Unstable INR Has Implications for Healthcare Resource Use Janssen Pharmaceuticals, Inc.
Stable INR is essential for effective anticoagulation treatment Achieving a stable international normalized ratio (INR), defined as an INR of 2.0 to 3.0, is a critical aspect of anticoagulation therapy. A patient s INR informs the dosage of warfarin, which has to be adjusted as the patient s INR changes. 1 Patients given warfarin can be complex to manage because INR stability is challenging to achieve. A patient s diet, lifestyle, concomitant medication use, and adherence to warfarin and other medications taken at the same time all have the potential to cause fluctuations in INR. 1,2 A meta-analysis of 95 studies of patients with atrial fibrillation (AF) found that patients spent an average of 56% of their time in therapeutic INR range. 3 In another analysis of 53 studies, patients with venous thromboembolism (VTE) spent 61% of their time out of range. 4 INR fluctuations have implications for health outcomes, resource use, and costs. In patients with AF, INR instability is a predictor of ischemic stroke and major bleeding. 3,5 In patients who have experienced VTE, lack of INR control is associated with VTE recurrence and hemorrhage. 4 INR instability also has been linked to higher risk of major bleeding, fatal bleeding, and ischemic stroke. 6
The difficulty of achieving stable INR The challenges associated with INR management were illustrated in a large retrospective study of a national anticoagulation management service database. 7 Among more than 15,000 patients initiated on warfarin...* 7 Instability: by the numbers Even after achieving stabilization, fluctuation of INR values above or below therapeutic range of 2.0 to 3.0 for the duration of the study was common. 7 Moreover, stabilization was a predictor of persistence with warfarin therapy. Not achieving stabilization was associated with discontinuation of therapy within 4 months. Patients whose INR was stabilized within 1 year were 10 times more likely to remain on warfarin therapy than those whose INR was not. 7 The average time required to stabilize INR in patients taking warfarin 7 Increase in likelihood of remaining on warfarin therapy when INR was stabilized within 1 year 7 Share of patients who never achieved INR stability 7 Share of patients with INR above or below therapeutic range after stabilization 7
Implications for healthcare resource use For payers, INR instability has substantial clinical and cost implications. For example, a large integrated health system examined records of more than 6000 patients prescribed warfarin. Patients whose INR was not stabilized over 6 months had more than a fivefold increase in the risk of death than those who achieved INR values within the defined therapeutic range. Anticoagulation-related bleeding events or thrombosis were over 4 times more prevalent in the unstable cohort. 6 Other studies have examined the resource use and economic effects associated with the difficulties of warfarin management: The challenges of warfarin use may be underestimated. In patients with AF and VTE, INR instability has implications for healthcare resource use and costs. Emergency hospitalizations related to adverse drug events involving warfarin 8 A concomitant medication was implicated in 12.5% of hospitalizations attributed to warfarin 8 Incremental cost of treating hemorrhagic events in patients who used warfarin-potentiating medication 9
* Nelson study design: Patients anticoagulation management records from 2006 to 2010 were collected by decision support software. Adult patients with nonvalvular AF who had at least 3 INR values in the dataset were followed from warfarin initiation to the first 90-day gap in anticoagulation clinic visits or end of the data time frame. In total, 15,276 patients (55% male) met inclusion criteria. Mean follow-up time was 15 months. Mean ages of those achieving and not achieving INR stabilization were 72.4 and 70.7 years, respectively. Stabilization was defined as having 3 consecutive INR values between 2.0 and 3.0 after warfarin initiation. 7 Witt study design: Retrospective longitudinal cohort study. Inclusion criteria were duration of warfarin therapy >90 days, at least 1 INR determination during the study time frame (2000 2005), age >18 years, and warfarin therapy continuing throughout a 6-month observation period. Stability was defined as having all INR values within the strictly defined therapeutic reference interval for the first identifiable continuous 6-month period. 6 Budnitz study design: Adverse-event data from the National Electronic Injury Surveillance System Cooperative Adverse Drug Event Surveillance project was used to estimate the frequency and rates of hospitalizations after emergency department visits for adverse drug events in patients aged 65 from 2007 through 2009. 8 Suh study design: A nested-case control study of long-term warfarin-treated AF patients 18 years old using the Medstat MarketScan database of health insurance claims from 2004 to 2009. Patients with a hemorrhagic event were matched to control patients. Treatment costs were calculated during the 3-month time frame after the occurrence of the hemorrhagic event. Hemorrhage-related costs were costs associated with medical services involved in hemorrhagic treatment and prescription drug costs for hemostatic agents. 9 Study Designs
References 1. Hirsh J, Fuster V, Ansell J, Halperin JL. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation. 2003;107:1692 1711. 2. Eikelboom JW, Hart RG. Antithrombotic therapy for stroke prevention in atrial fibrillation and mechanical heart valves. Am J Hematol. 2012;87(S1):100 107. 3. Mearns ES, White CM, Kohn CG, et al. Quality of vitamin K antagonist control and outcomes in atrial fibrillation patients: a meta-analysis and meta-regression. Thromb J. 2014;12:14. doi: 10.1186/1477-9560-12-14. 4. Mearns ES, Kohn CG, Song JS, et al. Meta-analysis to assess the quality of international normalized ratio control and associated outcomes in venous thromboembolism patients. Thromb Res. 2014;134:310 319. 5. Razouki Z, Ozonoff A, Zhao S, et al. Improving quality measurement for anticoagulation: adding international normalized ratio variability to percent time in therapeutic range. Circ Cardiovasc Qual Outcomes. 2014;7:664 669. 6. Witt DM, Delate T, Clark NP, et al. Outcomes and predictors of very stable INR control during chronic anticoagulation therapy. Blood. 2009:114:952 956. 7. Nelson WW, Desai S, Damaraju CV, et al. International normalized ratio stabilization in newly initiated warfarin patients with nonvalvular atrial fibrillation. Curr Med Res Opin. 2014:1 6. 8. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011;365:2002 2012. 9. Suh D-C, Nelson WW, Choi JC, Choi I. Risk of hemorrhage and treatment costs associated with warfarin drug interactions in patients with atrial fibrillation. Clin Ther. 2012;34:1569 1582. Sebastian Ferreira, Untitled Artwork from the National Art Exhibitions of the Mentally Ill, Inc. (NAEMI) Janssen Pharmaceuticals, Inc. 1000 Route 202 Raritan, NJ 08869 www.janssenpharmaceuticalsinc.com Janssen Pharmaceuticals, Inc. 2014 December 2014 023695-141023