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Atrial fibrillation & stroke prevention : What’s new ?

Atrial fibrillation & stroke prevention : What’s new ?. Prof. John Camm St Georges University of London London, United Kingdom. CHA 2 DS 2 -VASc Assessment of Thromboembolic Risk. C ongestive heart failure/ 1 LV dysfunction H ypertension 1 A ge  75 2 D iabetes mellitus 1

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Atrial fibrillation & stroke prevention : What’s new ?

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  1. Atrialfibrillation & strokeprevention: What’snew? Prof. John Camm StGeorgesUniversity of London London, United Kingdom

  2. CHA2DS2-VAScAssessment of Thromboembolic Risk • Congestive heart failure/ 1 LV dysfunction • Hypertension 1 • Age  75 2 • Diabetes mellitus 1 • Stroke/TIA/TE 2 • Vascular disease 1 • (CAD, AoD, PAD) • Age 65-74 1 • Sex category (female) 1 Score 0 – 9 Validated in 1084 NVAF patients not on OAC with known TE status at 1 year in Euro Heart Survey OR for stroke if: Female: 2.53 (1.08 – 5.92), p=0.029; Vascular disease: 2.27 (0.94 – 5.46), p=0.063 Olesen JB et al. BMJ 2011;342:124 Lip GYH, et al. Chest 2009

  3. CHADS2 vs CHA2DS2VASc All patients with atrial fibrillation not treated with VKAs in Denmark 1997- 2006 73 538 fulfilled the study inclusion criteria CHA2DS2VASc score = 0 Female sex Heart failure Hypertension Vascular disease Age 65–74 years Diabetes mellitus CHADS2 score = 0 Heart failure Hypertension Diabetes mellitus Age ≥75 years 100 90 80 70 60 0 100 90 80 70 60 0 Proportion of patients freeof thromboembolism (%) Proportion of patients freeof thromboembolism (%) 0 2 4 6 8 10 0 2 4 6 8 10 Years of follow-up Years of follow-up Kaplan-Meier estimate of probability of remaining free of thromboembolism with CHADS2 score 0 and 1. Onlypatients with CHADS2 scores 0 and 1 were included, and patients were censored at death for causes other than thromboembolism Kaplan-Meier estimate of probability of remaining free of thromboembolism with CHA2DS2VASc score 0 and 1. Only patients with CHA2DS2VASc scores 0 and 1 were included, and patients were censored at death for causes other than thromboembolism Olesen JB et al, BMJ 2011;342:d124

  4. VKA Therapy in Atrial Fibrillation 1933 - A dead Bull and Blood that would not Clot 6 Trials, 2,900 patients with AF Wisconsin Alumni Research Foundation COUMARIN Relative Risk Reduction(95 % CI) Target INR Range 2.8 - 4.2 2.0 - 4.5 1.5 - 2.7 2.0 - 3.0 1.4 - 2.8 2.5 - 4.0 AFASAK, 1989, 1990 SPAF I, 1991 BAATAF, 1990 CAFA, 1991 SPINAF, 1992 EAFT, 1993 RRR: 64% All trials (n = 6) In 1941, Karl Paul Link isolated the anticoagulant factor, which found application as a rodent-killer, but is now one of the most widely prescribed medicines in the world.  100 % 50 % 0 - 50 % - 100 % Favours Placeboor Control Favours Warfarin Hart et al. Ann Intern Med 2007;146:857-67

  5. Warfarin Use in Primary Care in the UK Initiation of VKA 100 Age 40–64 80 Age65–69 60 Age70–74 Age75–79 40 Age80–84 Age85+ 20 0 0 2 4 6 • 41,000 chronic AF treated by GPs in UK • Administrative database study • Diagnosed after January 2000 100 80 60 Percent Percent 40 20 0 0 2 4 6 Years after diagnosis Years after starting treatment Gallagher AM, et al. J Thromb Haemost 2008;6:1500–1506 GPs, general practitioners; UK, United Kingdom

  6. 1.0 0.9 0.8 0.7 0.6 0 500 1000 1500 2000 Sub-optimal TTR and Risk of Stroke Warfarin TTR groupa 71%–100% 61%–70% 51%–60% 41%–50% 31%–40% ≤30% Cumulative survival No warfarin 20 40 60 80 % TTR (95% CI) Survival to stroke (days) • Meta-analysis of TTR (%) of AF patients treated with warfarin in the community • TTR >70% is necessary to reduce stroke risk in patients with CHADS2 score ≥2 compared with the non-warfarin treatment group (p=0.025) aNo. of warfarin-treated patients in each group is defined by proportion of time spent within INR target range TTR, time in therapeutic range Baker WL et al. J Manag Care Pharm 2009;15:244–252. Morgan CL et al. Thromb Res 2009;124:37–41.

  7. By any other name ……! ADIOS – Antiarrhythmic Drugs Improves Outcomes Study KAPUT KAPUT ADIOS

  8. Stroke Prevention: OAC Effect Stroke or systemic embolism Intracranial haemorrhage Relative Hazard Ratio (95% CI) W vs Dabigatran 110 W vs Rivaroxaban W vs Dabigatran 150 W vs Apixaban 5 Category W vs Placebo W vs Wlow dose W vs Aspirin W vs Aspirin + Clop W vs Ximelagatran W vs Dabigatran 110 W vs Rivaroxaban W vs Dabigatran 150 W vs Apixaban 5 0 0.3 0.6 0.9 1.2 1.5 1.8 2.0 Major bleeding W vs Dabigatran 110 W vs Rivaroxaban W vs Dabigatran 150 W vs Apixaban 5 0 0.3 0.6 0.9 1.2 1.5 1.8 2.0 Favours warfarin Favours other Rx 0 0.3 0.6 0.9 1.2 1.5 1.8 2.0 Favours warfarin Favours other Rx Modified from Camm A.J. EHJ 2009;30:2554-5

  9. Efficacy and Safety of NOACs vs. Warfarin Systematic Reviews and Meta-analyses Stroke or SE in trials of warfarin vs comparators NOACs vs warfarin in ‘modern’ phase II/III trials (n = 54,875) RR (95% CI) RR (95% CI) ACM CVM Stroke/SE Ischemic stroke Major bleeding ICH MI 11% W vs Placebo W vs Wlow dose W vs Aspirin W vs Aspirin + Clop* W vs Ximelagatran 11% 23% 8% 14% 54% 1% 0 0.3 0.6 0.9 1.2 1.5 1.8 2.0 Favours warfarin Favours comparator 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 Favours NOACs Favours warfarin Ximelagatran was withdrawn in 2006 because of severe liver injury observed during longer-term treatment. ACM, all-cause mortality; CVM, cardiovascular mortality; ICH, intracranial haemorrhage; MI, myocardial infarction; RR, relative risk; SE, systemic embolism; W, warfarin Dentali F, et al. Circulation 2012;126:2381-91. Modified from: Lip GY, et al. Thromb Res 2006;118:321–33; *data provided by Gregory Lip.

  10. Network Meta-Analysis of NOACs Graphical presentation derived from the work of Fadda et al.4,6 • Multiple publications using the network meta-analysis method have been published so far.1-5 • These analyses yielded comparable findings. Dabigatran 110 mg Dabigatran 150 mg Apixaban Rivaroxaban Randomised controlled trial Indirect comparison Warfarin 1. Harenberg et al. InternAngiol 2012;31:330-9. 2. Schneeweiss et al. CircCardiovascQualOutcomes 2012;5:480-6. 3. Lip et al. J Am CollCardiol 2012;;60:738-46. 4. Mantha & Ansell. ThrombHaemost 2012;e-published June 28. 5. Wells et al. April 2012. Availableat: http://www.cadthca/media/pdf/NOAC_Therapeutic_Review_final_report.pdf. Accessed 29/08/12.6. Fadda et al. BMJ 2011;342;d1555.

  11. NOAC Rx in AF: Indirect Comparison 10 efficacy (stroke or Systemic embolus [ITT]) 10 efficacy in CHADS2 ≥ 3 Dabigatran150 HRD v W = 0.65 Dabigatran150 HRD v W = 0.70 HRD v R = 0.80 (0.56 to 1.13) HRD v A = 0.82 (0.62 to 1.10) HRD v A = 1.03 (0.69 to 1.54) Rivaroxaban HRR v W = 0.88 Apixaban HRA v W = 0.79 Apixaban HRA v W = 0.68 HRA v R = 0.77 (0.56 to 1.06) Safety (major haemorrhage as treated) Safety (major haemorrhage in CHADS2 ≥ 3) Dabigatran150 HRD v W = 0.98 Dabigatran150 HRD v W = 1.05 HRD v R = 1.04 (0.80 to 1.34) HRD v A = 1.42 (1.16 to 1.74) HRD v A = 1.52 (1.11 to 2.07) Rivaroxaban HRR v W = 1.01 HRA v R = 0.77 (0.52 to 0.90) Apixaban HRA v W = 0.69 Apixaban HRA v W = 0.69 Schneeweeisss S, et al. Circ Cardiovasc Qual Outcomes. 2012;5:480-486.

  12. Left Atrial Occlusion Devices • PLAATO(terminated) • Watchman (EU and investigational in USA) • Cardiac Plug (EU and investigational in USA) • WaveCrest(investigational only)

  13. PROTECT-AF: Latest Results 463 patients received the Watchman and 244 warfarin management Average CHADS2 scores 2.2 and 2.3, respectively Mean follow-up: 45 months Rate Ratios (95% CI) for Primary Efficacy and Safety End Points and Secondary End Points in PROTECT-AF, by Intention to Treat Reddy VY, et al. Abstract HRS Denver 2013

  14. LARIAT - Percutaneous LAA Ligation Patients screened N=119 Patients excluded N=16 (13.4%) Eligible patients 103 (86.5%) LAA > 40 mm (8) Unsuitable LAA orientation (8) Excluded at procedure N = 14 (13.6%) Patients to be treated N=89 (86.4%) Adhesions (3) Mobile thrombus (11) Residual leak (3) Severe pericarditis(1) Late effusion (1) Unexplained SCD (1) Non-embolic late CVA (2) Failure N=4 (4.5%) Success N=85 (95.5%) One year follow-up Bartus K et al. JACC 2012

  15. LAA Closure/Occlusion/Excision European Heart Journal 2012 - doi:10.1093/eurheartj/ehs253 European Heart Journal 2012 - doi:10.1093/eurheartj/ehs253

  16. ESC 2012 Update AF Guidelines AF Paroxysmal, Persistent or Permanent Non-valvular Valvular* No anti-thrombotic therapy < 65 years, no cardiovascular disease Dose-adjusted VKA INR:2-3) CHA2DS2-VASc Dotted lines indicate options not well validated; Dashed lines: less preferable or less validated * = mechanical or rheumatic † = not “female” only §= dual antiplatelet therapy preferred ‡ = see Summary of Product Characteristics for specific indications Modified from the 2012 focused update of the ESC Guidelines for the management of AF 1† ≥2 OAC therapy Camm AJ, et al. Europace. 2012;14(10):1385-413. Assess bleeding risk (HAS-BLED) Consider patient values and preferences CHA2DS2-VASc:1 and not suitable for, or refusing NOAC or VKA Suitable for OAC therapy CHA2DS2-VASc:2refusing OAC CHA2DS2-VASc:2unsuitable for OAC Consider aspirin + clopidogrel or aspirin only§ Consider aspirin + clopidogrel or aspirin only§ Consider LAAO, or LAA excision Dose-adjusted VKA (INR:2–3) NOAC drugs‡ Apixaban Dabigatran Rivaroxaban ESC, European Society of Cardiology; LAA, left atrial appendage; LAAO, left atrial appendage occlusion EUAPI355cUK

  17. Thank you for your attention

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