β-Blockers as Initial Therapy for HypertensionCharles S. Wiysonge, MD, PhD; Lionel H. Opie, MD, DPhil

β-Blockers are associated with lower mortality and cardiovascu-lar events than placebo when prescribed for patients with heart fail-ure or acute myocardial infarction.1 However, the benefits of β-block-ers for initial treatment of hypertension are less clear. This JAMAClinical Evidence Synopsis summarizes a recently published Coch-rane review of randomized clinical trials (RCTs) regarding associa-tions of β-blockers with all-cause mortality and cardiovascular eventswhen used as initial therapy for hypertension.2

Summary of FindingsThere was no difference in all-cause mortality between β-blockers andplacebo or no treatment. β-Blockers were associated with lower ratesof cardiovascular events compared with placebo or no treatment (4trials,522of9109participants[5.7%]takingβ-blockersvs935of14 504participants [6.5%] taking placebo or no treatment; RR, 0.88 [95% CI,0.79-0.97]), primarily due to an association of β-blockers with lowerrates of strokes (166 participants [1.8%] taking β-blockers vs 333 par-ticipants[2.3%]takingplaceboornotreatment;RR,0.80[95%CI,0.66-0.96]). The corresponding number of patients needed to treat withβ-blockers for 5 years to prevent 1 event was 140 for all cardiovascularevents and 200 for strokes. There was no difference in rates of fatal andnonfatalcoronaryheartdiseaseandwithdrawalsduetoadverseeventsbetween β-blockers and placebo or no treatment.

Therewerenodifferencesinall-causemortalitybetweenβ-blockersanddiureticsorrenin-angiotensinsystem(RAS)inhibitors(Figure).Ratesof all-cause mortality were higher for β-blockers (1768 of 22 525 par-ticipants [7.8%]) compared with calcium channel blockers (CCBs; 1637of 22 300 participants [7.3%]). The number needed to harm (NNH) (ie,the corresponding number of patients needed to treat with β-blockersrather than CCBs for 5 years to prevent 1 excess death) was 200. Therewasnodifferenceincardiovasculareventratesbetweenβ-blockersanddiureticsorRASinhibitors.β-Blockerswereassociatedwithhigherratesof cardiovascular events compared with CCBs (2 trials, 950 of 10 059participants[9.4%]takingβ-blockersvs800of9856participants[8.1%]takingCCBs;RR,1.18[95%CI,1.08-1.29];NNH, 80)andstrokes(3trials,637 of 22 084 participants [2.9%] taking β-blockers vs 512 of 22 083participants[2.3%]takingCCBs;RR,1.24[95%CI,1.11-1.40];NNH, 180).β-Blockers were also associated with higher rates of stroke than RAS

inhibitors (2 trials, 326 of 4946 participants [6.6%] taking β-blockersvs 253 of 5005 participants [5.1%] taking RAS inhibitors; RR, 1.30 [95%CI, 1.11-1.53]; NNH, 65). Finally, rates of adverse events (eg, depression,fatigue, and sexual dysfunction) and discontinuing treatment werehigher for β-blockers than RAS inhibitors (951 participants [19.2%] tak-ingβ-blockersvs687participants[13.7%]takingRASinhibitors;RR,1.42[95% CI, 1.28-1.58]; NNH, 18).

DiscussionThe lower efficacy of β-blockers could not be explained by a lesserdecline in blood pressure level associated with β-blocker treat-ment. Findings may be related to the suboptimal capacity of β-block-ers to reduce central blood pressure and to delay or regress left ven-tricular hypertrophy, carotid intima-media thickness, aortic stiffness,and small artery remodeling.3

Evidence Profile

No. of randomized clinical trials: 13

Study years: Conducted, 1969-2000; published, 1981-2005

No. of participants: 91 562, mostly treatment-naive prior to studyinclusion

Men: 53 826 (59%) Women: 37 736 (41%)

Race/ethnicity: Unavailable

Age, mean (range): 61 (18-80) years

Settings: Hospitalized patients and primary care settings

Countries: Australia, Belgium, Canada, Cuba, Czechoslovakia, Den-mark, Dominican Republic, El Salvador, Finland, France, Germany,Greece, Guatemala, Hungary, Iceland, Ireland, Israel, Italy, Mexico, theNetherlands, New Zealand, Norway, Panama, Spain, Sweden, Tur-key, United Kingdom, United States

Comparison: β-Blockersasmonotherapyorinitialdruginastepped-careapproach vs placebo or no treatment (4 trials) or another drug (12 trials)

Primary outcome: All-cause mortality

Secondaryoutcomes:Fatalandnonfatalstrokes,coronaryheartdisease(definedasmyocardial infarctionorsuddendeath),cardiovasculardeath,cardiovascularevents(coronaryheartdisease,strokes,andheartfailure),adverse events, degree of reduction in blood pressure

CLINICAL QUESTION Are β-blockers associated with lower rates of all-cause mortality andcardiovascular events when used as initial treatment in individuals with hypertensioncompared with placebo, no treatment, or other drugs?

BOTTOM LINE Initial therapy of hypertension with β-blockers is not associated with reducedall-cause mortality but is associated with modest reductions in cardiovascular eventscompared with placebo or no treatment. Calcium channel blockers and renin-angiotensinsystem inhibitors are associated with greater reductions in cardiovascular event rates thanβ-blockers. This evidence derives from trials of traditional β-blockers (eg, atenolol andpropranolol), because there are currently no mortality and cardiovascular event data on thenew vasodilating β-blockers (eg, carvedilol and nebivolol).

Clinical Review & Education

JAMA Clinical Evidence Synopsis

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LimitationsIt is possible that the hypertension trials did not have sufficient sta-tistical power or were not sufficiently long in duration to detect asignificant decrease in all-cause mortality. The data are old (col-lected 8-44 years ago) and three-quarters of active β-blocker therapyin the RCTs was with atenolol.2 Results for newer β-blockers (eg,carvedilol and nebivolol), which combine antihypertensive and va-sodilatory properties, may be distinct from those of atenolol andother traditional β-blockers.4,5 There are currently no mortality andcardiovascular event data on these vasodilating β-blockers as ini-tial therapy for hypertension.

Comparison of Findings With Current GuidelinesThe European Society of Hypertension recommends β-blockers forhypertension only in selected patients in the 2013 guidelines.3 Theseventh report of the US Joint National Committee recommendsβ-blockers, CCBs, and RAS inhibitors as initial therapy for hyperten-sion when a diuretic cannot be used. However, these guidelines havenot been updated since 2003.6

Areas in Need of Further StudyFurther RCTs should explore whether β-blocker effects are influ-enced by subtype of β-blockers and patient age or ethnicity.

ARTICLE INFORMATION

Author Affiliations: Centre for Evidence-BasedHealth Care, Stellenbosch University, Cape Town,South Africa (Wiysonge); Hatter Institute for Cardio-vascular Research in Africa, University of Cape TownMedical School, Cape Town, South Africa (Opie).

Corresponding Author: Charles S. Wiysonge, MD,PhD, Centre for Evidence-Based Health Care,Stellenbosch University, Tygerberg Campus, PO Box19063, Cape Town 7505, South Africa (charlesw@sun.ac.za).

Section Editor: Mary McGrae McDermott, MD,Senior Editor.

Conflict of Interest Disclosures: The authors havecompleted and submitted the ICMJE Form forDisclosure of Potential Conflicts of Interest. Dr

Wiysonge reports receiving grant funding from theNational Research Foundation of South Africa. DrOpie reports receiving grant funding from theNational Research Foundation of South Africa.

Additional Contributions: We acknowledgeOlalekan Uthman, MBBS, MPH, PhD (University ofWarwick), for assistance with data analysis. He didnot receive compensation for his contribution.

REFERENCES

1. Opie LH. β-Blocking agents. In: Opie LH, GershBJ, eds. Drugs for the Heart. 8th ed. Philadelphia,PA: Elsevier Saunders; 2013:1-37.

2. Wiysonge CS, Bradley HA, Volmink J, Mayosi BM,Mbewu A, Opie LH. β-Blockers for hypertension.Cochrane Database Syst Rev. 2012;11:CD002003.

3. Mancia G, Fagard R, Narkiewicz K, et al; TaskForce Members. 2013 ESH/ESC guidelines for themanagement of arterial hypertension. J Hypertens.2013;31(7):1281-1357.

4. Lewin A, Punzi H, Luo X, Stapff M. Nebivololmonotherapy for patients with systolic stage IIhypertension. Clin Ther. 2013;35(2):142-152.

5. Vanhoutte PM, Gao Y. β-Blockers, nitric oxide,and cardiovascular disease. Curr Opin Pharmacol.2013;13(2):265-273.

6. Chobanian AV, Bakris GL, Black HR, et al. Theseventh report of the Joint National Committee onPrevention, Detection, Evaluation, and Treatmentof High Blood Pressure. JAMA.2003;289(19):2560-2572.

Figure. Associations of β-Blocker Therapy With All-Cause Mortality Among Patients With Hypertension vs Placebo, No Treatment, and Other Drugs

Favors

β-Blocker

Favors

Comparator

β-Blocker

Study

Compared with placebo or no treatment

Risk Ratio

(95% CI)

Events,

No.

Total No.

Participants

Comparator

Events,

No.

Total No.

Participants

IPPPSH, 1985 0.94 (0.73-1.22)108 3185 114 3172MRC, 1985 0.93 (0.75-1.15)120 4403 253 8654Coope, 1986 0.97 (0.70-1.33)60 419 69 465

167 1102 315 2213MRCOA, 1992 1.06 (0.90-1.27)455

β-Blocker

OxprenololPropranolol

PropranololPropranololPropranolol

Atenolol

Atenolol

AtenololAtenololAtenolol

Atenolol

Atenolol

Atenolol

Metoprolol

Metoprolol

Atenolol

Duration of

Study, y

4.04.94.45.8

10.01.04.93.85.8

4.13.82.75.5

8.44.14.8

9109 751 14 504Subtotal (I 2 = 0.0%, P = .77) 0.99 (0.88-1.11)

Compared with calcium channel blocker

AASK, 2002 1.44 (0.78-2.64)38 441 13 217ELSA, 2002 1.33 (0.65-2.73)17 1157 13 1177INVEST, 2003 1.02 (0.93-1.11)893 11 309 873 11 267

820 9618 738 9639ASCOT, 2005 1.11 (1.01-1.22)1768 22 525 1637 22 300Subtotal (I 2 = 2.2%, P = .38) 1.07 (1.00-1.14)

Compared with renin-angiotensin system inhibitor

UKPDS-39, 1998 0.70 (0.44-1.11)27 358 43 400AASK, 2002 1.30 (0.81-2.06)38 441 29 436LIFE, 2002 1.13 (0.99-1.29)431 4588 383 4605

496 5387 455 5441Subtotal (I 2 = 53.6%, P = .12) 1.10 (0.98-1.24)

Compared with diuretic

Berglund, 1981 1.25 (0.36-4.40)5 53 4 53VA COOP, 1982 1.01 (0.06-16.06)1 340 1 343MRC, 1985 0.91 (0.72-1.17)120 4403 128 4297

96 3297 101 3272HAPPHY, 1987 0.94 (0.72-1.24)167 1102 134 1081MRCOA, 1992 1.22 (0.99-1.51)389 9195 368 9046Subtotal (I 2 = 0.0%, P = .43) 1.04 (0.91-1.19)

5.01.00.3Risk Ratio (95% CI)

Source: Data have been adapted with permission from Wiley.2 The size of the data markers is proportional to the number of participants and deaths.

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