ArticlesInitial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose monotherapy in patients with hypertension (QUARTET): a phase 3, randomised, double-blind, active-controlled trial
Introduction
High blood pressure remains the leading modifiable cause of disease burden globally.1 Even in countries where blood pressure-lowering medications are available and affordable, many—if not most—treated individuals do not achieve blood pressure control.2 Still, by far the most common approach to hypertension management globally is to start patients on monotherapy. Although multiple medications are usually required to achieve blood pressure control, treatment inertia and concerns regarding adverse events are common barriers to the effective use of multiple medications, resulting in persistent monotherapy for many patients with hypertension.
Low-dose, single-pill combinations hold considerable promise to help overcome these barriers.3, 4 Dose-response studies of individual agents indicate most benefits are achieved and most side-effects avoided at low doses.3, 5 The quadpill concept describes that of a single pill combining four types of blood pressure-lowering medications, with each medicine included at a quarter of the standard dose for hypertension.5 Previous small short-term studies suggested the quadpill had better blood pressure-lowering efficacy than standard dose monotherapy,6 and large benefits compared with placebo.4 A larger trial testing triple half dose7 against usual care in Sri Lanka also provided promising results but was open label, so could not provide blinded assessment of comparative tolerability and also did not have long-term follow-up to assess whether these initial benefits were sustained.8 This quadruple ultra-low-dose treatment for hypertension (QUARTET) trial was designed to examine the potential of a simple and scalable hypertension management strategy, which might address multiple barriers to hypertension control, including treatment inertia and concerns about adverse events.
The primary objective of QUARTET was to determine whether hypertension management starting with a single pill containing quarter-standard doses of four types of blood pressure-lowering medicines (ie, the quadpill) is more effective than an approach that starts with standard dose monotherapy. Our secondary aims were to assess the tolerability and safety of this approach, and the long-term durability of blood pressure control in an extended analysis.
Section snippets
Study design
QUARTET was a multicentre, parallel-group, active control, double-blind, randomised, controlled, phase 3 trial of patients with high blood pressure. The primary outcome assessment was at 12 weeks and a subgroup continued follow-up to 12 months to examine long-term efficacy and tolerability. Patients were recruited from ten primary care centres and hospital outpatient clinics in four states of Australia (ie, NSW, TAS, VIC, and WA). The Western Sydney Local Health District Human Research Ethics
Results
From June 8, 2017, to August 31, 2020, 591 participants were recruited, with 743 assessed for eligibility, 152 ineligible or declined, and 300 randomly assigned to intervention of initial quadpill treatment and 291 to control of initial standard dose monotherapy treatment. Of the 591 randomly assigned to quadpill or control, 271 (90%) of 300 intervention participants and 272 (93%) of 291 control participants had complete primary outcome data at 12 weeks (figure 1).
The mean age of the 591
Discussion
This trial showed that a strategy of starting with quarter-dose quadruple combination therapy achieved and maintained blood pressure control more effectively than starting with standard dose monotherapy. The study used a range of blood pressure measurement methods, including the method most used in clinic settings, and a consistent treatment effect was seen. There were no differences in rates of severe adverse events or adverse event-related treatment discontinuations between the two approaches.
Data sharing
De-identified participant data will be made available to researchers 1 year after the publication date of the Article. Data shared will include individual participant data that underlie the results reported in this Article, after de-identification. The study protocol and statistical analysis plan will be available. Access will be via application with a study proposal to the study steering committee via the chair (the corresponding author of this Article). Data will only be shared with the
Declaration of interests
The George Institute for Global Health (TGI) has submitted patent applications with respect to low fixed-dose combination products for the treatment of cardiovascular or cardiometabolic disease. AR and CKC are listed as inventors. AR is employed by TGI and seconded part-time to George Medicines (GM). George Health Enterprises (GHE) and its subsidiary, GM, have received investment funds to develop fixed-dose combination products, including combinations of blood pressure-lowering drugs. GHE is
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