Abstract: This update included one new study in which a subgroup of participants met our inclusion criteria. As none of the four included studies focused solely on people initiating antihypertensive treatment, we asked investigators for data for this subgroup. One study (PREVER-treatment 2016) used a combination of thiazide-type diuretic/potassium-sparing diuretic; as the former is not indicated in monotherapy, we analysed this study separately. The three original trials in the main comparison (monotherapy: 335 participants; combination therapy: 233 participants) included outpatients, mostly European and white people. Two trials only included people with type 2 diabetes; the remaining trial excluded people treated with diabetes, hypocholesterolaemia, or cardiovascular drugs. The follow-up was 12 months in two trials and 36 months in one trial. It is very uncertain whether combination therapy versus monotherapy reduces total mortality (RR 1.35, 95% CI 0.08 to 21.72), cardiovascular mortality (zero events reported), cardiovascular events (RR 0.98, 95% CI 0.22 to 4.41), serious adverse events (RR 0.77, 95% CI 0.31 to 1.92), or withdrawals due to adverse effects (RR 0.85, 95% CI 0.53 to 1.35); all outcomes had 568 participants, and the evidence was rated as of very low certainty due to serious imprecision and for using a subgroup that was not defined in advance. The confidence intervals were extremely wide for all important outcomes and included both appreciable harm and benefit. The PREVER-treatment 2016 trial, which used a combination therapy with potassium-sparing diuretic (monotherapy: 84 participants; combination therapy: 116 participants), included outpatients. This trial was conducted in Brazil and had a follow-up of 18 months. The number of events was very low and confidence intervals very wide, with zero events reported for cardiovascular mortality and withdrawals due to adverse events. It is very uncertain if there are differences in clinical outcomes between monotherapy and combination therapy in this trial. The numbers of included participants, and hence the number of events, were too small to draw any conclusion about the relative efficacy of monotherapy versus combination therapy as initial treatment for primary hypertension. There is a need for large clinical trials that address the review question and report clinically relevant endpoints.

Plain-language summary: We searched for clinical studies that compared starting treatment of hypertension in adults with monotherapy versus starting with combination therapy. Studies had to report results in terms of deaths, events due to diseases of the heart or the vessels (heart attack, stroke, or heart failure), deaths due to diseases of the heart or the vessels, or any health-related serious side effects. We only selected studies with 50 or more people per group and that lasted at least 12 months. The evidence is current to April 2019. In this update we included one new study, for a total of four studies in the review involving 349 people treated with combination therapy and 419 treated with monotherapy. However, data were insufficient to answer our review question. There is a need for more and larger studies that compare monotherapy with combination therapy as the initial treatment of hypertension.