Using a Simple Prescription Gap to Determine Warfarin Discontinuation Can Lead to Substantial Misclassification

Kueiyu Joshua Lin; Sebastian Schneeweiss; Ajinkya Pawar; Daniel E. Singer; Jun Liu; Joshua J. Gagne

doi:10.1055/a-1508-8187

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2022; 122(03): 386-393
DOI: 10.1055/a-1508-8187

Stroke, Systemic or Venous Thromboembolism

Using a Simple Prescription Gap to Determine Warfarin Discontinuation Can Lead to Substantial Misclassification

Kueiyu Joshua Lin

¹Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States

²Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States

,

Sebastian Schneeweiss

¹Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States

,

Ajinkya Pawar

¹Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States

,

Daniel E. Singer

²Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States

,

Jun Liu

¹Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States

,

Joshua J. Gagne

¹Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States

› Author Affiliations

Abstract

Background Warfarin remains widely used and a key comparator in studies of other direct oral anticoagulants. As longer-than-needed warfarin prescriptions are often provided to allow for dosing adjustments according to international normalized ratios (INRs), the common practice of using a short allowable gap between dispensings to define warfarin discontinuation may lead to substantial misclassification of warfarin exposure. We aimed to quantify such misclassification and determine the optimal algorithm to define warfarin discontinuation.

Methods We linked Medicare claims data from 2007 to 2014 with a multicenter electronic health records system. The study cohort comprised patients ≥65 years with atrial fibrillation and venous thromboembolism initiating warfarin. We compared results when defining warfarin discontinuation by (1) different gaps (3, 7, 14, 30, and 60 days) between dispensings and (2) having a gap ≤60 days or bridging larger gaps if there was INR ordering at least every 42 days (60_INR). Discontinuation was considered misclassified if there was an INR ≥2 within 7 days after the discontinuation date.

Results Among 3,229 patients, a shorter gap resulted in a shorter mean follow-up time (82, 95, 117, 159, 196, and 259 days for gaps of 3, 7, 14, 30, 60, and 60_INR, respectively; p < 0.001). Incorporating INR (60_INR) can reduce misclassification of warfarin discontinuation from 68 to 4% (p < 0.001). The on-treatment risk estimation of clinical endpoints varied significantly by discontinuation definitions.

Conclusion Using a short gap between warfarin dispensings to define discontinuation may lead to substantial misclassification, which can be improved by incorporating intervening INR codes.

Keywords

warfarin discontinuation - stroke prevention - exposure misclassification

Full Text

References

References
1 Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. and American College of Chest P. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (06) 160S-198S
2 Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146 (12) 857-867
3 Huisman MV, Rothman KJ, Paquette M. et al; GLORIA-AF Investigators. The changing landscape for stroke prevention in AF: findings from the GLORIA-AF Registry phase 2. J Am Coll Cardiol 2017; 69 (07) 777-785
4 Coleman CI, Peacock WF, Bunz TJ, Alberts MJ. Effectiveness and safety of apixaban, dabigatran, and rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and previous stroke or transient ischemic attack. Stroke 2017; 48 (08) 2142-2149
5 Graham DJ, Reichman ME, Wernecke M. et al. Stroke, bleeding, and mortality risks in elderly medicare beneficiaries treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation. JAMA Intern Med 2016; 176 (11) 1662-1671
6 Hernandez I, Baik SH, Piñera A, Zhang Y. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern Med 2015; 175 (01) 18-24
7 Vinogradova Y, Coupland C, Hill T, Hippisley-Cox J. Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: cohort study in primary care. BMJ 2018; 362: k2505
8 Graham DJ, Reichman ME, Wernecke M. et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation 2015; 131 (02) 157-164
9 Schwartz J, Merrill S, de Leon N, Thompson A, Fang M. Dosing accuracy of direct oral anticoagulants in an academic medical center. J Hosp Med 2017; 12 (07) 544-550
10 Moudallel S, Steurbaut S, Cornu P, Dupont A. Appropriateness of DOAC prescribing before and during hospital admission and analysis of determinants for inappropriate prescribing. Front Pharmacol 2018; 9: 1220
11 Cancino RS, Hylek EM, Reisman JI, Rose AJ. Comparing patient-level and site-level anticoagulation control as predictors of adverse events. Thromb Res 2014; 133 (04) 652-656
12 Rose AJ, Delate T, Ozonoff A, Witt DM. Comparison of the abilities of summary measures of international normalized ratio control to predict clinically relevant bleeding. Circ Cardiovasc Qual Outcomes 2015; 8 (05) 524-531
13 Connolly SJ, Pogue J, Eikelboom J. et al; ACTIVE W Investigators. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 2008; 118 (20) 2029-2037
14 Go AS, Hylek EM, Chang Y. et al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice?. JAMA 2003; 290 (20) 2685-2692
15 Ho CW, Ho MH, Chan PH. et al. Ischemic stroke and intracranial hemorrhage with aspirin, dabigatran, and warfarin: impact of quality of anticoagulation control. Stroke 2015; 46 (01) 23-30
16 Singer DE, Chang Y, Fang MC. et al. Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation?: the ATRIA study. Circ Cardiovasc Qual Outcomes 2009; 2 (04) 297-304
17 Hennessy S. Use of health care databases in pharmacoepidemiology. Basic Clin Pharmacol Toxicol 2006; 98 (03) 311-313
18 Johnson ES, Bartman BA, Briesacher BA. et al. The incident user design in comparative effectiveness research. Pharmacoepidemiol Drug Saf 2013; 22 (01) 1-6
19 Wahl PM, Rodgers K, Schneeweiss S. et al. Validation of claims-based diagnostic and procedure codes for cardiovascular and gastrointestinal serious adverse events in a commercially-insured population. Pharmacoepidemiol Drug Saf 2010; 19 (06) 596-603
20 Birman-Deych E, Waterman AD, Yan Y, Nilasena DS, Radford MJ, Gage BF. Accuracy of ICD-9-CM codes for identifying cardiovascular and stroke risk factors. Med Care 2005; 43 (05) 480-485
21 Tamariz L, Harkins T, Nair V. A systematic review of validated methods for identifying venous thromboembolism using administrative and claims data. Pharmacoepidemiol Drug Saf 2012; 21 (Suppl. 01) 154-162
22 Cushman M, Tsai AW, White RH. et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med 2004; 117 (01) 19-25
23 Andrade SE, Harrold LR, Tjia J. et al. A systematic review of validated methods for identifying cerebrovascular accident or transient ischemic attack using administrative data. Pharmacoepidemiol Drug Saf 2012; 21 (Suppl. 01) 100-128
24 Cunningham A, Stein CM, Chung CP, Daugherty JR, Smalley WE, Ray WA. An automated database case definition for serious bleeding related to oral anticoagulant use. Pharmacoepidemiol Drug Saf 2011; 20 (06) 560-566
25 Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69 (03) 236-239
26 Granger CB, Alexander JH, McMurray JJ. et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
27 Connolly SJ, Ezekowitz MD, Yusuf S. et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
28 Patel MR, Mahaffey KW, Garg J. et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
29 Giugliano RP, Ruff CT, Braunwald E. et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
30 Yao X, Abraham NS, Sangaralingham LR. et al. Effectiveness and safety of dabigatran, rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation. J Am Heart Assoc 2016; 5 (06) 5
31 Chan YH, Yen KC, See LC. et al. Cardiovascular, bleeding, and mortality risks of dabigatran in asians with nonvalvular atrial fibrillation. Stroke 2016; 47 (02) 441-449
32 Agnelli G, Buller HR, Cohen A. et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369 (09) 799-808
33 Bauersachs R, Berkowitz SD, Brenner B. et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
34 Coleman CI, Peacock WF, Bunz TJ, Beyer-Westendorf J. Effectiveness and safety of rivaroxaban versus warfarin in patients with unprovoked venous thromboembolism: a propensity-score weighted administrative claims cohort study. Thromb Res 2018; 168: 31-36
35 January CT, Wann LS, Alpert JS. et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64 (21) e1-e76
36 Stevens LA, Viswanathan G, Weiner DE. Chronic kidney disease and end-stage renal disease in the elderly population: current prevalence, future projections, and clinical significance. Adv Chronic Kidney Dis 2010; 17 (04) 293-301
37 Lip GYH, Keshishian A, Li X. et al. Effectiveness and safety of oral anticoagulants among nonvalvular atrial fibrillation patients. Stroke 2018; 49 (12) 2933-2944
38 Viera AJ, Garrett JM. Understanding interobserver agreement: the kappa statistic. Fam Med 2005; 37 (05) 360-363
39 Graham DJ, Baro E, Zhang R. et al. Comparative stroke, bleeding, and mortality risks in older medicare patients treated with oral anticoagulants for nonvalvular atrial fibrillation. Am J Med 2019; 132 (05) 596-604
40 Cox DR. Regression models and life-tables. J R Stat Soc B 1972; 34: 187-220
41 Lin KJ, Schneeweiss S. Considerations for the analysis of longitudinal electronic health records linked to claims data to study the effectiveness and safety of drugs. Clin Pharmacol Ther 2016; 100 (02) 147-159
42 Lin KJ, Singer DE, Glynn RJ. et al. Prediction score for anticoagulation control quality among older adults. J Am Heart Assoc 2017; 6 (10) 6
43 Wurster M, Doran T. Anticoagulation management: a new approach. Dis Manag 2006; 9 (04) 201-209

Supplementary Material

Supplementary Material