Indications of Anticoagulants; Which Agent to Use for Your Patient? Marc Carrier MD MSc FRCPC Thrombosis Program Ottawa Hospital Research Institute

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1 Indications of Anticoagulants; Which Agent to Use for Your Patient? Marc Carrier MD MSc FRCPC Thrombosis Program Ottawa Hospital Research Institute

2 Disclosures Research Support/P.I. Employee Leo Pharma (PERIOP 01 Trial) BMS (AVERT trial) No relevant conflict of interest to declare Consultant No relevant conflict of interest to declare Major Stockholder No relevant conflict of interest to declare Speakers Bureau No relevant conflict of interest to declare Honoraria Scientific Advisory Board Sanofi Aventis, Pfizer, Boehringer Ingelheim, Leo Pharma, Bayer. Sanofi Aventis, Leo pharma.

3 Objectives Discuss latest practice changing research pertaining to the prevention of stroke in patients t with non-valvular l atrial fibrillation. Review key VTE treatment trials Identify which oral anticoagulant to chose based on patients characteristics

4 Atrial Fibrillation

5 CHADS2 score 1 point for Congestive Heart Failure 1 point for Hypertension 1 point for Age 75 years 1 point for Diabetes Mellitus 2 points for Prior Stroke or TIA CHADS 2 Score* Stroke Rate, %/yr (95 %CI) ( ) ( ) ( ) 3 59( (4.6 73) 7.3) ( ) ( ) ( ) Gage BF, et al. JAMA. 2001;285: *Score 0: Patients can be administered aspirin *Score 1: Patients can be administered aspirin or anticoagulant therapy *Score 2: Patients should be administered anticoagulant therapy

6 CHA 2 DS 2 -VASc score 1 point for Congestive Heart Failure/ One year event rate (95% CI) of hospital CHA 2 DS 2 -VASc LV Dysfunction admission and death due to Score* thromboembolism 1 point for Hypertension per 100 person year 2 points for Age 75 years ( ) 1 point for Diabetes Mellitus 1 201( ( ) 2 points for Prior Stroke or TIA 1 or TE ( ) 1 point for Vascular Disease ( ) 1 point for Age years ( ) 1 point for Sex category (female gender) ( ) ( ) ( ) ( ) ( ) Lip GY et al. Chest 2010;137: p Olesen JB, et al. BMJ 2011;342:d124 Eur Heart J 2010;31: *Score 0: Patients can be administered aspirin *Score 1: Patients can be administered aspirin or anticoagulant therapy *Score 2: Patients should be administered anticoagulant therapy Includes peripheral artery embolism, ischemic stroke, and pulmonary embolism

7 CCS 2012 Update to AF guidelines Assess Thromboembolic b Risk (CHADS 2 ) CHADS 2 =0 CHADS 2 =1 CHADS 2 2 Increasing stroke risk No antithrombotic ASA OAC* OAC* OAC No additional risk factors for stroke Either female sex or vascular disease Age 65 yrs or combination of female sex and vascular disease *Aspirin is a reasonable alternative in some as indicated by risk/benefit Consider stroke risk vs. bleeding risk Only when the stroke risk is low and bleeding risk is high does the risk/benefit ratio favour no antithrombotic therapy Skanes AC, et al. Can J Cardiol 2012;28:

8 Warfarin is highly effective for the prevention of stroke in patients with AF 64% RRR 38% RRR 40% RRR Warfarin vs. Placebo Warfarin vs. ASA Warfarin vs. ASA+ Clopidogrel l Favours Warfarin Favours Comparator Hart et al Ann Intern Med. 2007;146: Connolly et al. Lancet. 2006;367:

9 Warfarin Advantages Active by oral route Once daily dosing Can be monitored Rapidly-acting acting antidote available Low cost Disadvantages Delayed onset of action Long-half life i.e. Needs to be held for many days pre-op Many drug-drug and drug-food interactions Needs monitoring

10 New oral anticoagulants (NOACs) Figure from: Steffel et al. J Cardiovasc Med 2009;10:616-23

11 Kaatz et al. Am J Hematol 2012 May;87 Suppl 1:S141-5 NOACs

12 Trials of NOACs for nonvalvular atrial fibrillation RELY ROCKET AF ARISTOTLE No patients Drug Dabigatran 150 mg, 110 mg Rivaroxaban 20 mg Apixaban 5 mg Study design Open label Double blind Double blind CHADS Warfarin, rivaroxaban, dabigatran and apixaban are effective in preventing strokes and systemic embolism in patients with atrial fibrillation 1. Connolly et al. NEJM 2009; 2. Patel et al. NEJM 2011; 3. Granger et al. NEJM 2011

13 NOACs vs. warfarin NOACs are associated with a RRR of 20% compared to warfarin Ruff CT et al. Lancet 2014;383:

14 NOACs vs. warfarin NOACs reduce hemorrhagic stroke, overall mortality and ICH but increase GI bleeding Ruff CT et al. Lancet 2014;383:

15 Similarities NOACs: All the same? Non-inferior to warfarin for efficacy Less ICH than with warfarin Decrease overall mortality compared to warfarin No hepatic toxicity Differences Increase risk of MI in patients taking dabigatran compared to warfarin More GI bleeding with rivaroxaban and dabigatran Dabigatran (150 mg BID) is associated with lower risk of ischemic strokes compared to warfarin Apixaban is associated with both lower risk of stroke and major bleeding compared with warfarin Weitz JL et al. Hematology Am Soc Hematol Educ Program;2012:

16 Choice of anticoagulation based on patients characteristics Weitz JL et al. Hematology Am Soc Hematol Educ Program;2012:

17 DVT and PE: Anatomy Tapson VF. N Engl J Med 2008; 358(10):

18 Traditional Treatment of VTE Initial treatment 5-7 days LMWH or UFH* Long-term therapy >3 months VKA** (INR ) ) *UFH = unfractionated heparin UFH unfractionated heparin **VKA = vitamin K antagonist INR = international normalization ratio

19 Trials of NOACs for VTE EINSTEIN (PE +DVT) RE-COVER (1 + 2) AMPLIFY No patients Drug Rivaroxaban 15 mg PO BID X 21 days then 20 mg Enoxaparin X 5 days then dabigatran 150 mg PO BID Apixaban 10 mg BID X 7 days then 5 mg PO BID Study design Open label Double blind Double blind Follow-up 3, 6 or 12 months 6 months 6 months Warfarin, rivaroxaban, dabigatran and apixaban are effective in preventing recurrent VTE in patients with acute DVT or PE Rivaroxaban and apixaban are associated with less bleeding compared to warfarin Einstein investigators N Engl J Med 2010; 363: Einstein investigators N Engl J Med 2012; 363: Schulman S et al. NEJM. 2009;361: Agnelli G et al. N Engl J Med 2013; 368:

20 Licensed indications of NOACS in Canada Stroke prevention in patients with non-valvular atrial fibrillation Dabigatran 150 or 110 mg PO BID Rivaroxaban 20 mg PO daily Apixaban 5 mg PO BID Acute Treatment of DVT and PE Rivaroxaban 15 mg PO BID X 21 days then 20 mg PO daily

21 Licensed indications of NOACS in Canada Th b h l i f hi k th l t Thromboprophylaxis for hip or knee arthroplasty Dabigatran 220 mg or 150 mg PO daily Rivaroxaban 10 mg PO daily Apixaban 2.5 mg PO BID Minimum of 10 days Extension to 28 to 35 days should be considered after THR

22 Thank You!