AF stroke prevention in the Canadian context

AF stroke prevention in the Canadian context 5 th Annual State of the Heart Toronto, May 31, 2014 Andrew C.T. Ha, MD, MSc, FRCPC Cardiac Electrophysiology Toronto General Hospital, University Health Network Department of Medicine, University of Toronto

Faculty/Presenter Disclosure Faculty: Andrew C. T. Ha, MD Relationship(s) with commercial interests: Advisory board: Bayer Inc. Speaker s Honoraria: Bayer Inc.

Non-valvular atrial fibrillation (NVAF) Definition: AF in the absence of rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair. ACC/AHA/HRS 2014 AF guidelines. January CT et al. Circulation 2014 epub March 28 2014.

Oral anticoagulation for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) Stroke prevention with oral anticoagulation is one of the most important goals in AF management, particularly for patients at elevated stroke risk.

AF stroke prevention in the Canadian context: What are the important goals of care? 1) Accurate, systematic assessment of patients stroke and bleeding risk. 2) Identification of patients who would benefit from oral anticoagulation (OAC) for stroke prevention. 3) Individualization of OAC therapy (ie: warfarin vs. novel oral anticoagulant) for a given patient.

AF stroke prevention in the Canadian context: What are the important goals of care? 1) Accurate, systematic assessment of patients stroke and bleeding risk. 2) Identification of patients who would benefit from oral anticoagulation (OAC) for stroke prevention. 3) Individualization of OAC therapy (ie: warfarin vs. novel oral anticoagulant) for a given patient.

Assessment of stroke risk in non-valvular AF patients: CHADS 2 Risk of stroke without OAC therapy Stroke risk categorization: 0 point = low risk ; 1 point = intermediate risk ; 2 points = high risk ACC/AHA/ESC AF guidelines. Fuster V et al. Circulation 2006;114:e237-e354.

Assessment of stroke risk in non-valvular AF patients: CHA 2 DS 2 -VASc Stroke risk categorization: 0 point = low risk ; 1 point = intermediate risk ; 2 points = high risk Lip GYH et al. Chest 2010;137:263-272.

Assessment of bleeding in NVAF patients: HAS-BLED Clinical Characteristic Score H Hypertension 1 A Abnormal renal or liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding 1 L Labile INR 1 E Elderly age 1 D Drugs or alcohol (1 point each) 1 or 2 Maximum Score 9 Hypertension: SBP > 160 mmhg; Abnormal renal function: Chronic dialysis, renal transplant, serum creatinine 200μmol/L; Abnormal liver function: Chronic hepatitis, bilirubin > 2x upper limit of normal (ULN) in association with AST/ALT/ALP > 3 x ULN; Bleeding: Previous history, predisposition; Labile INRs: unstable/high INRs, in therapeutic range < 60%; Age > 65 years; Drugs/alcohol: Concomitant use of antiplatelet agents, nonsteroidal anti-inflammatory drugs, etc. Pisters et al. Chest, 2010;138:1093-100.

Relationship between HAS-BLED score and annual bleeding risk Bleeding risk categorization: < 3 points = lower risk ; 3 points = higher risk Gallego P et al. Circulation A & E 2012;5:312-3

AF stroke prevention in the Canadian context: What are the important goals of care? 1) Accurate, systematic assessment of patients stroke and bleeding risk. 2) Identification of patients who would benefit from oral anticoagulation (OAC) for stroke prevention. 3) Individualization of OAC therapy (ie: warfarin vs. novel oral anticoagulant) for a given patient.

2012 Canadian Cardiovascular Society Anticoagulation Guidelines (NVAF) C = congestive heart failure; H = hypertension; A = age 75; D = Diabetes; S = History of stroke or TIA (2 points) Skanes A. et al. 2012 CCS AF guideline update. OAC = oral anticoagulant

The benefit of warfarin in reducing stroke in patients with NVAF Hart RG et al. Annals of Internal Medicine 2007;146:857-

Novel oral anticoagulants (NOAC) Dabigatran (Pradaxa) (RE-LY) Rivaroxaban (Xarelto) (ROCKET- AF) Apixiban (Eliquis) (ARISTOTLE)

NOAC vs. Warfarin in the reduction of stroke or systemic embolic events: Meta-analysis of 4 randomized trials Ruff CT et al. Lancet 2013; Dec 3. pii: S0140-6736(13)623

Bleeding rates of NOAC vs. Warfarin: Randomized trials Miller CS et al. American Journal of Cardiology

Absolute difference in events (per 1000 patients treated) Net clinical benefit of NOAC versus Warfarin in NVAF patients: Meta-analysis of 4 RCTs 5 1 0 0-5 -10 Favours warfarin Favours NOAC Stroke or SE Ischemic stroke - (- 117 to - 3)* - (- 63 to 1) SE NOAC vs. Warfarin 0 (- 2 to 1) Any stroke Mortality Major bleed - -7 - (- 18 6 to 6) (- 11 to -3)* (- 7 12 to 2) Baker W and Phung O. Circulation: Cardiovascular Q & O 2012;5:711-719. Hem. stroke GI bleed - (- 64 to -2)* 6 (- 5 to 17) * p < 0.05 SE = systemic embolism

Oral anticoagulation for stroke prevention in patients with non-valvular atrial fibrillation (NVAF) Key Messages 1) For AF patients at elevated stroke risk, the most important thing we can do to reduce their chance of stroke is to prescribe an oral anticoagulant. 2) Both warfarin and NOAC agents are effective in reducing stroke rates in patients with AF. 3) Based on randomized clinical trials, NOAC use is associated with lower stroke and intracranial bleeding rates when compared to warfarin (absolute risk difference ~0.7%). 4) Based on randomized clinical trials, there is a trend toward higher GI bleeding rates with the use of NOAC (as a class) when compared to warfarin.

AF stroke prevention in the Canadian context: What are the important goals of care? 1) Accurate, systematic assessment of patients stroke and bleeding risk. 2) Identification of patients who would benefit from oral anticoagulation (OAC) for stroke prevention. 3) Individualization of OAC therapy (warfarin vs. novel oral anticoagulant) for a given patient.

What are the absolute differences in clinical benefits between warfarin and NOAC agents for NVAF stroke prevention? If you treat 1000 AF patients with NOAC agents instead of warfarin, you will prevent, on average, 7 strokes or systemic embolic events. If you treat 1000 AF patients with NOAC agents instead of warfarin, you will prevent, on average, 4 intracranial bleeds. Baker W and Phung O. Circulation: Cardiovascular Q & O 2012;5:711-71

(Partial) list of factors which I consider when prescribing warfarin vs. NOAC for stroke prevention Side effects Efficacy Safety Perceived risks/benefits Need for INR monitoring Warfarin vs. NOAC Drug interactions Availability of reversal agents Costs Compliance

Key important exclusion criteria in RE-LY, ROCKET-AF, ARISTOTLE Prosthetic heart valves. Significant heart valve disease (e.g. mitral stenosis). Recent cerebrovascular accident. Conditions associated with an increased risk of bleeding. Severe renal impairment [CrCl < 30 ml/min (RE-LY, ROCKET- AF); < 25 ml/min (ARISTOTLE)]. Active liver disease. Pregnancy. Connolly SJ et al. NEJM 2009;361:1139-1151. Patel M et al. NEJM 2011;365:883-891. Granger CB et al NEJM 2011;365:981-992.

What is the real-world practice pattern of AF stroke prevention in Canada? Multicentre, observational Canadian registry of NVAF patients. Primary objective: To determine how Canadian physicians assess stroke risk in AF patients and make therapeutic decisions around anticoagulation. Phase 1: Retrospective chart audit from > 100 practices (Family Medicine, Cardiology, Internal Medicine) across Canada. Phase 2: Prospective registry of ~ 3,000 subjects across Funded by an unrestricted research grant from Bayer Inc.

What are some factors which influence the choice of warfarin vs. NOAC agents? Insights from SPRINT-AF (phase 1) In SPRINT-AF, patient-centred factors such as side effect profile and costs appeared to be important factors in the choice of warfarin vs. NOAC agents. Gupta MK et al. ACC Scientific Sessions 2014. JACC 2014;63(12 Supp A):

Principles in selecting the type of oral anticoagulant for NVAF stroke prevention 1) Both warfarin and NOAC are effective drugs in reducing stroke risk in patients with NVAF. 2) Based on randomized clinical trials, NOAC use is associated with lower stroke and intracranial bleeding rates when compared to warfarin (absolute risk difference ~ 0.7%). 3) Patient-centred factors such as: convenience, need for INR monitoring, cost, and side effect profile are important factors in the choice of warfarin vs. NOAC agents. 4) Individualization of OAC therapy is key.

Concomitant use of antiplatelet agents with oral anticoagulants in patients with non-valvular atrial fibrillation (NVAF) A sizeable proportion of AF patients treated with oral anticoagulants (OAC) are also treated with antiplatelet (AP) agents. In randomized trials (RE-LY, ROCKET-AF, ARTISTOTLE), the rates of OAC+AP use ranged from 33-40%. In a large American AF registry (ORBIT-AF, n=7,374), the rate of OAC+AP use was 35%. In SPRINT-AF, ~ 1 out of 5 patients treated with OAC was also treated with an antiplatelet agent. Connolly SJ et al. NEJM 2009;361:1139-1151; Patel M et al. NEJM 2011;365:883-891; Granger CB et al NEJM 2011;365:981-992; Steinberg BA et al.

Incidence of major bleeding from concomitant use of antiplatelet agents and oral anticoagulation: RE- LY trial HR 2.16 HR 2.34 (95% CI: 1.53,3.57) (95% CI: 1.34,3.47) HR 2.39 (95% CI: 1.53,3.74) Rates of major bleeding (%) % HR 1.50 (95% CI: 1.23,1.80) 2.8% 4.6% 6.3% HR 1.81 (95% CI: 1.46, 2.24) 4.3% 2.6% 5.5% HR 1.53 (95% CI: 1.21,1.92) 3.8% 2.2% 5.4% No antiplatelet Single antiplatelet Dual antiplatelet Major bleeding: Reduction in Hb 20g/L; Transfusion of 2 units of blood; Symptomatic bleeding in a critical area or organ. (median follow- Dans A et al. Circulation 2013;127:634-640.

Concomitant use of antiplatelet agents with oral anticoagulants in patients with non-valvular atrial fibrillation (NVAF) The use of concomitant OAC + antiplatelet agents is associated with an increased risk of bleeding (~1.5 fold increased risk). The use of OAC + dual antiplatelet therapy should be avoided, if possible. There are currently no guideline recommendations on the use of NOAC + antiplatelet agents. In AF patients already treated with OAC, the role of antiplatelet agents in the reduction of cardiovascular ischemic events is not well defined.

AF stroke prevention in the Canadian context: What are the important goals of care? 1) Accurate, systematic assessment of patients stroke and bleeding risk. 2) Identification of patients who would benefit from oral anticoagulation (OAC) for stroke prevention. 3) Individualization of OAC therapy (ie: warfarin vs. novel oral anticoagulant) for a given patient.

AF stroke prevention in the Canadian context: 3 Key messages 1) Both warfarin and new oral anticoagulant (NOAC) agents are effective in reducing stroke rates for at-risk NVAF patients. When prescribing OAC for AF patients, accurate assessment of their stroke and bleeding risks should be done. The choice of warfarin vs. NOAC needs to be individualized. 2) In randomized trials, stroke and intracranial bleeding rates were lower with NOAC agents when compared with warfarin (~ 0.7% absolute difference in favour of NOAC agents). 3) Patients treated with OAC + antiplatelet agents are at increased risk of bleeding (~1.5 fold when compared to patients treated with OAC alone). We should carefully scrutinize the reasons for using an antiplatelet agent in a patient who is already treated with OAC.

Thank you for your attention andrew.ha@uhn.ca