title: Pillbox Use and INR Stability in a Prospective Cohort of New Warfarin Users.
abstract: BACKGROUND
  Warfarin, a frequently prescribed oral anticoagulant, is well known for its narrow therapeutic index. Adherence to warfarin may help to achieve a stable international normalized ratio (INR), but little data are available regarding the impact of using a pillbox as a potential adherence aid device.
  
  
  OBJECTIVE
  To evaluate the association between pillbox use and time in therapeutic range (TTR) < 60% and INR instability pattern.
  
  
  METHODS
  This study was based on a prospective cohort of 1,069 new warfarin users who initiated warfarin between May 2010 and July 2013 within 17 hospitals in Quebec, Canada. Demographic, lifestyle, and clinical data were collected for 3 months to a year after warfarin initiation, and genetic factors were assessed. Patients usingh self-prepared and pharmacist-prepared pillboxes were compared with nonusers for the 3- to 12-month follow-up period. The primary outcome was a TTR < 60%, which represents a low percentage of time in the INR therapeutic range or an unstable patient. The secondary outcome was the INR instability pattern (unstable below range; unstable over range; unstable with erratic pattern; and stable) to better describe patient INR profiles. A multivariate generalized linear mixed model was used for the primary outcome, along with a multivariate multinomial linear mixed model for the secondary outcome.
  
  
  RESULTS
  The cohort included patients with a mean age of 70.4 ± 11.7 years; 61.8% of patients were men; 76.3% had atrial fibrillation as warfarin's primary indication; and 35.6% had a previous history of myocardial infarction or angina. Self-prepared and pharmacist-prepared pillbox use was not associated with TTR < 60% or a specific INR instability pattern. A sensitivity analysis showed that self-prepared pillbox users had a higher TTR than nonusers (3.55% ± 1.69%; P = 0.036). This effect was greater among patients aged < 70 years (5.48% ± 2.50%; P = 0.029) than among older patients (1.92% ± 2.31%; P =0.406).
  
  
  CONCLUSIONS
  Pillbox use was not associated with TTR < 60% or a specific INR instability pattern. The impact of self-prepared pillbox use was greater among younger patients, but results were not clinically significant. Future studies adjusting for concomitant drug use are needed to clarify these results.
  
  
  BACKGROUND
  This study was funded by Canadian Institutes of Health Research (CIHR) and the Centre for Excellence in Personalised Medicine. Both funding sources were not involved in the design, conduct, and reporting of this study. The data used for this study came from the Quebec Warfarin Cohort Study (QWCS), which was supported by the CIHR and the Centre for Excellence in Personalised Medicine. Dumas received a doctoral training award from the CIHR. Perreault and Dubé received a salary award from the Fonds Québécois de Recherche en Santé. Study concept and design were contributed by Talajic, Tardif, Dubé, and Perreault. Dumas, Rouleau-Mailloux, Bouchama, and Lahcene collected the data, which was interpreted by Dumas, Dubé, and Perreault. The manuscript was written and revised by Dumas, Dubé, and Perreault.
authors.affiliation: 1 Faculty of Pharmacy, Université de Montréal, and Montreal Heart Institute, Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Montreal, Quebec, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dumas
authors.affiliation: 2 Montreal Heart Institute, Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, and Faculty of Medicine, Department of Pharmacology, Université de Montréal, Quebec, Canada.
authors.forename: Etienne
authors.initials: E
authors.lastname: Rouleau-Mailloux
authors.affiliation: 3 Faculty of Pharmacy, Université de Montréal, Quebec, Canada.
authors.forename: Nawal
authors.initials: N
authors.lastname: Bouchama
authors.affiliation: 3 Faculty of Pharmacy, Université de Montréal, Quebec, Canada.
authors.forename: Halema
authors.initials: H
authors.lastname: Lahcene
authors.affiliation: 4 Montreal Heart Institute, Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, and Faculty of Medicine, Department of Medicine, Université de Montréal, Quebec, Canada.
authors.forename: Mario
authors.initials: M
authors.lastname: Talajic
authors.affiliation: 5 Montreal Heart Institute, Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, and Faculty of Medicine, Department of Medicine, Université de Montréal, Quebec, Canada.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.affiliation: 7 Montreal Heart Institute, Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Montreal, Quebec, Canada.
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Gaulin
authors.affiliation: 7 Montreal Heart Institute, Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Montreal, Quebec, Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Provost
authors.affiliation: 6 Montreal Heart Institute, Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, and Faculty of Medicine, Department of Medicine, Université de Montréal, Quebec, Canada.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.affiliation: 3 Faculty of Pharmacy, Université de Montréal, Quebec, Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Perreault
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000097:blood / Q000627:therapeutic use*; D015331:Cohort Studies; D004356:Drug Storage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D019934:International Normalized Ratio / Q000592:standards*; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D011446:Prospective Studies; D011792:Quebec / Q000453:epidemiology; D014859:Warfarin / Q000097:blood / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D014859:Warfarin