Combination Therapy Is Superior to Sequential Monotherapy for the Initial Treatment of Hypertension: A Double‐Blind Randomized Controlled Trial

Abstract

BackgroundGuidelines for hypertension vary in their preference for initial combination therapy or initial monotherapy, stratified by patient profile; therefore, we compared the efficacy and tolerability of these approaches.Methods and ResultsWe performed a 1‐year, double‐blind, randomized controlled trial in 605 untreated patients aged 18 to 79 years with systolic blood pressure (BP) ≥150 mm Hg or diastolic BP ≥95 mm Hg. In phase 1 (weeks 0–16), patients were randomly assigned to initial monotherapy (losartan 50–100 mg or hydrochlorothiazide 12.5–25 mg crossing over at 8 weeks), or initial combination (losartan 50–100 mg plus hydrochlorothiazide 12.5–25 mg). In phase 2 (weeks 17–32), all patients received losartan 100 mg and hydrochlorothiazide 12.5 to 25 mg. In phase 3 (weeks 33–52), amlodipine with or without doxazosin could be added to achieve target BP. Hierarchical primary outcomes were the difference from baseline in home systolic BP, averaged over phases 1 and 2 and, if significant, at 32 weeks. Secondary outcomes included adverse events, and difference in home systolic BP responses between tertiles of plasma renin. Home systolic BP after initial monotherapy fell 4.9 mm Hg (range: 3.7–6.0 mm Hg) less over 32 weeks (P<0.001) than after initial combination but caught up at 32 weeks (difference 1.2 mm Hg [range: −0.4 to 2.8 mm Hg], P=0.13). In phase 1, home systolic BP response to each monotherapy differed substantially between renin tertiles, whereas response to combination therapy was uniform and at least 5 mm Hg more than to monotherapy. There were no differences in withdrawals due to adverse events.ConclusionsInitial combination therapy can be recommended for patients with BP >150/95 mm Hg.Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00994617.

Modern antihypertensive therapy: the effectiveness of a unique Russian fixed-dose combination of ramipril and indapamide

“…Клинические рекомендации "Артериальная гипертензия у взрослых" 2019г всем пациентам с АГ (кроме пациентов низкого риска с АД <150/90 мм рт.ст., пациентов ≥80 лет, пациентов с синдромом старческой астении) в качестве стартовой терапии рекомендуют комбинацию антигипертензивных препаратов, предпочтительно, фиксированную комбинацию, для улучшения приверженности к терапии. Предпочтительные комбинации должны включать блокатор РААС (иАПФ или БРА) и диуретик или дигидропиридиновый АК [68][69][70][71][72]. Сложный вопрос выбора между комбинациями блокатора РААС с диуретиком или дигидропиридиновым АК можно решить назначением фиксированной комбинации рамиприла с индапамидом в силу наличия у индапамида прямого вазодилатирующего действия за счет блокирования медленных кальциевых каналов в гладкомышечных клетках сосудистой стенки, подобного дигидропиридиновым АК.…”

Latin American recommendations for the management of hypertension in adults (RELAHTA 2)

“…Existe evidencia de que la mayoría de los pacientes requerirán más de un fármaco para lograr los (61)(62)(63) objetivos de control de PA .…”

Initial Single‐Pill Blood Pressure–Lowering Therapy: Should It Be for Most People?

“…1 In this issue of JAHA, the efficacy of initial combination antihypertensive therapy versus either of its individual components to achieve a BP goal was assessed by MacDonald and colleagues. 16 They evaluated 605 untreated hypertensive patients in a double-blind, randomized, controlled trial to see if combination therapy with losartan plus hydrochlorothiazide would result in better BP control compared with the individual monotherapies. The authors evaluated differences from baseline in home systolic BP, averaged over different durations of the study.…”

“…18,19 The STITCH (Simplified Treatment Intervention to Control Hypertension) study supports the authors' findings of earlier achievement of BP targets with combination therapy. 20 STITCH used a cluster randomization of an initial single-pill combination, similar to MacDonald et al, 16 and compared it with the Canadian Hypertension Education Program guidelines monotherapy approach. The primary end point was the proportion of patients treated to <140/90 mm Hg at 6 months.…”

“…1,24 The authors assert that neither the STITCH trial nor the meta-analyses evaluating adverse events on combination therapy have changed practice patterns. MacDonald and colleagues 16 should appreciate, however, that most guidelines around the world advocate for initial combinations of BP-lowering therapies when BP is >20/10 mm Hg higher than the goal or ≥160/100 mm Hg. [25][26][27] In addition, initial single-pill combinations in hypertensive patients at high cardiovascular risk have demonstrated cardiovascular outcome benefits in randomized trials.…”