CADTH 2015 Symposium

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. Warfarin NOAC
Many indications Limited indications
Individualized dosing
Regular INR monitoring
Multiple fixed doses
INR monitoring not required
Drug interactions Fewer drug interactions
Less studied
Long half-life Short half-life
Antidote is Vitamin K No 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 CHADS2 Score?
CHADS2 Risk Criteria Score
Congestive heart failure 1
Hypertension 1
Age > 75 years 1
Diabetes mellitus 1
prior Stroke or TIA 2
CHADS2 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. CHADS2 score correlates with
stroke risk.
Points Annual Stroke Risk 95% Confidence Interval
0 1.9% 1.2-3.0
1 2.8% 2.0-3.8
2 4.0% 3.1-5.1
3 5.9% 4.6-7.3
4 8.5% 6.3-11.1
5 12.5% 8.2-17.5
6 18.2% 10.5-27.4
CHADS2 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

20. NOAC pivotal trials
Trial Characteristics RE-LY ROCKET-AF ARISTOTLE
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
18,113 14,264 18,201
Median follow-up 2 years 1.9 years 1.8 years
Age 71.5 years 73 years 70 years
Prior stroke/TIA ~20% ~55% ~20%
CHADS2 score 2.1 3.4 2.1
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)