Figure. Persistence with warfarin therapy among patients with atrial fibrillation newly treated with warfarin, overall and stratified by CHADS2 category. Survival curves for warfarin therapy discontinuation, from start of treatment among Ontario, Canada, residents 66 years and older with a past diagnosis of atrial fibrillation. CHADS2 indicates congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and prior stroke or transient ischemic attack.
Gomes T, Mamdani MM, Holbrook AM, Paterson JM, Juurlink DN. Persistence with therapy among patients treated with warfarin for atrial fibrillation.. Arch Intern Med.. Published online October 22, 2012. doi:10.1001/archinternmed.2012.4485
eAppendix. Detailed Description of Databases
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Gomes T, Mamdani MM, Holbrook AM, Paterson JM, Juurlink DN. Persistence With Therapy Among Patients Treated With Warfarin for Atrial Fibrillation. Arch Intern Med. 2012;172(21):1687–1689. doi:10.1001/archinternmed.2012.4485
Author Affiliations: The Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada (Ms Gomes, Drs Mamdani and Juurlink, and Mr Paterson); Department of Medicine (Dr Mamdani), Keenan Research Centre of the Li Ka Shing Knowledge Institute (Dr Mamdani), and The Sunnybrook Research Institute (Dr Juurlink), St Michael's Hospital, Toronto, Ontario, Canada; Departments of Medicine (Drs Mamdani and Juurlink), Pediatrics (Dr Juurlink), Health Policy, Management, and Evaluation (Drs Mamdani, Paterson, and Juurlink), and the Leslie Dan Faculty of Pharmacy (Ms Gomes and Drs Mamdani and Juurlink), University of Toronto, Toronto, Ontario, Canada; Division of Clinical Pharmacology & Therapeutics (Dr Holbrook) and Department of Family Medicine (Mr Paterson), McMaster University, Hamilton, Ontario, Canada; and Centre for Evaluation of Medicines, St Joseph's Healthcare, Hamilton, Ontario, Canada (Dr Holbrook and Mr Paterson).
The major challenges of warfarin therapy relate to poor adherence and persistence, the need for regular monitoring, and the risk of hemorrhage. In clinical trials, persistence with warfarin treatment ranges from 75% to 79% at 1 year,1,2 but persistence in clinical practice is thought to be poorer. Small observational studies suggest that approximately one-quarter of patients cease warfarin treatment within a year of initiation.3,4 To our knowledge, there are currently no large studies offering real-world estimates of persistence among warfarin users.
The objective of this study was to examine persistence with warfarin therapy in a large population-based cohort of newly treated patients with atrial fibrillation (AF).
We conducted a population-based cohort study among residents of Ontario, Canada, 66 years and older, who commenced treatment with warfarin between April 1, 1997, and March 31, 2008. We used multiple linked administrative data sets from Ontario, the most populous province in Canada, to identify outpatient prescription records, hospitalizations, emergency department visits, physician services, patient demographics, and comorbidities. Details of these databases are given in the eAppendix. The data were held securely in a linked, deidentified form and analyzed at the Institute for Clinical Evaluative Sciences.
For each study subject, we identified a period of continuous warfarin use beginning with the first prescription dispensed after their 66th birthday and defined by successive prescription refills within 180 days, thereby allowing for periodic dose adjustments, brief lapses in adherence, and variable timing of prescription refills. To create an inception cohort of patients with AF, patients with any prescription for warfarin in the preceding year were excluded, and the analysis was restricted to patients who had a physician visit, emergency department assessment, or hospital admission for AF or flutter in the 100 days preceding the first prescription for warfarin. We followed patients from their cohort entry date until the first instance of discontinuation of warfarin therapy, death, or the end of the study period (March 31, 2010), with a maximum follow-up of 5 years.
We constructed Kaplan-Meier curves to characterize drug therapy discontinuation. Secondary analyses described persistence with warfarin therapy according to age (66 to 75 years, 76 to 85 years, and ≥86 years), sex, CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack) score,5 and date of warfarin therapy initiation (before or after April 1, 2003; presuming progressive improvements in anticoagulation management over time).6,7 The log-rank test was used to examine differences in persistence among patient subgroups. This research was approved by the research ethics board of Sunnybrook Health Sciences Centre, Toronto, Ontario.
Over the 13-year study period, we identified 125 195 new users of warfarin in Ontario 66 years or older with a recent diagnosis of AF. Of these, 86 432 (69.0%) had a CHADS2 score of 2 or higher at the outset of therapy, and 62 851 (50.2%) initiated treatment within a week of their AF diagnosis.
Of 125 195 patients who started warfarin therapy for AF, 8.9% did not fill a second warfarin prescription during follow-up, 31.8% discontinued therapy within 1 year, 43.2% discontinued therapy within 2 years, and 61.3% discontinued therapy within 5 years (Figure). The median time to discontinuation (MTD) was 2.9 years. Men discontinued warfarin therapy earlier than women (MTD, 2.6 years vs 3.2 years, respectively; P < .001), while patients aged 66 to 75 years were more likely to discontinue therapy compared with older patient groups (MTD, 2.7 years vs 3.1 years for patients >85 years; P < .001). Persistence with warfarin therapy increased with stroke risk, as reflected by the CHADS2 score (MTD, 2.3 years, 2.9 years, and 3.3 years among people with a CHADS2score of 0, 3, and 6, respectively; P < .001; Figure). Finally, patients who started warfarin therapy during the latter part of the study period (fiscal years 2003 through 2007) adhered to therapy longer than those who initiated treatment earlier (fiscal years 1997 through 2002) (MTD, 3.2 years vs 2.6 years, respectively; P < .001).
We found that persistence with warfarin therapy among older patients with AF is lower than generally appreciated and that male sex, younger age, and lower stroke risk predicted poorer persistence with drug therapy. Furthermore, we found that persistence with warfarin therapy improved over the 13-year study period, with patients who initiated treatment later in the study period adhering to therapy for approximately 8 months longer than those initiating treatment earlier in the study period. These findings highlight the importance of considering recent, real-world estimates of warfarin therapy persistence, particularly when comparing warfarin with newer anticoagulants that also carry a risk of hemorrhage yet require no routine monitoring.
A limitation that merits emphasis is our inability to generalize these findings to younger patients. It is also possible that early discontinuation of warfarin therapy among people with low CHADS2 scores may be planned by the treating physician. Our study's key strengths are its large sample size, extended follow-up, and inclusiveness. Furthermore, our cohort members have comprehensive health insurance, including prescription drug coverage, thereby minimizing selection bias. To our knowledge, this is the first large study to characterize persistence with warfarin therapy in an entire population in which anticoagulant clinics are scarce.
Correspondence: Ms Gomes, Ontario Drug Policy Research Network, Institute for Clinical Evaluative Sciences, 2075 Bayview Ave, Ste G1-06, Toronto, ON M4N 3M5, Canada (Tara.Gomes@ices.on.ca).
Published Online: October 22, 2012. doi:10.1001/archinternmed.2012.4485
Author Contributions: Ms Gomes had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Gomes, Mamdani, Holbrook, Paterson, and Juurlink. Acquisition of data: Gomes. Analysis and interpretation of data: Gomes, Mamdani, Holbrook, Paterson, and Juurlink. Drafting of the manuscript: Gomes. Critical revision of the manuscript for important intellectual content: Mamdani, Holbrook, Paterson, and Juurlink. Statistical analysis: Gomes and Mamdani. Obtained funding: Juurlink. Administrative, technical, and material support: Mamdani and Holbrook.
Financial Disclosure: Dr Mamdani has received honoraria from Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, and Bayer. Drs Holbrook and Juurlink are members of the Ontario Ministry of Health and Long-Term Care (MOHLTC) Committee to Evaluate Drugs.
Funding/Support: This study was supported by a grant from the Ontario MOHLTC Drug Innovation Fund and the Institute for Clinical Evaluative Sciences (ICES), a nonprofit research institute sponsored by the Ontario MOHLTC.
Disclaimer: The opinions, results, and conclusions reported in this article are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred.
Additional Contributions: We thank Brogan Inc for use of their Drug Product and Therapeutic Class Database. Chelsea Hellings, MSc, from ICES, provided input on the study design and general project support. Ms Hellings received no compensation for this work.
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