Atrial Fibrillation: Stroke and Thromboprophylaxis. Derek Waller

Transcription

1 Atrial Fibrillation: Stroke and Thromboprophylaxis Derek Waller

2 Atrial Fibrillation in the Elderly: Risk of Stroke Framingham study AGE Prevalence of AF % Attributable Risk of AF for Stroke % Wolf et al, Stroke 1991

3 Annual risk of stroke (%) Stroke Risk in Paroxysmal AF Observed rate of ischaemic stroke 14 Paroxysmal AF Sustained AF Low Moderate High Stroke risk category Hart RG et al. J Am Coll Cardiol 2000;35:183 7; 2. Flaker GC et al. Am Heart J 2005;149:657 63

4 Stroke as a Complication of AF AF doubles the risk of stroke when adjusted for other risk factors Without preventive treatment, when transient ischaemic attacks and clinically silent strokes are considered, the rate of brain ischaemia associated with non-valvular AF exceeds 7% per year Estimated that 15% of all strokes are caused by AF

5 Stroke Morbidity and AF 55% of strokes in people with AF cause moderate or severe disability or are fatal Compared with other patients with stroke, those with AF are more likely to: Have cortical deficit (e.g. aphasia), severe limb weakness and diminished alertness Have longer in-hospital stay with a lower rate of discharge to their own home The mortality rate for patients with AF and stroke is double that in people with normal heart rhythm

6 Thromboprophylaxis in Atrial Fibrillation

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8 Efficacy of Aspirin Compared with No. of Events Patientyears AFASAK SPAF EAFT Combined * Control Risk Reduction (%) Aspirin Better Aspirin Worse

9 Efficacy of Warfarin No. of Events Patientyears AFASAK Risk Reduction, % BAATAF CAFA SPAF SPINAF Combined* Warfarin Better Warfarin Worse

10 Warfarin or Aspirin? Warfarin RRR 69% Aspirin RRR 22%

11 Survival Probability Warfarin, INR and Stroke Survival None Aspirin Warfarin, INR< 2 Warfarin, INR>=2 p = Hylek, et al. NEJM Days Since Admission

12 Cumulative Hazard Rates Active A: Stroke, Non-CNS Systemic Embolism, MI & Vascular Death HR=0.72 ( ) p= Placebo+Aspirin Clopidogrel+Aspirin No. at Risk C+A ASA Years

13 Cumulative Hazard Rates Active W: Stroke, Non-CNS Systemic Embolism, MI & Vascular Death RR = 1.45 P = Clopidogrel+ASA 5.64 %/year 3.93 %/year OAC # at Risk C+A OAC Years

14 Cumulative Hazard Rates Active W: Major Bleeding 2.4 %/year RR = 1.06 P = %/year OAC Clopidogrel+ASA # at Risk C+A OAC Years

15 Cumulative Hazard Rates ACTIVE W Primary outcome by centre INR control % INR in Range RR = 1.83 P < C+A OAC <65% INR in Range RR = 1.11 P = 0.47 C+A OAC Interaction P= Years Connolly S et al. Lancet 2006; 367:

16 AFFIRM 4060 patients who could tolerate AF Randomized to rhythm or rate control Rate control: digoxin 51%, beta blocker 49%, calcium antagonist 41% Rhythm control: amiodarone 39%, sotalol 33%, propafenone 10% Follow-up 3.5 years Rhythm control: 60% in SR, 70% warfarin Rate control: 85-90% warfarin Trend to more strokes in rhythm control group Stroke risk most closely related to use of warfarin, not rhythm NHLBI AFFIRM Investigators. Am J Cardiol. 1997;79:

17 (5.7) (7.3) * 69% 79% Implications: Don t stop anticoagulation even if SR restored Follow the INR guidelines (>2.0)

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19 Risk Factors for Stroke in AF Risk Factor Prior stroke Age Hypertension Diabetes Heart failure or Mod/severe LVSD Relative Risk (multivariate) (per decade) The Atrial Fibrillation Investigators Arch Intern Med 1994;154:1449

20 CHADS 2 and CHA 2 DS 2 VASc CHADS2 Risk Score CHA2DS2-VASc Risk Score CHF 1 Hypertension 1 Age > 75 1 Diabetes 1 CHF or LVEF < 40% Hypertension 1 Age > 75 2 Diabetes 1 Stroke/TIA/ Thromboembolism 1 2 Stroke or TIA 2 Vascular Disease 1 From ESC AF Guidelines guidelines/guidelinesdocuments/guidelines-afib- FT.pdf Age Female 1

21 CHADS 2 -> CHA 2 DS 2 VASc CHADS2 score Patients (n = 1733) Stroke rate %/year CHA2DS2- VASc score Patients (n = 7329) Stroke rate (%/year) From ESC AF Guidelines:

22 Risk factors for stroke CHF: HFREF or any recent decompensation requiring hospitalisation Female sex is not a risk factor if <65 years old and lone AF CKD predicts stroke risk, but also increased bleeding risk Hart RG et al. Stroke 2005;36: Camm et al Eur Heart J 2012; 33: 2719

23 Clinical flowchart for the use of oral anticoagulation for stroke prevention in AF. Eur Heart J 2010;eurheartj.ehq278

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25 Warfarin vs Aspirin after Stroke in Atrial Fibrillation Annual absolute risk of stroke in patients with atrial fibrillation Untreated (%) Aspirin (%) Warfarin (%) NNT* Previous ischaemic stroke or TIA 12% 10% 5% 13 * number needed to treat with warfarin instead of aspirin for 1 year to prevent one 1 stroke adapted from SIGN guidelines 1999

26 Intracerebral Haemorrhage with Thromboprophylaxis >10% of intracerebral haemorrhages occur in patients on antithrombotic therapy Similar risk of major haemorrhage and ICH in elderly with aspirin and warfarin Hart RG et al. Stroke 2005;36: Camm et al Eur Heart J 2012; 33: 2719

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28 Anticoagulation With Warfarin: A Risk-Benefit Balance Odds Ratio for an Adverse Event According to Prothrombin Time Ratio (red line) and INR Value (blue line) STROKE BLEEDING Hylek. Ann Intern Med. 1994;120:897. Hylek. N Engl J Med. 1996;335:540.

29 Major Hemorrhagic Events and Warfarin Terminations by CHADS 2 Score CHADS 2 Score N Major Bleed (N) Bleeding Rates % Taken Off Therapy (N) Taken Off Rates % Total Hylek EM et al, Circulation 2007;115(21):

30 Cumulative Proportion with Major Hemorrhage Major Bleeding in the First Year Among Patients Newly Starting Warfarin by Age Age > 80 Age < Days on Warfarin Hylek EM et al, Circulation 2007;115(21):

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32 HAS-BLED and Outcome Bleeds % per year Score 0: 1.13 Score 1: 1.02 Score 2: 1.88 Score 3: 3.74 Score 4: 8.70 Score 5: 12.5 Lip et al JACC 2011; 57:

33 Warfarin and Falls Risk of accidental fall and cerebral bleed aged >65 years A person must fall approximately 300 times in 1 year for warfarin not to be the optimal therapy Risk of falling not a determinant of optimal antithrombotic therapy if CHADS 2 2 When risk of stroke < 2% (CHA 2 DS 2 Vasc), then warfarin may not be the best choice in fallers

34 Warfarin for AF INR 2.5 Treat paroxysmal AF and atrial flutter as persistent AF Continue even after restoring SR if high risk of recurrence and risk stratification when in AF suggests using warfarin

35 Combination of Warfarin and Aspirin No benefit for routine use Increased bleeding risk May be advantageous if previous MI

36 Combination Antiplatelet Therapy with Warfarin Discuss with a cardiologist Triple therapy with aspirin, clopidogrel and warfarin may be appropriate after a stent if CHADS 2 is 2 or more If low stroke risk, consider clopidogrel with aspirin for first 12 months, then warfarin alone

37 Warfarin for Atrial Fibrillation Adequacy of Anticoagulation in Patients with AF in Primary Care No warfarin 65% INR above target 6% INR in target range 15% INR Subtherapeutic 13% Samsa GP, et al. Arch Intern Med 2000;160:967.

38 Targets for Antithrombotic Agents in the Coagulation Cascade Tissue factor/viia Vitamin K antagonist: Warfarin X IX VIIIa IXa Direct factor Xa inhibitors: Rivaroxaban Apixaban Va Xa AT II Thrombin Direct thrombin inhibitor: Dabigatran etexilate Fibrinogen Fibrin

39 Novel Oral Anticoagulants

40 Novel Oral Anticoagulants 1. Dabigatran: DTI (renal clearance) - twice daily fixed dose 2. Apixaban: direct factor Xa inhibitor (hepatic clearance) - twice daily fixed dose 3. Rivaroxaban: direct factor Xa inhibitor (renal clearance) - once daily fixed dose

41 The Demise of Warfarin? Ecstatic or Dead

42 RE-LY Comparison of dabigatran with warfarin Mean 2 year follow-up Dabigatran 150 mg superior to warfarin for stroke/systemic embolism (1.11% v 1.69%); dabigatran 110 mg non-inferior (1.53%) Major bleeding higher with warfarin compared with dabigatran 110 mg, but similar to dabigatran 150 mg

43 Haemorrhagic stroke (no. of events) RE-LY: Haemorrhagic stroke 50 RR 0.31 (95% CI: ) P<0.001 (Sup) RR 0.26 (95% CI: ) P<0.001 (Sup) % RRR 69% RRR 74% % Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin n: % BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority Connolly SJ et al. N Engl J Med 2009;361:

44 Cumulative event rate (%) ROCKET-AF: Stroke and non-cns Embolism Event Rate Rivaroxaban Warfarin Warfarin Rivaroxaban HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: < Days from Randomization No. at risk: Rivaroxaban Warfarin Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population

45 ROCKET-AF: Bleeding Major and non-major Clinically Relevant Rivaroxaban Event Rate Warfarin Event Rate HR (95% CI) P- value (0.96, 1.11) Major (0.90, 1.20) Non-major Clinically Relevant (0.96, 1.13) Event Rates are per 100 patient-years Based on Safety on Treatment Population

46 INR: Time in Therapeutic Range Warfarin INR range Median (25 th, 75 th ) < ( ) 1.5 to < ( ) 1.8 to < ( ) 2.0 to ( ) >3.0 to ( ) >3.2 to ( ) > ( ) Based on Rosendaal method with all INR values included Based on Safety Population

47 ARISTOTLE Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism P (non-inferiority)< % RRR Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, ); P (superiority)=0.011 No. at Risk Apixaban Warfarin

48 ARISTOTLE: Efficacy Outcomes Outcome Apixaban (N=9120) Event Rate (%/yr) Warfarin (N=9081) Event Rate (%/yr) HR (95% CI) P Value Stroke or systemic embolism (0.66, 0.95) Stroke (0.65, 0.95) Ischemic or uncertain (0.74, 1.13) 0.42 Hemorrhagic (0.35, 0.75) <0.001 Systemic embolism (SE) (0.44, 1.75) 0.70 All-cause death* (0.80, 0.998) Stroke, SE, or all-cause death (0.81, 0.98) Myocardial infarction (0.66, 1.17) 0.37

49 ARISTOTLE: Major Bleeding 31% RRR Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, ); P<0.001 No. at Risk Apixaban Warfarin

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51 New Oral anticoagulants: Primary prevention Apixaban superior to dabigatran 110mg BD for stroke reduction (HR 0.59; ) Apixaban less effective than dabigatran 150mg BD for stroke reduction (HR 1.45; ) Apixaban produced fewer major bleeds than dabigatran 150mg BD (HR 0.75; ) Apixaban produces fewer major bleeds than rivaroxaban (HR 0.61; ) Efficacy of dabigatran 150mg BD and rivaroxaban, and rivaroxaban and apixaban similar

52 New Oral Anticoagulants: Secondary Prevention Apixaban, rivaroxaban and both doses of dabigatran similar efficacy for stroke prevention Dabigatran 150mg BD more MI than apixaban Less haemorrhagic stroke, major bleeding, vascular death with dabigatran 110mg BD than rivaroxaban Larsen et al BMJ 2012

53 Danish Registry Data: calculated benefit for new anticoagulants Net clinical benefit for new anticoagulants compared to warfarin, especially CHA 2 DS 2 - Vasc 2 Probable benefit at lower risk Banerjee et al Thromb Haemost 2012; 107:

54 Who should take warfarin? INR is easy to control (therapeutic >70% of time) If patient not likely to comply with twice daily dosing (dabigatran, apixaban) Chronic kidney disease (GFR < 30 ml/min) (dabigatran, rivaroxaban and probably apixaban)

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