Quadruple vs triple therapy for resistant hypertension: the QUADRO trial

Background and Aims True resistant hypertension leads to higher rates of target-organ damage, cardiovascular morbidity, and mortality compared with general hypertension. Guidelines recommend adding a fourth drug to triple therapy if blood pressure (BP) remains uncontrolled. This Phase 3 trial aimed to demonstrate superior BP reduction with the first full-dose quadruple single-pill combination (SPC) vs triple antihypertensive therapy for uncontrolled BP. Methods QUADRO was a multicentre, Phase 3, randomized, controlled, double-blind trial in resistant hypertension. After an 8-week run-in period on perindopril/indapamide/amlodipine, participants were randomized 1:1 to quadruple SPC perindopril/indapamide/amlodipine/bisoprolol or continued the same triple therapy for 8 weeks. Efficacy assessments included office systolic BP (SBP) at Week 8 (primary outcome) and 24 h ambulatory BP monitoring (ABPM). The primary analysis examined all randomized patients with uncontrolled SBP; safety analyses included all patients who received at least one dose of study medication. This trial is registered under EudraCT No. 2020-004891-16. Results Overall, 183 patients (quadruple SPC, n = 89; triple therapy, n = 94) were randomized. After 8 weeks, decreases in office SBP [−8 mmHg; 95% confidence interval (CI): −11.99, −4.09; P < .0001] and 24 h-ABPM (−8 mmHg; 95% CI: −10.95, −4.11; P < .0001) were greater with quadruple SPC vs triple therapy. Both treatments were well tolerated; 10 participants (11%) receiving quadruple SPC and 8 (8%) receiving triple therapy had at least one treatment-emergent adverse event (TEAE), and no serious or severe TEAEs were reported. Conclusions The first full-dose quadruple antihypertensive SPC (perindopril/indapamide/amlodipine/bisoprolol) demonstrated superiority over perindopril/indapamide/amlodipine, offering an effective alternative therapy for confirmed resistant hypertension.