Improved hypertension control with quarter-dose combinations of BP-lowering agents

17-7-2017 • Bennett A, et al.

Efficacy and Safety of Quarter-Dose Blood Pressure–Lowering Agents

A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Bennett A, Chow CK, Chou M, et al.
Hypertension. 2017;70:85-93.

Introduction and Methods

Control of hypertension is suboptimal, since only 1 in 3 individuals on treatment achieve their blood pressure (BP) targets [1,2]. Studies suggest that low-dose combinations of antihypertensive medications may provide the best balance between side effects and BP reduction, because at low doses most side effects are avoided and most benefit is realized, which may be particularly true for combinations containing quarter doses of several BP-lowering agents [3-5].
In this systematic review of randomized trials, the potential clinical role of quarter-dose monotherapy and combination therapy was assessed. For this, randomized controlled trials (either parallel or crossover) with a treatment and follow-up of at least two weeks were included in the analysis, only if there were efficacy or safety data that were measured for at least 1 of the 5 major classes of BP–lowering medications: calcium channel blockers, β-blockers, ARBs, ACEis, and thiazide diuretics. Studies were only considered when at least one arm was allocated quarter-dose therapy (with one or multiple agents) and at least one arm allocated placebo or standard-dose monotherapy. Up-titration studies must have had BP or safety data for at least the first two weeks before titration occurred.

Main results

  • A total of 42 studies were included in the meta-analysis, with 20,284 participants who had a mean age of 54 years and a mean baseline BP of 154/101 mmHg.
  • The efficacy in BP-lowering of single quarter-dose therapy versus placebo, which was assessed in 4721 participants in 36 trials, showed that single quarter-dose therapy reduced systolic BP (SBP) by −4.7 (95% CI −5.4 to −3.9) and diastolic (DBP) by −2.4 mmHg (95% CI −2.8 to −1.9).
  • Dual quarter-dose combination caused an overall SBP drop of −6.7 (95% CI −8.6 to −4.8) and a DBP reduction of −4.4 mmHg (95% CI −5.5 to −3.3).
  • No studies measured triple quarter-dose therapy versus placebo.
  • One study measured efficacy of quadruple quarter-dose therapy versus placebo and showed an office SBP reduction of −22.4 (95% CI −28.3 to −16.5) and DBP reduction of −13.1 (95% CI −17.3 to −8.8).
  • Single quarter-dose therapy was less efficacious than standard-dose monotherapy, dual quarter-dose therapy showed an equivalent BP–lowering effect compared with standard-dose monotherapy, and quadruple quarter-dose therapy versus standard-dose monotherapy showed a substantially greater BP-reduction in the quarter-dose group of SBP −13.1 (95% CI −20.1 to −6.1) and DBP −7.9 mmHg (95% CI −12.1 to −3.7).
  • Compared with placebo, there was no significant difference in risk of adverse events in single quarter-dose comparisons or dual quarter-dose comparisons, or the quadruple quarter-dose placebo comparison.
  • No individual medication class was associated with a greater risk of adverse events compared with placebo.
  • Single and dual quarter-dose therapies produced significantly fewer adverse events compared with standard-dose monotherapy.


In a meta-analysis of 42 randomized studies, dual quarter-dose combinations of BP-lowering agents were as effective as standard-dose monotherapy with fewer side effects. Moreover, a quadruple quarter-dose combination treatment was twice as efficacious as standard-dose monotherapy. Quarter-dose combinations could improve the efficacy and tolerability of BP–lowering therapy.

Editorial comment [6]

In their editorial article [6], Grassi and Mancia emphasize the unmet medical need for more effective BP-lowering therapies: ‘…BP control may not be easily achievable even when optimal treatment is used, as exemplified by the frequent inability to meet this goal also in randomized trials despite large use of combination treatment and environmental conditions that minimize therapeutic inertia and maximize treatment adherence.’
They also discuss the limitations of the meta-analysis of Bennet et al:
  • the quadruple quarter dose combination treatment results are based on a single study with a small sample size
  • the on-treatment duration was on average short
  • there are no data on the effects of a quarter dose triple combination
The authors conclude: ‘Finally, it would be important to expand the information provided by the meta-analysis of Bennett et al to ambulatory or home BP to see whether the remarkable ability of the quarter dose combination treatment to lower BP is consistent over the 24 hours or the low dose attenuates the effect at times farther from the drug administration or in conditions in which treatment has to successfully oppose the effect of pressure influences. These limitations, however, do not detract from the interest of the study data and their favourable clinical implications.’
Find this article online at Hypertension


1. Kotseva K, Wood D, De Backer G, et al; EUROASPIRE Study Group. Cardiovascular prevention guidelines in daily practice: a comparison of EUROASPIRE I, II, and III surveys in eight European countries. Lancet. 2009;373:929–940.
2. Chow CK, Teo KK, Rangarajan S, et al; PURE (Prospective Urban Rural Epidemiology) Study investigators. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-,and low-income countries. JAMA. 2013;310:959–968.
3. Law MR, Wald NJ, Morris JK, et al. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003;326:1427.
4. Mahmud A, Feely J. Low-dose quadruple antihypertensive combination: more efficacious than individual agents–a preliminary report. Hypertension. 2007;49:272–275.
5. Chow CK, Thakkar J, Bennett A, et al. Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review. Lancet. 2017;389:1035–1042.
6. Grassi G, Mancia G. Quarter Dose Combination Therapy Good News for Blood Pressure Control. Hypertension 2017;70:32-34.

bp-loweringhypertensionquarter dose

Upcoming meetings

Meeting reports & resources

EPCCS 2017 Report of the Cardiovascular Summit held in Dublin, Ireland
EPCCS Guidance Documents Evidence- and meeting-based guidance for primary care
EPCCS 2015 Report of 8th Annual EPCCS meeting held in Prague.
EPCCS 2014 Report of 7th Annual EPCCS meeting held in Brussels.
All meeting reports...