Hemorrhagic and Thrombotic Events Associated with Generic Substitution of Warfarin in Patients with Atrial Fibrillation: A Retrospective Analysis

Abstract

Spanish

French

BACKGROUND:

Substitution of generic warfarin for imprint warfarin (Coumadin; DuPont/Bristol-Myers Squibb) has been a controversial issue due to bioavailability and bioequivalence concerns.

OBJECTIVE:

To assess the risk of thrombotic and hemorrhagic events following substitution of warfarin formulations in patients with atrial fibrillation (AF).

METHODS:

Historical cohort analysis was performed using a commercial insurance claims database. Adults with a diagnosis of AF between January 2003 and December 2007, with 16 or more months of continuous eligibility, a warfarin prescription within 30 days after index AF diagnosis, and at least 3 warfarin prescription fills during the follow-up period were included. Individuals with AF diagnosis or warfarin prescription during the pre-index period were excluded. Cox proportional hazard regression models controlling for sex and baseline comorbidities (Charlson comorbidity index, CCI) were used to evaluate the risks of thrombotic and hemorrhagic events following warfarin formulation switches.

RESULTS:

Of 37,756 subjects included in the analysis (mean age 70.96 years, 42.3% females), 12,996 (34.4%) switched warfarin formulations, 20,292 (53.7%) used only 1 generic product, and 4468 (11.8%) used only Coumadin during follow-up. Compared with continued use of Coumadin, switching from that product to the generic formulation was associated with a significantly higher risk of thrombotic events (HR = 1.81; 95% CI 1.42 to 2.31). Similar findings were observed for switching from generic warfarin to Coumadin (HR = 1.76; 95% CI 1.35 to 2.30), and from 1 generic to another generic product (HR = 1.89; 95% CI 1.57 to 2.29). Similarly, switching from Coumadin to generic warfarin (HR = 1.51; 95% CI 1.17 to 1.93), generic warfarin to Coumadin (HR = 1.60; 95% CI 1.23 to 2.1), and from 1 generic to another generic product (HR = 1.74; 95% CI 1.45 to 2.11) were associated with significantly higher risk of hemorrhage than remaining on Coumadin.

CONCLUSIONS:

Switching warfarin formulations exposed patients with AF to a higher risk of bleeding events compared to remaining on a single product. Maintaining patients on a product with consistent bioavailability may optimize the risk-benefit balance of anticoagulation therapy.

Keywords

atrial fibrillation bleeding Coumadin generic ischemic stroke switching thromboembolism warfarin

Get full access to this article

View all access options for this article.

References

The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. N Engl J Med 1990;323:1505–11. DOI 10.1056/NEJM199011293232201.

Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. EAFT (European Atrial Fibrillation Trial) Study Group. Lancet 1993;342:1255–62.

Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996;348:633–8. DOI 10.1016/S0140-6736(96)03487-3.

Connolly

Laupacis

Gent

Roberts

Cairns

Joyner

. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991;18:349–55. DOI 10.1016/0735-1097(91)90585-W.

Ezekowitz

Bridgers

James

Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med 1992;327:1406–12. DOI 10.1056/MEJM199211123272002.

Olsson

Halperin

. Prevention of stroke in patients with atrial fibrillation. Semin Vasc Med 2005;5:285–92. DOI 10.1055/s-2005-916168.

Hylek

Skates

Sheehan

Singer

. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996;335:540–6. DOI 10.1056/NEJM199608223350802.

Dolan

Smith

Collins

Plumb

. Effect of setting, monitoring intensity and patient experience on anticoagulation control: a systematic review and meta-analysis of the literature. Curr Med Res Opin 2008;24:1459–72. DOI 10.1185/030079908X297349.

Jacobs

. Warfarin pharmacology, clinical management, and evaluation of hemorrhagic risk for the elderly. Cardiol Clin 2008;26:157–67, v. DOI 10.1016/j.ccl.2007.12.010.

10.

Mittmann

Walker

Bartle

. Warfarin in the secondary prevention of thromboembolism in atrial fibrillation: impact of bioavailability on costs and outcomes. Pharmacoeconomics 2004;22:671–83.

11.

Holbrook

Pereira

Labiris

Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005;165:1095–106. DOI 10.1001/archinte.165.10.1095.

12.

Orange Book: approved drug products with therapeutic equivalence evaluations. US Government Publications, Washington, DC, 2010.

13.

Approved drug products and legal requirements. 18th ed. Rockville, MD: The United States Pharmacopeia, 1998.

14.

FDA position on product selection for 'narrow therapeutic index' drugs. Am J Health Syst Pharm 1997;54:1630–2.

15.

Meredith

. Generic drugs. Therapeutic equivalence. Drug Saf 1996;15:233–42.

16.

Pope

. Generic substitution of narrow therapeutic index drugs. US Pharmacist 2009;34(6):12–9.

17.

Handler

JNT

Rush

Pham

. A blinded, randomized crossover study comparing the efficacy and safety of generic warfarin sodium to Coumadin. Prevent Cardiol 1998;4:13–20.

18.

Milligan

Banet

Waterman

Gatchel

Gage

. Substitution of generic warfarin for Coumadin in an HMO setting. Ann Pharmacother 2002;36:764–8. DOI 10.1345/aph.1A327.

19.

Neutel

Smith

. Hypertension: where have we gone wrong and how can we fix it? Am J Hypertens 1998;11:150S–7S. DOI 10.1016/S0895-7061(98)00192-7.

20.

Pereira

Holbrook

Dolovich

Are brand-name and generic warfarin interchangeable? Multiple n- of-1 randomized, crossover trials. Ann Pharmacother 2005;39:1188–93. DOI 10.1345/aph.1G003.

21.

Weibert

Yeager

Wittkowsky

A randomized, crossover comparison of warfarin products in the treatment of chronic atrial fibrillation. Ann Pharmacother 2000;34:981–8. DOI 10.1345/aph.10068.

22.

Swenson

Fundak

. Observational cohort study of switching warfarin sodium products in a managed care organization. Am J Health Syst Pharm 2000;57:452–5.

23.

Halkin

Shapiro

Kurnik

Loebstein

Shalev

Kokia

. Increased warfarin doses and decreased international normalized ratio response after nationwide generic switching. Clin Pharmacol Ther 2003;74:215–21. DOI 10.1016/S0009-9236(03)00166-8.

24.

Witt

Tillman

Evans

Plotkin

Sadler

. Evaluation of the clinical and economic impact of a brand name-to-generic warfarin sodium conversion program. Pharmacotherapy 2003;23:360–8.

25.

Kim

Lin

Hussein

Kreilick

Battleman

. Cost of atrial fibrillation in United States managed care organizations. Adv Ther 2009;26:847–57. DOI 10.1007/s12325-009-0066-x.

26.

Naccarelli

Johnston

Lin

Patel

Schulman

. Cost burden of cardiovascular hospitalization and mortality in ATHENA-like patients with atrial fibrillation/atrial flutter in the United States. Clin Cardiol 2010;33:270–9. DOI 10.1002/clc.20759.

27.

Naccarelli

Varker

Lin

Schulman

. Increasing prevalence of atrial fibrillation and flutter in the United States. Am J Cardiol 2009;104:1534–9. DOI 10.1016/j.amjcard.2009.07.022.

28.

Taylor

Davis

Torner

Holmes

Meyer

Jacobson

. Lifetime cost of stroke in the United States. Stroke 1996;27:1459–66.

29.

Zimetbaum

Thosani

Are atrial fibrillation patients receiving warfarin in accordance with stroke risk?

Am J Med 2010;123:446–53. DOI 10.1016/j.amjmed.2009.11.015.

30.

Drug topics red book. Montvale, NJ: Thomson Reuters, 2008.

31.

Schauer

Moomaw

Wess

Webb

Eckman

. Psychosocial risk factors for adverse outcomes in patients with nonvalvular atrial fibrillation receiving warfarin. J Gen Intern Med 2005;20:1114–9. DOI 10.1111/j.1525-1497.2005.0242.x.

32.

Edelsberg

Hagiwara

Taneja

Oster

. Risk of venous thromboembolism among hospitalized medically ill patients. Am J Health Syst Pharm 2006;63(suppl):S16–22. DOI 10.2146/ajhp060389.

33.

White

Beyth

Zhou

Romano

. Major bleeding after hospitalization for deep-venous thrombosis. Am J Med 1999;107:414–24. DOI 10.1016/S0002-9343(99)00267-3.

34.

Walker

Bennett

. Epidemiology and outcomes in patients with atrial fibrillation in the United States. Heart Rhythm 2008;5:1365–72. DOI 10.1016/j.hrthm.2008.07.014.

35.

Karni

Holtzman

Bass

Traumatic head injury in the anticoagulated elderly patient: a lethal combination. Am Surg 2001;67:1098–100.

36.

D'Hoore

Sicotte

Tilquin

. Risk adjustment in outcome assessment: the Charlson comorbidity index. Methods Inf Med 1993;32:382–7.

37.

van Walraven

Hart

Singer

Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis. JAMA 2002;288:2441–8. DOI 10.1001/jama.288.19.2441.

38.

Hylek

Chang

Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice?

JAMA 2003;290:2685–92. DOI 10.1001/jama.290.20.2685290.

39.

201 KAR 2:116. Drug products with therapeutic problems. www.lrc.state.ky.us/kar/201/002/116.htm (accessed 2010 Apr 20).

40.

South Carolina Code of Laws (unannotated). www.scstatehouse.net/code/t39c024.htm (accessed 2010 Apr 20).

41.

Commonwealth of Pennsylvania generic drug equivalency/substitution laws & regulations. http://ecapps.health.state.pa.us/pdf/ddc/generic33.ps.pdf (accessed 2010 Apr 20).

42.

North Carolina Board of Pharmacy. Pharmacy rules, statutes, and board policies. www.ncbop.org/LawRules/StatutesMay2007.pdf (accessed 2010 Apr 20).

43.

Rose

Ozonoff

Grant

Henault

Hylek

. Epidemiology of subtherapeutic anticoagulation in the United States. Circ Cardiovasc Qual Outcomes 2009;2:591–7. DOI 10.1161/CIRCOUTCOMES.109.862763.