1. Cross-Canada Collaboration to Promote Evidence-Based Use of Anticoagulants CADTH SYMPOSIUM APRIL 14, 2015

2. Speakers Sarah Jennings, BSc, BScPhm, RPh, PharmD Knowledge Mobilization Officer, CADTH Lynette Kosar, BSP, MSc (Pharm) Information Support Pharmacist, RxFiles Academic Detailing Isobel Fleming, BScPharm, ACPR Director of Academic Detailing Service, Dalhousie Bronwen Jones, MD, CCFP Director of Evidence Based Medicine, Dalhousie Cait O’Sullivan, PharmD, BScPh, BA Clinical Pharmacist, BC Provincial Academic Detailing Service

3. 350,000 Canadians have A-fib. They are 3 to 5 times more likely to have a stroke. Most need lifelong anticoagulant therapy.

4. Warfarin (Coumadin) has been the mainstay of therapy for many years. Newer oral anticoagulants (NOACs) approved in Canada for stroke prevention in people with atrial fibrillation: dabigatran (Pradaxa) rivaroxaban (Xarelto) apixaban (Eliquis)

5. WarfarinNOAC Many indicationsLimited indications Individualized dosing Regular INR monitoring Multiple fixed doses INR monitoring not required Drug interactions Fewer drug interactions Less studied Long half-lifeShort half-life Antidote is Vitamin KNo antidote, and no proven way to reverse anticoagulation effects if bleeding occurs

7. CADTH Systematic Review Absolute risk reduction per 1,000 patients treated each year Stroke / Systemic Embolism Major bleeding Intracranial bleeding Major GI bleeding MI Mortality dabigatran 110 mg 2 fewer (2 more, 4 fewer) 7 fewer (2 fewer, 11 fewer) 5 fewer (4 fewer, 6 fewer) 1 more (4 more, 1 fewer) 2 more (5 more, 0 more) 3 fewer (2 more, 8 fewer) dabigatran 150 mg 6 fewer (3 fewer, 8 fewer) 2 fewer (3 more, 6 fewer) 4 fewer (3 fewer, 5 fewer) 4 more (8 more, 1 more) 2 more (5 more, 0 more) 4 fewer (0 more, 9 fewer) rivaroxaban 3 fewer (1 more, 6 fewer) 1 more (6 more, 3 fewer) 3 fewer (1 fewer, 4 fewer) 8 more (13 more, 4 more) 2 fewer (1 more, 4 fewer) 4 fewer (2 more, 8 fewer) apixaban 3 fewer (1 fewer, 5 fewer) 8 fewer (6 fewer, 11 fewer) 4 fewer (3 fewer, 5 fewer) 1 fewer (1 more, 2 fewer) 1 fewer (1 more, 2 fewer) 4 fewer (0 more, 8 fewer)

8. Results – TTR > 66% Statistically significant reduction relative to adjusted dose warfarin? Stroke / Systemic Embolism Major bleeding dabigatran 110 mg 1 fewer (3 more, 5 fewer) 4 fewer (2 more, 10 fewer) dabigatran 150 mg 3 fewer (2 more, 6 fewer) 5 more (13 more, 2 fewer) rivaroxaban 5 fewer (2 more, 10 fewer) 11 more (25 more, 0 more) apixaban 3 fewer (1 more, 5 fewer) 6 fewer (0 more, 10 fewer)

9. Approximate Daily Costs Warfarin with monitoring ~$1 NOAC ~$3 Warfarin $0.06

10. CADTH messages Warfarin is the recommended first-line therapy for preventing stroke in patients with atrial fibrillation. New oral anticoagulants are a second-line option for some patients with non-valvular atrial fibrillation not doing well on warfarin. If a new oral anticoagulant is prescribed, patients must be monitored. For people who are able to use an anticoagulant, anticoagulant drugs should be used in preference to antiplatelet drugs.

12. On slideshare: http://www.slideshare.net/CADTH- ACMTS/fmf2013-debate-cox-andcarrier

13. What is academic detailing?

14. Education on anticoagulants: a priority across Canada

15. For More Information www.cadth.ca/clots Sarah Jennings sarahj@cadth.ca

16. EXTRA SLIDES prn

17. What is the CHADS 2 Score? CHADS 2 Risk CriteriaScore Congestive heart failure1 Hypertension1 Age > 75 years1 Diabetes mellitus1 prior Stroke or TIA2 CHADS 2 Score Determination Gage BF, et al. Validation of Clinical Classification Schemes for Predicting Stroke: Results From the National Registry of Atrial Fibrillation. JAMA 2001;285(22):2864-2870. A common method of estimating stroke risk in patients with A-fib

18. CHADS 2 score correlates with stroke risk. PointsAnnual Stroke Risk95% Confidence Interval 01.9%1.2-3.0 12.8%2.0-3.8 24.0%3.1-5.1 35.9%4.6-7.3 48.5%6.3-11.1 512.5%8.2-17.5 618.2%10.5-27.4 CHADS 2 Risk Score and Corresponding Risk for Stroke in AF Patients Not Treated With Anticoagulant Therapy Gage BF, et al. Validation of Clinical Classification Schemes for Predicting Stroke: Results From the National Registry of Atrial Fibrillation. JAMA 2001;285(22):2864-2870.

19. ISMP Report – Adverse events reported to FDA ISMP QuarterWatch. May 31, 2012. https://www.ismp.org/quarterwatch/pdfs/2011Q4.pdf https://www.ismp.org/quarterwatch/pdfs/2011Q4.pdf

20. NOAC pivotal trials Trial CharacteristicsRE-LYROCKET-AFARISTOTLE Intervention / Comparator dabigatran (110 mg or 150 mg) twice daily vs warfarin rivaroxaban 20 mg once daily vs warfarin apixaban 5 mg twice daily vs warfarin Randomized Sample Size 18,11314,26418,201 Median follow-up2 years1.9 years1.8 years Age71.5 years73 years70 years Prior stroke/TIA~20%~55%~20% CHADS 2 score2.13.42.1 Time in therapeutic range (TTR) 64%55%62%

21. Network Meta-Analysis (NMA)

22. Absolute risk reductions compared to warfarin are small: 2 to 6 fewer strokes and systemic embolism per 1000 patients treated per year 1 more to 8 fewer major bleeding events per 1000 patients treated per year Relative cost-effectiveness of the new agents is uncertain: depends on pricing of the new agents varies according to patient population heterogeneity of the underlying clinical data Expert Committee Deliberations

23. CADTH Current Practice report Findings – health professionals: Warfarin usually started by specialists, managed by family MDs Most are not using dosing tools Patient education a team effort? Specialists most open to the new agents Family MDs and allied health more cautious

24. CADTH Current Practice report Findings – patients: Satisfied with therapy, mixed in openness to taking new drugs Acknowledge inconvenience, but liked regular contact Felt confident in their level of knowledge, but actually had a limited understanding of warfarin therapy: MOST did not know they were taking warfarin to prevent stroke. MANY attributed benefits or side effects to warfarin that were unlikely to be due to the drug.

25. Warfarin Therapy – Knowledge and Practice Gaps  A well-coordinated, structured approach to warfarin therapy is recommended BUT:  The approach to warfarin therapy is sometimes “casual” or “ad hoc” with no definitive care plan  Dosing tools are an important part of a well-coordinated, structure approach to warfarin therapy BUT:  Most specialists and Family MDs are not using them  Patient education is a component of a well-coordinated, structured approach to warfarin therapy  Health professionals believe they are doing a good job of educating their patients about warfarin BUT  Patients’ level of understanding is quite low

26. What is a structured plan? Warfarin Management Plan Checklist Things to consider when developing a structured plan of care: Patient Follow-up INR Monitoring Dose adjustments (including dosing tool) Monitoring for complications/side effects Other health professionals involved in care/patient education Caregiver engagement Patient Education – ongoing

27. NOAC monitoring Indication Renal function Drug interactions Bleeding risk Patient education Compliance, compliance, compliance

28. Warfarin Clinical & Economic Reports Bottom Line: Unclear whether specialized anticoagulation clinics result in improved clinical outcomes compared with usual care. Evidence on patient self-testing/management was mixed, but they may lead to improvements in some patient outcomes. Uncertainty in terms of cost and cost-effectiveness.

29. Optimizing Warfarin Therapy – Recommendations The COMPUS Expert Review Committee (CERC) recommends: Patients with NVAF requiring warfarin be managed by a well- coordinated, structured approach dedicated to their anticoagulation therapy.* * Does not need to be restricted to specialized anticoagulation clinics. CERC does not recommend: Self-management for most patients with NVAF requiring warfarin. CERC determined: There is no evidence to make a recommendation on the role of warfarin management options in remote areas. NVAF (non-valvular atrial fibrillation)