First-line combination therapy versus first-line monotherapy for primary hypertension

Abstract

This is the first update of a review originally published in 2017. Starting with one drug and starting with a combination of two drugs are strategies suggested in clinical guidelines as initial treatment of hypertension. The recommendations are not based on evidence about clinically relevant outcomes. Some antihypertensive combinations have been shown to be harmful. The actual harm‐to‐benefit balance of each strategy is unknown. To determine if there are differences in clinical outcomes between monotherapy and combination therapy as initial treatment for primary hypertension. The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to April 2019: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 2005), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We used no language restrictions. We also searched clinical studies repositories of pharmaceutical companies, reviews of combination drugs on the US Food and Drug Administration and European Medicines Agency websites, and lists of references in reviews and clinical practice guidelines. We included randomised, double‐blind trials with at least 12 months' follow‐up in adults with primary hypertension (systolic blood pressure/diastolic blood pressure 140/90 mmHg or higher, or 130/80 mmHg or higher if participants had diabetes), which compared combination of two first‐line antihypertensive drugs with monotherapy as initial treatment. Trials had to include at least 50 participants per group and report mortality, cardiovascular mortality, cardiovascular events, or serious adverse events. Two review authors independently selected trials for inclusion, evaluated the risk of bias, and performed data entry. The primary outcomes were mortality, serious adverse events, cardiovascular events, and cardiovascular mortality. Secondary outcomes were withdrawals due to drug‐related adverse effects, reaching blood pressure control (as defined in each trial), and blood pressure change from baseline. Analyses were based on the intention‐to‐treat principle. We summarised data on dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CI). 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. Beginning treatment of hypertension with one medicine versus with a combination of two medicines Background This is the first update of a review originally published in 2017. Hypertension (high blood pressure) is a long‐term condition that increases the risk of health problems such as heart attack, stroke, or kidney disease. Several types of medicines are used to treat hypertension. It is frequently the case that over time a person with hypertension will need more than one type of medicine to control their blood pressure. A doctor prescribing medicines to reduce the blood pressure for the first time in a patient has two options: using only one medicine (monotherapy) or using two medicines (combination therapy). Combination therapy can be in the same tablet or in different tablets. The potential advantage of using combination therapy is that blood pressure may fall faster, however it is unclear if this is better or worse in terms of avoiding health problems. Study characteristics 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. Key results and certainty of the evidence 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.