Elsevier

The Lancet

Volume 398, Issue 10305, 18–24 September 2021, Pages 1043-1052
The Lancet

Articles
Initial 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

https://doi.org/10.1016/S0140-6736(21)01922-XGet rights and content

Summary

Background

Treatment inertia is a recognised barrier to blood pressure control, and simpler, more effective treatment strategies are needed. We hypothesised that a hypertension management strategy starting with a single pill containing ultra-low-dose quadruple combination therapy would be more effective than a strategy of starting with monotherapy.

Methods

QUARTET was a multicentre, double-blind, parallel-group, randomised, phase 3 trial among Australian adults (≥18 years) with hypertension, who were untreated or receiving monotherapy. Participants were randomly assigned to either treatment, that started with the quadpill (containing irbesartan at 37·5 mg, amlodipine at 1·25 mg, indapamide at 0·625 mg, and bisoprolol at 2·5 mg) or an indistinguishable monotherapy control (irbesartan 150 mg). If blood pressure was not at target, additional medications could be added in both groups, starting with amlodipine at 5 mg. Participants were randomly assigned using an online central randomisation service. There was a 1:1 allocation, stratified by site. Allocation was masked to all participants and study team members (including investigators and those assessing outcomes) except the manufacturer of the investigational product and one unmasked statistician. The primary outcome was difference in unattended office systolic blood pressure at 12 weeks. Secondary outcomes included blood pressure control (standard office blood pressure <140/90 mm Hg), safety, and tolerability. A subgroup continued randomly assigned allocation to 12 months to assess long-term effects. Analyses were per intention to treat. This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry, ACTRN12616001144404, and is now complete.

Findings

From June 8, 2017, to Aug 31, 2020, 591 participants were recruited, with 743 assessed for eligibility, 152 ineligible or declined, 300 participants randomly assigned to intervention of initial quadpill treatment, and 291 to control of initial standard dose monotherapy treatment. The mean age of the 591 participants was 59 years (SD 12); 356 (60%) were male and 235 (40%) were female; 483 (82%) were White, 70 (12%) were Asian, and 38 (6%) reported as other ethnicity; and baseline mean unattended office blood pressure was 141 mm Hg (SD 13)/85 mm Hg (SD 10). By 12 weeks, 44 (15%) of 300 participants had additional blood pressure medications in the intervention group compared with 115 (40%) of 291 participants in the control group. Systolic blood pressure was lower by 6·9 mm Hg (95% CI 4·9–8·9; p<0·0001) and blood pressure control rates were higher in the intervention group (76%) versus control group (58%; relative risk [RR] 1·30, 95% CI 1·15–1·47; p<0·0001). There was no difference in adverse event-related treatment withdrawals at 12 weeks (intervention 4·0% vs control 2·4%; p=0·27). Among the 417 patients who continued, uptitration occurred more frequently among control participants than intervention participants (p<0·0001). However, at 52 weeks mean unattended systolic blood pressure remained lower by 7·7 mm Hg (95% CI 5·2–10·3) and blood pressure control rates higher in the intervention group (81%) versus control group (62%; RR 1·32, 95% CI 1·16–1·50). In all randomly assigned participants up to 12 weeks, there were seven (3%) serious adverse events in the intervention group and three (1%) serious adverse events in the control group.

Interpretation

A strategy with early treatment of a fixed-dose quadruple quarter-dose combination achieved and maintained greater blood pressure lowering compared with the common strategy of starting monotherapy. This trial demonstrated the efficacy, tolerability, and simplicity of a quadpill-based strategy.

Funding

National Health and Medical Research Council, Australia.

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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