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Journal of the American College of Cardiology Vol. 52, No. 18, 2008© 2008 by the American College of Cardiology Foundation ISSN 0735-1097/08/$34.00Published by Elsevier Inc. doi:10.1016/j.jacc.2008.08.008

EDITORIAL COMMENT

eta-Blockers in Hypertensiondding Insult to Injury*

orman M. Kaplan, MD

allas, Texas

eta-blockers have been found not to be effective forrimary prevention of cardiovascular disease in patients withrimary hypertension. The problem was first recognized byesserli et al. (1) in 1998. They pointed out the signifi-

antly lesser benefit of beta-blocker therapy in 2 trials versusiuretic-based therapy in 7 separate trials. Their presenta-ion could not have been clearer: “Diuretic therapy wasuperior to blockade with regard to all end points. . .-blocker therapy only reduced the odds for cerebrovascularvents but was ineffective for preventing coronary heartisease, cardiovascular mortality and all-cause mortality.”

See page 1482

This clear distinction was not referenced in the 2003 Jointational Committee (JNC) report (2), which favored a

iuretic for first drug but indicated that beta-blockers wereuitable alternatives, particularly when a “compelling” indi-ation was present, including heart failure, post-myocardialnfarction, high coronary disease risk, or diabetes mellitus.

A few months after the 2003 JNC report was published,esserli et al. (3), with 3 well-established hypertension ex-

erts, said it again, even more clearly: “The time has come todmit that beta-blockers should no longer be considered appro-riate for first-line therapy of uncomplicated hypertension.”

he British and European Hedges

ven after this indictment, however, the 2004 Britishypertension Society (BHS) guidelines (4) put beta-

lockers alongside angiotensin-converting enzyme inhibi-ors (ACEIs) and angiotensin II receptor blockers (ARBs)s initial therapy for hypertensive patients under age 55ears and for nonblack patients. The 2004 BHS guidelinesid, however, hedge their position, stating that according toheir AB/CD algorithm, either an ACEI or an ARB (A) or

beta-blocker (B) should be chosen for younger and

Editorials published in the Journal of the American College of Cardiology reflect theiews of the authors and do not necessarily represent the views of JACC or themerican College of Cardiology.

wFrom the University of Texas Southwestern Medical Center, Hypertensionivision, Dallas, Texas.

onblack patients whereas either a calcium-channel blockerC) or a diuretic (D) should be chosen for patients who arever age 55 years or black, but the algorithm does place theB” in brackets. The report says, “the reason is to emphasizehe fact that recent trials have reported an increase in onsetf diabetes in patients treated with B or D drugs comparedith A or C drugs, especially when B and D are combined.e advise caution when using B�D in patients at especially

igh risk of developing diabetes as for example, patientsith a strong family history of type 2 diabetes, obesity,

mpaired glucose tolerance, features of metabolic syndromer of South Asian and African-Caribbean descent” (4).Note that the warning did not relate to the lesser benefit

f beta-blockers in general, only to their propensity to bringut diabetes.The British did amend their position in a statement on

heir website on June 28, 2006, providing a new algorithmithout a B (beta-blocker) anywhere to be found and

ncluding the statement that “beta-blockers are no longerreferred as a routine initial therapy for hypertension” (5).This good advice, however, did not get through to the

riters of the 2007 European Society of Hypertension anduropean Society of Cardiology guidelines (6). They stated:

Beta-blockers may still be considered an option for initialnd subsequent antihypertensive treatment strategies. Be-ause they favor an increase in weight, have adverse effectsn lipid metabolism and increase (compared with otherrugs) the incidence of new-onset diabetes, they should note preferred, however, in hypertensives with multiple met-bolic risk factors including the metabolic syndrome. . .” (6).

he Swedish Explosion

esserli et al. (7) said it again in 2007, in this Journal,dding a litany of side effects from beta-blockers, including:) precipitation of diabetes; 2) little effect on regression ofeft ventricular hypertrophy; 3) likely failure to improvendothelial function; 4) weight gain; and 5) decrease inxercise endurance.

To emphasize their position, they added: “For everyyocardial infarction or stroke prevented in the Medicalesearch Council study (8), 3 patients treated with atenololithdrew from the study secondary to impotence and

nother 7 withdrew because of fatigue” (7).Despite the persistence of Messerli et al. (1), the beta-

locker atenolol was the fourth most prescribed drug in the.S. in 2005, with 44 million prescriptions per year (7). It

equired 2 papers in the Lancet from 3 Swedish authors9,10), with their accompanying editorials, to bring the issueo the currently almost unanimous agreement that beta-lockers are no longer an appropriate choice for initial or, astated in the 2006 BHS addendum, subsequent therapy ofncomplicated hypertension. In retrospect, it took thexhortation of Messerli et al. (1) to set the stage but, perhaps

ith Americans being generally less accepted in the rest of

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1491JACC Vol. 52, No. 18, 2008 KaplanOctober 28, 2008:1490–1 Beta-Blockers in Hypertension

he world these days, it took the Swedes to lower theurtain.

Rather surprisingly, in view of the prior analyses byesserli et al. (1) showing equal protection against stroke by

eta-blockers, the problem shown by the Swedish meta-nalyses was lesser protection against strokes by beta-lockers.

he Additional Blow

he paper by Bangalore et al. (11) in this issue of the Journaldds another post-mortem explanation for the fall of beta-lockers, showing higher mortality associated with thelower heart rate they induce. Of interest, the fall in pulseate is an obvious mechanism for the higher central bloodressure with beta-blocker–based therapy noted by Williamst al. (12) in the CAFE (Conduit Artery Function Evaluation)tudy. With this addition to the evidence, beta-blockers willurely remain as indicated for heart failure, for after myocardialnfarction, and for tachyarrhythmias, but no longer for hyper-ension in the absence of these compelling indications.

eprint requests and correspondence: Dr. Norman M. Kaplan,niversity of Texas Southwestern Medical Center, Hypertensionivision, 5323 Harry Hines Boulevard, Dallas, Texas 75390.-mail: Norman.kaplan@utsouthwesern.edu.

EFERENCES

1. Messerli F, Grossman E, Goldbourt U. Are beta-blockers efficaciousas first-line therapy for hypertension in the elderly? A systematic

review. JAMA 1998;279:1903–7. h

2. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of theJoint National Committee on prevention, detection, evaluation, andtreatment of high blood pressure: the 2003 JNC report. JAMA2003;289:2560–72.

3. Messerli FH, Beevers DG, Franklin SS, Pickering TG. Beta-blockersin hypertension—the emperor has no clothes: an open letter to presentand prospective drafters of new guidelines for the treatment ofhypertension. Am J Hypertens 2003;16:870–3.

4. Williams B, Poulter NR, Brown MJ, et al. British HypertensionSociety guidelines for hypertension management 2004 (BHS-IV):summary. BMJ 2004;328:634–40.

5. The National Collaborating Centre for Chronic Conditions. Hyperten-sion. Management in adults in primary care: pharmacological update.Available at: http://www.nice.org.uk/nicemedia/HypertensionGuide.pdf.Accessed July 15, 2008.

6. Mancia G, De Backer G, Dominiczak A, et al. 2007 guidelines for themanagement of arterial hypertension: the Task Force for the Manage-ment of Arterial Hypertension of the European Society of Hyperten-sion (ESH) and of the European Society of Cardiology (ESC).J Hypertens 2007;25:1105–87.

7. Bangalore S, Messerli FH, Kostis JB, Pepine CJ. Cardiovascularprotection using beta-blockers: a critical review of the evidence. J AmColl Cardiol 2007;50:563–72.

8. Medical Research Council. Medical Research Council trial of treat-ment of hypertension in older adults: principal results. MRC WorkingParty. BMJ 1992;304:405–12.

9. Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension:is it a wise choice? Lancet 2004;364:1684–9.

0. Lindholm LH, Carlberg B, Samuelsson O. Should beta blockersremain first choice in the treatment of primary hypertension? Ameta-analysis. Lancet 2005;366:1545–53.

1. Bangalore S, Sawhney S, Messerli FH. Relation of beta-blocker–induced heart rate lowering and cardioprotection in hypertension.J Am Coll Cardiol 2008;52:1482–9.

2. Williams B, Lacy PS, Thom SM, et al. Differential impact of bloodpressure-lowering drugs on central aortic pressure and clinical out-comes: principal results of the Conduit Artery Function Evaluation(CAFE) study. Circulation 2006;113:1213–25.

ey Words: beta-blockers y cardiovascular events y heart rate y

ypertension.