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Whats new in EP? Say no to drugs? Lionel Faitelson MD FACC FHRS Tucson Heart Group TMC Cardiovascular Symposium 2012.

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Presentation on theme: "Whats new in EP? Say no to drugs? Lionel Faitelson MD FACC FHRS Tucson Heart Group TMC Cardiovascular Symposium 2012."— Presentation transcript:

1 Whats new in EP? Say no to drugs? Lionel Faitelson MD FACC FHRS Tucson Heart Group TMC Cardiovascular Symposium 2012

2 New devices for arrhythmias? Anti-arrhythmic drugs: VT and VF Defibrillators ICDs; ablation Anti-arrhythmic drugs: SVT and AFL and AF Ablation Anti-heart failure drugs Biventricular pacemakers and ICDs Anticoagulant drugs in AF: NEW Alternatives to anticoagulant drugs NEW

3 AF: Managing the LA appendage Relevance Magnitude of AF issue Risk scores and anticoagulant therapies Surgical options Percutaneous options – Lariat – Watchman – Amplatzer cardiac plug – Other

4 Atrial Fibrillation Update 2012 Philadelphia 1.5 million San Francisco 700,000 Miami 400,000 Los Angeles 3.8 million 6.4 million (H.Weitz MD)

5 Atrial Fibrillation Update 2035 Philadelphia 1.5 million San Francisco 700,000 Boston 600,000 Houston 2 millionLos Angeles 3.8 million Chicago 2.8 million 11.4 million

6 Atrial fibrillation treatment

7 Atrial fibrillation March 2010: 1,980,000 hits March 2011: 2,550,000 hits January 2012: 9,500,000 hits

8 AF: Public awareness September 2012 is Atrial Fibrillation Awareness Month

9 How do we determine stroke risk ? CHADS2 (Gage, et al.: JAMA 2001) –Congestive heart failure - 1pt –Hypertension - 1pt –Age > pt –Diabetes - 1pt –Stroke or TIA - 2 pts –0 points – low risk ( strokes per 100 patient years) –1-2 points – moderate risk ( strokes per 100 patient years) –> 3 points – high risk ( strokes per 100 patient years)

10 How do we determine stroke risk ? CHADS2 (Gage, et al.: JAMA 2001) –Congestive heart failure - 1pt –Hypertension - 1pt –Age > pt –Diabetes - 1pt –Stroke or TIA - 2 pts –0 points – low risk ( strokes per 100 patient years) –1-2 points – moderate risk ( strokes per 100 patient years) –> 3 points – high risk ( strokes per 100 patient years)

11 Lip Y, et al. Chest 2010, 137(2):263

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13 CHADS 2 vs. CHA 2 DS 2 VASc CHADS 2 score 0: 1.4% events CHA 2 DS 2 -VASc score 0: 0 events CHA 2 DS 2 -VASc score 1: 0.6% events CHA 2 DS 2 -VASc score 2: 1.6 events

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15 Non-Valvular Atrial Fibrillation Stroke Prevention Medical Rx Warfarin Problematic Narrow therapeutic window Narrow therapeutic window Multiple drug-drug/drug-food interactions Multiple drug-drug/drug-food interactions Genetic variability Genetic variability Long half-life Long half-life PCI issues – triple therapy PCI issues – triple therapy Compliance Compliance Contraindications Contraindications Bleeding risks Bleeding risks

16 Non-Valvular Atrial Fibrillation Warfarin Use in AF Patients by Age % Ann Int Med 131(12), 1999 Only 55% of AF patients with no contraindications have evidence of warfarin use in previous 3 months Only 55% of AF patients with no contraindications have evidence of warfarin use in previous 3 months Other studies cite warfarin use in AF patients from 17-50% Other studies cite warfarin use in AF patients from 17-50% Elderly patients with increased absolute risk least likely to be taking warfarin Elderly patients with increased absolute risk least likely to be taking warfarin Contraindications 30-40% Contraindications 30-40%

17 Atrial fibrillation 2009 Target INR 2-3

18 Non-Valvular Atrial Fibrillation Adequacy of Anticoagulation in Clinic % Bungard: Pharmacotherapy 20:1060, 2001 Low INR <1.6 Therapeutic INR 2-3 High INR >3.2 Efficacy 4-fold

19 Non-Valvular Atrial Fibrillation Stroke Pathology Brass. Stroke 28(12), 1997 VanWalraven: JAMA 288, 2002 Major fatal bleed with age >75 = 3%/year (30% over 10 years) Major fatal bleed with age >75 = 3%/year (30% over 10 years) Intracranial hemorrhage Intracranial hemorrhage %/100 patient-years %/100 patient-years 3% in INR >4.0 3% in INR >4.0 10% if INR >4.5 10% if INR >4.5

20 Non-Valvular Atrial Fibrillation Stroke Pathology Blackshear: Ann Thoracic Surg 61, 1996 Johnson: Eur J Cardiothoracic Surg 17, 2000 Fagan: Echocardiography 17, 2000 Insufficient contraction of LAA leads to stagnant blood flow Insufficient contraction of LAA leads to stagnant blood flow Most likely culprit: embolization of LAA clot Most likely culprit: embolization of LAA clot 90% of thrombus found in LAA 90% of thrombus found in LAA TEE-based risk factors TEE-based risk factors Enlarged LAA Enlarged LAA Reduced inflow and outflow velocities Reduced inflow and outflow velocities Spontaneous Echo contrast Spontaneous Echo contrast

21 Warfarin Effective Reversible Inexpensive Slow onset of action Regular monitoring Food interraction Medication interraction Difficult titration-regular dose adjustments

22 Warfarin Effective Reversible Inexpensive Slow onset of action Regular monitoring Food interraction Medication interraction Difficult titration-regular dose adjustments

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24 RELY Dabigatran 110 mg twice daily –Equal to warfarin in stroke prevention Warfarin 1.69%/yr – dabigatran (110mg) 1.53%/yr –Less bleeding than warfarin Warfarin 3.36%/year – dabigatran (110mg) 2.71%/yr Dabigatran 150 mg twice daily –More effective than warfarin in stroke prevention Dabigatran (150mg) 1.11%/yr –Equivalent bleeding to warfarin less hemorrhagic stroke than warfarin

25 ACC AHA HRS Afib Focused Update (Dabigatran), March 2011 Non-inferior to warfarin re thromboembolism (afib) Caution when CrCl < 30ml/min Increased dabigatran levels with amiodarone, verapamil Half life hours No reversal re hemorrhage –dialysis ? shelf life once bottle opened (FDA alert March 30, 2011) –Tablets must stay in manufacturers container –Label: discard product 30 days after opening container Coagulation testing ??? aPTT, dilute thrombin time

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27 Dabigatran compared to control (warfarin, enoxaparin, placebo) Increased absolute risk of MI or ACS 0.27% Increased relative risk of MI or ACS 33% Dabigatran compared to control (warfarin, enoxaparin, placebo) Increased absolute risk of MI or ACS 0.27% Increased relative risk of MI or ACS 33%

28 Rivaroxaban Once daily As effective or better than warfarin Less hemorrhagic stroke than warfarin Similar reduction in ischemic stroke Less bleeding than warfarin No routine lab testing No reversal –Half life 5-9 hours Coagulation testing: aPTT Discontinuation : increased stroke

29 Apixaban Twice daily As effective or better than warfarin Less hemorrhagic stroke than warfarin Similar reduction in ischemic stroke Less bleeding than warfarin Lower overall mortality No routine lab testing No reversal –Half life 8-15 hours Coagulation testing: PT, aPTT

30 New anticoagulants Short half life – less bleeding –Subtherapeutic if misses one or two doses Lack of need for routine monitoring –No standard available test to asses if anticoagulated Generally safer than warfarin –No antidote –??? Dabigatran Cost of medication –Overall cost of care

31 How about Clopidogrel + Aspirin ? N Engl J Med online publication March 31, 2009

32 How about Clopidogrel + Aspirin ? N Engl J Med online publication March 31, 2009 Aspirin: stroke 3.4% per year major bleed 1.27% per year Aspirin + clopidogrel: stroke 2.4% per year major bleed 2.0% per year Warfarin still first line ? Role of aspirin + clopidogrel Aspirin: stroke 3.4% per year major bleed 1.27% per year Aspirin + clopidogrel: stroke 2.4% per year major bleed 2.0% per year Warfarin still first line ? Role of aspirin + clopidogrel

33 LAA: Focus of interest in AF Anticoagulants contra-indicated in 14 – 44% AF patients Stroke risk 2-5% even with therapeutic INR LAA – 90% of thrombi in nonvalvular nonrheumatic AF LAA volume 0.77 – cc LAA variable anatomy – multimodality imaging Luis, Roper et al; Cardiology Research and Practice 2012

34 LAA: Surgical options Excision with oversew or staples Exclusion with clips or sutures LAA Occlusion Study: success 45-72% LAA Surgery: excision 73% > exclusion 23% LAA Atriclip: EXCLUDE trial: 98% success Current surgical practice

35 Ligation of the Left Atrial Appendage Using an Automatic Stapler VJ DiSesa, S Tam, LH Cohn Division of Cardiac Surgery, Brigham & Women s Hospital, Boston, MA Appendage Obliteration to Reduce Stroke in Cardiac Surgical Patients with Atrial Fibrillation JL Blackshear, MD, JA Odell, FGRCS(Ed) Division of Cardiovascular Diseases, Mayo Clinic Jacksonville FL & Mayo Clinic, Rochester, MN Resection of the Left Auricular Appendix A Prophylaxis for Recurrent Arterial Emboli JOHN L. MADDEN, M.D. Department of Surgery, Long Island College of Medicine, Kings County Hospital, Brooklyn, NY Amputation of the Canine Atrial Appendages Hellerstein, HK USE OF THE SURGICAL STAPLER TO OBLITERATE THE LEFT ATRIAL APPENDAGE Laurence H. Coffin, M.D., F.A.C.S., Burlington, VT SYSTEMIC EMBOLISM AND LEFT AURICULAR THROMBOSIS IN RELATION TO MITRAL VALVOTOMY BY AND J. R. BELCHER, M.S., F.R.C.S. Surgeon, London Chest Hospital; Assistant Thoracic Surgeon, the Middlesex Hospital History of Suture Closure

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37 LAA: Lariat Prospective study; 82 pts; 3 month FU Indications: AF; warfarin intolerance or CI, or embolic event on warfarin 96% of pts with successful closure have closure at 1 month Need epicardial and endocardial access (CABG, XRT, valve surgery, pericarditis) Unsuitable if pericardial adhesions present FDA and CE approved Lee at al; Heart Rhythm 2011

38 Pre-Clinical Results Objective Evaluate safety & effectiveness in canine model of percutaneous LAA closure with the LARIAT N=26 canines Complete Acute Closure: 26/26 (100%) Histological Examination (all) 1 attempt: 23/26 ( 88%) Attempts to Capture 2 attempt: 3/26 ( 12%) 7d Closure: 3/3 (100%) 30d Closure: 3/3 (100%) 90d Closure: 4/4 (100%) Inflammatory response: 0/10 ( 0%) Complete Endothelioization: 10/10 (100%) Circ Cardiovasc Interv: June 2010

39 Clinical Results – PLACE I Total Patients N=13 AF History Persistent 12 (92%) Flutter 1 ( 8%) AgeAvg: 57.3; Hi 64, Low 43 SexM = 8 (62%) Type Procedure LAA w/ MVR 2 (15%) LAA w/ ablation 10 (77%) Ablation w/ LAA 1 ( 8%) Type Access Median Sternotomy 2 (15%) Minimally Invasive 2 (15%) Percutaneous 9 (70%) Intent to Treat 12/13 (92%) Acute Closure 12/12 (100%) Complicatio ns 1/13 (8%) non-serious (anatomic) Procedural Times Avg: 85.7 min; Median min Heart Rhythm: 2011:8:

40 Closure Without Compromise LAA Pre-procedure30 day Post-procedure

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42 PLACE TM Procedure Permanent Ligation Approximation Closure and Exclusion

43 PLACE TM Procedure

44 Clinical Results – Confidence in Closure In a single center, non randomized study(PLACE II)*, 85 patients underwent closure of their left atrial appendage using the LARIAT Suture Delivery Device and accessories. Patients were followed at 1 day, 30 days, 90 days and 1 year with transesophageal echocardiography to determine closure quality. The results were as follows: * PLACE II Clinical Study -KBET/90/B/2008; Dec Jun Submitted for publication. ** All non-serious: 2 pericardial access related. 1 transseptal access related. Intent-to-Treat85/89 (96%) Adverse Events (defined as access related or device failure) 3/89 (3.3%)** Access 3/89 (3.3%) Device 0/89 (0.0%) Closure (defined as < 1mm residual flow) 1 day 81/85 (95%) 30 day 81/85 (95%) 90 day 77/81 (95%) 1 year 65/66 (98%)

45 LAA: Watchman

46 WATCHMAN® LAA Closure Technology

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48 LAA: Watchman PROTECT AF (RCT); 707 pts; 18 month FU Indication: Permanent or Paroxysmal AF; CHADS >1; suitable for warfarin Noninferiority of the intervention demonstrated CE approved Reddy et al; Circulation 2011

49 PROTECT AF Clinical Trial Design Prospective, randomized study of WATCHMAN LAA Device vs long-term warfarin therapy Prospective, randomized study of WATCHMAN LAA Device vs long-term warfarin therapy 2:1 allocation ratio device to control 2:1 allocation ratio device to control 800 patients enrolled from Feb 2005 to Jun patients enrolled from Feb 2005 to Jun 2008 Device group (463) Device group (463) Control group (244) Control group (244) Roll-in group (93) Roll-in group (93) 59 enrolling centers (U.S. & Europe) 59 enrolling centers (U.S. & Europe) Follow-up requirements Follow-up requirements TEE follow-up at 45 days, 6 months and 1 year TEE follow-up at 45 days, 6 months and 1 year Clinical follow-up biannually up to 5 years Clinical follow-up biannually up to 5 years Regular INR monitoring while taking warfarin Regular INR monitoring while taking warfarin Enrollment continues in Continued Access Protocol (CAP Study) Enrollment continues in Continued Access Protocol (CAP Study)

50 Key Participation Criteria Key inclusion criteria Age 18 years or older Age 18 years or older Documented non-valvular AF Documented non-valvular AF Eligible for long-term warfarin therapy, and has no other conditions that would require long-term warfarin therapy Eligible for long-term warfarin therapy, and has no other conditions that would require long-term warfarin therapy Calculated CHADS2 score 1 Calculated CHADS2 score 1 Key exclusion criteria NYHA class IV congestive heart failure NYHA class IV congestive heart failure ASD and/or atrial septal repair or closure device ASD and/or atrial septal repair or closure device Planned ablation procedure within 30 days of potential WATCHMAN Device implant Planned ablation procedure within 30 days of potential WATCHMAN Device implant Symptomatic carotid disease Symptomatic carotid disease LVEF <30% LVEF <30% TEE criteria: suspected or known intracardiac thrombus (dense spontaneous Echo contract TEE criteria: suspected or known intracardiac thrombus (dense spontaneous Echo contract

51 PROTECT AF Trial Endpoints Primary efficacy endpoint Primary efficacy endpoint All stroke: ischemic or hemorrhagic All stroke: ischemic or hemorrhagic Deficit with symptoms persisting more than 24 hours or Deficit with symptoms persisting more than 24 hours or Symptoms less than 24 hours confirmed by CT or MRI Symptoms less than 24 hours confirmed by CT or MRI Cardiovascular and unexplained death: includes sudden death, MI, CVA, cardiac arrhythmia and heart failure Cardiovascular and unexplained death: includes sudden death, MI, CVA, cardiac arrhythmia and heart failure Systemic embolization Systemic embolization Primary safety endpoint Primary safety endpoint Device embolization requiring retrieval Device embolization requiring retrieval Pericardial effusion requiring intervention Pericardial effusion requiring intervention Cranial bleeds and gastrointestinal bleeds Cranial bleeds and gastrointestinal bleeds Any bleed that requires 2uPRBC Any bleed that requires 2uPRBC Some events will be counted as both safety and efficacy endpoints

52 Intent-to-Treat Primary Safety Results ITT cohort: patients analyzed based on their randomly assigned group (regardless of treatment received) Event-free probability Days Device Control EventsTotalRateEventsTotalRateRR Cohort(no.)pt-yr(95% CI)(no.)pt-yr(95% CI)(95% CI) 600 pt-yr (8.5, 15.3)(1.9, 7.2)(1.48, 6.43) 900 pt-yr (6.4, 11.3)(2.2, 6.7)(1.18, 4.13) DeviceControl 900 patient-year analysis Randomization allocation (2 device:1 control)

53 Specific Safety Endpoint Events Pericardial effusions – largest fraction of safety events in device group Pericardial effusions – largest fraction of safety events in device group Stroke events – most serious fraction of safety events in control group Stroke events – most serious fraction of safety events in control group Bleeding events were also frequent Bleeding events were also frequent

54 Pericardial Effusions by Experience Throughout PROTECT AF Trial, procedural modifications and training enhancements were implemented Throughout PROTECT AF Trial, procedural modifications and training enhancements were implemented Procedural events would be expected to decrease over time Procedural events would be expected to decrease over time Pericardial effusions within 7 days of the procedure are most relevant to the device performance Pericardial effusions within 7 days of the procedure are most relevant to the device performance No.%No.%No.% Early patients (1-3)13/ / / Late patients ( 4)27/ / / Total40/ / / Site implant group (includes roll-in subjects) Any Any procedure/ device related Any serious

55 Effusions in Recent Implant Experience Rates obtained in the CONTINUED ACCESS Study confirm that the lower rates are sustained Rates obtained in the CONTINUED ACCESS Study confirm that the lower rates are sustained No.%No.%No.% 1/881.11/881.11/881.1 Any Any procedure/ device related Any serious

56 Intent-to-Treat Primary Efficacy Results ITT cohort: patients analyzed based on their randomly assigned group (regardless of treatment received) Event-free probability Days WATCHMAN Control patient-year analysis EventsTotalRateEventsTotalRateRRNon-Superiority Cohort(no.)pt-yr(95% CI)(no.)pt-yr(95% CI)(95% CI)inferiority pt-yr(2.6, 6.7)(3.0, 9.1)(0.39, 1.67) pt-yr(2.1, 5.2)(2.8, 7.6)(0.37, 1.41) DeviceControl Posterior probabilities Randomization allocation (2 device:1 control)

57 Intent-to-Treat Hemorrhagic Stroke ITT cohort: patients analyzed based on their randomly assigned group (regardless of treatment received) Event-free probability Days Device Control patient-year analysis EventsTotalRateEventsTotalRateRRNon-Superiority Cohort(no.)pt-yr(95% CI)(no.)pt-yr(95% CI)(95% CI)inferiority pt-yr(0.0, 0.9)(0.5, 3.9)(0.00, 0.80) > pt-yr(0.0, 0.6)(0.7, 3.7)(0.00, 0.45) DeviceControl Posterior probabilities Randomization allocation (2 device:1 control)

58 Risk/Benefit Analysis Intent-to-treat analysis Intent-to-treat analysis Primary endpoint (intent to treat) achieved Primary endpoint (intent to treat) achieved Other statistically significant endpoint findings Other statistically significant endpoint findings Noninferiority for the primary efficacy event rate – 32% lower in device group Noninferiority for the primary efficacy event rate – 32% lower in device group Noninferiority for stroke rate – 26% lower in device group Noninferiority for stroke rate – 26% lower in device group Superiority for hemorrhagic stroke – 91% lower in device group Superiority for hemorrhagic stroke – 91% lower in device group Noninferiority for mortality rate – 39% lower rate in device group Noninferiority for mortality rate – 39% lower rate in device group Increased rate of primary safety events for the device group relative to the control group Increased rate of primary safety events for the device group relative to the control group Most events in the device group were procedural effusions that decreased over the course of the study Most events in the device group were procedural effusions that decreased over the course of the study 87% of patients discontinued warfarin at 45 days 87% of patients discontinued warfarin at 45 days Death/disability conclusion Death/disability conclusion

59 Risk / Benefit Analysis Per-protocol analysis Superiority for the primary efficacy event rate Superiority for the primary efficacy event rate Approximately 86% of patients in the device group were able to be successfully implanted and discontinue warfarin therapy Approximately 86% of patients in the device group were able to be successfully implanted and discontinue warfarin therapy Study demonstrates the role of the left atrial appendage in the pathogenesis of stroke due to AF Study demonstrates the role of the left atrial appendage in the pathogenesis of stroke due to AF Based on average age, patients will experience a 56% reduction in safety events Based on average age, patients will experience a 56% reduction in safety events Risk/Benefit Analysis

60 Summary Long-term warfarin treatment of patients with AF has been found effective, but presents difficulties and risk Long-term warfarin treatment of patients with AF has been found effective, but presents difficulties and risk PROTECT AF trial was a randomized, controlled, statistically valid study to evaluate the WATCHMAN device compared to warfarin PROTECT AF trial was a randomized, controlled, statistically valid study to evaluate the WATCHMAN device compared to warfarin In PROTECT AF, hemorrhagic stroke risk is significantly lower with the device. In PROTECT AF, hemorrhagic stroke risk is significantly lower with the device. When hemorrhage occurred, risk of death was markedly increased When hemorrhage occurred, risk of death was markedly increased In PROTECT AF, all cause stroke and all cause mortality risk are equivalent to that with warfarin In PROTECT AF, all cause stroke and all cause mortality risk are equivalent to that with warfarin In PROTECT AF, there are early safety events, specifically pericardial effusion; these events have decreased over time In PROTECT AF, there are early safety events, specifically pericardial effusion; these events have decreased over time

61 Conclusion The WATCHMAN LAA Technology offers a safe and effective alternative to warfarin in patients with non-valvular atrial fibrillation at risk for stroke and who are eligible for warfarin therapy

62 LAA: Amplatzer Cardiac Plug Different from Amplatzer Septal Occluder Registry; 141 pts; 24 hour FU Indication: Permanent/paroxysmal AF Early experience: Stroke 2.1%, device embolization 1.4%, tamponade 3.5% Clinical trial pending CE 12/2008 Park et al; CCI 2011

63 LAA CLOSURE: Amplatzer Cardiac Plug CE Marked December 2008 US IDE feasibility phase enrollment is completed: 45 patients, randomized 2:1 US IDE pivotal phase to commence 2012 Evaluate safety & efficacy of ACP vs. warfarin in AF patients Prospective, randomized 2:1 (device : warfarin) Estimated 400 to 2000 patients Primary efficacy endpoint: stroke & peripheral ischemic events Acute safety endpoint Long-term safety endpoint: death and major bleeds Park et al; Cath and CV Intervention 2011

64 LAA: Other devices Coherex Wave Crest – self expanding nitinol with coils and anchors and PTFE covering toward LA; LAA plug – actively recruiting PLAATO – self expanding nitinol cage with anchors and PTFE covering – 2 prospective trials: 111 and 64 pts – FU 10 months to 5 years – TIA/CVA 2.2% - CVA 3.8% – no longer available for clinical use

65 Left Atrial Appendage Closure Multiple indications Multiple approaches CE and FDA issues Closure


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