OUTCOMES RESEARCH IN REVIEW
Fixed-Dose Combination Pills Enhance Adherence and Persistence to Antihypertensive Medications
Lauffenburger JC, Landon JE, Fischer MA. Effect of combination therapy on adherence among US patients initiating therapy for hypertension: a cohort study. J Gen Intern Med 2017;32:619–25.
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Objective. To evaluate long-term adherence to antihypertensive therapy among patients on fixed-dose combination medication as well as antihypertensive monotherapy; and to identify demographic and clinical risk factors associated with selection of and adherence and persistence to antihypertensive medication therapy.
Design. Retrospective cohort study using claims data from a large nationwide insurer.
Setting and participants. The study population included patients older than age 18 who initiated antihypertensive medication between 1 January 2009 and 31 December 2012 and who were continually enrolled at least 180 days before and 365 days after the index date, defined as the date of initiation of antihypertensive therapy. Patients were excluded from the study if they had previously filled any antihypertensive medication at any time prior to the index date. Patients were categorized based on the number and type of antihypertensive medications (fixed-dose combination, defined as a single pill containing multiple medications; multi-pill combination, defined as 2 or more distinct antihypertensive tablets or capsules; or single therapy, defined as only 1 medication) using National Drug Codes (NDC). Study authors also measured patient baseline characteristics, such as age, region, gender, diagnoses as defined by ICD-9 codes, patient utilization characteristics (both outpatient visits and hospitalizations) and characteristics of the initiated medication, including patient copayment and number of days of medication supplied.
Main outcome measures. The primary outcome of inte-rest was persistence, defined as having supply for any antihypertensive medication that overlapped with the 365th day after initiation (index date), whether the initiated medication or other antihypertensive. Additional outcomes included adherence to at least 1 antihypertensive in the 12 months after initiation and refilling at least 1 antihypertensive medication. To determine adherence, the study authors calculated the proportion of days the patient had any antihypertensive available to them (proportion of days covered; PDC). PDC > 80% to at least 1 antihypertensive in the 12 months after initiation was defined as “fully adherent.”
Statistical analysis utilized modified multivariable Poisson regression models and sensitivity analyses were performed. The main study comparisons focused on patients initiating fixed-dose combination therapy and monotherapy because these groups were more comparable in terms of baseline characteristics and medications initiated than the multi-pill combination group.
Main results. The study sample consisted of 484,493 patients who initiated an oral antihypertensive, including 78,958 patient initiating fixed-dose combinations, 380,269 filled a single therapy, and 22,266 who initiated multi-pill combinations. The most frequently initiated fixed-dose combination was lisinopril-hydrochlorothiazide. Lisinopril, hydrochlorothiazide, and amlodipine with the most frequently initiated monotherapy. The mean age of the study population was 47.2 years and 51.8% were women. Patients initiating multiple pill combinations were older (mean age 52.5) and tended to be sicker with more comorbidities than fixed-dose combinations or monotherapy. Patients initiating fixed-dose combination had higher prescription copayments than patients using single medication (prescription copay $14.4 versus $9.6). Patients initiating fixed-dose combinations were 9% more likely to be persistent (relative risk [RR] 1.09, 95% CI 1.08–1.10) and 13% more likely to be adherent (RR 1.13, 95% CI 1.11–1.14) than those who started on a monotherapy. Refill rates were also slightly higher among fixed-dose combination initiators (RR 1.06, 95% CI 1.05-1.07).
Conclusion. Compared with monotherapy, fixed-dose combination therapy appears to improve adherence and persistence to antihypertensive medications.
Approximately half of US of individuals with diagnosed hypertension obtain control of their condition based on currently defined targets . The most effective approach to blood pressure management has been controversial. The JNC8  guidelines liberalized blood pressure targets, while recent results from the SPRINT (systolic blood pressure intervention trial)  indicates that lower blood pressure targets are able to prevent hypertension-related complications without significant additional risk. Given these conflicts, there is clearly ambiguity in the most effective approach to initiating antihypertensive treatment. Prior studies have shown that fewer than 50% of patients continue to take their medications just 12 months after initiation [4,5].
Fixed-dose combination therapy for blood pressure management has been cited as better for adherence and is now making its way into clinical guidelines [6–8]. However, it should be noted that fixed-dose combination therapy for blood pressure management limits dosing flexibility. Dose titration may be needed, potentially leading to additional prescriptions, thus potentially complicating the drug regimen and adding additional cost. Complicating matters further, quality metrics and reporting requirements for hypertension require primary care providers to achieve blood pressure control while also ensuring patient adherence and concomitantly avoiding side effects related to medication therapy.
This study was conducted using claims data for commercially insured patients or those with Medicare Advan-tage and is unlikely to be representative of the entire population. Additionally, the study authors did not have detailed clinical information about patients, limiting the ability to understand the true clinical implications. Further, patients may have initiated medications for indications other than hypertension. In addition, causality cannot be established given the retrospective observational cohort nature of this study.
Applications for Clinical Practice
Primary care physicians face substantial challenges in the treatment of hypertension, including with respect to selection of initial medication therapy. Results from this study add to the evidence base that fixed-dose combination therapy is more effective in obtaining blood pressure control than monotherapy or multiple-pill therapy. Medication adherence in primary care practice is challenging. Strategies such as fixed-dose combination therapy are reasonable to employ to improve medication adherence; however, costs must be considered.
—Ajay Dharod, MD, Wake Forest School of Medicine, Winston-Salem, NC
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