Agreement and Accuracy of Medication Persistence Identified by Patient Self-report vs Pharmacy Fill: A Secondary Analysis of the Cluster Randomized ARTEMIS Trial

Abstract

Importance: Pharmacy fill data are increasingly accessible to clinicians and researchers to evaluate longitudinal medication persistence beyond patient self-report.

Objective: To assess the agreement and accuracy of patient-reported and pharmacy fill-based medication persistence.

Design, setting, and participants: This post hoc analysis of the cluster randomized clinical trial ARTEMIS (Affordability and Real-world Antiplatelet Treatment Effectiveness After Myocardial Infarction Study) enrolled patients at 287 US hospitals (131 randomized to intervention and 156 to usual care) from June 5, 2015, to September 30, 2016, with 1-year follow-up and blinded adjudication of major adverse cardiovascular events. In total, 8373 patients with myocardial infarction and measurement of P2Y12 inhibitor persistence by both patient self-report and pharmacy data were included. Serum P2Y12 inhibitor drug levels were measured for 944 randomly selected patients. Data were analyzed from May 2018 to November 2019.

Interventions: Patients treated at intervention-arm hospitals received study vouchers to offset copayments at each P2Y12 inhibitor fill for 1 year after myocardial infarction.

Main outcomes and measures: Nonpersistence was defined as a gap of 30 days or more in P2Y12 inhibitor use (patient report) or supply (pharmacy fill) and as serum P2Y12 inhibitor levels below the lower limit of quantification (drug level). Among patients in the intervention arm, a "criterion standard" definition of nonpersistence was a gap of 30 days or more in P2Y12 inhibitor use by both voucher use and pharmacy fill. Major adverse cardiovascular events were defined as adjudicated death, recurrent myocardial infarction, or stroke.

Results: Of 8373 patients included in this analysis, the median age was 62 years (interquartile range, 54-70 years), 5664 were men (67.7%), and 990 (11.8%) self-reported as nonwhite race/ethnicity. One-year estimates of medication nonpersistence rates were higher using pharmacy fills (4042 patients [48.3%]) compared with patient self-report (1277 patients [15.3%]). Overall, 4185 patients (50.0%) were persistent by both pharmacy fill data and patient report, 1131 patients (13.5%) were nonpersistent by both, and 3057 patients (36.5%) were discordant. By application of the criterion standard definition, the 1-year nonpersistence rate was 1184 of 3703 patients (32.0%); 892 of 3318 patients (26.9%) in the intervention arm who self-reported persistence were found to be nonpersistent, and 303 of 1487 patients (20.4%) classified as nonpersistent by pharmacy fill data were actually persistent. Agreement between serum P2Y12 inhibitor drug levels and either patient-reported (κ = 0.11-0.23) or fill-based (κ = 0.00-0.19) persistence was poor. Patients who were nonpersistent by both pharmacy fill data and self-report had the highest 1-year major adverse cardiac event rate (18.3%; 95% CI, 16.0%-20.6%) compared with that for discordant patients (9.7%; 8.7%-10.8%) or concordantly persistent patients (8.2%; 95% CI, 7.4%-9.0%).

Conclusions and relevance: Patient report overestimated medication persistence rates, and pharmacy fill data underestimated medication persistence rates. Patients who are nonpersistent by both methods have the worst clinical outcomes and should be prioritized for interventions that improve medication-taking behavior.

Trial registration: ClinicalTrials.gov Identifier: NCT02406677.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Fanaroff reported receiving a career development grant from the American Heart Association, research grant support to the Duke Clinical Research from Boston Scientific, and consulting fees from the American Heart Association. Dr Peterson reported receiving grants and/or personal fees from the American Heart Association Get With The Guidelines–Stroke, Amgen, AstraZeneca, Bayer Pharmaceuticals, Genentech, Janssen Pharmaceuticals, and Sanofi outside the submitted work; and serving as a consultant/advisory board member for AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, Livongo, Merck & Co, Sanofi, and Signal Path. Dr Cannon reported receiving research grant support from Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Merck & Co, Pfizer, and Takeda; receiving personal fees from AstraZeneca during the conduct of the study; and receiving personal fees from Aegerion Pharmaceuticals, Alnylam Pharmaceuticals, Amarin Corporation, Amgen, Applied Therapeutics, Ascendia Pharmaceuticals, Arisaph Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Corvidia Therapeutics, Eisai Co Ltd, GlaxoSmithKline, HLS Therapeutics, Innovent Biologics Inc, Janssen, Kowa Pharmaceuticals America, Lipomedix, Merck & Co, Pfizer, Regeneron, Sanofi, and Takeda outside the submitted work. Dr Choudhry reported receiving research grant support to Brigham and Women’s Hospital from AstraZeneca, CVS Health, Merck & Co, Medisafe, and Sanofi and outside the submitted work. Dr Henry reported receiving a steering committee honorarium for ARTEMIS from AstraZeneca. Dr Anstrom reported receiving grants from AstraZeneca during the conduct of the study. Dr Cohen reported receiving research grant support from Abbott Vascular, AstraZeneca, Boston Scientific, Corvia Medical, Daiichi Sankyo, Edwards Lifesciences, Medtronic, Merck & Co, and Svelte Medical Systems outside the submitted work; and receiving grants and personal fees from Abbott Vascular, Edwards Lifesciences, and Medtronic. Ms Fonseca and Dr Khan were employees of AstraZeneca during the conduct of the study. Dr Fonarow reported receiving personal fees from Abbott Laboratories, Amgen, AstraZeneca, Bayer, Janssen, and Novartis outside the submitted work. Dr Wang reported receiving research grant support to the Duke Clinical Research Institute from Amgen, Bristol-Myers Squibb, Chiesi, Cryolife, Merck & Co, Novartis, Pfizer, Portola Pharmaceuticals, and Regeneron Pharmaceuticals; and receiving personal fees from AstraZeneca, Gilead Sciences Inc, Grifols, and Sanofi during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

Medication persistence was measured in 4 ways in ARTEMIS, in 4 separate cohorts of patients. Self-reported persistence was measured in the population of patients discharged alive who received clopidogrel or ticagrelor during follow-up interviews (91.4% of patients completed the interview at 3 months, 85.7% at 6 months, 83.1% and 9 months, and 81.1% at 12 months). Persistence by pharmacy fill was measured in the subset of patients who could have their records linked to pharmacy claims data. Among this subset, persistence by combined voucher use and pharmacy fill was measured in the intervention arm for patients who used a copayment assistance voucher at least once. A random subset of the full ARTEMIS population was selected to undergo phlebotomy to measure serum P2Y12 inhibitor drug levels.

Figure 2.. Noncumulative Medication Nonpersistence by Method of Measurement

Bars show the proportion of patients who were medication nonpersistent by self-report, pharmacy fill, and randomly obtained blood samples from 0 to 3 months, from 3 to 6 months, from 6 to 9 months, and from 9 to 12 months of follow-up; error bars depict 95% CIs. Medication nonpersistence increased with time as measured by pharmacy fill and randomly obtained blood samples, but only increased by self-report at 12 months. Noncumulative persistence indicates no gap for 30 days or more in P2Y12 inhibitor use or supply during the specified 3-month window.

Figure 3.. Major Adverse Cardiovascular Events (MACEs) by Self-reported and Pharmacy Fill Persistence

Cumulative incidence curves show MACEs during a 1-year follow-up. Rates of MACEs were highest for patients concordantly medication nonpersistent, lowest in patients concordantly persistent, and intermediate for both groups of discordant patients.