Disappearing LAA Thrombus Resulting in Stroke Parekh A, Parekh Ezekowitz M et al: Circ 1 Ezekowitz 14:e513, 2006 M et al: Circ 1

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1 LAA Ablation for Atrial Fibrillation Saudi Heart ACC Riyadh, Saudi Arabia February 2011 David R. Holmes, MD Mayo Clinic Rochester, MN

2 Presenter Disclosure Information David R. Holmes, Jr., M.D. LAA Ablation for Atrial Fibrillation The following relationships exist related to this presentation: "Both Mayo Clinic and I have a financial interest in technology related to this research. That technology has been licensed to Atritech. "

3 The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. If the red x still appears, you may have to delete the image and then insert it again. The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. If the red x still appears, you may have to delete the image and then insert it again. The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. If the red x still appears, you may have to delete the image and then insert it again. The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. If the red x still appears, you may have to delete the image and then insert it again. Disappearing LAA Thrombus Resulting in Stroke Parekh A, Ezekowitz M et al: Circ 114:e513,

4 How Big is the Problem? AF is the most common arrhythmia Affects more than 3 million individuals in the U.S. Projected to increase to 16 million by 2050 Lifetime risk in men and women >40 is 1 in 4 Patients with AF have a 5-fold higher risk of stroke Over 87% of strokes are thromboembolic b >90% of thrombus originates in the left atrial appendage Stroke is the #1 cause of long-term disability and the third leading cause of death in patients with AF

5 Stroke in AF Paroxysmal, persistent and permanent AF all appear to increase the risk of ischemic stroke to a similar degree As age increases, the percent of total stroke attributable to AF increases In the Framingham study, risk of ischemic stroke attributable to atrial fibrillation increased from 1.5% at age 50-59, 59, to 23.5% at age

6 os dds ratio Od ATRIA Study INR, TE and ICH Thromboembolism Intracranial hemorrhage International normalized ratio level >4.5 Singer DE et al: Circ Cardiovasc Qual Outcomes 2:297,

7 The Search for a Candidate ASA Clopidogrel ASA and clopidogrel Extended release dipyridamole Tecarfarin Dabigatran Dabigatran and ASA Dronedarone Aurintricarboxylic acid Monoclonal antibodies to rabbit TF

8 Design of RE-LY Atrial fibrillation 1 risk factor Absence of contraindications 951 centers in 44 countries PROBE = Prospective Randomized Open Trial with Blinded Adjudication of Events R Open Warfarin (INR ) n=6,000 Dabigatran Etexilate 110 mg bid n=6,000 Dabigatran Etexilate 150 mg bid n=6,000 1 efficacy outcome = stroke or systemic stemic embolism 1 safety outcome = major bleeding Noninferiority margin

9 Cumulative HR for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group Cumulative hazard rate Months No. at risk Warfarin 6,022 5,862 5,718 4,593 2,890 1,322 Dabigatran, 110 mg 6,015 5,862 5,710 4,593 2,945 1,385 Dabigatran, 150 mg 6,076 5,939 5,779 4,682 3,044 1,429 Connolly SJ et al: NEJM 361:1139,

10 Permanent Discontinuation 0.4 Stopping rates Dabigatran 150 Warfarin Dabigatran 110 No. at risk Follow-up (yr) , ,336 5, ,950 2, ,176 6,076 5,329 5,015 3,955 2,528 1,172 6,022 5,563 5,269 4,158 2,561 1,

11 ates azard ra lative ha Cumul No. at risk Major Bleeding Warfarin Dabigatran Follow-up (yr) ,015 5, , ,510 2, , ,076 5,839 5,638 4,557 2,928 1,366 6,022 5,801 5,600 4,474 2,797 1,269 Dabigatran

12 RELY Trial at 2.5 years More patients discontinue Dabigatran than warfarin Depending on specific dose schedule, Dabigatran is either non inferior i to warfarin in preventing stroke/embolization or is somewhat better HOWEVER, bleeding rates increase over time with either Dabigatran or warfarin

13 The Bottom Line So far, there is no free lunch. If you interfere with coagulation in any manner, it will be associated with excess bleeding. The challenge is to find the sweet spot between efficacy and safety. Dr. Eugene Braunwald

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16 Setting Total no. thrombi found in LAA and atrium Thrombi Location in LA Found LAA Found in left atrium No. % No. % Location of thrombi in non-rheumatic atrial fibrillation Reference TEE Stoddard: JACC, 95 TEE Manning: Circ, 94 Autopsy Aberg: Acta Med Scan, 69 TEE Tsai: JFMA, 90 TEE Klein: Int J Card Imag, 93 TEE & operation Manning: Circ, 94 SPAF III & TEE Klein: Circ, 94 TEE Leung: JACC, 94 TEE Hart: Stroke, 94 Total Ann Thor Surg 61:755, 1996 CP

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18 PROTECT AF Trial History Hypothesis: Left atrial appendage occlusion can decrease all stroke, death, systemic embolization and avoid the need for chronic anticoagulation in patients with non-rheumatic valvular atrial fibrillation

19 PROTECT AF Trial Timelines Protocol developed 2004 Granted conditional FDA approval for enrollment November 2004 Statistical analysis plan approved by FDA 2004, 2005, September 2007 Clinical Trial (NCT ) 2005 First enrollment February 2005

20 PROTECT AF Trial Timelines August 2008: FDA granted expedited review Trial presented as ACC-LBCT (March 28, 2009) Panel meeting April 23, :5 in favor of approval with conditions 34 days later NEJM editorial published May 27

21 PROTECT AF Trial Timelines (N Engl J Med 2009; 360: )

22 PROTECT AF Pivotal study designed to demonstrate safety and effectiveness of the Watchman implant in patients with non- valvular paroxysmal, persistent or permanent atrial fibrillation (AF) who require treatment for potential thrombus formation, are eligible for warfarin therapy, and have a CHADS 2 stroke risk stratification score 1

23 PROTECT-AF Clinical Trial Prospective, randomized d study of WATCHMAN LAA Device vs Long-Term Warfarin Therapy 2:1 allocation ratio device to control Non-inferiority study Bayesian Hierarchical sequential design Analysis at 600 pt-yr and every 150 pt-yr after

24 PROTECT AF 704 randomized patients with non- valvular l atrial fibrillation ill Mean age 72 years Permanent atrial Fib 36% Paroxysmal atrial fib 41% CHADS % CHADS %

25 PROTECT AF Trial Bayesian Hierarchical model to determine if Watchman implant is non- inferior to control with respect to event rate of all stroke, systemic embolization and major bleeding (per 100 patient years f/u) 1500 patients

26 Safety Events Also Counted in Efficacy Endpoint Efficacy events Stroke ischemic Systemic embolism CV/unexplained death Stroke hemorrhagic Stroke procedural related Both efficacy and safety Safety events Device embolization Major bleeding events Pericardial effusions "Primary effectiveness endpoint captures the events that would also be considered significant safety events (ie, stroke, death and systemic embolism)."

27 Device Intent-to-Treat Primary Efficacy Results Randomization allocation (2 device : 1 control) Control Posterior Probabilities Events Total Rate Events Total Rate Rel. Risk Non- Cohort (no.) pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) inferiority Superiority 900 pt-yr (2.1, 5.2) (2.8, 7.6) (0.37, 1.41) 1.0 Event-fre e probabilit ty 0.9 WATCHMAN Control ITT Cohort: Non-inferiority criteria met ,095 Days

28 Intent-to-Treat Primary Safety Results Randomization allocation (2 device : 1 control) Device Control Events Total Rate Events Total Rate Rel. Risk Cohort (no.) pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) 900 pt-yr (6.4, 11.3) (2.2, 6.7) (1.18, 4.13) 1.0 Event-fre e probabilit ty 0.9 WATCHMAN Control ,095 Days

29 Warfarin Discontinuation 87% of implanted subjects were able to cease warfarin at 45 days and the rate further increased at later timepoints Visit Watchman No. % 45 day 349/ month 347/ month 261/ month 95/ Reasons for remaining on warfarin therapy after 45 days Observation of flow in the LAA (n=30) Physician order (n=13) Other (n=9)

30 Summary 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 In PROTECT AF, hemorrhagic stroke risk is significantly lower with the device. When hemorrhagic stroke occurred, risk of death was markedly increased In PROTECT AF, all cause stroke and all cause mortality risk are non-inferior to warfarin In PROTECT AF, there are early safety events, specifically pericardial effusion; these events have decreased over time

31 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

32 Interpretation The efficacy of percutaneous closure of the LAA with this device was non-inferior to that of warfarin therapy. Although there was a higher rate of adverse safety events in the intervention group than in the control group, events in the intervention group were mainly a result of periprocedural complications. Closure of the LAA an alternative strategy to chronic warfarin therapy for stroke prophylaxis. Lancet 2009:374;

33 PROTECT AF Trial Panel meeting April 23, :5 in favor of approval with conditions FDA non approval letter: March 10, 2010

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35 PROTECT AF FDA Issues % of CHADS 2 patients Early (45 day) warfarin use in both groups Subsequent concomitant use of ASA + clopidogrel in both groups Insufficient longer-term follow-up Safety

36 PROTECT AF Trial Issues Safety Early warfarin Subsequent other events Clinical need for warfarin Classification of stroke Hemorrhagic versus ischemic

37 Average Follow-up Months Patient Years

38 Intent-to-Treat: Primary Efficacy Results Cohort WATCHMAN Control Rate (95% CI) Rate (95% CI) Rel risk Posterior probabilities (95% CI) Noninferiority Superiority 600 pt-yr 4.4 ( ) 6.7) 5.8 ( ) 0.76 ( ) pt-yr 3.4 ( ) 5.0 ( ) 0.68 ( ) ,065 pt-yr 3.0 ( ) 4.9 ( ) 0.62 ( ) > ,350 pt-yr 2.9 ( ) 4.2 ( ) 0.69 ( ) > ,500 pt-yr 3.0 ( ) 4.3 ( ) 0.71 ( ) > Noninferiority criteria met 29% lower relative risk in WATCHMAN group

39 Primary Efficacy Over Time ty robabilit t-free pr Event Watchman Control ,095 1,460 Days from randomization

40 Primary Efficacy Kaplan-Meier Estimates Event t-free proba ability WATCHMAN Control Years from randomization WATCHMAN Control Cohort 1-year event rate 2-year event rate 3-year event rate (95% CI) (95% CI) (95% CI) WATCHMAN 3.7 ( ) 6.1 ( ) 8.5) 7.9 ( ) Control 4.3 ( ) 8.0 ( ) 12.5 ( ) 1,500 patient-year analysis

41 Intent-to-Treat: All Stroke Cohort WATCHMAN Control Rate (95% CI) Rate (95% CI) Rel risk Posterior probabilities* (95% CI) Noninferiority Superiority 600 pt-yr 3.4 ( ) 3.6 ( ) 0.96 ( ) pt-yr 2.6 ( ) 3.5 ( ) 0.74 ( ) ,065 pt-yr 2.3 ( ) 3.2 ( ) 0.71 ( ) ,350 pt-yr 2.1 ( ) 3.3) 2.7 ( ) 4.3) 0.78 ( ) 1.75) ,500 pt-yr 2.0 ( ) 3.1) 2.7 ( ) 0.77 ( ) % lower relative risk in WATCHMAN group *No adjustment made for multiple comparisons

42 Intent-to-Treat: All-Cause Mortality Cohort WATCHMAN Control Rate (95% CI) Rate (95% CI) Rel risk Posterior probabilities* (95% CI) Noninferiority Superiority 600 pt-yr 3.4 ( ) 4.9 ( ) 0.69 ( ) pt-yr 2.9 ( ) 4.7 ( ) 0.61 ( ) ,065 pt-yr 3.0 ( ) 4.8 ( ) 0.62 ( ) > ,350 pt-yr 3.1 ( ) 4.4 ( ) 6.1) 0.70 ( ) > ,500 pt-yr 3.2 ( ) 4.5 ( ) 0.71 ( ) > % lower relative risk in WATCHMAN group *No adjustment made for multiple comparisons

43 Intent-to-Treat: Primary Efficacy Results Cohort CHADS 2 Score WATCHMAN Events/pt-yr Control Event/pt-yr RR (95% CI) All patients 21/ / ( ( ) CHADS 2 1 3/ / ( ) CHADS 2 >1 18/ / ( ( ) 36) Composite endpoint Stroke CV death Systemic embolism

44 Primary Efficacy Results Age Cohort WATCHMAN Events/pt-yr Control Event/pt-yr RR (95% CI) All patients 21/ / ( ( ) Age <73 9/ / ( ) Age 73 12/ / ( ( )

45 Watchman LAA Occlusion Implantation ti Success % Interventional Cardiology Electrophysiology

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47 Now open even wider, Mr. Stevens. Now open even wider, Mr. Stevens. Just out of curiosity, we re going to see if we can also cram in this tennis ball.

48 PROTECT AF Root Cause Analysis of the Pericardial Effusions Events (%) Initial transseptal puncture 2/22 (9%) From adjunctive device to enter LAA (such as a guidewire or catheter) Manipulating delivery system within LAA Protruding delivery sheath from transseptal access sheath 4/22 (18%) 3/22 (14%) 2/22 (9%) Watchman deployment process 4/22 (18%) No definitive cause identified 7/22 (32%) Reddy: Circ (in press)

49 Primary Safety Over Time ty robabilit t-free pr Event Watchman Control ,095 1,460 Days from randomization

50 Intent to Treat: Primary Safety Results WATCHMAN Control Cohort Rate (95% CI) Rate (95% CI) Rel risk(95% CI) 600 pt-yr 11.6 ( ) 4.1 ( ) 2.85 ( ) 900 pt-yr 8.7 ( ) 4.2 ( ) 2.08 ( ) 1,065 pt-yr 7.4 ( ) 4.4 ( ) 1.69 ( ) 1,350 pt-yr 6.2 ( ) 3.9 ( ) 1.60 ( ) 1,500 pt-yr (4271) ( ) 36(2253) 3.6 ( ) (0952 ( )

51 Primary Safety Kaplan-Meier Estimates 1.0 Event t-free proba ability Control WATCHMAN Years from randomization WATCHMAN Control Cohort 1-year event rate 2-year event rate 3-year event rate (95% CI) (95% CI) (95% CI) WATCHMAN 10.1 ( ) 10.4 ( ) 13.6 ( ) Control 4.3 ( ) 6.7 ( ) 8.9 ( ) 1,500 patient-year analysis

52 PROTECT AF & CAP Registry Safety Events 1.0 bability Ev vent/pro CAP PROTECT AF later PROTECT AF early Days from implant Reddy: Circ (in press)

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54 Proof of Concept Device Intent-to-Treat All Stroke bility free probab Event-f WATCHMAN Control Randomization allocation (2 device:1 control) Key Implication: Confirms Role 900 patient-year analysis of LAA in CVA Days Holmes et al, Lancet 2009

55 Conclusions The PROTECT AF trial substantiates the hypothesis that in patients with non-valvular atrial fibrillation, stroke typically originates in the LAA Occlusion of the LAA is feasible and offers an alternate for stroke prevention in patients who are not candidates for long-term anticoagulation New devices are being evaluated and tested in multiple groups of patients Documentation of the results of these evaluations has the potential to dramatically change the field of stroke prevention for the large group of patients with atrial fibrillation

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57 Statistical Analysis Intent-to to-treat treat Per protocol Terminal therapy Specific co-variates: CHADs score Age

58 Warfarin Discontinuation WATCHMAN Group 76% of randomized patients discontinued warfarin at 45 days 87% of implanted patients discontinued warfarin at 45 days Visit Warfarin discontinuation Total implanted No. % 45 day 348/ month 355/ month 345/ month 293/ Reason for continuation/reinitiation At 45 days At 6 months No. % No. % Observation of flow in the LAA Physician discretion

59 Per-Protocol Protocol Analysis Assess only those successfully treated with randomized therapy 87% of WATCHMAN patients no longer require warfarin Includes only yp patients who received their assigned therapy WATCHMAN: received device and discontinued warfarin, count time going forward Control: taking warfarin at baseline or by 45 days Helps to isolate sole device effect

60 Per Protocol: Primary Efficacy Results Cohort WATCHMAN Control Rate (95% CI) Rate (95% CI) Rel risk Posterior probabilities* (95% CI) Noninferiority Superiority 600 pt-yr 2.5 ( ) 5.4 ( ) 0.47 ( ) 1.21) pt-yr 2.1 ( ) 4.7 ( ) 0.44 ( ) > ,065 pt-yr 1.9 ( ) 4.6 ( ) 6.8) 0.40 ( ) 0.91) > ,350 pt-yr 1.9 ( ) 4.0 ( ) 0.47 ( ) > ,500 pt-yr 2.3 ( ) 4.1 ( ) 5.7) 0.56 ( ) > % lower relative risk in WATCHMAN group *No adjustment made for multiple comparisons

61 Summary of Relative Risks Between Data Sets Intent to treat ,050 1,200 1,350 1,500 pt-yr pt-yr pt-yr pt-yr pt-yr pt-yr Primary efficacy Pi Primary safety Stroke Mortality Results are consistent demonstrating approximately a 30% reduction in primary efficacy, stroke and mortality risk over multiple time points beginning with 11 months of average follow-up at 600 patient-years to 27 months of average follow-up at 1,500 patient-years

62 1.Guidance Current evidence suggests that percutaneous occlusion of the left atrial appendage (LAA) is efficacious in reducing the risk of thromboembolic complications associated with non- valvular atrial fibrillation (AF). With regard to safety, there is a risk of life-threatening complications from the procedure, but the incidence of these is low. Therefore, this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.

63 Design of RE-LY Atrial fibrillation 1 risk factor Absence of contraindications 951 centers in 44 countries PROBE = Prospective Randomized Open Trial with Blinded Adjudication of Events R Open Warfarin (INR ) n=6,000 Dabigatran Etexilate 110 mg bid n=6,000 Dabigatran Etexilate 150 mg bid n=6,000 1 efficacy outcome = stroke or systemic stemic embolism 1 safety outcome = major bleeding Noninferiority margin 1.46

64 Nancy always had thick ankles, but no one really noticed.

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66 PROTECT AF Trial History Hypothesis Protocol developed Statistical ti ti analysis FDA review Clinical trial (NCT )

67 Pivotal Trial #2 PREVAIL Multicenter randomized trial of 475 patients with nonvalvular lar AF and similar inclusion criteria to PROTECT AF 2:1 randomization Primary endpoint: Hemorrhagic stroke Ischemic stroke Systemic embolism CV/unexplained death Adaptive study design, Bayesian piecewise exponential model, noninferiority

68 Pivotal Trial #2 PREVAIL CHADS 2 2, selected CHADS 2 1 patients t Patients treated with Clopidogrel excluded (FDA mandate) History recurrent thrombosis/thromboembolism on AC

69 Left Atrial Appendage Closure What do we need PROTECTION from? Stroke and systemic embolization Bleeding related to chronic anticoagulant therapy Need for a chronic therapy and frequent monitoring The combination of dual anti-platelet therapy and warfarin

70 Non-Valvular Atrial Fibrillation Stroke Prevention Medical Rx Warfarin cornerstone of therapy Assuming 51 ischemic strokes/1000 pt-yr Adjusted standard dose warfarin prevented 28 strokes at expense of 11 fatal bleeds Aspirin prevented 16 strokes at expense of 6 fatal bleeds Warfarin 60-70% risk reduction vs no treatment t t 30-40% risk reduction vs aspirin Cooper: Arch Int Med 166, 2006 Lip: Thromb Res 118,

71 LAA Exclusion Devices What do we Need? Validation of the hypothesis Patient selection criteria Risk of bleeding versus stroke Device performance Risk benefit ratio Technical approaches Adjunctive therapy

72 PROTECT-AF Trial Endpoints Primary efficacy endpoint All stroke: ischemic or hemorrhagic Deficit with symptoms persisting >24 hr or symptoms <24 hr confirmed by CT/MRI Cardiovascular or unexplained death: includes sudden death, MI, CVA, cardiac arrhythmia and heart failure Systemic embolism Primary safety endpoint

73 Hypothesis In patients with nonvalvular atrial fibrillation, stroke or systemic embolism is related to the LAA

74 CHADS 2 Score, Mean ± SD CHADS 2 Score: Patient Risk Factors Baseline Risk Factors PROTECT AF CAP N= 542 N= ± ± 1.2 < % 25% % 19% 8% 4% 34% P 21% % 6% 6 <1% <1%

75 Performance Metrics PROTECT AF vs CAP PROTECT AF PROTECT AF Early Late CAP p- p- value* value± Procedure Time (Mean ± SD) 62 ± ± ± ± 21 <0.001 <0.001 Implant Success 45-day Warfarin Discontinuation Among Implanted 485/542 (89.5%) 239/271 (88.2%) 246/271 (90.8%) 437/460 (95.0%) 414/ / / /371 (86.6%) 6%) (82.6%) (90.5%) (94.9%) 9%) <0.001 <0.001 Improvements seen over time in PROTECT AF Shorter implant time, higher implant success rate, higher warfarin discontinuation rate Trends confirmed in CAP *From tests comparing the PROTECT AF cohort with CAP ±From tests for differences across three groups (early PROTECT AF, late PROTECT AF, and CAP)

76 Safety Event Rates PROTECT AF vs CAP PROTECT AF PROTECT AF Early Late CAP p- value* p- value± Procedure/Device Related Safety 42/542 27/271 15/271 17/460 Adverse Events within 7 Days (7.7%) (10.0%) (5.5%) (3.7%) Serious Pericardial Effusions within 7 Days 27/542 (5.0%) 17/271 (6.3%) 10/271 (3.7%) 10/460 (2.2%) Procedure Related Stroke 5/542 (0.9%) 3/271 (1.1%) 2/271 (0.7%) 0/460 (0.0%) Improvements seen over time for acute safety events Fewer total procedure/device related events *From tests comparing the PROTECT AF cohort with CAP ±From tests for differences across three groups (early PROTECT AF, late PROTECT AF, and CAP)

77 PROTECT AF Root Cause Analysis of the Pericardial Effusions Watchman Group Events (per 100 pt-yrs) Warfarin Group Events (per 100 pt-yrs) Relative Risk (95% CI) MRS increase 1 or death 1.8 (19/1042.2) 4.3 (24/559.5) 0.43 (0.24, 0.82) MRS increase or death (16/1047.1) (21/563.9) (0.22, 0.82) MRS increase or death (15/1048.5) (19/567.5) (0.22, 0.88) Reddy: Circ (in press)

78 Left Atrial Appendage Closure What Can We Learn The hypothesis that in patients with nonvalvular atrial fibrillation that stroke results from thrombus in the LAA is correct Benefit of LAA occlusion remains stable >90% of patients can be taken off of warfarin without harm

79 Safety Event Rates in PROTECT AF & CAP PROTECT AF CAP Procedure time 62±34 50±21 (mean ± SD) Implant success (n/total %) 485/542 (89.5%) 437/460 (95.0%) Procedure/device related safety adverse event within 7 days 42/542 (7.7%) 17/460 (3.7%) (n/total %) Serious pericardial effusion within 7 days (n/total %) 27/542 (5.0%) 10/460 (2.2%) Procedure related stroke 5/542 0/460 (n/total %) (0.9%) (0%) Presented as abstract at 2009 & 2010 ACC & 2009 HRS by Dr. Vivek Reddy

80 Safety Event Rates in PROTECT AF Procedure time (mean ± SD) Implant success (n/total %) Early Late 1 st 3 Pts Other Pts 67±36 58±33 82±40 55±29 239/271 (88.2%) 246/271 (90.8%) 133/154 (86.4%) 352/388 (90.7%) Procedure/device related safety adverse event within 7 days (n/total %) 27/271 (10.0%) 15/271 (5.5%) 19/154 (12.3%) 23/388 (5.9%) Serious pericardial effusion within 7 days (n/total %) 17/271 (6.3%) 10/271 (3.7%) 10/154 (6.5%) 17/388 (4.4%) Procedure related stroke (n/total %) 3/271 (1.1%) 2/271 (0.7%) 1/154 (0.7%) 4/388 (1.0%) Presented as abstract at 2009 & 2010 ACC & 2009 HRS by Dr. Vivek Reddy

81 Functional Impact of Safety Events Watchman Group Events Warfarin Group Events RR (95% CI) (per 100 pt-yrs) (per 100 pt-yrs) MRS increase 1 or death 1.8 (19/1042.2) 2) 4.3 (24/559.5) 5) 0.43 (0.24/0.82) MRS increase 2 or death 1.5 (16/1047.1) 3.7 (21/563.9) 0.41 (0.22/0.82) MRS increase 3 or death 1.4 (15/1048.5) 3.3 (19/567.5) 0.43 (0.22/0.88) Presented as abstract at 2009 & 2010 ACC & 2009 HRS by Dr. Vivek Reddy

82 Stroke (Intent-to-Treat) 1350 Patient Years WATCHMAN n=463 Control N=244 Rate (events/pt-yr) Rate (event/pt-yr) Rel risk (95% CI) / / (95% CI ) 3.3) (95% CI ) 4.3) This yielded a relative risk, or rate ratio, of 0.78, a 22% lower rate of stroke in the WATCHMAN group than in the Control group. The 95% credible interval for the rate ratio was

83 Safety Events Pericardial Effusion Pericardial effusions 47% of total device events 22 classified as serious (4.8% of patients) 7 required surgical intervention: ti extended d hospitalization by 6 days 15 treated percutaneously: extended hospitalization by 4 days None resulted in death

84 Concept Most strokes in AF result from thromboembolism from the left atrial appendage (LAA) Exclude LAA from central circulation to prevent stroke without anticoagulation

85 Mortality (Intent-to-Treat) 1350 Patient Years WATCHMAN n=463 Control N=244 Rate (events/pt-yr) Rate (event/pt-yr) Rel risk (95% CI) / / (95% CI ) (95% CI ) 6.1) This yielded a relative risk, or rate ratio, of 0.70, a 30% lower rate of death in the WATCHMAN group than in the Control group. The 95% credible interval for the rate ratio was

86 Left Atrial Appendage Closure What Can We Learn The left atrial appendage is fragile and the landscape is unforgiving With changes in equipment, implant technique and improved operator experience that safety improves The risk of device embolization is very low

87 Watchman Left Atrial Appendage Closure What Can We Learn Both interventional cardiologists and electrophysiologist can implant the device safely and effectively Temporal profile of risk is different for an implantable device versus chronic medication Not all patients are candidates for this device

88 Issues Unable to take warfarin Persistent LAA thrombus Risk/benefit ratio Early hazard vs no warfarin

89 Key inclusion criteria Age 18 years Key Participation Criteria Key exclusion criteria 18 years Mechanical valve or long-term warfarin needed Documented AF Paroxysmal Contraindication to warfarin Persistent Unable to take ASA/Plavix Permanent NYHA class IV CHF Calculated CHADS 2 1 ASD and/or atrial septal repair or closure device Planned ablation procedure within 30 days Symptomatic carotid disease LVEF 30% TEE criteria: suspected or know intracardiac thrombus

90 Characteristic Patient Demographics Baseline Characteristics WATCHMAN Control n=463 n=244 Age (yr) 71.7± , ± , Female 137/ % 73/ % 9% Male 326/ % 171/ % Asian 4/ % 1/ % African Amer 6/ % 5/ % Caucasian 425/ % 222/ % Hispanic 25/ % 15/ % Pac Islander 1/ % 1/ % Other 2/ % 0/ % P %

91 Patient Risk Factors Baseline Risk Factors WATCHMAN Control Characteristic n=463 n=244 P CHADS 2 score / % 66/ % 2 158/ % 88/ % 3 88/ % 51/ % 4 37/ % 24/ % 5 19/ % 10/ % 6 4/ % 5/ % AF pattern 0.76 Paroxysmal 200/ % 99/ % Persistent 97/ % 50/ % Permanent 160/ % 93/ % Unknown 6/ % 2/ % LVEF (%) 57.3± , ± ,

92 Warfarin and Atrial Fibrillation ATRIA Study 13,559 adults with nonvalvular atrial fibrillation Assess net clinical benefit of warfarin Net clinical benefits: Annual rate of ischemic i stroke and systemic emboli prevented by warfarin multiplied by impact weighting factor Singer DE et al: Ann Intern Med 151:297, 2009

93 Primary Efficacy (Intent-to-Treat) Relative Risk Summary ive Risk acy Relati mary Effica Prim Patient Years

94 WATCHMAN LAA Closure Device in Situ

95 Post-Procedure Procedure Analysis Cohort WATCHMAN Events/pt-yr Control Events/pt-yr RR (95% CI) All pt 15/ / ( ) 0.90) CHADS 2 1 3/ / ( ( ) CHADS 2 >1 12/ / ( ) 0.98) Paroxysmal 6/ / ( ( ) 1.55) Persistent 2/ / ( ) Permanent 7/ / ( ( ) Age <73 6/ / ( ) 1.41) Age 73 9/ / ( )

96 Per-Protocol: Protocol: Primary Efficacy Results Cohort WATCHMAN Events/pt-yr Control Events/pt-yr RR (95% CI) All pt 11/ / ( ) 0.86) CHADS 2 1 3/ / ( ( ) 07) CHADS 2 >1 8/ / ( ) 0.88) Paroxysmal 4/ / ( ( ) 1.62) Persistent 2/ / ( ) Permanent 5/ / ( ( ) 1.96) Age <73 5/ / ( ) 1.40) Age 73 6/ / ( ) 1.08)

97 Conclusions Older patients t (>73 yr) and those with CHADS 2 scores >1 had higher event rates for both the device and control groups The WATCHMAN device is a safe and reasonable alternative option to oral anticoagulation for the reduction of stroke in nonvalvular AF

98 Primary Efficacy Results AF Pattern Endpoint Paroxysmal Persistent Permanent Efficacy end point, 1,050 ( ) 2.06) ( ) 0.98) ( ) patient-yr HR (95% CI)

99 Safety Events Stroke Also counted as efficacy events in efficacy analyses 5 events in device group classified as "ischemic stroke" All periprocedural: extended hospitalization by 7 days 3wererelated 3 related to air embolism 1 hemorrhagic stroke in device group vs 6 in control group Device event occurred 15 days post implant while patient was on warfarin 4/6 stroke events in control group patients t resulted in death

100 Endpoint Post-Procedure Procedure Efficacy Results All patients CHADS 2 1 CHADS 2 >1 Efficacy end point, 1,050 ( ) 0.90) ( ) ( ) 0.98) patient-yr HR (95% CI) Endpoint All patients Age <73 Age 73 Efficacy end point, 1,050 ( ) 0.90) 090) ( ) 1.41) 141) ( ) 112) patient-yr HR (95% CI) Endpoint All patients Paroxysmal Persistent Permanent Efficacy end point, 1,050 ( ) 0.90) ( ) 1.55) ( ) ( ) patient-yr HR (95% CI)

101 Post-ProcedureProcedure CHADS 2 End point All patients CHADS 2 1 CHADS 2 >1 Efficacy end point, ( ) 0.90) ( ) ( ) 0.98) HR (95% CI)

102 Post-ProcedureProcedure Age End point All patients Age <73 Age 73 Efficacy end point, ( ) 0.90) ( ) 1.41) ( ) HR (95% CI)

103 Post-ProcedureProcedure AF Pattern End point All patients Paroxysmal Persistent Permanent Efficacy end point, ( ) 0.90) ( ) 1.55) ( ) ( ) HR (95% CI)

104 Per-ProtocolProtocol CHADS 2 End point All patients CHADS 2 1 CHADS 2 >1 Efficacy end point, ( ) 0.86) ( ) ( ) 0.88) HR (95% CI)

105 Per-ProtocolProtocol Age End point All patients Age <73 Age 73 Efficacy end point, ( ) 0.86) ( ) 1.40) ( ) 1.08) HR (95% CI)

106 Per-ProtocolProtocol AF Pattern End point All patients Paroxysmal Persistent Permanent Efficacy end point, ( ) 0.86) ( ) 1.62) ( ) ( ) 1.96) HR (95% CI)

107 CHADS 2 Risk Criteria for Stroke in Nonvalvular AF CHADS 2 risk criteria Score Prior stroke or TIA 2 Age >75 yr 1 Hypertension 1 Diabetes mellitus 1 Heart failure 1 Patients Adjusted stroke rate CHADS 2 (n=1,733) %/yr 95% CI score ACC/AHA/ESC 2006 Atrial Fibrillation Management Guidelines

108 PROTECT AF Trial Endpoints Primary Efficacy Endpoint All stroke: ischemic or hemorrhagic deficit with symptoms persisting more than 24 hours or symptoms less than 24 hours confirmed by CT or MRI Cardiovascular and unexplained death: includes sudden death, MI, CVA, cardiac arrhythmia and heart failure Systemic embolization Primary Safety Endpoint Device embolization requiring retrieval Pericardial effusion requiring intervention Cranial bleeds and gastrointestinal bleeds Any bleed that requires 2uPRBC NB: Primary effectiveness endpoint contains safety events

109 Summary of Relative Risks between Data Sets Intent-to-Treat 600 Pt- yrs 900 Pt-yrs Relative Risk 1050 Pt-yrs 1200 Pt-yrs 1350 Pt-yrs Primary Efficacy Primary Safety Stroke Mortality

110 Intent-to-Treat: Primary Efficacy Results Cohort CHADS 2 Score WATCHMAN Events/pt-yr Control Event/pt-yr RR (95% CI) All patients 21/ / ( ( ) CHADS 2 1 3/ / ( ) CHADS 2 >1 18/ / ( ( ) 36) Composite endpoint Stroke CV death Systemic embolism

111 Watchman Left Atrial Appendage Closure What Can We Learn Risk/benefit ratio of LAA occlusion does not depend on CHADS 2 score or other high risk features

112 ATRIA Study 13,559 patients with nonvalvular atrial fibrillation treated within a large integrated health care delivery system Current analysis: a nested case control study of patients on Warfarin to assess whether INR target should be adjusted according to: 1. Hx of stroke 2. Age >75 or 75 years 3. CHADS 2 score Singer DE et al: Circ Cardiovasc Qual Outcomes 2:297, 2009

113 Dog Heart 45d After Device Implantation

114 Human Heart 200d After Implantation

115 Human Heart 852d After Implantation

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117 Terminal Therapy We assess the hypothesis that LAA closure is non-inferior to warfarin in the prevention of adverse events in patients implanted with the WATCHMAN device and able to discontinue both warfarin and clopidogrel (terminal therapy)

118 Terminal Therapy Results WATCHMAN Control Hazard ratio Endpoint (n=332) (n=241) (95% CI) P Primary efficacy 2.3 (16/705) 4.1 (23/562) 0.60 ( ) 1.16) Primary safety 1.3 (9/709) 3.6 (20/554) 0.39 ( ) 0.87) event Serious adverse 4.6 (32/693) 8.6 (46/535) 0.55 ( ) 0.87) event All-cause mortality 2.9 (21/714) 4.4 (25/573) 0.81 ( ) % relative risk reduction in the primary efficacy endpoint 61% relative risk reduction in the primary safety events

119 ASA Plavix Feasibility Study with WATCHMAN LAA Closure Technology (ASAP)

120 ASAP Study Synopsis To characterize the performance of the WATCHMAN LAA Closure Device in nonvalvular AF patients for which long-term warfarin therapy is contraindicated Contraindicated defined as: history of hemorrhagic and bleeding tendencies, hypersensitivity to warfarin Multicenter, prospective p non-randomized feasibility study Up to 150 patients at 4 sites Follow-up at 3, 6, 12, 18 and 24 months TEE at 3 and 12 months Post procedure anti-platelet regimen Clopidogrel through 6 months ASA indefinitely AE s collected throughout the study

121 ASAP Patient Characteristics Baseline risk factors ASAP n=64 Age (5388) (53-88) CHADS 2 score (mean SD) (1-5) CHADS 2 criteria CHF (%) 25 Hypertension (%) 91 Age 75 (%) 39 Diabetes (%) 31 Prior stroke or TIA (%)

122 ASAP Results 64 patients enrolled at 4 centers (80 now) Successful implantation in 59/64 pt (92%) 2 serious procedure-related related AE s 1 pericardial effusion (1.6%) 1 hypoxemia during procedure Follow-up 37 patients at 3 months 25 patients at 6 months 7 patients at 1 year 1 patient with device-related thrombus at 3-mo TEE follow-up Resolved with 2 mo SQ heparin No strokes or TIA s

123 ASAP Conclusions Early experience reveals that WATCHMAN implantation without warfarin overlap is safely feasible in AF patients with contraindications to oral anticoagulation LAA closure may prove to be a viable alternative for AF patients with warfarin contraindications

124 Title/drp author: WT/BK Holmes, David Sub/drp Job#: YW105/BK Subject: Protect AF 1500 Pt. Yr Background: BU3 Plot/brdr: open/bu41 Banner/brdr: /BU41 x, y only Side title: YW105 /colhdgs: YW105 Text: WT/BK Highlight: YO114 Subdue: BU31 Footnotes: BU41 COLOR REFERENCE ONLY PPT shooting instructions PPT File to Server (17 images) Artist: jmn Due Date: Match: Mayo2bu (CP )

125 ates azard ra lative ha Cumul No. at risk RELY Trial Warfarin Dabigatran Follow-up (yr) ,015 5, , ,510 2, , ,076 5,839 5,638 4,557 2,928 1,366 6,022 5,801 5,600 4,474 2,797 1,269 Dabigatran

126 The Watchman Trial (with extended f/u): Design, Results and Conclusions TCT 2010 Washington, DC September 2010 David R. Holmes, MD Mayo Clinic Rochester, MN

127 Presenter Disclosure Information David R. Holmes, Jr., M.D. What is to be Expected from Left Atrial Appendage Exclusion Devices The following relationships exist related to this presentation: "Both Mayo Clinic and I have a financial interest in technology related to this research. That technology has been licensed to Atritech, and Mayo Clinic and I have contractual rights to receive future royalties from this license. To date, no royalties have been received by either Mayo Clinic or me."

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