Controversies in Risk Stratification

Transcription

1 Controversies in Risk Stratification There are more questions than answers So---Let me pose the questions Banff MFMER

2 Relative importance Triggers vs Substrate in Pathophysiology of AF AF burden Paroxysmal? Persistent? Permanent P vein isolation/ WACA pts Trials of pharmacologic rhythm vs rate control Incl AFFIRM and RACE Modulating factors Triggers ( lone AF) Triggers & diseased substrate Genetics? vagal tone Age Obesity Atherosclerotic risk factors Wyse & Gersh: Circ, MFMER

3 The Epidemic of Atrial Fibrillation is It a Vascular Disease? Hypothesis Obesity Hypertension Age Atherosclerosis Role of inflammation Increased arterial stiffness Diastolic dysfunction LVH Increased LA volume Electrical heterogeneity A fibrillation Myasaka: Circ, MFMER

4 AFib as a Vascular Disease Suggestive Evidence Obesity Hypertension Metabolic syndrome Sleep apnea? Arterial stiffness Diastolic dysfunction LA volume Cause Surrogate Atrial fibrillation Diastolic dysfunction LA volume Ang II TGF 1 Neurohormonal factors CTGF Tissue factors MMPs Vascular and hemostatic factors Oxidative stress and inflammation Galactin PDGF Endothelin-I Tsang and Gersh: EHJ 2008; JACC 2008; AJC 2008; AJC 2006; JACC 2006; JACC 2003; JACC MFMER

5 Meta-Analysis of Stroke 5 Randomized Trials Placebo Stroke Rate 4.5%/yr Risk factors RR Previous stroke/tia 2.5 Hx of HTN 1.6 Advanced age (continuous) 1.4/10 yr Diabetes mellitus 1.7 Hx of CHF 1.4 Collaborative Analysis AFib Investigators Arch Intern Med, 1994 Age related Pt aged 60 yr + No risk factors Stroke rate 1%/yr Kopecky: NEJM, MFMER

6 Performance of Contemporary Risk Stratification Schemes Study AFI, 94 SPAF, 95 CHADS 2 CHADS 2 revised Framingham NICE, 2006 ACC/AHA/ESC, 2006 ACCP, 2008 Birmingham, 2009 Low Intermediate High Range C statistic Lip: Chest,

7 CHADS 2 Score and Left Atrial Thrombi in AF Case control study Cases 110 pt NVAF LAA thrombus TEE % Distribution of Scores Controls (mean 1.6) Cases (mean 2.8) Considerable overlap Scores 4.5 Wysosinski: AHJ, MFMER

8 Atrial Fibrillation Guidelines Risk Recommended therapy ESC 2012 AHA/ACC/HRS 2014 Risk factors (no.) CHA 2 DS 2 -VASc = 0 No antithrombotic therapy No antithrombotic therapy CHA 2 DS 2 -VASc = 1 NOAC > VKA (IIa A) None or OAC or ASA CHA 2 DS 2 -VASc 2 NOAC > VKA (IA) NOAC or VKA Mechanical prosthetic valve VKA: INR (AVR) VKA: INR (MVR) ESC Guidelines: Eur Heart J, 2012 AHA/ACC/HRS Guidelines Circulation, MFMER

9 Stroke and TE Rates Based on CHADS 2 and CHA 2 DS 2 -VASc Scores 47,574 Subjects Danish Registries 1-year follow-up 12-year follow-up CHADS 2 Score = 0 CHA 2 DS 2 -VASc score = 0 CHA 2 DS 2 -VASc score = 1 CHA 2 DS 2 -VASc score = 2 CHA 2 DS 2 -VASc score = 3 CHADS 2 Score = 1 CHA 2 DS 2 -VASc score = 1 CHA 2 DS 2 -VASc score = 2 CHA 2 DS 2 -VASc score = 3 CHA 2 DS 2 -VASc score = Hazard ratio for stroke/thromboembolism 10 Olesen: Thromb and Hemostasis, MFMER

10 100 person-years of follow-up Comparisons of Scores for Stroke Prediction in a Taiwanese Population 186,570 AF pts. Follow-up 3.4 years mean 12.1% ischemic stroke Ischemic Strokes (no.) Taiwan AF Cohort (CHADS 2 Score = 0) CHA 2 DS 2 -VASc score CHA 2 DS 2 -VASc score No. HR (95% CI) Score = 0 (reference group) 9, Score = 1 12, ( ) Score = 2 3, ( ) Score = ( ) HR (95% CI) Chao et al: Heart Rhythm MFMER

11 Risk Factors for Thromboembolic Events in Atrial Fibrillation Patients Risk Factor Are all 1 pointers equal Hazard ratio estimates CHA 2 DS 2 -VASc Points Age 75 years (reference <65 years) 2 Age years (reference <65 years) 1 Previous Ischemic Stroke Female Gender Vascular Disease Hypertension Diabetes Mellitus History of heart failure History of intracranial bleeding Reference Argulian: Am J Med, 2015; Camm: EHJ, 2012; Friberg: EHJ, MFMER

12 Annual Stroke Rates in Different Cohort Studies Patients With CHADS 2 -VASc of 1 %/yr * Annual Stroke Rates Men Women ** Registry 0.0 Denmark* Sweden** Taiwan*** Ref Oleson BMJ 2011 Friberg JACC 2015 Chao JACC 2015 *Hospital admission and death due to TE ** Ischemic stroke only *** Other thromboembolic events and TIA 2015 MFMER

13 Annual stroke event rate (%) JACC, ,420 patients Swedish nationwide health registry Exclusions Valvular AF Warfarin exposure 4 week quarantine period after diagnosis Annual Event Rates CHA 2 DS 2 -VASc Score Tipping point 1.7%/yr Warfarin 0.9%/yr NOAC +TIA +Pulmonary Embolism +Unspecified Stroke/+Systemic Embolism Ischemic stroke only 2016 MFMER

14 Hazard ratio Adherence to Warfarin and NOAC Clinical Outcomes Insurance Administrative Claims Database (USA 100 Million Enrollees Over 20 Yr Period) 64,661 pt AF (OAC) Warfarin Dabigatran Rivaroxatan Apixiban Stroke or Systemic Embolism NS HR 2.73 HR 3.36 Adherence ( 80 days covered by OAC) Cumulative time off OACs (<1 wk as reference) % 1 wk-1 mo 1-3 mo 3-6 mo 6 mo 0 CHA 2 DS 2 VASc 0, 1 CHA 2 DS 2 VASc 2, 3 CHA 2 DS 2 VASc 4 Noseworthy P (In Press) 2015 MFMER

15 Comparison of Stroke and Bleeding Scores in Patients on NOACS 39,539 patients U.S. commercial insurance database HA 2 DS 2 -VASc Stratification of Bleeding Risk C-statistic Major bleeding Intracranial bleeding CHADS 2 HAS-BLED ORBIT ATRIA % Low Intermediate High Yao and Noseworthy in press 2016 MFMER

16 Stroke events per 1,000 patient years Excessive Atrial Ectopy and Short Runs Increase the Risk of Stroke Beyond Incident AF Copenhagen Holter Study Cohort 678 pt (age 55-75) No history of CVD, stroke or AF Excessive supraventricular ectopic activity (ESVEA) 30 PAC s/hour daily or Any runs of 20 PACs Incidence of Stroke per 1,000 Patient-Years According to ESVEA and CHA 2 DS 2 -VASc Score ESVEA +ESVEA Adjusted analysis for risk of ischemic stroke (pt censored at home of AF) ESVEA H Ratio 1.96 ( ) CHA 2 DS 2 -VASc Score Larsen: JACC, MFMER

17 Stroke or systemic embolism (%) Cardiac death (%) Outcomes in Patients With AF Stratified by CHA 2 DS 2 -VASc Score and hs-tnt ,892 Patients ARISTOTLE Trial Stroke and Systemic Embolism hs-troponin-t (ng/l) 1.5 > > > Cardiac Death hs-troponin-t (ng/l) 1.5 > > > CHA 2 DS 2 VASc score CHA 2 DS 2 VASc score Hijazi: JACC 2013 MFMER

18 Major bleeding (%) Outcomes in Patients With AF Stratified by CHA 2 DS 2 -VASc Score and hs-tnt 12,892 Patients ARISTOTLE Trial Major Bleeding hs-troponin-t (ng/l) 1.5 > > > CHA 2 DS 2 VASc score Hijazi JACC MFMER

19 Stroke and Systemic TE and NT-proBNP in Patients With AFib 18,201 Patients ARISTOTLE Trial 3 Stratified by CHAD 2 VASc Score Stroke or systemic embolism (%) CHA 2 DS 2 VASc score > NT-proBNP (ng/l) Hijazi: JACC,l MFMER

20 Independent Relationship Between hs Troponin and Events Multifactorial Myocyte stress Apoptosis Necrosis Aging Tissue vulnerability? Comorbidities or variable heart rates Possible contributory mechanisms Inflammation Fibrosis Hypercoagulable state Endothelial dysfunction myocyte turnover Cellular integrity and permeability Ischemia Myocardial dysfunction and remodeling 2013 MFMER

21 BNP as a Prognostic Marker for Stroke in Atrial Fibrillation Potential Mechanisms BNP secreted by myocytes NT-proBNP Reflects LV size and function LV filling pressures Renal function Age Sex Levels of BNP in AFib vs SR Reflects Atrial function and pressure 2013 MFMER

22 Atrial Fibrillation and the Risk of Stroke Potential Role of Biomarkers Risk marker? Surrogate? Atrial Fibrillation Risk factor Hypertension egfr Cystatin Inflammation? CRP IL-6 compliance Aortic plaque Cerebrovascular disease BNP IL-6 CRP D-dimer Dilatation/fibrosis AFib Stasis LA & LAA flow velocity Stroke risk LVH Diastolic Troponins BNP dysfunction D-dimer Prothrombotic state Stretch induced Inflammation? Von Willebrand factor 2015 MFMER

23 Appendage Morphology and Stroke Risk Chicken wing Cactus Windsock Cauliflower % % OR 0.2 Chicken wing Chicken wing Stroke Rate OR 1.1 OR 2.5 Windsock Cactus Cauliflower Stroke Rate OR 2.0 Non-chicken wing Di Biase et al: JACC 60:531, MFMER

24 Limitations of Risk Stratification Scores for Atrial Fibrillation The AF population is very heterogeneous regarding stroke risk Different classifications in measuring stroke rates lead to overestimates Incorporation of other embolic episodes into determinants of stroke risk Current risk stratification schema are based primarily upon clinical risk factors Differential weight of individual risk factors Performance varies according to baseline risk of stroke which is variable among populations What will be the role of biomarkers and imaging 2015 MFMER