1. Frequency of Monitoring, Non-adherence, and Other Anticoagulation Topics Nathan Clark, Pharm D, BCPS Clinical Pharmacy Supervisor Anticoagulation and Anemia Services Kaiser Permanent Colorado

2. Objectives Review recommendations from ACCP regarding INR monitoring intervals Discuss the consequences of non-adherence with INR monitoring Review recommendations from ACCP regarding the management of first episode, near-miss INR Discuss the risk of thromboembolism among stable patients presenting with a significantly low INR

3. Survey: What is the maximum duration between INR checks at your institution for stable warfarin patients? a.4 weeks b.8 weeks c.12 weeks d.Something else?

4. Frequency of INR Monitoring …VKA therapy with consistently stable INRs, we suggest INR testing up to every 12 weeks rather than every 4 weeks (Grade 2B) CHEST 2012; 141(2)(Suppl):e152S–e184S

5. Frequency of INR Monitoring Frequency of INR testing has evolved from expert opinion Data regarding extended INR recall intervals is conflicting

6. 4 weeks versus 12 weeks 250 patients were randomized to either 4 week or 12 week recheck INR intervals Target INR 2–3 or 2.5–3.5 No dose change in previous 6 months Primary outcome was TTR Ann Intern Med. 2011;155:653-659

7. 4 weeks versus 12 weeks Outcome4 week (n=126) 12 week (n=124) TTR % (SD %) 74.1 (18.8)71.6 (20.0) 1 1 dose changes; n (%) 70 (55.6)46 (37.1) 2 INR 4.5; n (%) 15 (11.9)8 (6.5) INR 1.5; n (%) 12 (9.5)11 (8.9) Clinical Events; n (%) Major bleeding 1 (0.8)2 (1.6) Thromboembolism 1 (0.8)0 (0) Death 5 (4.0)2 (1.6) TTR – time in therapeutic range; SD – standard deviation; INR – international normalized ratio 1-Noninferiority established, absolute difference = 2.5% (1 sided 97.5% CI upper bound 7.3%) 2- Absolute difference = 18.5% (6.1 to 30.0); p=0.004

8. Survey: How much staff time is spent reminding patients to come in for repeat INR testing each week at your center? a.Less than one hour b.1 to 5 hours c.More than 5 hours d.No idea, but more time than I care to think about

9. Nonadherence Most studies of adherence have evaluated pill taking behavior Less reliable pill taking = poor INR control ART-DECO study evaluated adherence with lab monitoring Less reliable INR monitoring = greater risk of TE Arch Intern Med 2007 Feb 12;167(3):229-35

10. Improving Adherence with INR Monitoring Interactive voice response (IVR) calls Study evaluated IVR to provide INR results, warfarin dose details and recheck INR plus reminders No change in INR control 80.3% vs 79.9% Reduced workload CMAJ 2009 Apr 28;180(9):927-33

11. Improving Adherence with INR Monitoring Down side to IVR? Many patients dont like the calls (some strongly dislike them) Elderly patients are often unable to interact or operate IVR 1 in 5 patients older than 65 were unable perform any IVR task J Gerontol B Psychol Sci Soc Sci 2012 Oct 25. [Epub ahead of print]

12. Improving Adherence with Pill Taking Lottery-based incentive program RCT Lottery arm: 1 in 5 chance of getting $10 each day 1 in 100 chance of getting $100 each day Control arm: No incentive Am Heart J 2012;164:268-74

13. Improving Adherence with Pill Taking Overall, no change in out of range INRs: 23.0% lottery vs 25.9% control; p>0.05 In-range INR at study entry: No change in out of range INRs: OR=1.26 (95% CI, 0.76-2.09, p=0.37) Low INR at study entry: Reduction in out of range INRs; OR=0.39 (95% CI, 0.25-0.62, p<0.001) Am Heart J 2012;164:268-74

14. Case 1 C.Y. is a 76 yoF with AF and HTN. No other notable risk factors for stroke or bleeding. Her warfarin dose has been stable for months with therapeutic INR control. Today she presents with an INR of 1.7 (target 2-3). There are no identifiable causes for the low INR.

15. Survey: Which do you recommend? a.Increase weekly warfarin dose 10% b.Increase weekly warfarin dose 15% and start LMWH bridge c.No change in warfarin dose d.Follow DAWN AC suggestion e.Something else?

16. Isolated out-of-range INRs …previously stable therapeutic INRs who present with a single out-of-range INR of 0.5 below or above, we suggest continuing the current dose… (Grade 2C) CHEST 2012 141(2)(Suppl):e152S–e184S

17. Survey: When would you recheck the INR for C.Y.? a.1 week b.2 weeks c.4 weeks d.Follow DAWN AC suggestion e.Something else?

18. Isolated out-of-range INRs …single out-of-range INR of 0.5 below or above, we suggest continuing the current dose and testing the INR within 1 to 2 weeks (Grade 2C) CHEST 2012; 141(2)(Suppl):e152S–e184S

19. Low INRs Over 2 years of follow up, 1 in 3 patients will have an INR 1.5 Causes of subtherapeutic INR include: Nonadherence (17%) Invasive procedures (16%) Dose reduction (15%) Unexplained (15%) Second or greater consecutive low INR (13%) Circ Cardiovasc Qual Outcomes 2009; 2: 591-597

20. Low INR: Risk of Thromboembolism Retrospective cohort studies have attempted to isolate and quantify the risk of significantly low INR values INR target range INR 0.5 below target range 90 day follow up for TE 2 weeks

21. Low INR: Risk of Thromboembolism Anticoagulation characteristics were comparable: Therapeutic doses of LMWH for bridging were uncommon (1.2 to 3.2%) Median index INR 1.4 to 1.75 Mean duration of subtherapeutic anticoagulation ~ 16 days (2 studies) 1. Am J Hematol 2012; 87:384–387 2. J Thorac Cardiovasc Surg 2009;137:91-3 3. Pharmacotherapy 2008;28(8):960–967

22. Low INR: Risk of Thromboembolism Indication for VKA (n) 1 23

23. Influence of LMWH Bridge Therapy Dentali [2] described LMWH bridging in 12.8% (64 of 501 patients) Prophylactic dose (n=11, 2.2%) Intermediate dose (n=37, 7.4%) Therapeutic dose (n=16, 3.2%) Baseline characteristics did not differ between those who did or did not receive LMWH bridging Am. J. Hematol 2012; 87:384–387

24. Low INR: Risk of Thromboembolism Am. J. Hematol 2012; 87:384–387 MVR or AF patients

25. The Low INR Study: Case-Control Design INR target range Index INR 0.5 below target range Index INR within target INR range 90 day follow up: No INR criteria 90 day follow up: No INR 0.2 below target Low INR Cohort Therapeutic Cohort 2 weeks

26. The Low INR Study Pharmacotherapy 2008;28(8):960–967

27. Thromboembolic Outcomes Thromboembolic events(3 studies) (n,%) Stroke, SE, or valve thrombosis (7, 58%) Transient ischemic attack (4, 33%) Myocardial infarction (1, 8%) 1. Am J Hematol 2012; 87:384–387 2. J Thorac Cardiovasc Surg 2009;137:91-3 3. Pharmacotherapy 2008;28(8):960–967

28. Low INRs For patients with stable therapeutic INRs presenting with a single subtherapeutic INR value, we suggest against routinely administering bridging with heparin (Grade 2C) CHEST 2012; 141(2)(Suppl):e152S–e184S