ARBITER 2 was a prospective double-blind, randomized clinical trial comparing the efficacy of extended-release prescription niacin (Niaspan®, Kos Pharmaceuticals Inc., Cranbury, NJ) and matching placebo on the rate of atherosclerosis progression. The study was conducted from December 2001 to May 2004. By study design, all patients had known coronary heart disease and were required to already be taking a statin medication prior to study entry and continue taking the statin medication throughout the duration of the study. The trial was conducted at Walter Reed Army Medical Center, a tertiary medical center, and the protocol was approved by the institution’s Department of Clinical Investigation. All volunteers provided written, informed consent.
A dedicated research pharmacy, which manages all medications provided for approved protocols, dispensed the study medication. Statin therapy was dispensed by the main outpatient pharmacy of the facility along with the remainder of the participant’s medications. The majority (93%) of patients in the study used simvastatin, the primary statin provided by the Department of Defense, with the remainder prescribed atorvastatin. All participants met with one of the six clinical pharmacists, per study protocol, for planned adherence assessments of their study drug and statin medication. After an initial meeting at 30 days, adherence assessments were performed at 90, 180, 270, and 365 days for the 148 study patients. Of these, 14 participants (9.5%) forgot to bring their statin bottles to their study visit, (but did partake in study drug pill counts). These subjects are excluded from some analyses where noted. Participants were instructed to bring their medication bottles to each visit. Pill counts were calculated as the number of pills taken (the number of pills dispensed – the number of pills counted). The number of pills expected to have been taken was calculated by multiplying the daily dose (1/2, 1 or 2 tablets) by the number of days since the date dispensed. We a priori and rigorously defined successful adherence on pill counts as 85–100% of the pills taken during each follow-up period (Krueger et al 2003
). Adherence per drug use by twenty-four hour recall was assessed based on the patient’s verbal response (from memory or with an aid of a personal medication list) of all of the chronic medications taken (including the study and statin medications) within 24 hours prior to each pharmacy visit. We considered the patients to be adherent according to the twenty-four hour recall if they were able to report taking all of their chronic medications. Adherence per refill history was determined by assessing the electronic pharmacy record system (Composite Health Care System, CHCS) to quantify the number of pills dispensed relative to time. Adherence was noted if all of the patient’s chronic medication refills were consistent with the number of days dispensed by the pharmacy, always within 90-days. All patients received statin and study medications from the military health care system.
The 148 study participants were seen and interviewed in a Pharmacy Outcomes Clinic at Walter Reed Army Medical Center throughout the study duration (up to 1 year). Pharmacists working in the clinic received training in each of the adherence assessment and documentation. Data were collected on a custom data collection form including written reminders on adherence assessment methods and adherence definitions. A data dictionary was collectively reviewed and discussed among the participating pharmacists in order to minimize the potential for inter-rater variability.
At the conclusion of each visit, the remaining study medication was taken and returned to the research pharmacy and a new drug supply was provided. This ensured that the exact start and end date of the pill count assessment was clearly documented. Participants were responsible for refilling their statin medication through the main outpatient pharmacy on schedule.
Mean pill counts for statin and study drug were computed and expressed as the mean ± standard deviation. Means were compared using paired t-tests or t-tests for independent groups, as appropriate. Temporal changes in pill count adherence were assessed using general linear models during a monitoring phase of up to 1 year. All analyses were conducted using SPSS statistical software (v 13.0; Chicago, IL). A P value ≤0.05 was considered statistically significant.