Quarter-dose combinations of antihypertensive meds appear safe, effective versus placebo, standard doses

Low-dose antihypertensive regimens could have a broader role in clinical practice, as they yield similar reductions in blood pressure but are better tolerated.


Quarter-dose combinations of antihypertensive medications appear to be safe and effective when compared with placebo and standard doses, according to a recent study.

Researchers performed a systematic review and meta-analysis of randomized controlled trials published through June 2016 that included at least one quarter-dose arm and one placebo and standard-dose monotherapy arm. Included trials needed to measure efficacy and safety data for at least one of the following classes of antihypertensive drugs: calcium-channel blockers, beta-blockers, angiotensin receptor II antagonists, angiotensin-converting enzyme inhibitors, and thiazide diuretics. They also needed to have a treatment and follow-up of at least two weeks; those that studied uptitration needed to include data on blood pressure or safety for two or more weeks before titration occurred.

The researchers assessed efficacy by using the mean absolute difference between the mean changes in systolic blood pressure and diastolic blood pressure from baseline until the end of the study. They defined safety as adverse events at follow-up and change in potassium and uric acid from baseline to follow-up. A fixed-effect model was used to pool data on blood pressure and adverse events. The study results were published online June 5 by Hypertension.

Overall, 42 trials with 20,284 patients were included in the study. Thirty-eight trials examined quarter-dose monotherapy, seven examined dual quarter-dose combination therapy, and two reported quadruple quarter-dose therapy, compared with placebo or a standard dose of each component. Average follow-up was seven weeks. Among 36 comparisons of quarter-dose regimens with placebo, blood pressure reduction was −4.7/−2.4 mm Hg, while among six comparisons of dual quarter-dose therapy and placebo, blood pressure reduction was −6.7/−4.4 mm Hg (P<0.001 for both). One study compared a quadruple quarter-dose regimen with placebo and found a blood pressure reduction of −22.4/−13.1 mm Hg (P<0.001). When quarter-dose therapy was compared with standard monotherapy, blood pressure differences were 3.7/2.6 mm Hg in 37 comparisons of single quarter-dose therapy, 1.3/−0.3 mm Hg in seven comparisons of dual quarter-dose therapy, and −13.1/−7.9 mm Hg in one trial of quadruple quarter-dose therapy. P values were less than 0.001 for single and quadruple quarter-dose therapy but nonsignificant for dual quarter-dose therapy. No trials compared triple quarter-dose therapy with placebo or with standard-dose monotherapy. Adverse event rates for single and dual quarter-dose therapy did not differ significantly from placebo and were significantly lower compared with standard-dose monotherapy.

The authors noted that trials in languages other than English were not included in their study, that some data were missing, and that individual-patient data were not used, among other limitations. However, they concluded that according to their results, low-dose antihypertensive regimens could have a broader role in clinical practice. In particular, they noted that dual quarter-dose therapy may be preferred to standard-dose monotherapy in some cases because it yielded similar reductions in blood pressure but was better tolerated. “Alternatively, addition of a single quarter-dose agent to existing therapy is likely to confer an extra 3 to 4 mmHg systolic blood pressure reduction without additional side effects and thus could be preferable to doubling the dose of the existing agent,” the authors wrote. They called for more research on the potential role of triple or quadruple quarter-dose combinations.

The authors of an accompanying editorial also pointed out the study's limitations and called for more research in this area but noted that quarter-dose regimens appear to lead to blood pressure values similar to those seen in previous randomized trials of full-dose regimens, including SPRINT. “[T]he quarter dose treatment strategy deserves to be mentioned among the therapeutic options that are characterized by a good therapeutic efficacy/tolerability balance, as future hypertension guidelines will likely discuss in their recommendations,” the editorialists wrote.