New options in Stroke Prevention in AF Paul Dorian University of Toronto St Michael s Hospital

Transcription

1 New options in Stroke Prevention in AF Paul Dorian University of Toronto St Michael s Hospital Disclosures: Honoraria, research support, and consulting f Sanofi, Boehringer-Ingleheim, Portola, BMS, Bayer, Pfizer

2 Reduction of cardiovascular morbidity & mortality New treatment goals in AF Therapy to reduce major morbid events ( CHF, ischemic events, stroke, hospitalizations) Thromboembolism prevention More consistent use of Anticoagulants Symptom control Individualized treatmentpatient specific therapeutic contract

3 AF is an independent risk factor for stroke and the attributable risk increases with Framingham age Stroke Risk Attributableto AF % % 2.8% 9.9% Significant increase with age p< % Age (years) Wolf et al. Stroke 1991;22:

4 CHADS(2) Score : Is it incomplete? Combination of AFI and SPAF schemes 1 Congestive Heart Failure 1 Hypertension 1 Age > 75 years 1 Diabetes Mellitus 2 Prior Stroke or TIA Score* Stroke rate 1.9 ( ) 2.8 ( ) 4.0 ( ) 5.9 ( ) 8.5 ( ) 12.5 ( ) 18.2 ( ) *Score 0: Patients can be administered aspirin *Score 1: Patients can be on aspirin and Vitamin K antagonists *Score 2: Patients should be on Vitamin K antagonists Gage BF, et al. JAMA. 2001;285:

5 Reweighted CHADS2 Patient Age, sex and history of stroke/tia important Am Heart J 2008; 156:

6 CHA 2 DS 2 -VASc Guidelines for the management of atrial fibrillation European Heart Journal doi: /eurheartj/ehq278

7 RRR = 64% Hart Ann Int Med 1999;131:492 Atrial Fibrillation Guidelines

8 RCTs Warfarin vs ASA RRR=39% Hart. Ann Int Med 2007;147:590 Atrial Fibrillation Guidelines

9 Predictors of Underuse of Antithrombotic Therapy in AF Age (years) Gender Hospital Location Antithrombotic Therapy Prescribed at Discharge Warfarin (%) Aspirin (%) Neither (%) > Male Female Urban Rural Gage B, et al. Stroke. 2000;31: Medicare patients with AF

10 Stroke prevention in AF: The Treatment Gap Warfarin is very effective in stroke prevention In clinical practice, using warfarin is HARD: Pts don t want to take it MDs don t want to prescribe it Stroke risk is underestimated Bleeding risk is overestimated The pharmacology is complex and requires pts, MDs, pharmacists to understand interactions ; and some variability is due to chance and spontaneous changes in Vit K activity and individual genotype Systems to improve INR control are absent in Canada ( INR clinics, algorithms to improve control, education to optimize testing frequency and response re dose changes) As a result: warfarin is underused, dosed imperfectly, and overall stroke risks remain high despite cheap and available warfarin and INR blood tests

11 ACTIVE-W Benefit of Oral Anticoagulant Over Antiplatelet Therapy in Atrial Fibrillation Depends on the Quality of International Normalized Ratio Control Achieved by Centers and Countries as Measured by Time in Therapeutic Range Stroke Outcome; TTR= time in therapeutic range Connolly et al. Circulation 2008; 118:

12 ACTIVE W:Major Bleeding and INR Control 65% INR in Range Cumulative Hazard Rates RR = 1.55 P = C+A OAC Interaction P = <65% INR in Range RR = 0.68 P = 0.08 OAC C+A ACTIVE Writing Group: Lancet 2006;367: Years

13 INR control: clinical trials v. clinical practice INR* control in clinical trial versus clinical practice (TTR**) 66% Clinical trial 1 % of eligible patients receiving warfarin 25% 38% 44% 9% Clinical practice 2 18% *INR = International normalized ratio < >3.0 INR ** TTR = Time in Therapeutic Range (INR ) 1. Kalra L, et al. BMJ 2000;320: * Pooled data: up to 83% to 71% in individualized trials; 2. Matchar DB, et al. Am J Med 2002; 113:42-51.

14 Drug vs. warfarin Features of phase III RCTs of oral anticoagulants for stroke prevention in AF ARISTOTLE 1 ROCKET-AF 2 RE-LY 3 Apixaban 5 mg bd rivaroxaban 20 mg od dabigatran 110 mg or 150 mg bid Design double-blind, non-inferiority double-dummy, non-inferiority PROBE design non-inferiority (re-volution program) Patients with AF 15,000 (Dec 06 to Nov 10) 14,266 (June 07 May 10) 18,113 (Nov 05 - Apr 09) Outcome confirmed stroke or systemic embolism composite of major and non-major clinically relevant bleeding events; any stroke or non-cns systemic embolism stroke (incl. haemorrhagic) and systemic embolism (1) NCT; NCT ; (2) NCT ; (3) NCT

15 Time to first stroke / SSE Cumulative hazard rates Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg RR 0.90 (95% CI: ) p<0.001 (NI) p=0.30 (Sup) RRR 35% RR 0.65 (95% CI: ) p<0.001 (NI) p<0.001 (Sup) Years RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superior Connolly SJ., et al. N Engl J Med 2009; 361: Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

16 Life threatening bleeding 2.00 RR 0.67 (95% CI: ) p<0.001 (sup) RR 0.80 (95% CI: ) p=0.03 (sup) 1.50 RRR 33% 1.49 RRR 20% 1.85 % per year D110 mg BID D150 mg BID Warfarin Connolly SJ., et al. N Engl J Med 2009; 361: / 6, / 6, / 6,022 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

17 Hemorrhagic stroke 50 RR 0.31 (95% CI: ) p<0.001 (sup) RR 0.26 (95% CI: ) p<0.001 (sup) Number of events RRR 69% RRR 74% % % 0.10% 0 D110 mg BID D150 mg BID Warfarin 6,015 6,076 6,022 Connolly SJ., et al. N Engl J Med 2009; 361: Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

18 Connolly et al N Engl J Med; 361:

19 CCS 2010 AF guidelines We recommend that all patients with AF or AFL (paroxysmal, persistent or permanent), should be stratified using a predictive index for the risk of stroke (e.g. CHADS2) and for the risk of bleeding (e.g. HAS-BLED), and that most patients should receive antithrombotic therapy. (Strong Recommendation,) We recommend that patients at very low risk of stroke (CHADS2 = 0) should receive aspirin ( mg/ day). (Strong Recommendation, High Quality Evidence) We recommend that in most patients at low risk of stroke (CHADS2 = 1) should receive either warfarin (INR 2 3) or dabigatran. (Strong recommendation) However, based on individual risk/benefit considerations, we suggest that aspirin is a reasonable alternative for some. (Conditional Recommendation,).

20 CCS 2010 AF guidelines We recommend that patients at moderate to high risk of stroke (CHADS2 2) should receive either warfarin (INR 2 3) or dabigatran. (Strong Recommendation, High Quality Evidence) We suggest, based on its safety and efficacy profile, that dabigatran is preferred over warfarin. In general, the dose of dabigatran 150 mg po bid is preferred over a dose of 110 mg po bid for overall stroke reduction. (Conditional Recommendation, High Quality Evidence)

21 Overview of Thromboembolic Management Assess Thromboembolic Risk (CHADS 2 ) and Bleeding Risk (HAS- BLED) CHADS 2 = 0 CHADS 2 = 1 CHADS 2 1 aspirin OAC* OAC No antithrombotic may be appropriate in selected young patients with no stroke risk factors *Aspirin is a reasonable alternative in some as indicated by risk/benefit Dabigatran is preferred OAC over warfarin in most patients. Atrial Fibrillation Guidelines

22 Antithrombotic Management of AF/AFL in CAD Stable CAD Recent ACS PCI Choose antithrombotic based on stroke risk Choose antithrombotic based on balance of risks and benefits Choose antithrombotic based on balance of risks and benefits CHADS 2 = 0 CHADS 2 1 CHADS 2 1 CHADS 2 2 CHADS 2 1 CHADS 2 2 Aspirin OAC* monotherap y aspirin + clopidogre l Triple anti- thrombotic Rx aspirin + clopidogre l Triple anti- thrombotic Rx * Warfarin is preferred over dabigatran for patients at high risk of coronary events Atrial Fibrillation Guidelines

23 Potential problems with dabigatran Renal elimination: poor or sudden worsening of renal function Adverse effects causing discontinuation Non-reversible effect- no antidote In practice, no easy way to measure drug effect (extent of anticoagulation) 23

24 No diet will remove all the fat from your body because the brain is entirely fat. Without a brain, you might look good, but all could do is run for public office. George Bernard Shaw