RESPECT Safety Findings

Transcription

1 CO-1 SCAI Town Hall Meeting Monday, October 31, 2016 Washington, DC RESPECT Safety Findings John D. Carroll, M.D., MSCAI Professor of Medicine Cardiology University of Colorado School of Medicine University of Colorado Hospital

2 Similar SAE Profile Between Arms Through Extended Follow-up CO-2 SAE Type AMPLATZER PFO Occluder (N=499) n (%) Rate per 100 PYs Medical Management (N=481) n (%) Rate per 100 PYs Any SAE 189 (37.9%) (34.9%) 12.5 Unanticipated adverse device effect Deaths related to procedure or device 0 (0%) (0%) SAE related to procedure 12 (2.4%) SAE related to device 10 (2.0%) Extended Follow-up

3 2.4% of Device Patients Had a Procedure-related SAE (n=12) CO-3 Event Type n (%) Pericardial tamponade (required pericardiocentesis) 2 (0.4%) Cardiac perforation (no treatment required) 1 (0.2%) Pericardial effusion (no treatment required) 1 (0.2%) Access site bleeding (1 required a stitch, 1 required transfusion, 1 required no treatment) 3 (0.6%) Right atrial thrombus (detected during procedure - procedure abandoned) 1 (0.2%) Deep vein thrombosis 1 (0.2%) Atrial fibrillation (successfully cardioverted) 1 (0.2%) Other (allergic drug reaction, vasovagal response) 2 (0.4%) No SAEs of acute ischemic stroke due to air or thromboemboli or device embolization Extended Follow-up

4 2.0% of Device Patients Had a Device-related SAE (n=10) CO-4 Event Type n (%) Ischemic stroke (primary endpoint) 2 (0.4%) Pulmonary embolism 2 (0.4%) Thrombus in right atrium (not attached to device) 1 (0.2%) Explant/surgical intervention 2 (0.4%) Atrial fibrillation (cardioverted medically) 1 (0.2%) Residual shunt (requiring closure with septal occluder device) 1 (0.2%) Other (chest tightness, atrial flutter, non-sustained VT, sepsis) 4 (0.8%) No SAEs of thrombus on device or device erosion Extended Follow-up

5 Rate of Atrial Fibrillation Similar Between Arms after Accounting for Peri-procedural Events CO-5 AMPLATZER PFO Occluder (N=499) Medical Management (N=481) Adverse Event # Patients # Events Rate Per 100 PYs # Patients # Events Rate Per 100 PYs Atrial fibrillation Peri-procedural Post-procedural Includes both serious and non-serious events All 7 peri-procedural AF events in Device arm resolved prior to discharge 1 AF-related stroke in Device arm, 3 in MM arm Extended Follow-up

6 CO-6 Higher Rate of Venous Thromboembolic Events (VTE) in Device Arm Event AMPLATZER PFO Occluder (N=499) # Patients # Events Rate Per 100 PYs Medical Management (N=481) # Patients # Events Rate Per 100 PYs All VTEs DVT PE Cryptogenic stroke patients are likely at high risk for thromboembolic events Device prevents paradoxical embolism, but does not prevent clots from forming in the first place Extended Follow-up

7 Most VTEs in Device Arm Occurred > 1 Year After Implant Procedure CO Number of Events Time to VTE from Procedure (Years) Extended Follow-up

8 CO-8 Protocol-driven Differences in Medical Therapy is a Likely Explanation for Imbalance in VTE History of DVT impacts underlying risk 12 times more likely to have VTE during trial Protocol-driven imbalance of warfarin therapy offers likely explanation for imbalance in VTEs MM patients 9 times as likely as Device patients to be on warfarin during follow-up Device patients discontinued warfarin upon device implant No device patient with DVT history was on warfarin at time of VTE

9 Current Evidence Does Not Suggest VTE Imbalance is Due to Device CO-9 Most events occurred after device would likely have been endothelialized No thrombus on device at 6 months No thrombus on device on any other echo No physiologic rationale for device causing DVT Of the 18 Device patients with VTEs: 11 had DVTs (with or without PE) 7 had isolated PEs

10 CO-10 Summary of Safety Findings Overall SAE rates were similar in the two arms 4.2% rate of serious device- or procedure-related complications 0.4% rate of cardiac tamponade No intra-procedure strokes or device embolizations No thrombus on device or device erosions Peri-procedural AF was transient;; post-procedural AF rate was comparable to AF rate in MM arm VTE events more common in Device arm Anticoagulation recommended for patients with history of DVT

11 CO-11 Clinical Perspectives and Benefit-Risk Assessment John Carroll, M.D. Professor of Medicine Cardiology University of Colorado School of Medicine University of Colorado Hospital

12 PFO Closure is Mechanistic Therapy for the Prevention of Paradoxical Embolism CO-12 Targeted therapy for carefully selected patients Surgical / device closure is standard of care for managing many congenital heart diseases Closing the PFO does not prevent: Venothromboembolic disease Strokes due to known risk factors Strokes related to other causes highlights need for comprehensive risk factor modification

13 Challenging Environment to Answer Straightforward Clinical Question CO-13 Can we lower the risk of recurrent stroke by mechanically closing the PFO? Many clinicians did not have equipoise to conduct a RCT Difficult to enroll and retain patients in randomized PFO closure trials Hampered by off-label PFO closure

14 Patients Reported in PFO Closure Publications from 1994 to 2010 CO-14 Cumulative Number of Enrolled Patients RCT (CLOSURE I) Comparative Studies (Observational) Single Arm Closure Studies Single Arm Medical Studies 2000 Kitsios et al. Stroke 2011;;43: Year of Publication

15 Importance of Need for Randomized Evidence Recognized in Cardiology and Neurology CO-15 JAMA 2005;;294: JACC 2009;;53:

16 RESPECT History Data Locks First patient enrolled 25 th Primary Endpoint Event RESPECT 2012 Primary analysis RESPECT 2015 Additional analysis RESPECT 2016 Final analysis

17 CO-17 AMPLATZER PFO Occluder Provides Reasonable Assurance of Effectiveness and Safety Effectiveness Medical therapy provides only partial protection from recurrent stroke PFO closure further reduces risk in select patients Safety Closing the PFO with AMPLATZER PFO Occluder has acceptable risk profile

18 AMPLATZER PFO Occluder is a Needed Therapeutic Option CO-18 Approval of AMPLATZER PFO Occluder would replace off-label closure with regulated device that is designed specifically for PFO anatomy Reasonable assurance of safety and effectiveness from RCTs SJM would provide clinical community with rational dispersion of first-in-class therapy: Proper physician training Appropriate patient selection Post-market surveillance

19 RESPECT: Final Analysis 2016 Following a Food and Drug Administration (FDA) Advisory Panel in May 2016 an analysis of long-term outcomes was performed, at the request of FDA, from this multicenter, randomized, outcome-adjudication blinded trial. The trial protocol requires subjects to be followed until FDA reaches a decision on product approval Please join us: RESPECT Final Long-term Outcomes from a Prospective, Randomized Trial of PFO closure in patients with Cryptogenic Stroke David E. Thaler Tuesday: 12:15pm Main Area III Ballroom Level 3

20 FDA Approval 10/28/16 Device Indication The AMPLATZER PFO Occluder is indicated for percutaneous transcatheter closure of a patent foramen ovale (PFO) to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke.

21 Shared Decision Making Neurologist AMPLATZER PFO closure Patient Cardiologist

22 Training plan based on FDA Panel Physician training will be categorized based on total previous experience with either AMPLATZER Septal Occluder or AMPLATZER Cribriform Occluder GREATER Than or Equal to 25 Total Implants LESS Than 25 Total Implants Mandatory physician didactic and in-service demonstration Proctored first cases with an SJM certified personnel Mandatory physician didactic and in-service demonstration Proctored cases with a SJM certified physician proctor and SJM certified personnel 22

23 PFO Physician Training Programs ~50 AMPLATZER Traveling Proctors AMPLATZTER PFO Centers of Excellence Workshops Regionally located Quarterly workshops Collaboration with Top Stroke Centers

24 Reimbursement of PFO Closure Hospital and physician reimbursement are adequate PFO can be more financially viable than other cath lab procedures, TAVR, LAA closure, stenting Private payers will pay if medical necessity is demonstrated during pre-authorization/appeal for each case Additional reimbursement info, such as medical policies, payment rates, templates for payer communication Support materials on SCAI webpage ST Jude Medical Reimbursement Hot Line services via SJM Professional.com

25 RESPECT Post Approval Study

26 RESPECT PAS: Objectives To demonstrate safety of the AMPLATZER PFO Occluder by assessing the 30-day rate of device- or procedurerelated serious adverse events including those that led to death To demonstrate that the AMPLATZER PFO Occluder is effective by assessing the rate of recurrent ischemic stroke through 5 years To demonstrate effectiveness of the training program for new operators

27 RESPECT PAS: Endpoints Primary Effectiveness: 5-year rate of recurrent ischemic stroke Ischemic stroke is defined as acute focal neurological deficit presumed to be due to focal ischemia, and either 1) symptoms persisting 24 hours or greater, or 2) symptoms persisting less than 24 hours but associated with MR or CT findings of a new, neuroanatomically relevant, cerebral infarct. Primary Safety: Device- or procedure-related serious adverse events (as adjudicated by a Clinical Events Committee) through 30 days, including: Atrial Fibrillation Pulmonary Embolism Deep Vein Thrombosis Device Thrombus Device Erosion Device Embolization Ischemic stroke if subject was not successfully implanted with a device Hemorrhagic Stroke Major Bleeding requiring transfusion, or surgical or endovascular intervention Vascular Access Site Complication requiring surgical intervention Device- or Procedure-Related Serious Adverse Event leading to death

28 RESPECT PAS: Design Single arm, multi-center study Approximately 1200 subjects Total duration of the study is expected to be 10 years.

29 RESPECT PAS: Status Site nominations underway Q enrollments begin Enrollment completion expected in 2021 Study complete expected in 2026