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Warfarin or Watchman?

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Warfarin is an anticoagulant normally used in the prevention of thrombosis and thromboembolism, the formation of blood clots in the blood vessels and their migration elsewhere in the body, respectively.

WATCHMAN™ Left Atrial Appendage Closure Device is a first-of-its-kind, proven alternative to long-term warfarin therapy for stroke risk reduction in patients with non-valvular atrial fibrillation.

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Warfarin or Watchman?

  1. 1. SH-102103-AD-APR2013 Which Wins? Warfarin or Watchman? Innovations in atrial fibrillation Dr Jason Sharp Consultant & Interventional Cardiologist Sydney Adventist Hospital Hornsby Ku-ring-gai Hospital
  2. 2. SH-102103-AD-APR2013 Thrombus in LAA
  3. 3. SH-102103-AD-APR2013 91% of stroke in AF is caused by blood clots that form in the left atrial appendage (LAA)1 1 Blackshear JL. Odell JA., Annals of Thoracic Surgery. 1996;61:755-759 Fibrillation causes blood to stagnate in the LAA The stagnant blood becomes an ideal environment for a thrombus or blood clot to form The blood clot, or portion of it, dislodges from the LAA and travels through arterial system The embolism lodges itself in the blood vessels of the brain, restricting blood flow and causing a stroke Images on file at Boston Scientific Corporation Thrombus in the LAA
  4. 4. SH-102103-AD-APR2013 0% 3% 6% 9% 12% 15% 18% 0 1 2 3 4 5 6 7 8 9 0.0% 1.3% 2.2% 3.2% 4.0% 6.7% 9.8% 9.6% 6.7% 15.2% RiskofStroke CHA2DS2VASc Score Annual Risk of Stroke European Society of Cardiology Guidelines2 CHA2DS2VASc is a newer scoring system • CHA2DS2VASc, developed by Lip et al, is a refinement of the older CHADS2 Score which includes additional stroke risk factors and puts greater emphasis on age as a risk factor1 1 Lip GY et al, Chest. 2010;137(2):263-72 2 Camm AJ et al, Eur Heart J. 2010;31:2369–2429 Condition/Risk Factor Points C Congestive heart failure 1 H Hypertension 1 A Age ≥75 years 2 D Diabetes mellitus 1 S2 Previous stroke or TIA 2 V Vascular disease 1 A Age 65-74 years 1 Sc Sex (female gender) 1 CHA2DS2-VASc Score Treatment 0 No treatment 1 Aspirin or warfarin or dabigatran ≥2 Warfarin or dabigatran
  5. 5. SH-102103-AD-APR2013 • HAS-BLED, developed by Pisters et al, allows clinicians to assess an individual’s risk of bleeding based on comorbidities1 • In determining when oral anticoagulation is appropriate, clinicians must balance the CHADS2 or CHA2DS2VASc score against HAS-BLED • Unfortunately, a high CHADS score often correlates with a high HAS-BLED score and these patients do not receive anticoagulation due to the high bleeding risk HAS-BLED risk of bleeding HASBLED Risk of major bleeding in patients with AF in the Euro Heart Survey 1 Pisters R et al. Chest 2010;138(5):1093-100 Hypertension, stroke and age are also variables in the CHADS scores Condition Points H Hypertension 1 A Abnormal liver and renal function (1 point each) 1 or 2 S Stroke 1 B Bleeding 1 L Labile INR 1 E Elderly (age >65) 1 D Drugs or alcohol (1 point each) 1 or 2 Score Bleeds Per 100 Patient Years 0 1.13 1 1.02 2 1.88 3 3.74 4 8.7
  6. 6. SH-102103-AD-APR2013 WATCHMAN LAA Closure Technology The WATCHMAN device reduces the risk of stroke by closing off the left atrial appendage, which is known to be the main source of blood clots in patients with atrial fibrillation Johnson, Eur J Cardiothoracic Surg 2000:17
  7. 7. SH-102103-AD-APR2013 WATCHMAN Device Nitinol Frame  Radially expands to maintain position in LAA  Available sizes:  21, 24, 27, 30, 33 mm (diameter)  10 Active fixation anchors around device perimeter designed to engage LAA tissue for stability and retention  Contour shape accommodates most LAA anatomies 160 Micron Membrane  Polyethylene terephthalate (PET) cap  Designed to block emboli from exiting the LAA  Intended to promote healing process Anchors 160 Micron Membrane
  8. 8. SH-102103-AD-APR2013 45-day follow-up: healing process Canine Model – 30 day Canine Model – 45 day Human Pathology - 9 months post-implant (non-device related) Schwartz J Am Coll Cardiol Inv 2010:3
  9. 9. SH-102103-AD-APR2013 PROTECT AF1,6 CAP2 ASAP3,4 PREVAIL5 Trial Design Prospective RCT with patients able to take warfarin Prospective registry with patients able to take warfarin Prospective registry with patients contraindicated for warfarin Prospective RCT with patients able to take warfarin Outcome WATCHMAN was non-inferior to warfarin in patients at high-risk of thromboembolism Significantly improved safety results from early PROTECT AF experience Ischemic stroke rate significantly reduced in warfarin contra-indicated patients WATCHMAN device was safely implanted by new operators Mean age /CHADS2 72/2.2 74/2.4 72.4/2.8 74/2.6 Total Enrolled Subjects 707 randomized1 93 pts rolled in2 460 150 407 Total Patients Implanted 5422 437 142 269 Implantation Success 89.5%2 95.0% 94.7% 95.1% Primary Efficacy (all-stroke, CV/unexplained death, and systemic embolism) 40% reduction vs. warfarin6 29% reduction vs. warfarin N/A 0.064 Identical 18-month rates for WATCHMAN and warfarin All-Stroke 32% reduction vs. warfarin6 23% reduction vs. warfarin 77% reduction vs. expected rate per CHADS₂ score Data not yet available Safety (7 day procedure-related*) 8.7%5 4.1%5 53% reduction vs. PROTECT AF Pericardial effusion with tamponade=1.3% Major bleeding=2.7% 4.4% 49% reduction vs. PROTECT AF *Composite of vascular complications includes cardiac perforation, pericardial effusion with tamponade, ischemic stroke, device embolization, and Includes observed PE not necessitating intervention, AV fistula, major bleeding requiring transfusion, pseudoaneurysm, hematoma and groin bleeding 1 Holmes DR et al. Lancet 2009;374:534–42; 2 Reddy VY et al. Circulation. 2013; 127:720-729; 3 Sievert H. TCT 2011; 4 Reddy, JACC 2013; 5 Homes DR PREVAIL Mar 201 6 Reddy, et al. HRS LBCT 2013 WATCHMAN™ Clinical Program At 4yrs WATCHMAN was superior to warfarin in primary efficacy, all-cause mortality, & cardiovascular death SH-AA-159901-MAY2013
  10. 10. SH-102103-AD-APR2013 WATCHMAN™ PROTECT AF Holmes, et al., Lancet 2009; 374: 534–42 Study Objective Effectiveness and safety of LAA closure for prevention of stroke in comparison to Coumadin for non-valvular A-fib patients Study Design Prospective, randomized (2:1), non-inferiority trial of LAA closure vs. warfarin in A-fib patients for prevention of stroke Primary Endpoint Efficacy: Composite end point of stroke, cardiovascular death or systemic embolization Safety: Major bleeding, device embolization or pericardial effusion Patient Population n = 707 Mean CHADS2=2.2 Mean Follow-Up 1065 Patient-years, 18 months (Holmes, et al., Lancet 2009; 374: 534–42) 1588 Patient-years, 2.3±1.1 years (Reddy, et al., Circ 2013) 2,621 patient-years, 4 years (Reddy, et al., HRS LBCT 2013) Number of Sites 59 in the United States and Europe SH-AA-159901-MAY2013
  11. 11. SH-102103-AD-APR2013 WATCHMAN™ PROTECT AF  WATCHMAN therapy is non-inferior to warfarin in the prevention of stroke and death.  38% reduction with WATCHMAN for the composite endpoint for efficacy (including strokes, CV or unexplained death, and systemic embolism) when compared to warfarin  Following the periprocedural period, the rate of ischemic stroke with the WATCHMAN Device was 1.3 per 100 patient years vs. 1.6 with warfarin 3 2.3 0.7 0.3 4.9 3.2 2.7 0 0 1 2 3 4 5 6 7 8 9 10 Primary Efficacy All Stroke CV or Unexplained Death Systemic embolism Holmes, et al., Lancet 2009; 374: 534–42 Events in PROTECT AF trial at 1065 patient years (18m) PNI >99.9% PNI >99.9%PNI > 99% 38% lower 29% lower 38% lower WATCHMAN Group N=463 Warfarin Group N=244 PNI = Posterior non inferiority Probabilities Rateper100patientyears Indications, contraindications, warnings and instructions for use can be found in the product labeling supplied with each device. Information for the use only in countries with applicable health authority product registrations
  12. 12. SH-102103-AD-APR2013 WATCHMAN™ PROTECT AF 4 Yrs. 2.3 1.5 1 3.2 3.8 2.2 2.4 4.8 0 1 2 3 4 5 6 7 8 9 10 Primary Efficacy All Stroke CV or Unexplained Death All-Cause Death Reddy, et al., HRS LBCT 2013 “Local” therapy with WATCHMAN was superior to Warfarin  40% reduction of stroke / systemic embolism / CV death  60% reduction in Cardiovascular Mortality  34% reduction in All-Cause Mortality Events in PROTECT AF trial at 2,621 patient years (4y) Rateper100patientyears WATCHMAN Group N=463 Warfarin Group N=244 PS >99% PS > 82.5% 40% lower 32% lower 60% lower Ps = Posterior Probability for Superiority SH-AA-159901-MAY2013 Indications, contraindications, warnings and instructions for use can be found in the product labeling supplied with each device. Information for the use only in countries with applicable health authority product 34% lower P=0.0379P=0.0045
  13. 13. SH-102103-AD-APR2013 WATCHMAN™ Net Clinical Benefit Study Objective Evaluate the net clinical benefit of using the WATCHMAN ™ device by combining annualized rates of ischemic stroke, intracranial haemorrhage, major extracranial bleeding, pericardial effusion, and death, weighted to reflect the impact of these events relative to death and disability Study Design Post-hoc analysis of outcomes in 707 patients in the PROTECT AF trial and 566 patients in the CAP registry undergoing LAA closure with the WATCHMAN ™ device compared to standard anticoagulation Follow-Up 2,364 total patient years Gangireddy, S.R., et al., European Heart Journal 2012; DOI: 10.1093/eurheartj/ehs292 SH-AA-159901-MAY2013
  14. 14. SH-102103-AD-APR2013 WATCHMAN™ Net Clinical Benefit  In PROTECT AF the NCB shifted from warfarin to WATCHMAN between 6-9 months post implant.  Due to PEs and procedure-related stroke events.  NCB favored WATCHMAN as early as 3 mo’s post implant in CAP registry. Gangireddy, S.R., et al., European Heart Journal 2012; DOI: 10.1093/eurheartj/ehs292 SH-AA-159901-MAY2013
  15. 15. SH-102103-AD-APR2013 WATCHMAN™ PROTECT-AF Analysis of Older Patients >75 yrs. 4.1 3.1 5.2 6.2 4.3 5.7 0 2 4 6 8 Primary Efficacy All Stroke All-cause Mortality Rate (Events/Pt-yrs) WATCHMAN® Control 95% of stroke were ischemic, non-inferiority P-values ITT Patient Population  Fewer events were shown in the WATCHMAN group in the primary efficacy endpoints, all stroke, and all-cause mortality. P<0.01 P=0.01 P=0.02 16/ 391.6 16/ 256.1 12/ 391.6 11/ 256.1 21/ 404.5 15/ 262.1 Kar, S. TCT 2012; PROTECT-AF: Watchman LAA Closure in AF Patients ≥ 75 Years SH-AA-159901-MAY2013
  16. 16. SH-102103-AD-APR2013 WATCHMAN™ PROTECT-AF Analysis of Older Patients >75 yrs. ITT Patient Population  Older patients have a higher risk of bleeding, making it important to manage this risk (Mean CHADS2 score of 2.8 vs. 2.2 in the full study population).  WATCHMAN had a lower major bleeding rate than warfarin once procedure- related events were excluded. EVENT Device (n=190) Rate (events/patient-years) Control (n=115) Rate (events/patient-years) Major bleeding 6.1 (23/374.8) 5.1 (13/252.8) Procedure related major bleeding 2.9 (11/385.9) Or 11 events/190 pts (5.8% pts) NA Non-procedure related major bleeding 3.3 (13/393.3) 5.1 (13/252.8) Kar, S. TCT 2012; PROTECT-AF: Watchman LAA Closure in AF Patients ≥ 75 Years SH-AA-159901-MAY2013
  17. 17. SH-102103-AD-APR2013 Mr AC  78yo retired publican. Hypertension. Mild coronary disease. NIDDM diet controlled.  CVA 2008 documented on MRI. Minimal residual problems. Found to be in AF at the time. Failed cardioversion. Started on warfarin.  Presents with bright rectal bleeding. INR 2.2. Significant blood loss requiring 3 units packed cells.  Colonoscopy: severe diverticular disease – likely diverticular bleed  PLAN?
  18. 18. SH-102103-AD-APR2013 But not everyone with a high CHADS –VASC score is suitable for oral anticoagulation Even with the NOACs
  19. 19. SH-102103-AD-APR2013 WATCHMAN™ Preliminary Results ASA Plavix Feasibility Study Study Objective To evaluate the safety and feasibility of the WATCHMAN® Left Atrial Appendage Closure device for the treatment of non-valvular atrial fibrillation in patients with a contraindication to warfarin Study Design Multicenter, nonrandomized, feasibility study Primary Endpoint The primary efficacy endpoint was defined as the combined events of ischemic stroke, hemorrhagic stroke, systemic embolism, and cardiovascular/unexplained death. Patient Population n = 150 Mean age 72.5 ± 4 yrs. Mean CHADS2=2.8 Mean CHA2DS2-VASc=4.4 Mean Follow-Up 14.4 months Number of Sites 4 centers (Prague, Leipzig, Regensburg, and Frankfurt) Reddy, et al. JACC. 2013; In Press. SH-AA-159901-MAY2013
  20. 20. WATCHMAN™ Preliminary Results ASA Plavix Feasibility Study WATCHMAN Implantation for contra- indicated AF warfarin patients is:  Feasible  Low, but manageable, rate of device thrombus  Decreases the rate of stroke by 77% 5.0% 64% Reddy, et al. JACC. 2013; In Press. SH-AA-159901-MAY2013
  21. 21. SH-102103-AD-APR2013 Discussion on patient profiles 1 - Non-valvular AF: excluding rheumatic valvular disease or prosthetic heart valves 2 - For contraindications, refer to Instructions for use of the anticoagulants drugs NOACs (dabigatran, rivaroxaban, and apixaban) are not recommended in patients with severe renal impairme (CrCl <30 mL/min) - 2012 focus update of the ESC Guidelines for the management of atrial fibrillation 3 - Transient Ischemic Attack 4 - Examples: difficulties to stabilize INR (International Normalized Ratio) in the therapeutic range, compliance issues, discontinuation… 18 Refer to glossary for reference of supporting data

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