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Fixed-dose combination antihypertensive medications, adherence, and clinical outcomes: a population-based retrospective cohort study


Background — The majority of people with hypertension require more than one medication to achieve blood pressure control. Many patients are prescribed multi-pill antihypertensive regimens rather than single-pill fixed-dose combination (FDC) treatment. Although FDC use may improve medication adherence, the impact on patient outcomes is unclear. We compared clinical outcomes and medication adherence with FDC therapy versus multi-pill combination therapy in a real-world setting using linked clinical and administrative databases.

Methods and Findings — We conducted a population-based retrospective cohort study of 13,350 28 individuals 66 years and older in Ontario, Canada with up to 5 years of follow-up. We included individuals who were newly initiated on one angiotensin-converting-enzyme inhibitor or angiotensin II-receptor blocker plus one thiazide diuretic. High dimensional propensity score matching was used to compare individuals receiving FDC versus multi-pill therapy. The primary outcome was a composite of death or hospitalization for acute myocardial infarction, heart failure, or stroke. We conducted two analyses to examine the association between adherence and patient outcomes. First, we performed an on-treatment analysis to determine whether outcomes differed between groups while patients were on treatment, censoring patients when they first discontinued treatment, defined as not receiving medications within 150% of the previous days’ supply. Second, we conducted an intention-to-treat analysis that followed individuals allowing for breaks in treatment to quantify the difference in drug adherence between groups and assess its impact on clinical outcomes. As expected, there was no significant difference in the primary outcome between groups in the on-treatment analysis (HR 1.06, 95% CI: 0.86-1.31, p=0.60). In the intention-to-treat analysis, the proportion of total follow-up days covered with medications was significantly greater in the FDC group (70%, IQR: 19 to 98) than in the multi-pill group (42%, IQR: 11 to 91, p<0.01), and the primary outcome was less frequent in FDC recipients (3.4 44 vs 3.9 events per 100 person-years, HR 0.89, 95% CI: 0.81 to 0.97, p<0.01). The main limitations of this study were the lack of data regarding cause of death and blood pressure measurements and the possibility of residual confounding.

Conclusions — Among older adults initiating combination antihypertensive treatment, FDC therapy was associated with a significantly lower risk of composite clinical outcomes, which may be related to better medication adherence.



Verma AA, Khuu W, Tadrous M, Gomes T, Mamdani MM. PLoS Med. 2018; 15(6):e1002584. Epub 2018 Jun 11.

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