Individual patient data pooled analysis of randomised trials in Australia and United States assessing a quadruple combination single pill in patients with hypertension:results from the QUARTET studies

Abstract Background Hypertension is a major cause of premature death worldwide, and only one in five adults with hypertension have it under control. Two trials from Australia and the US suggest that a single quadpill containing a quarter dosage of an angiotensin receptor blocker, a calcium channel blocker, a diuretic and a beta blocker is effective in reducing blood pressure (BP) among patients with hypertension. Purpose In a pre-planned analysis of these two trials, we assessed the generalisability of observed benefits and two important barriers for BP control: clinician medication inertia and patient medication adherence. Methods Both QUARTET trials were randomised, multicentre, double-blinded trials in people with hypertension ≤1 medication, comparing a quadpill containing 37·5mg of irbesartan (2mg candesartan in US), 1·25mg of amlodipine, 0·625mg of indapamide, and 2·5mg of bisoprolol with initial monotherapy (150mg of irbesartan in Australia, 8mg of candesartan in US). The primary outcome was mean difference in unattended office systolic blood pressure (SBP) at 12 weeks, assessed by a linear mixed model with random effects for site and participant and fixed effects for treatment, visit (6 and 12 weeks), visit-by-treatment interaction and baseline SBP. Treatment effect heterogeneity was tested using an interaction between covariates and treatment. Results A total of 653 patients were randomised, 591 (91%) from the Australian and 62 (9%) from the US trial. Baseline BP was 141/85, mean age 58 years with 40% female. Up-titration occurred significantly more often in the control versus the quadpill arm (p0.001), especially in the US trial where it was mandated for uncontrolled BP at week 6 (53% vs 19%) compared to Australia (25% vs 7%) where it was recommended but left to site clinician decision. Adherence was high and similar across countries and treatment arms. The pooled individual participant data analysis showed a significant mean SBP difference at 12 weeks of 6.5mmHg (95% CI 4·8,8·8; p0·001) and lower DBP of 5.6mmHg (95% CI 4.5,6.9; p0.001) in favour of the quadpill, despite the higher rates of up titration in the control arm. There was no evidence the treatment effect varied by country, age, sex, body mass index, baseline BP, while there was some evidence of heterogeneity by self-identified ethnicity – SBP differences white: 6.9 (4.7,9.2), Hispanic: 3.3 (4.0,10.6), Asian: 12.3 (6.2, 18.5) and other: 1.4 (-9.0, 6.3), p=0.03. There was no evidence of a difference in serious adverse events between the control and quadpill arms (1% vs 3%, p=0.09). Conclusion This prospective individual participant data pooled analysis provides further evidence that the quadpill strategy is superior to usual care, with improved efficacy despite much lower up titration rates.