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. 2018 Jun 11;15(6):e1002584.
doi: 10.1371/journal.pmed.1002584. eCollection 2018 Jun.

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

Amol A Verma  1   2 , Wayne Khuu  3 , Mina Tadrous  3   4 , Tara Gomes  3   4   5 , Muhammad M Mamdani  3   4   5
Affiliations

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

Amol A Verma et al. PLoS Med. .

Abstract

Background: The 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 findings: We 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.

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.

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Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: MMM has served on the following advisory boards and reports personal fees from Bristol-Myers Squibb, Eli Lilly and Company, Glaxo Smith Kline, Hoffman La Roche, Novartis, Novo Nordisk, Pfizer, and Astra Zeneca, outside of the submitted work. All other authors have no competing interests to disclose.

Figures

Fig 1
Fig 1. Cohort creation diagram.
ACEI, angiotensin-converting enzyme inhibitor; AMI, acute myocardial infarction; ARB, angiotensin II-receptor blocker; ED, emergency department; FDC, single-pill fixed-dose combination; TIA, transient ischemic attack.
Fig 2
Fig 2. Survival estimates among individuals initiated on FDC versus multipill combination therapy.
Legend: Kaplan-Meier estimates of survival probability. FDC, single-pill fixed-dose combination.
See this image and copyright information in PMC

References

    1. Forouzanfar MH, Liu P, Roth GA, Ng M, Biryukov S, Marczak L, et al. Global Burden of Hypertension and Systolic Blood Pressure of at Least 110 to 115 mm Hg, 1990–2015. JAMA. 2017;317: 165–182. doi: 10.1001/jama.2016.19043 - DOI - PubMed
    1. Forouzanfar MH, Afshin A, Alexander LT, Anderson HR, Bhutta ZA, Biryukov S, et al. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388: 1659–1724. doi: 10.1016/S0140-6736(16)31679-8 - DOI - PMC - PubMed
    1. Gradman AH, Basile JN, Carter BL, Bakris GL. Combination therapy in hypertension. J Am Soc Hypertens. Elsevier Ltd; 2010;4: 90–98. doi: 10.1016/j.jash.2010.03.001 - DOI - PubMed
    1. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults. JAMA. 2014;311: 507 doi: 10.1001/jama.2013.284427 - DOI - PubMed
    1. Leung AA, Daskalopoulou SS, Dasgupta K, McBrien K, Butalia S, Zarnke KB, et al. Hypertension Canada’s 2017 Guidelines for Diagnosis, Risk Assessment, Prevention, and Treatment of Hypertension in Adults. Can J Cardiol. Elsevier Inc.; 2017;33: 557–576. doi: 10.1016/j.cjca.2017.03.005 - DOI - PubMed

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