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.