Comparison of 3 Dual Single-Pill Combinations for Blood Pressure Lowering: A Secondary Analysis of an International Randomized Trial

Abstract

Recent clinical practice guidelines recommend dual low-dose single-pill combination therapy for initial treatment of hypertension, given the improvements in efficacy, adherence, and reduction in therapeutic inertia that they impart without compromising tolerability.1 However, randomized comparisons between different dual single-pill combinations are limited. We therefore report the comparative efficacy of 3 dual combinations, each containing 2 of the major antihypertensive drug classes: an angiotensin receptor blocker (telmisartan), a dihydropyridine calcium channel blocker (amlodipine), and a thiazide-like diuretic (indapamide). This analysis was embedded in a previously reported trial in 7 countries.2 Ethics approval was obtained in each country; all participants provided informed consent. After a 4-week single-blind run-in with low-dose triple therapy (20 mg of telmisartan, 2.5 mg of amlodipine, and 1.25 mg of indapamide), participants were randomized to triple therapy or one of its 3 dual combinations at the same doses as the triple therapy: telmisartan-indapamide (TI), telmisartan-amlodipine (TA), or amlodipine-indapamide (AI). After 6 weeks, doses were doubled unless contraindicated. The primary efficacy outcome was change in mean home systolic blood pressure (BP) from randomization to week 12, analyzed using hierarchical linear modeling with final systolic BP (SBP) as the model outcome and controlling for baseline SBP, treatment arm, and visit. Huber-White sandwich estimation and covariance matrices accounted for clustering within patient and site. The primary safety outcome was treatment withdrawal attributable to adverse events. Because the parent trial was designed to compare triple therapy with each dual therapy, dual-versus-dual comparisons should be interpreted as exploratory (Trial registration: NCT04518293). Documentation around the analyses presented here will be made available to qualified scientific and medical researchers, upon researcher’s request, as necessary for conducting legitimate research. Patient data will be deidentified and will be shared via a secure means. Requests for data will only be reviewed after approval of the product in the United States and the European Union, and after approval by George Medicines of its data access request and receipt of its executed data sharing agreement. A request form can be obtained by email to the corresponding author or to info@georgemedicines. com. After the 4-week run, 834 participants with an SBP 110 to 154 mm Hg were randomized to dual therapy, with similar baseline characteristics across groups