RESPECT Extended Follow-up Results John D. Carroll, M.D. Jeffrey - - PowerPoint PPT Presentation

RESPECT

Extended Follow-up Results

John D. Carroll, M.D. Jeffrey L. Saver, M.D. David E. Thaler, M.D., Ph.D. Richard Smalling, M.D., Ph.D. Lee A. MacDonald, M.D. David S. Marks, M.D. David L. Tirschwell, M.D.

for the RESPECT Investigators

Disclosure Statement of Financial Interest

• Consulting Fees



Steering Committee Member for RESPECT

• St Jude Medical

Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company

Unmet Need for Secondary Prevention

• f Recurrent PFO-Related Strokes
• Young patients exposed to decades of

risk for PFO-related stroke

 1-2% event rate per year

• RESPECT assessed PFO closure as a

treatment option

Hart et al. Lancet Neurol 2014;13(4):429-38.

Key Aspects of RESPECT Trial

• Device trial for secondary prevention
• Superiority trial: PFO closure vs. guideline-

directed medications

• Largest randomized PFO trial: 980 patients

 499 AMPLATZER™ PFO Occluder; 481 MM

• Assumptions

 Paradoxical embolism was cause of initial stroke  Recurrent strokes would be due to recurrent

paradoxical embolism

RESPECT Trial Population

• Included:

 Subjects with a PFO who have had a

cryptogenic stroke within the last 270 days

• Excluded:

 Subjects aged <18 years or >60 years  Subjects with identified stroke etiology  Subjects who are unable to discontinue

anticoagulants

Carroll et al. NEJM 2012;368:1092-100.

RESPECT Primary Endpoint Results

• Enrollment ended when 25 ischemic stroke events
• ccurred - results were reported in NEJM

Analysis Population Relative Risk Reduction P-Value Intention-to-Treat

50%

0.089 Per-Protocol

58%

0.048 As Treated

67%

0.013

Carroll et al. NEJM 2012;368:1092-100. Note: Per Protocol and As Treated analysis modified from NEJM analysis in response to FDA questions.

Extended Follow-up Provides Considerable New Data

AMPLATZER™ PFO Occluder (N=499) Medical Management (N=481) Mean Follow-up (years) Initial Analysis 3.0 2.7 Extended Follow-up 5.5 4.9 Total Patient-Years of Follow-up Initial Analysis 1476 1284 Extended Follow-up 2769 2376

Higher Discontinuation Rate in MM Arm

11% of MM Subjects Have Undergone Off-Label PFO Closure

HR: 0.560 Log-rank p-value: <0.0001

0% 50% 1 2 3 4 5 6 7 8 9 10

Time to Event (Years)

Discontinuation Rate

10% 20% 30% 40%

AMPLATZER™ PFO Occluder (N=499) Medical Management (N=481)

499 463 369 212 86 20 481 394 307 168 71 10 AMPLATZER MM # at Risk (Discontinuation Rate) (0%) (4.9%) (10.0%) (15.4%) (22.8%) (30.3%) (0%) (14.4%) (18.8%) (26.5%) (33.5%) (43.3%)

Important Consideration for Extended Follow-up Analysis

• 19% of RESPECT patients now >60 years

 As patients age, increase in non-cryptogenic

strokes expected

• PFO closure can only reduce risk for

recurrent strokes mediated by paradoxical embolism

 Appropriate clinical interpretation of trials requires

adjudication for stroke mechanism

• ASCOD coding captures presence of possible stroke

etiologies, and assigns a probability of relatedness (post-hoc)

• Five phenotypes:

 A = atherosclerosis  S = small vessel disease  C = cardiac pathology  O = other cause  D = dissection

• Recurrent strokes classified as either cryptogenic or
• f known cause

Amarenco et al. Cerebrovasc Dis 2013;36:1-5

Blinded Adjudication of Stroke Cause Using ASCOD Phenotyping

29 13

5 10 15 20 25 30

Recurrent Stroke Mechanism

Nearly 1/3 of Strokes in Extended Follow-up Are Not Cryptogenic

Subjects with Recurrent Ischemic Stroke Cryptogenic (Possibly Paradoxical Embolism) Known Mechanisms

Atherosclerosis = 1 Small Vessel Disease = 6 Cardioembolic = 5 (AF = 4, endocarditis = 1) Other = 1 (radiation arteriopathy) Dissection = 0

How Do Recurrent Strokes from Known Mechanisms Confound Interpretation of RESPECT?

Confounding Issue: 1 out of 3 Recurrent Strokes Had a Mechanism That PFO Closure Cannot Prevent

Extended Follow-up in ITT Population 0.85 0.90 0.95 1.00 1 2 3 4 5 6 7 8 9 10

AMPLATZER™ PFO Occluder (N=499; # strokes = 18)

Event-free Probability

Time to Event (Years)

HR: n/a (non-proportional hazards) Log-rank p-value: 0.16

Stroke of Known Mechanism

499 463 369 212 86 20 481 394 307 168 71 10 AMPLATZER MM # at Risk (KM Estimates) (0%) (1.6%) (1.9%) (3.6%) (6.0%) (6.0%) (0%) (3.2%) (4.8%) (5.1%) (7.0%) (12.4%)

Medical Management (N=481, # strokes = 24)

Significant Reduction in Recurrent Cryptogenic Stroke

54% Relative Risk Reduction in ITT Population

0.85 0.90 0.95 1.00 1 2 3 4 5 6 7 8 9 10

Time to Event (Years)

Event-free Probability HR: 0.460 Log-rank p-value: 0.042

AMPLATZER™ PFO Occluder (N=499; # cryptogenic strokes = 10) Medical Management (N=481, # cryptogenic strokes = 19)

499 463 369 212 86 20 481 394 307 168 71 10 AMPLATZER MM # at Risk (KM Estimates) (0%) (1.2%) (1.5%) (2.5%) (2.5%) (2.5%) (0%) (2.7%) (4.1%) (4.1%) (5.2%) (10.8%)

Device not in place

70% Relative Risk Reduction in Recurrent Cryptogenic Stroke With Device In Place

0.85 0.90 0.95 1.00 1 2 3 4 5 6 7 8 9 10

Event-free Probability HR: 0.302 Log-rank p-value: 0.004

AMPLATZER™ PFO Occluder Implanted (N=464; # cryptogenic strokes = 7) Not Implanted (N=516, # cryptogenic strokes = 22) Time to Event (Years)

464 445 357 206 82 20 516 412 319 174 75 10 AMPLATZER Not Implanted # at Risk (KM Estimates) (0%) (0.9%) (0.9%) (1.9%) (1.9%) (1.9%) (0%) (3.0%) (4.6%) (4.6%) (5.7%) (11.2%)

Additional Sensitivity Analysis

Is the superiority of PFO Closure more clearly seen in younger patients? Analysis not dependent on stroke etiology phenotyping

Freedom from Recurrent Stroke of Any Mechanism: <60 Yrs

52% Relative Risk Reduction in ITT Sensitivity Analysis

0.85 0.90 0.95 1.00 1 2 3 4 5 6 7 8 9 10

Time to Event (Years)

Event-free Probability HR: 0.476 Log-rank p-value: 0.035

AMPLATZER™ PFO Occluder (N=475, # strokes = 12) Medical Management (N=463, # strokes = 22)

475 417 308 166 69 15 463 353 254 124 51 9 AMPLATZER MM # at Risk (KM Estimates) (0%) (1.8%) (2.1%) (3.3%) (3.3%) (3.3%) (0%) (3.4%) (4.9%) (5.4%) (6.9%) (14.7%)

Does anatomy and physiology

• f PFO matter in terms of

treatment effect?

Atrial septal aneurysm (ASA) and substantial right-to-left shunts are used by clinicians to identify PFOs that may not be incidental

Additional Benefit in Substantial Shunt or ASA Subgroup

75% Relative Risk Reduction in Recurrent Cryptogenic Stroke in ITT Population 0.85 0.90 0.95 1.00 1 2 3 4 5 6 7 8 9 10

HR: 0.245 Log-rank p-value: 0.007

AMPLATZER™ PFO Occluder (N=319, # cryptogenic strokes = 4) Medical Management (N=301, # cryptogenic strokes = 13)

Event-free Probability

319 299 229 134 52 11 301 243 186 105 45 7 AMPLATZER MM # at Risk (KM Estimates) (0%) (0.6%) (1.0%) (1.5%) (1.5%) (1.5%) (0%) (3.6%) (4.8%) (4.8%) (6.6%) (6.6%)

Time to Event (Years)

Summary of Efficacy Findings in Extended Follow-up

Analysis Population (Endpoint) Relative Risk Reduction P-Value Analysis Conclusion ITT (All-Cause Stroke)

n/a*

0.16 Confounded by non- cryptogenic strokes ITT (Cryptogenic Stroke)

54%

0.042 Efficacy for cryptogenic stroke prevention Device In Place (Cryptogenic Stroke)

70%

0.004 Accounting for device placement increases efficacy ITT: <60 years old (All-Cause Stroke)

52%

0.035 Supportive sensitivity analysis ITT: ASA/SS Subgroup (Cryptogenic Stroke)

75%

0.007 Additional benefit in patients with ASA or SS

* non-proportional hazards (not appropriate to estimate)

Procedure or Device Related SAEs

SAEs Adjudicated by DSMB

• No intra-procedure strokes
• No device embolization
• No device thrombosis
• No device erosion
• Very low rate of major vascular

complications (0.9%) and device explants (0.4%)

Adjudicated SAEs of Interest

Favorable SAE Profile for AMPLATZER™ PFO Occluder

* Rate expressed as number of events per 100 patient-years

Event Type

AMPLATZER™ PFO Occluder (N=499) [2769 Pt-Yrs] Medical Management (N=481) [2376 Pt-Yrs]

Events Rate* Events Rate* Atrial fibrillation 7 0.25 4 0.17 Major bleeding 17 0.61 14 0.59 Death from any cause 6 0.22 10 0.42 DVT/PE 17 0.61 3 0.12

• DVT/PE rate of unclear significance

 Not associated with procedure/access site, thrombophilia

evaluation not done in trial, and warfarin was allowed in MM group

Strengths and Limitations of RESPECT

• Strengths

 High procedural success and effective closure rates  Longest follow-up of PFO closure RCTs  Adjudication of stroke mechanism

• Limitations

 Powered to detect overly optimistic treatment effect  Differential dropout rate could lead to bias  Significant rate of off-label PFO closure (11%)

Conclusions

• AMPLATZER™ PFO Occluder is superior

to medical management in reducing recurrent cryptogenic ischemic stroke

 Treatment effect is fully manifest in types of

strokes for which closure is intended

 Superiority is substantial and sustained

• Procedure and device are safe
• RESPECT reinforces need for

comprehensive risk factor modification