Are the Data Supportive? Academic View CRT 2012 Washington, DC, USA, Feb 4-7, 2012 CHALLENGES TO DEVICE INNOVATION: ATRIAL APPENDAGE CLOSURE DEVICES CASE STUDIES 3:14PM 4:00PM Mitchell W. Krucoff, MD (Moderator) Robert S. Schwartz, MD (Moderator) Empire Ballroom Patient Selection: Are the Data Supportive? - Academic View 3:15PM 3:25PM Horst Sievert, MD Patient Selection: Are the Data Supportive? - Industry View 3:35PM Keith D. Dawkins, MD Patient Selection: FDA View 3:45PM Andrew Farb, MD Panel Discussion: Which Patients to Study Post-Market Versus Pre-Market? Maurice Buchbinder, MD (Panelist) Kenneth J. Cavanaugh, PhD (Moderator) Keith D. Dawkins, MD (Panelist) Andrew Farb, MD (Panelist) Horst Sievert, MD (Panelist) Ashwani P. Sastry, MD (Panelist) Xu Yan, PhD (Panelist) …….. min Patient Selection: Are the Data Supportive? Academic View ……………………… Horst Sievert, Ilona Hofmann, Ann-Kathrin Ziegler CardioVascular Center Frankfurt, Frankfurt, Germany .

Horst Sievert, MD Consulting Fees: CSI Epitek Gore HLT Lifetech NDC Recor

Consulting Fees: Trireme Veryan Trivascular My presentation will include off label discussions: Not yet decided

Conflict of Interest Statement Physician name Company Relationship Horst Sievert Abbott, Access Closure, AGA, Angiomed, Ardian, Arstasis, Atritech, Atrium, Avinger, Bard, Boston Scientific, Bridgepoint, Cardiac Dimensions, CardioKinetix, CardioMEMS, Coherex, Contego, CSI, EndoCross, EndoTex, Epitek, Evalve, ev3, FlowCardia, Gore, Guidant, InSeal Medical, Lumen Biomedical, HLT, Kensey Nash, Kyoto Medical, Lifetech, Lutonix, Medinol, Medtronic, NDC, NMT, OAS, Occlutech, Osprey, Ovalis, Pathway, PendraCare, Percardia, pfm Medical, Rox Medical, Sadra, Sorin, Spectranetics, SquareOne, Trireme, Trivascular, Velocimed, Veryan Consulting fees, Travel expenses, Study honoraria Cardiokinetix, Access Closure, Lumen Biomedical, Coherex Stock options, Stocks

Patient Selection: Are the Data Supportive? What does that mean? After more than 10 yrs of experience with LAA closure! Does it mean When is LAA closure indicated clinically? Which patients should be enrolled into future clinical trials?

I can use the same slides to answer all these questions In the US they may help to design future trials for the next decade In the rest of the world (95.6% of the world population) they may help to define the clinical indication

Unfortunately it could happen ... ... that not all of the 95.6 % of the OUS population can afford the procedure ... that the US can not afford enough trials to achieve approval of the devices

Potential indications for LAA closure Patients with non-valvular atrial fibrillation Patients with valvular atrial fibrillation Patients who can take anticoagulation Patients who can not take anticoagulation

Valvular Afib, can take anticoagulation That's what has been evaluated in the PROTECT AF trial

Protect AF (System for Embolic PROTECTion in Patients with Atrial Fibrillation) Multicenter Prospective randomized WATCHMAN gen 2 vs coumadin 2:1 Non-inferiority trial 800 pts 2011: 1500 patient-years Holmes D, et al Lancet 2009

In- & Exclusion Major inclusion criteria Major exclusion criteria Non valvular AF with Chads2 score ≥ 1 No contraindications to coumadin No co-morbidities mandating chronic warfarin use other than AF Major exclusion criteria LAA thrombus Large PFO with significant atrial septal aneurysm Mobile aortic atheroma Symptomatic carotid artery disease

Primary Efficacy Endpoint Freedom from Stroke, Death, Systemic Embolization Trend towards better outcome after LAA closure 31% lower relative risk in WATCHMAN Group WATCHMAN is non-inferior to Coumadin

All Stroke P<0.05 Events/100 patient years 22%

Hemorrhagic Stroke P<0.05 Events/100 patient years 75%

Mortality P<0.05 Events/100 patient years 30%

What are the concerns? Patient selection Technical success Safety 30% had CHADS2 1 and could have been treated with aspirin Technical success Implantation success only 90.9% Residual flow @ 45 days in 14% Safety Warfarin use was not optimal PROTECT did not show superiority of LAA closure

What are the concerns? Patient selection Technical success Safety 30% had CHADS2 1 and could have been treated with aspirin Technical success Implantation success only 90.9% Residual flow @ 45 days in 14% Safety Warfarin use was not optimal PROTECT did not show superiority of LAA closure

When to anticoagulate is a moving target When PROTECT AF was designed, it was recommended to consider anticoagulation in patients with CHADS2 1 During the trial the recommendations where changed to CHADS2 2 Nevertheless all trials with new anticoagulants included patients with CHADS2 1

When to anticoagulate is a moving target In daily practice, many patients with CHADS2 1 (with low bleeding risks) are anticoagulated Aspirin is now considered to be ineffective in atrial fibrillation We now have CHA2DS2-VASc

What is CHA2DS2-VASc ? Same principle as CHADS2 But Calculation of the annual stroke risk based on observed strokes in patients with atrial fibrillation But Including more risk factors into the calculation Many more patients (7329 vs 1733)

CHA2DS2 -VASc CHADS2 Cardiac failure 1 1 Hypertension 1 1 Age > 75 1 2 Diabetes 1 1 Stroke 2 2 Vascular disease (MI, PAD,...) - 1 Age 65-74 - 1 Female - 1 Lip et al, Am J Med 2010, Camm et al, Eur Heart J 2010

Annual stroke risk according to CHA2DS2-VASc Anticoagulation recommended in CHA2DS2-VASc ≥ 2

Most patients with atrial fibrillation have a CHA2DS2-VASc ≥2 Cardiac failure 1 Hypertension 1 Age > 75 2 Diabetes 1 Stroke 2 Vascular disease (MI, PAD,...) 1 Age 65-74 1 Female 1

So at least in retrospect it was appropriate to include patients with a lower CHADS2 Very simple!

But it is even simpler than that: Sooner or later almost all patients will reach a CHADS2 of 2 (age, hypertension,...) unless they die early and it does not make sense to take anticoagulation for several years and then close the LAA Anticoagulation does not work at all in clinical practice

What are the concerns? Patient selection Technical success Safety 30% had CHADS2 1 and could have been treated with aspirin Technical success Implantation success only 90.9% Residual flow @ 45 days in 14% Safety Warfarin use was not optimal PROTECT did not show superiority of LAA closure

Learning Curve Performance PROTECT AF vs CAP p-value* p-value± Early Late Procedure Time (Mean ± SD) 62 ± 34 67 ± 36 58 ± 33 50 ± 21 <0.001 Implant Success 485/542 (89.5%) 239/271 (88.2%) 246/271 (90.8%) 437/460 (95.0%) 0.001 45-day Warfarin Discontinuation Among Implanted 414/478 (86.6%) 194/235 (82.6%) 220/243 (90.5%) 352/371 (94.9%) *From tests comparing the PROTECT AF cohort with CAP ±From tests for differences across three groups (early PROTECT AF, late PROTECT AF, and CAP) Improvements seen over time in PROTECT AF Shorter implant time, higher implant success rate, higher warfarin discontinuation rate Trends confirmed in CAP 27 27

There is an important learning curve regarding performance! So I am sure that in future trials the FDA will insist that only very well trained operators participate

Is the performance also device dependend? Of course!! Let's look at Watchman Gen 4:

Performance PROTECT AF vs Gen IV CAP p-value* p-value± Early Late Procedure Time (Mean ± SD) 62 ± 34 67 ± 36 58 ± 33 50 ± 21 <0.001 Implant Success 485/542 (89.5%) 239/271 (88.2%) 246/271 (90.8%) 437/460 (95.0%) 0.001 45-day Warfarin Discontinuation Among Implanted 414/478 (86.6%) 194/235 (82.6%) 220/243 (90.5%) 352/371 (94.9%) Gen 4 97 % *From tests comparing the PROTECT AF cohort with CAP ±From tests for differences across three groups (early PROTECT AF, late PROTECT AF, and CAP) Improvements seen over time in PROTECT AF Shorter implant time, higher implant success rate, higher warfarin discontinuation rate Trends confirmed in CAP 30 30

"Great, we will have a device which is even better" "Unfortunately not! It is just too complicated to bring it into the market!"

What are the concerns? Patient selection Technical success Safety 30% had CHADS2 1 and could have been treated with aspirin Technical success Implantation success only 90.9% Residual flow @ 45 days in 14% Safety Warfarin use was not optimal PROTECT did not show superiority of LAA closure

LAA Closure is an interventional procedure Interventional (and surgical) procedures initially must have a higher risk than medical therapy Advantages of interventional procedures can only be expected during FU

Safety Freedom from device embolization, pericardial effusion, severe bleeding Days from Randomization Event Free Probability 365 730 1095 0.70 0.80 0.90 1.00 244 212 155 53 Control 463 364 303 116 Watchman Mostly stroke and bleeding Mostly pericardial effusion without sequelae

Are the complications unavoidable or are they operator dependent? Mainly operator dependent!

Learning Curve Safety Event Rates PROTECT AF CAP p-value* p-value± Early Late Procedure/Device Related Safety Adverse Events within 7 Days 42/542 (7.7%) 27/271 (10.0%) 15/271 (5.5%) 17/460 (3.7%) 0.007 0.006 Serious Pericardial Effusions within 7 Days 27/542 (5.0%) 17/271 (6.3%) 10/271 10/460 (2.2%) 0.019 0.018 Procedure Related Stroke 5/542 (0.9%) 3/271 (1.1%) 2/271 (0.7%) 0/460 (0.0%) 0.039 Improvements seen over time for acute safety events Fewer total procedure/device related events Kar et al. TCT 2011 36 36

Learning Curve Safety Event Rates PROTECT AF CAP p-value* p-value± Early Late Procedure/Device Related Safety Adverse Events within 7 Days 42/542 (7.7%) 27/271 (10.0%) 15/271 (5.5%) 17/460 (3.7%) 0.007 0.006 Serious Pericardial Effusions within 7 Days 27/542 (5.0%) 17/271 (6.3%) 10/271 10/460 (2.2%) 0.019 0.018 Procedure Related Stroke 5/542 (0.9%) 3/271 (1.1%) 2/271 (0.7%) 0/460 (0.0%) 0.039 Improvements seen over time for acute safety events Fewer total procedure/device related events Kar et al. TCT 2011 37 37

What if we would repeat PROTECT AF today with the experience we now have? Freedom from device embolization, pericardial effusion, severe bleeding 1.00 0.90 Event Free Probability 0.80 Watchman Control 244 212 155 53 Control 0.70 463 364 303 116 Watchman 365 730 1095 Days from Randomization Well done, we just saved 5 yrs and millions of $

There is also an important learning curve regarding safety! So I am sure that in future trials the FDA will insist that only very well trained operators participate

Will new anticoagulants change the picture? Not really! Because there are no late complications of LAA closure

Dabigatran - Major Bleeding Everybody is looking at this difference Warfarin  Dabigatran 150 Cumulative hazard rates Dabigatran 110 Follow-up (yr) No. at risk 6,015 5,835 5,640 4,510 2,872 1,349 6,076 5,839 5,638 4,557 2,928 1,366 6,022 5,801 5,600 4,474 2,797 1,269 Connolly SJ et al: NEJM 361:1139, 2009

What are the concerns? Patient selection Technical success Safety 30% had CHADS2 1 and could have been treated with aspirin Technical success Implantation success only 90.9% Residual flow @ 45 days in 14% Safety Warfarin use was not optimal PROTECT did not show superiority of LAA closure

Correct, warfarin was not used optimal in PROTECT AF Why?

Because anticoagulation does not work INR within therapeutic range PROTECT AF 67 % ARISTOTLE 62% ROCKET AF 58% RELY 64% ACTIVE W SPORTIF V 68% SPORTIF III 66%

Warfarin Use in General Practice Discontinuation 40-64 65-69 Age 70-74 75-79 80-84 85 % Years after starting treatment Gallagher AM et al: J Thromb Haemost 6:1500, 2008

Dabigatran Permanent Discontinuation Stopping rates Warfarin Follow-up (yr) No. at risk 6,015 5,336 5,026 3,950 2,491 1,176 6,076 5,329 5,015 3,955 2,528 1,172 6,022 5,563 5,269 4,158 2,561 1,187 Connolly SJ et al: NEJM 361:1139, 2009

What are the concerns? Patient selection Technical success Safety 30% had CHADS2 1 and could have been treated with aspirin Technical success Implantation success only 90.9% Residual flow @ 45 days in 14% Safety Warfarin use was not optimal PROTECT did not show superiority of LAA closure

Because PROTECT AF was designed to show non-inferiority Of course not Because PROTECT AF was designed to show non-inferiority

Valvular Afib, can take anticoagulation LAA closure is an alternative to anticoagulation Based on the results of PROTECT AF and other trials with the Watchman device We do not need further trials (I know they will be done anyway) Instead, we should concentrate on improvements of the devices

Valvular Afib, can not take anticoagulation That's what has been evaluated in the ASAP trial

The ASAP Trial (=ASA Plavix Feasibility Study) Similar protocol as PROTECT AF Same inclusion/exclusion criteria But anticoagulation contraindicated Multicenter Preliminary results of 127 patients

ASAP – Results Successful implantation in 118/127 pts (93%) Periprocedural complications Pericardial tamponade 1 Pericardiocentesis, no sequelae Device embolization 2 Successful percutaneuos retrieval of the device Pseudoaneurysm (groin) 1 Surgical repair, no sequelae Mean follow up = 10.4 months 58 pts have been followed to one year

Valvular Afib, can not take anticoagulation LAA closure is an alternative to anticoagulation Based on the results of the ASAP registry We do not need further trials They will add minimal additional information Instead, we should concentrate on further improvements of the devices

Non - Valvular Afib I don't know yet, but I'll be back

Thank you