Janssen Pharmaceuticals, Inc.

Unstable INR Has Implications for Healthcare Resource Use

Stable INR is essential for eff ective anticoagulation treatmentAchieving a stable international normalized ratio (INR), defi ned 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 fl uctuations in INR.1,2

A meta-analysis of 95 studies of patients with atrial fi brillation (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 fl uctuations 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

Even after achieving stabilization, fl uctuation 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 diffi culty of achieving stable INRThe 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

Increase in likelihood of remaining on warfarin therapy when INR was stabilized within 1 year7

Share of patients who never achieved INR stability7

Share of patients with INR above or below therapeutic range after stabilization7

The average time required to stabilize INR in patients taking warfarin7

Implications for healthcare resource useFor 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 fi vefold increase in the risk of death than those who achieved INR values within the defi ned 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 eff ects associated with the diffi culties of warfarin management:

Emergency hospitalizations related to adverse drug

events involving warfarin‡8

Incremental cost of treating hemorrhagic events in patients who used warfarin-potentiating

medication§9

A concomitant medication was implicated in 12.5%

of hospitalizations attributed to warfarin‡8

The challenges

of warfarin use may

be underestimated.

In patients with AF and

VTE, INR instability

has implications for

healthcare resource

use and costs.

* 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 fi rst ≥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-uptime was 15 months. Mean ages of those achieving and not achieving INR stabilization were 72.4 and 70.7 years, respectively. Stabilization was defi ned 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 defi ned as having all INR values within the strictly defi ned therapeutic reference interval for the fi rst identifi able 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

StudyDesigns

© Janssen Pharmaceuticals, Inc. 2014 December 2014 023695-141023

References1. 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 fi brillation 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 fi brillation 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 fi brillation. 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 fi brillation. Clin Ther. 2012;34:1569–1582.

Sebastian Ferreira, UntitledArtwork from the National Art Exhibitions of the Mentally Ill, Inc. (NAEMI)

Janssen Pharmaceuticals, Inc.

1000 Route 202Raritan, NJ 08869

www.janssenpharmaceuticalsinc.com