L.B. Goldstein. MD Feb

Transcription

1 AHA 2011 Primary Stroke Prevention Guidelines What s New? Larry B. Goldstein, MD, FAAN, FAHA Professor of Medicine (Neurology) Director, Duke Stroke Center Missing Slides/ Graphics Slides containing copyrighted material have been replaced with descriptive text References to the relevant publications are provided on each slide US Stroke Mortality Age-Adjusted Mortlaity per 100, Goal 25% reduction % Year Data from National Center for Health Statistics US, 2010; CDC

2 Stroke Incidence vs. Case Fatality US National Data Ischemic Stroke Change Risk standardized 30- day case mortality rate % % 7% Hospitalization rate (per 100,000 p-y) 2 1,393 1,020 27% 1 Lichtman, Watanabe, Wang et al. Stroke 2010; 41:e46 2 Lichtman, Jones, Wang et al. ISC 2010 Stroke 2010; 41: e25 Primary Prevention of Stroke What s New? Scope Importance of lifestyle Atrial fibrillation Primary prevention in the ED Prevention of Stroke Lifestyle Recommendation Cigarette smoking Obesity Diet Exercise Alcohol Goldstein et al Stroke 2011;42: ! 2

3 Impact of Healthy Lifestyle 43,685 men, Health Professionals Follow-up Study 71,243 women, Nurses Health Study 5 Lifestyle factors - Not smoking - Healthy diet - At least 30 min per day of moderate or vigorous physical activity - Optimal weight (BMI < 25kg/m 2 ) - 1- alcoholic drink/day for women, 1-2 for men Chiuve et al. Circulation 2008; 118: Impact of Healthy Lifestyle Risk of First Stroke 80% lower stroke rate among those following all lifestyle factors Similar benefit in med and women Chiuve et al. Circulation 2008; 118: Atrial Fibrillation Epidemiology Estimated prevalence 2.7 million in 2010 Prevalence to exceed 12 million by 2050 Mean age - Men: 66.8 years - Women: 74.6 years Increases stroke risk ~ 4-5-fold Responsible for at least 15% to 20% of all ischemic strokes Roger et al. Circulation. 2011;123:e18 3

4 Application to SPAF-III Cohort Stroke rates vary dramatically among risk stratification schemes Stroke Risk in Atrial Fibrillation Working Group Stroke 2008; 39:1901 Atrial Fibrillation Risk Stratification CHADS 2 Prior stroke/tia*! Stroke rate 6-10%/year! Condition Points CHF 1 Hypertension 1 Age >75 1 Diabetes 1 Stroke or TIA* 2 Points Rate/Yr Treatment 0 1.9% ASA/None 1 2.8% ASA/Warfarin 2 4.0% Warfarin 3 5.9% Warfarin 4 8.5% Warfarin % Warfarin % Warfarin Gage et al. JAMA 2001; 285: 2864! Lip Am J Med 2011; 124: 111! *Hart et al. Neurology 2007; 69; 546! ~60% CHADS 2 =1 Atrial Fibrillation Risk Stratification CHA 2 DS 2 -VASc Condition Points CHF/ LV dysfunction 1 Hypertension 1 Age >75 2 Diabetes 1 Stroke or TIA* 2 Vascular Disease 1 Age Sex (women) 1 Vac Dis: MI, PAD, Aortic athero Lip et al. Chest 2010; 137:263! Lip Am J Med 2011; 124: 111! Points Rate/Yr Treatment 0 0% None 1 0.7% ASA/Warfarin 2 1.9% Warfarin 3 4.7% Warfarin 4 2.3% Warfarin 5 3.9% Warfarin 6 4.5% Warfarin % Warfarin % Warfarin 9 100% Warfarin 4

5 Stroke Risk Stratification Stratification Stroke Rate Percent in Strata Low Intermediate 44.7 High 75.7 CHADS2 CHA2D2-Vasc Percent Low Intermediate 3.1 High 3.0 CHADS2 CHA2D2-Vasc Risk Strata Risk Strata CHADS 2 ; c=0.586 ( ) CHA 2 DS 2 -Vasc; c=0.606 ( ) Lip et al. Chest 2010; 137:263! Euro Heart; 5,333 patients with AF 0, Low 1, Intermediate >2, High Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W) Atrial fibrillation plus- > 75 years old HTN Rx Prior stroke, TIA, or non- CNS systemic embolus EF < 45% PAD If only years old - Rx DM - CHD Design PROBE Warfarin (target INR ; n=3371) Clopidogrel (75 mg/d) + ASA( mg/d; n=3335). Primary outcome - First stroke, non-cns embolus, MI, or vascular death ACTIVE Writing Group Lancet. 2006;367:1903 Clopidogrel+Aspirin vs Anticoagulation ACTIVE-W Stroke, Non-CNS Embolism, MI, Vasc Death Clopidogrel + ASA 5.6% per year Warfarin 3.9% per year RR 1.44, p=0.003 ACTIVE Writing Group Lancet. 2006;367:1903 5

6 Major Bleeding ACTIVE-W Major Bleeding Clopidogrel + ASA 2.2% per year Warfarin 2.4% per year RR 1.06, p=0.53 ACTIVE Writing Group Lancet. 2006;367:1903 Clopidogrel+Aspirin vs Aspirin ACTIVE-A Stroke, Non-CNS Embolism, MI, Vasc Death Clopidogrel + ASA 6.8% per year ASA 7.6% per year RR 0.89, p=0.01 ACTIVE Investigators NEJM 2009;360: 2066 Warfarin, ASA, ASA+Clopidogrel ACTIVE-W, ACTIVE-A Study Group Primary %/Year /RRI ACTIVE-W Warfarin 3.9% 1.44 (1.18,1.76) p=0.003 Major Bleed ASA+Clop 5.6% 2.4% ACTIVE-A ASA 7.6% 0.89 (0.81, 0.98) p=0.01 /RRI 2.2% 1.10 (0.83,1.45) p=0.53 Primary + Major Bleed 1.41 ( ) p<0.001 ASA+Clop 6.8% 2.0% ASA+clopidogrel relative to comparator treatment 1.3% 1.57 (1.29,1.92) p<0.001 Primary + Major Bleed 0.97 (0.89, 1.06) p= 0.5 6

7 Randomized Evaluation of Long-Term Anticoagulation Therapy: RE-LY Dabigatran vs. warfarin - Direct thrombin inhibitor - Pro-drug - Independent of cytochrome P % renal excretion - T1/2: hr - P-glycoprotein inhibitors raise levels - Verapamil - Amiodarone - Quinidine - Rifampin PROBE design Double-blind dabigatran mg bid, n= mg bid, n= Open dose-adjusted warfarin - n=6022 Median 2-year follow-up Non-inferiority design Primary outcome - Stroke or systemic embolism Stroke/SE RE-LY Cumulative % per year hazard rates RR 0.90 (95% CI: ) p<0.001 (NI) NNT= Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg RR 0.90 RR 0.65 (95% CI: ) ) p<0.001 p<0.001 (sup) (NI) p=0.29 (Sup) NNT= % 35% RR 0.65 (95% CI: ) p<0.001 (NI) p<0.001 (Sup) D110 mg 0.5BID 1.0 D150 mg 1.5 BID 2.0 Warfarin / 6,015 Years 134 / 6, / 6,022 RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, Dabigatran superior etexilate is in clinical development and not licensed for Bleeding RE-LY Major hemorrhage" % per year / 6, / 6, / 6,022 RR 0.80 (95% CI: ) p=0.003 (sup) RR 0.93 (95% CI: ) p=0.31 (sup) % D110 mg BID D150 mg BID Warfarin Intracranial" hemorrhage" Number of events RR 0.30 (95% CI: ) p<0.001 (sup) RR 0.41 (95% CI: ) p<0.001 (sup) % 70% 59% % 0.23% D110 mg BID D150 mg BID Warfarin 7

8 RE-LY Primary and Secondary Stroke Outcomes Dabigatran 110 mg bid Dabigatran 150 mg bid Disabling or Fatal Nondisabling Ischemic/Not Specified Hemorrhagic Stroke Stroke/Systemic Embolism Disabling or Fatal Nondisabling Ischemic/Not Specified Hemorrhagic Stroke Stroke/Systemic Embolism Favors Dabigatran Favors Warfarin Relative Risk (95% CI) Favors Dabigatran Favors Warfarin Relative Risk (95% CI) 20% had prior stroke or TIA P-values for interaction: 0.65, 0.34 RE-LY Bleeding Dabigatran 110 mg bid Dabigatran 150 mg bid Extracranial Extracranial Intracranial Intracranial Minor Minor Major Major Favors Dabigatran Favors Warfarin Relative Risk (95% CI) Favors Dabigatran Favors Warfarin Relative Risk (95% CI) RE-LY Summary Dabigatran 110 mg bid vs warfarin - Similar rates of stroke and SE, lower major bleed - Net clinical benefit RR 0.92 ( ), p=0.10 Dabigatran 150 mg bid vs warfarin - Lower rates of stroke and SE, similar major bleed - Net clinical benefit RR ( ), p=0.04 Dabigatran 110 mg bid not approved 8

9 Dabigatran vs. Warfarin Issues Twice-daily dosing Short T1/2 - Can t miss doses No antidote - Short T1/2 - Dialysis? Drug interactions Monitoring IV-thrombolytics Cost Myocardial Infarction bid vs. warfarin - RR 1.35 ( ), p= bid vs. warfarin - RR 1.78 ( ), p=0.048 Severe renal impairment - CC< 30 ml/min - FDA approved 75 mg bid - No outcome data - Based on pharmacokinetics Primary Prevention in the ED ED based smoking cessation programs and interventions are recommended (Class I; Level of Evidence B). Identification of atrial fibrillation and evaluation for anticoagulation in the ED is recommended (Class I; Level of Evidence B) ED population screening for hypertension is reasonable (Class IIa; Level of Evidence C). When a patient is identified as having a drug or alcohol abuse problem, ED referral to an appropriate therapeutic program is reasonable (Class IIa; Level of Evidence C). The effectiveness of screening, brief intervention, and referral for treatment of diabetes and lifestyle stroke risk factors in the ED setting is not established (Class IIb; Level of Evidence C) 9