Clinical research study
Combination Therapy Versus Monotherapy in Reducing Blood Pressure: Meta-analysis on 11,000 Participants from 42 Trials

https://doi.org/10.1016/j.amjmed.2008.09.038Get rights and content

Abstract

Objective

To quantify the incremental effect of combining blood pressure-lowering drugs from any 2 classes of thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers over 1 drug alone and to compare the effects of combining drugs with doubling dose.

Methods

Meta-analysis of factorial trials in which participants were randomly allocated to 1 drug alone, another drug alone, both drugs together, or a placebo.

Results

We identified 42 trials (10,968 participants). With a thiazide used alone, the mean placebo-subtracted reduction in systolic blood pressure was 7.3 mm Hg and 14.6 mm Hg combined with a drug from another class. The corresponding reductions were 9.3 mm Hg and 18.9 mm Hg with a beta-blocker, 6.8 mm Hg and 13.9 mm Hg with an angiotensin-converting enzyme, and 8.4 mm Hg and 14.3 mm Hg with a calcium channel blocker. The expected blood pressure reduction from 2 drugs together, assuming an additive effect, closely predicted the observed blood pressure reductions. The ratios of the observed to expected incremental blood pressure reductions from combining each class of drug with any other over that from 1 drug were, respectively, for thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers: 1.04 (95% confidence interval [CI], 0.88-1.20), 1.00 (95% CI, 0.76-1.24), 1.16 (95% CI, 0.93-1.39), and 0.89 (95% CI, 0.69-1.09); the overall average was 1.01 (95% CI, 0.90-1.12). Comparison of our results with those of a published meta-analysis of different doses of the same drug showed that doubling the dose of 1 drug had approximately one fifth of the equivalent incremental effect (0.22 [95% CI, 0.19-0.25]).

Conclusion

Blood pressure reduction from combining drugs from these 4 classes can be predicted on the basis of additive effects. The extra blood pressure reduction from combining drugs from 2 different classes is approximately 5 times greater than doubling the dose of 1 drug.

Section snippets

Materials and Methods

Randomized trials using a factorial design were identified using a search of Medline, Cochrane Collaboration, and EMBASE databases in English from 1966 to March 2008. We used generic and trade names of all drugs in the 4 classes, thiazide, beta-blocker, ACE inhibitor, and calcium channel blocker taken from reference pharmacopoeias as key or text words and combined them in pairs. The resulting citations were limited to those of Medline publication type “clinical trial” or “randomized-controlled

Results

Table 1 shows details of the 42 randomized factorial trials included, involving 101 comparisons between pairs of drugs (some trials compared 2 drugs in different doses) and 10,698 participants (10,333 in parallel group design trials and 365 in crossover trials). All but 1 trial (conducted in general practice) recruited patients attending hospital outpatient hypertension clinics, generally without a history of coronary heart disease, stroke, diabetes, or renal disease. In the individual trials,

Discussion

The results from this meta-analysis show that for each of the 4 classes of blood pressure-lowering drug considered, the blood pressure reduction from each class of drug combined with 1 from another class is approximately additive. The additional effect of combining given doses of 2 classes of drug is approximately 5 times more effective than doubling the dose of 1 drug.

The incremental effect of an additional drug was expressed as the ratio of the observed to expected extra blood pressure

Conclusions

Combining blood pressure-lowering drugs from different classes is approximately 5 times more effective than doubling the dose of 1 drug. It follows that to maximize efficacy combination therapy, preferably using low doses to minimize side effects, is substantially better than monotherapy and should be considered as routine initial therapy.

Acknowledgments

We thank Andrew Archbold, Jan Mackie, and Mark Caulfield for comments on drafts of this article.

References (63)

  • M. Kochar et al.

    Matrix study of irbesartan with hydrochlorothiazide in mild-to-moderate hypertension

    Am J Hypertens

    (1999)
  • S.G. Chrysant et al.

    The Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High Blood Pressure: COACH, a randomized, double-blind, placebo-controlled, 8-week factorial efficacy and safety study

    Clin Ther

    (2008)
  • L. Hansson et al.

    Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial

    Lancet

    (1998)
  • R.W. Schrier et al.

    Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes (the second Appropriate Blood Pressure Control in Diabetes (ABCD) trial)

    Kidney Int

    (2002)
  • B. Williams et al.

    Guidelines for the management of hypertension: report of the fourth working party of the British Hypertension Society, 2004 – BHSIV

    J Hum Hypertens

    (2004)
  • CG18 Hypertension (persistently high blood pressure) in adults—NICE guideline. Available at:...
  • A.V. Chobanian et al.

    The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood PressureThe JNC 7 Report

    JAMA

    (2003)
  • Guidelines for the Management of Arterial Hypertension

    J Hypertens

    (2007)
  • M.R. Law et al.

    Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials

    BMJ

    (2003)
  • W.H. Frishman et al.

    A multifactorial trial design to assess combination therapy in hypertension

    Arch Intern Med

    (1994)
  • M. Moser et al.

    Low-dose combination therapy in hypertension

    Am Fam Physician

    (1997)
  • A. Fretheim et al.

    International variation in prescribing antihypertensive drugs: its extent and possible explanations

    BMC Health Serv Res

    (2005)
  • D.N. Bateman et al.

    Atenolol and chlorthalidone in combination for hypertension

    Br J Clin Pharmacol

    (1979)
  • J.P. Chalmers et al.

    Double-blind factorial trial of prindolol and hydrochlorothiazide in hypertension

    Med J Aust

    (1976)
  • J.P. Chalmers et al.

    Effects of once daily indapamide and pindolol on blood pressure, plasma aldosterone concentration and plasma renin activity in a general practice setting

    Eur J Clin Pharmacol

    (1982)
  • S.G. Chrysant et al.

    Antihypertensive and metabolic effects of single and combined atenolol regimens

    J Clin Pharmacol

    (1992)
  • L.A. Durel et al.

    Effectiveness of antihypertensive medications in office and ambulatory settings: a placebo-controlled comparison of atenolol, metoprolol, chlorthalidone, verapamil, and an atenolol-chlorthalidone combination

    J Clin Pharmacol

    (1992)
  • T.M. Erwteman et al.

    b Blockade, diuretics, and salt restriction for the management of mild hypertension: a randomised double blind trial

    BMJ

    (1984)
  • W.H. Frishman et al.

    First-line therapy option with low-dose bisoprolol fumarate and low-dose hydrochlorothiazide in patients with stage I and stage II systemic hypertension

    J Clin Pharmacol

    (1995)
  • Y. Lacourcière et al.

    Placebo-controlled comparison of the effects of nebivolol and low-dose hydrochlorothiazide as monotherapies and in combination on blood pressure and lipid profile in hypertensive patients

    J Hum Hypertens

    (1994)
  • P.K. Zachariah et al.

    Low-dose bisoprolol/hydrochlorothiazide: an option in first-line, antihypertensive treatment

    Clin Ther

    (1993)
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    Funding: None.

    Conflict of Interest: Nicholas J. Wald and Malcolm Law hold patents (EU1272220 and GB2361186) for a combination pill for the prevention of cardiovascular disease (Polypill) and together with David Wald have interests in its development.

    Authorship: All authors had access to the data and played a role in writing this manuscript.

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