heart failure and leftventricular dysfunction has been incontro-

vertibly established in multiple contemporary ran-domized clinical trials (1–5). The recommendationfor use of beta-blockers after acute myocardial in-farction (MI) is mainly based on studies (6–8) thatpredate routine implementation of a contemporarystrategy of early reperfusion and modern medicaltherapy, although some observational data suggestthat beta-blocker therapy may be associated withreduced long-term mortality after early percutaneouscoronary intervention for acute MI (9,10).

In stable coronary artery disease (CAD), there issolid evidence to show that beta-blockers effectivelyrelieve anginal symptoms and improve myocardialischemia (11), and are therefore recommended asfirst-line agents for symptom relief in both U.S. (12)and European (13) guidelines. However, the evi-dence base for the use of beta-blockers to improveprognosis in asymptomatic patients, who representw80% of the stable CAD population (14), is less robustand not supported by data from an appropriately

* 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.

From the yDépartement Hospitalo-Universitaire FIRE, Hôpital Bichat,

AP-HP, and Université Paris-Diderot, Paris, France; zINSERM U-1148,

Paris, France; xNational Heart and Lung Institute, Imperial College Lon-

don, United Kingdom; and the jjNIHR Cardiovascular Biomedical

Research Unit, Royal Brompton and Harefield NHS Foundation Trust,

London, United Kingdom. Dr. Steg has received research grants from

Sanofi and Servier (to INSERM U-1148); personal fees from Amarin,

AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers-Squibb, Daiichi-

Sankyo, GlaxoSmithKline, Janssen, Eli Lilly, Medtronic, Merck-Sharpe-

Dohme, Novartis, Otsuka, Pfizer, Roche, The Medicines Company,

Sanofi, Servier, and Vivus; and is a stockholder in Aterovax. Dr. De Silva

has reported that he has no relationships relevant to the contents of this

paper to disclose.

powered randomized trial. A recent report from theREACH registry has examined the benefit of beta-blockers in patients with stable CAD (15). In that anal-ysis of 21,860 patients, beta-blocker usage was notassociatedwith a reduced rate of cardiovascular death,nonfatal MI, nonfatal stroke, hospitalization for anatherothrombotic event, or revascularization, evenin patients with previous MI. These data challengethe extrapolation of the benefits of beta-blockadeobserved in patients with heart failure or left ventric-ular dysfunction to all patients with stable CAD.

In this issue of the Journal, Andersson et al. (16)conducted an important, rigorous analysis of the Kai-ser Permanente health records database. Theyobserved amodest benefit of beta-blockade in patientswith stable CAD. There was a clear interaction betweena prior history ofMI and treatment effect, with benefitsconfined to those patients with a history of priorMI. Although these data are informative, there are anumber of issues inherent to the study design, war-ranting consideration when interpreting the results.

Key clinical parameters, such as the presence andseverity of anginal symptoms, ischemic burden, leftventricular function, and importantly, the type anddose of beta-blocker therapy, were unavailable.For beta-blocker therapy to confer clinical benefit,significant pharmacological beta-blockade is likelyrequired, although it is well known that fullbeta-blockade is rarely achieved in routine clinicalpractice (15). The study population comprisedapproximately 80% of acute coronary syndrome(ACS) patients, while the remainder consisted of pa-tients referred for elective revascularization pro-cedures, which would exclude patients with incident,stable CAD who may be managed medically withoutrevascularization. Therefore, the results may be in

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part attributable to insufficient power to detect abenefit of beta-blockade in stable CAD patientswithout previous MI, and of uncertain relevance tothe broader population of stable CAD patients notcaptured in the current analysis.

Despite careful attempts by the authors to adjustfor potential confounders, interpretation of the cur-rent findings needs to be tempered by the weak-nesses inherent to observational studies, includingunmeasured confounders, nonuniformity of patientinclusion criteria and event adjudication, imbal-anced patient groups, and the retrospective ascer-tainment of the study cohort, which necessitates“on-treatment” rather than “intention-to-treat” ana-lyses. The assumption that patients are adherentto prescribed medication on the basis of filling ofprescriptions is also a potential weakness (17). Thatsaid, both the REACH (15) and Kaiser Permanentedata are consistent with lack of demonstrable prog-nostic benefit from beta-blocker therapy in a numberof settings of stable cardiovascular disease (18,19).

Beta-blockers may benefit patients with stable CADthrough both anti-ischemic and antiarrhythmic ef-fects. A major mechanism of action of beta-blockers isreduction of heart rate, which is thought to be adeterminant of clinical outcome and cardiovasculardisease progression (20). The SIGNIFY trial is testingwhether ivabradine, an If current channel blocker thatcauses selective heart rate reduction without alteringblood pressure, provides clinical benefits in patientswith stable CAD without left ventricular dysfunction(21). This type of study is relevant as undesirable ef-fects of beta-blockers such as impaired reductionof central aortic pressure (22), symptomatic brady-cardia, high-grade atrioventricular block, hypoten-sion, and depression may contribute to observeddifferences in clinical outcomes between patients onand off beta-blocker therapy. Importantly, both theREACH registry and the Kaiser Permanente analysisdid not suggest harm from beta-blockade.

Andersson et al. (16) argue that their findingssupport a prospective, randomized, controlled trial totest the prognostic benefit of beta-blockade in

asymptomatic patients with stable CAD. In an idealworld, that may be true. However, given the excellentclinical outcomes in this patient group with contem-porary treatment (23), it will be a major challenge toattract the resources needed to conduct what wouldnecessarily be an extremely large trial.

WHAT ARE THE CLINICAL IMPLICATIONS?

The analysis by Andersson et al. (16) strengthens theview that systematic use of beta-blockers is notmandated on prognostic grounds for all patients withstable CAD, especially in the absence of previous MI.These drugs should be used for symptomatic anginarelief, as recommended in the ACC/AHA (12) and ESC(13) guidelines. This recommendation will come aswelcome relief for stable CAD patients, the vast ma-jority of whom are asymptomatic and are prescribed aplethora of pharmacologic agents, including anti-platelet therapy, statins, and blockade of the renin-angiotensin system to improve prognosis. For thosepatients with a known history of MI, routine admin-istration of beta-blockers seems reasonable, althoughthe benefits of prolonged treatment in the asymp-tomatic patient without left ventricular dysfunctionremains debatable. While guidelines currentlyrecommend 3 years of beta-blocker treatment afterpresentation with ACS (12), should side effects occurthere is no definitive evidence to insist on continuedtreatment. The report by Andersson et al. (16) sup-ports tailoring treatment decisions for patients withstable CAD: defining the most parsimonious bespoketherapeutic regimen, which renders an individualpatient free of symptoms and improves prognosiswith minimal side effects, is particularly important,to ensure treatment compliance as well as optimizequality-of-life and clinical outcomes, especially in anera of constrained healthcare resources.

REPRINT REQUESTS AND CORRESPONDENCE:

Dr. Philippe Gabriel Steg, Hôpital Bichat, AssistancePublique–Hôpitaux de Paris, 46 rue Henri Huchard,75018 Paris, France. E-mail: gabriel.steg@bch.aphp.fr.

RE F E RENCE S

1. The Cardiac Insufficiency Bisoprolol Study II(CIBIS-II): a randomised trial. Lancet 1999;353:9–13.

2. Effect of metoprolol CR/XL in chronic heartfailure: Metoprolol CR/XL Randomised Interven-tion Trial in Congestive Heart Failure (MERIT-HF).Lancet 1999;353:2001–7.

3. Dargie HJ. Effect of carvedilol on outcomeafter myocardial infarction in patients with

left-ventricular dysfunction: the CAPRICORN ran-domised trial. Lancet 2001;357:1385–90.

4. Packer M, Bristow MR, Cohn JN, et al. Theeffect of carvedilol on morbidity and mortality inpatients with chronic heart failure. U.S. CarvedilolHeart Failure Study Group. N Engl J Med 1996;334:1349–55.

5. Packer M, Fowler MB, Roecker EB, et al., Car-vedilol Prospective Randomized Cumulative Survival

(COPERNICUS) Study Group. Effect of carvedilol onthe morbidity of patients with severe chronic heartfailure: results of the carvedilol prospective ran-domized cumulative survival (COPERNICUS) study.Circulation 2002;106:2194–9.

6. Freemantle N, Cleland J, Young P, Mason J,Harrison J. b-Blockade after myocardial infarction:systematic review and meta regression analysis.BMJ 1999;318:1730–7.

J A C C V O L . 6 4 , N O . 3 , 2 0 1 4 Steg and De SilvaJ U L Y 2 2 , 2 0 1 4 : 2 5 3 – 5 Beta-Blockers in Asymptomatic CAD

255

7. Hjalmarson A, Elmfeldt D, Herlitz J, et al. Effecton mortality of metoprolol in acute myocardialinfarction. A double-blind randomised trial. Lancet1981;2:823–7.

8. Chen ZM, Pan HC, Chen YP, et al., COMMIT(ClOpidogrel and Metoprolol in MyocardialInfarction Trial) collaborative group. Earlyintravenous then oral metoprolol in 45,852 pa-tients with acute myocardial infarction: rando-mised placebo-controlled trial. Lancet 2005;366:1622–32.

9. Choo EH, Chang K, Ahn Y, et al. Benefit ofb-blocker treatment for patients with acutemyocardial infarction and preserved systolicfunction after percutaneous coronary intervention.Heart 2014;100:492–9.

10. Juliard JM, Charlier P, Golmard JL, et al. Ageand lack of beta-blocker therapy are associatedwith increased long-term mortality after primarycoronary angioplasty for acute myocardial infarc-tion. Int J Cardiol 2003;88:63–8.

11. Heidenreich PA, McDonald KM, Hastie T, et al.Meta-analysis of trials comparing beta-blockers,calcium antagonists, and nitrates for stableangina. JAMA 1999;281:1927–36.

12. Fihn SD, Gardin JM, Abrams J, et al., AmericanCollege of Cardiology Foundation; American HeartAssociation Task Force on Practice Guidelines;American College of Physicians; American Asso-ciation for Thoracic Surgery; Preventive Car-diovascular Nurses Association; Society forCardiovascular Angiography and Interventions;Society of Thoracic Surgeons. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diag-nosis and management of patients with stableischemic heart disease: a report of the AmericanCollege of Cardiology Foundation/American Heart

Association Task Force on Practice Guidelines, andthe American College of Physicians, AmericanAssociation for Thoracic Surgery, Preventive Car-diovascular Nurses Association, Society for Car-diovascular Angiography and Interventions, andSociety of Thoracic Surgeons. J Am Coll Cardiol2012;60:e44–164.

13. Montalescot G, Sechtem U, Achenbach S, et al.2013 ESC guidelines on the management of stablecoronary artery disease: the Task Force on themanagement of stable coronary artery disease ofthe European Society of Cardiology. Eur Heart J2013;34:2949–3003.

14. Gehi AK, Ali S, Na B, Schiller NB, Whooley MA.Inducible ischemia and the risk of recurrent car-diovascular events in outpatients with stable cor-onary heart disease: the heart and soul study. ArchIntern Med 2008;168:1423–8.

15. Bangalore S, Steg G, Deedwania P, et al.,REACH Registry Investigators. b-Blocker use andclinical outcomes in stable outpatients with andwithout coronary artery disease. JAMA 2012;308:1340–9.

16. Andersson C, Shilane D, Go AS, et al. Beta-blocker therapy and cardiac events amongpatients with newly diagnosed coronary heartdisease. J Am Coll Cardiol 2014;64:247–52.

17. Harrison TN, Derose SF, Cheetham TC, et al.Primary nonadherence to statin therapy: patients’perceptions. Am J Manag Care 2013;19:e133–9.

18. Dahlof B, Sever PS, Poulter NR, et al. ASCOTInvestigators. Prevention of cardiovascular eventswith an antihypertensive regimen of amlodipineadding perindopril as required versus atenololadding bendroflumethiazide as required, in theAnglo-Scandinavian Cardiac Outcomes Trial-Blood

Pressure Lowering Arm (ASCOT-BPLA): a multi-centre randomised controlled trial. Lancet 2005;366:895–906.

19. POISE Study Group, Devereaux PJ, Yang H,et al. Effects of extended-release metoprololsuccinate in patients undergoing non-cardiac sur-gery (POISE trial): a randomised controlled trial.Lancet 2008;371:1839–47.

20. Fox K, Borer JS, Camm AJ, et al., Heart RateWorking Group. Resting heart rate in cardiovas-cular disease. J Am Coll Cardiol 2007;50:823–30.

21. Fox K, Ford I, Steg PG, Tardif JC, Tendera M,Ferrari R. Rationale, design, and baseline charac-teristics of the Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine inpatients with coronarY artery disease (SIGNIFYtrial): a randomized, double-blind, placebo-controlled trial of ivabradine in patients with sta-ble coronary artery disease without clinical heartfailure. Am Heart J 2013;166:654–661.e6.

22. Williams B, Lacy PS, Thom SM, et al., CAFEInvestigators; Anglo-Scandinavian Cardiac Out-comes Trial Investigators; CAFE Steering Com-mittee and Writing Committee. Differential impactof blood pressure-lowering drugs on central aorticpressure and clinical outcomes: principal results ofthe Conduit Artery Function Evaluation (CAFE)study. Circulation 2006;113:1213–25.

23. Steg PG, Greenlaw N, Tardif JC, et al., CLARIFYRegistry Investigators.Women andmenwith stablecoronary artery disease have similar clinical out-comes: insights from the international prospectiveCLARIFY registry. Eur Heart J 2012;33:2831–40.

KEY WORDS beta-blockers, coronary arterydisease