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

Date Published: June 11, 2018

Publisher: Public Library of Science

Author(s): Amol A. Verma, Wayne Khuu, Mina Tadrous, Tara Gomes, Muhammad M. Mamdani, Anushka Patel

Abstract: BackgroundThe majority of people with hypertension require more than one medication to achieve blood pressure control. Many patients are prescribed multipill 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 multipill combination therapy in a real-world setting using linked clinical and administrative databases.Methods and findingsWe conducted a population-based retrospective cohort study of 13,350 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 (ACEI) or angiotensin II-receptor blocker (ARB) plus one thiazide diuretic. High-dimensional propensity score matching was used to compare individuals receiving FDC versus multipill therapy. The primary outcome was a composite of death or hospitalization for acute myocardial infarction (AMI), heart failure, or stroke. We conducted 2 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 19–98) than in the multipill group (42%, IQR 11–91, P < 0.01), and the primary outcome was less frequent in FDC recipients (3.4 versus 3.9 events per 100 person-years; HR 0.89, 95% CI 0.81–0.97, 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.ConclusionsAmong 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.

Partial Text: Hypertension affects an estimated 900 million adults [1] and is the leading cause of global death or disability [2]. Approximately 75% of people with hypertension require more than one medication to achieve blood pressure control [3]. Although many hypertension management guidelines recommend initiating combination treatment with either separate drugs in multipill combinations or single-pill fixed-dose combinations (FDCs) [4–6], only half of national hypertension societies recommend FDC treatment [7], which may be due to a lack of evidence about effect on clinical outcomes. Both FDC and multipill regimens are common in clinical practice. Studies in high-income countries report that 22% to 43% of patients receive multipill regimens when initiated on combination antihypertensive therapy [8,9].

Among older adults initiating antihypertensive therapy, FDC treatment was associated with a significantly lower risk of composite clinical outcomes compared with multipill treatment, which may be related to better medication adherence. In the on-treatment analysis, outcomes were similar among adults who were actively receiving treatment. However, the intention-to-treat analysis revealed meaningful differences between groups with respect to adherence, with 70% of total days covered during follow-up in the FDC group compared with 42% in the multipill group. This was associated with a significantly lower risk of composite clinical outcomes among the FDC treatment group, with an absolute difference of 0.5 fewer primary outcome events and 0.4 fewer deaths per 100 person-years of follow-up.



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