| Summary: | There is a critical need for blood pressure lowering strategies that have greater efficacy and minimal side effects. Low-dose combinations hold promise in this regard, but there are few data on very low dose therapy. We therefore conducted a systematic review and meta-analysis of randomised controlled trials with at least one quarter-dose and one placebo and/or standard dose monotherapy arm. A search was conducted of Medline, Embase, Cochrane Registry, Food and Drug Administration and European Medicinal Agency websites. Data on blood pressure and adverse events were pooled using a fixed-effect model and bias was assessed using Cochrane risk of bias. The review included 42 trials involving 20,284 participants. Thirty six comparisons evaluated quarter-dose with placebo and indicated a blood pressure reduction of -4.7/ -2.4 mmHg (p<0.001). Six comparisons were of dual quarter-dose therapy vs. placebo, observing a -6.7/ -4.4 mmHg (p<0.001) blood pressure reduction. There were no trials of triple quarter-dose combination vs. placebo but one quadruple quarter-dose study observed a blood pressure reduction of -22.4/ -13.1 mmHg vs. placebo (p<0.001). Compared to standard dose monotherapy, the blood pressure differences achieved by single (37 comparisons), dual (7 comparisons) and quadruple (1 trial) quarter dose combinations were +3.7/+2.6 (p<0.001), +1.3/-0.3 (NS) and -13.1/-7.9 (p<0.001) mmHg respectively. In terms of adverse events, single and dual quarter-dose therapy was not significantly different from placebo and had significantly fewer adverse events compared to standard dose monotherapy. Quarter dose combinations could provide improvements in efficacy and tolerability of blood pressure lowering therapy.
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