Monotherapy vs combination treatments of different complexity: a meta-analysis of blood pressure lowering randomized outcome trials

Use of drug combinations is recommended by hypertension guidelines for most patients because of the greater blood pressure (BP)-lowering effect compared with monotherapy. However, no evidence is available on outcome benefits of treatment strategies based on drug combinations vs. simpler treatment regimens, using data from randomized clinical trials (RCTs). We evaluated drug combination therapies of different complexity. Electronic databases were searched for BP-lowering RCTs that compared combination treatment or monotherapy vs. placebo, no-treatment or less-complex treatment. Combination treatment was considered as follows: background treatment continued during follow-up on top of the trial drug(s) of interest and drug(s) were added to the initial drug(s) of interest in the majority of the patients. Monotherapy was considered whenever pre-randomization treatment was withdrawn or absent and a single drug was administered at randomization. Complexity of treatment indicates the higher averaged number of daily medications used in the eligible RCTs. We selected 93 trials (290 304 patients; follow-up, 3.9 years). The on-treatment mean number of drugs was 2.10 and 0.99 in the more and less actively treated patients, respectively. Compared with placebo, no-treatment or less-complex treatment, combination treatments of any complexity (mean number of drugs, 1.40 vs. 0.41, 2.32 vs. 0.48, 2.56 vs. 1.62 and 3.14 vs. 2.19) were associated with reduction of all or most fatal and nonfatal outcomes. There was also an increased rate of side effects leading to treatment discontinuation, although in absolute numbers the benefit usually prevailed. These data provide randomized-based trial evidence that antihypertensive combination treatment up to three or more drugs is protective. The net benefit, however, may be attenuated when side effects are considered.