Controversies in Risk Stratification Things are not as simple as they seem Banff 2017 2015 MFMER 3494750-5
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, 2004 2016 MFMER 3497046-8
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 2002 2016 MFMER 3516485-11
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 0.549-0.638 C statistic 0.573 0.549 0.561 0.586 0.638 0.598 0.571 0.571 0.606 0 20 40 60 80 100 Lip: Chest, 2010 3254956-9
CHADS 2 Score and Left Atrial Thrombi in AF Case control study Cases 110 pt NVAF LAA thrombus TEE % 50 40 30 20 10 0 Distribution of Scores 21.4 3.6 Controls (mean 1.6) Cases (mean 2.8) 29.2 28.7 21.8 20.9 19.1 19.1 11.4 Considerable overlap 5.7 3.4 10.9 0.3 0 1 2 3 4 5 6 Scores 4.5 Wysosinski: AHJ, 2010 2015 MFMER 3477336-14
Atrial Fibrillation Guidelines Risk Recommended therapy ESC 2016 AHA/ACC/HRS 2014 Risk factors (no.) CHA 2 DS 2 -VASc = 0 CHA 2 DS 2 -VASc = 1 * No antithrombotic therapy (IIIB) OAC > (Class IIaB) (NOAC > VKA) No antithrombotic therapy None or OAC or ASA CHA 2 DS 2 -VASc 2 NOAC > VKA (IA) NOAC or VKA Mechanical prosthetic valve VKA: INR 2.0-3.0 (AVR) VKA: INR 2.5-3.5 (MVR) *Female 2 ESC Guidelines: Eur Heart J, 2012 AHA/ACC/HRS Guidelines Circulation, 2014 2016 MFMER 3567759-05
Wide Variation in Reported Rates of Stroke Across Cohorts of Patients with AF 34 studies Patients with non-valvular AF Results Overall stroke rates ranged 0.45-9.28%/year Heterogeneity in stroke rates P<0.001 Mean North American stroke rate <1/3 of mean European stroke rate Pts (%) 100 80 60 40 20 0 Range of Ischemic Stroke Rates CHA 2 DS 2 -VASc =1 76 Stroke rate %/year CHA 2 DS 2 -VASc = 2 46 27 18 17 <1 2 <1 1-2 >2 Quinn: Circ, 2017 2017 MFMER 3620413-12
Annual stroke event rate (%) JACC, 2015 140,420 patients Swedish nationwide health registry Exclusions Valvular AF Warfarin exposure 4 week quarantine period after diagnosis 16 14 12 10 8 6 4 2 0 Annual Event Rates 0 1 2 3 4 5 6 7 8 9 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 3469683-2
Hazard ratio Adherence to Warfarin and NOAC Clinical Outcomes Insurance Administrative Claims Database (USA 100 Million Enrollees Over 20 Yr Period) 64,661 pt 2000-2014 AF (OAC) Warfarin Dabigatran Rivaroxatan Apixiban 6 5 4 3 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) 2 1 43.2% 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 3477336-11
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 65-74 years (reference <65 years) 1 Previous Ischemic Stroke Female Gender Vascular Disease Hypertension Diabetes Mellitus History of heart failure History of intracranial bleeding 2 1 1 1 1 1 0 Reference Argulian: Am J Med, 2015; Camm: EHJ, 2012; Friberg: EHJ, 2012 2016 MFMER 3497937-4
The CCS Algorithm for OAC Therapy in AF Age 65 No Prior Stroke or TIA or Hypertension or Heart failure or Diabetes Mellitus (CHADS 2 risk factors) No Yes Yes OAC* OAC* Consider and modify (if possible) all factors influencing risk of bleeding during OAC treatment (hypertension, antiplatelet drugs, NSAIDs, excessive alcohol, labile INRs) and specifically bleeding risks for NOACs (low egfr, age 75, low body weight). CAD or Arterial vascular disease (coronary, aortic, peripheral) Yes ASA No *NOAC preferred No Antithrombotic Verma: Canadian J Cardiol, 2014 2016 MFMER 3520769-2
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 0.65 0.64 0.64 0.60 0.60 0.61 0.66 0.63 0.55 0.55 0 20 40 60 80 100 % Low Intermediate High Yao and Noseworthy in press 2016 MFMER 3511528-7
1.5 >1.5-6.8 >6.8-13 >3 1.5 >1.5-6.8 >6.8-13 >3 Stroke or systemic embolism (%) Cardiac death (%) Outcomes in Patients with AF Stratified by CHADS 2 VASc Score and hs-tnt 12,892 Patients ARISTOTLE Trial Stroke and Systemic Embolism Cardiac Death 3.0 7 2.5 6 2.0 1.5 1.0 5 4 3 2 0.5 1 0.0 5 4 3 2 1 0 5 4 3 2 1 CHA 2 DS 2 VASc score CHA 2 DS 2 VASc score Hijazi: JACC, 2014 2015 MFMER 3477336-04
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 (%) 2 1 0 5 CHA 2 DS 2 VASc score 4 3 2 1 363 >1250 714-1250 364-713 NT-proBNP (ng/l) Hijazi: JACC,l 2013 2013 MFMER 3274425-7
Atrial Fibrillation and the Risk of Stroke Potential Role of Biomarkers Risk marker? Surrogate? Atrial Fibrillation Risk factor Hypertension risk factor 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 LV wall stress Diastolic dysfunction Muscle necrosis Prothrombotic state Stretch induced Troponins BNP Von Willebrand factor D-dimer Inflammation? 2017 MFMER 3610073-13
Assessment of Stroke Risk in AF Risk scores (CHADS2, CHA2DS2,-VASC and ATRIA) Crucial to basic risk assessment Modifying factors incl.laa morphology Role of comorbidities Patients represented in clinical trials? Impact of other disease states, eg. HCM, prosthetic valves 2016 MFMER 3576785-01
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 may be misleading 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 3477336-12
What gets us into trouble is not what we don t know It is what we know for sure that just ain t so Mark Twain 2015 MFMER 3516485-13