1. PFO FDA Considerations for Labeling and Future Trials
Andrew Farb, MD
Division of Cardiovascular Devices
Center for Devices and Radiological Health (CDRH)
Food and Drug Administration
Monday, February 20, 2017
7 mins
12:30 PM - 12:37 PM
Room: Blue
CRT Valve & Structural – FDA
CRT 2017
Washington, DC
February 20, 2017

2. Disclosures
No conflicts of interest to report

3. FDA Device Labeling Considerations
Indications for Use
Identifies the clinical condition in the target population in which the device will provide clinically significant results without an unreasonable risk of illness or injury
Other sections of the label include contraindications, warnings, precautions, adverse events, clinical studies (design and outcomes), and directions for use
For the Amplatzer PFO Occluder, approved 28 October 2016, labeling reflects the RESPECT trial investigational plan and outcomes

4. AMPLATZER PFO Occluder
Approved Indications for use:
For percutaneous transcatheter closure of a 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

5. RESPECT Primary Endpoint ITT Population
For percutaneous transcatheter closure of a 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
Initial Data Lock
Extended Follow-up
RESPECT
Primary Endpoint
ITT Population
Rate per 100 pt-yrs
Device MM
0.61
1.25
Rate per 100 pt-yrs
Device MM
0.65
1.01
Although the raw count analysis in the ITT population was the pre-specified primary analysis, recall that there was differential follow-up between treatment groups driven by a substantially larger number of MM subjects that withdrew from the trial. Therefore, event rates per pt-yr follow-up and Kaplan Meir estimates provide additional insights into the strength of the evidence supporting or not supporting a benefit of PFO closure and the magnitude of any potential benefit. In the initial data lock, the observed event rates per 100 pt-yrs in both treatment groups (shown in the Table on the left) were small and numerically favored the Device group, 0.61 vs In the K-M plot on the left, one can appreciate curve separation starting at around 1.5 years, with overlap of the 95% CIs. The HR is 0.50 with a wide CI, 0.22 to 1.13, and The p—value is non-significant at With extended F/U on the right, it’s important to note that the event rate has dropped in the MM group to 1.01, and the difference between treatment groups has narrowed. In the K-M plots on the right, the event curves approach each other, raising a question about the durability of any potential Device benefit
It is important to understand the benefit of PFO closure in context of an overall low risk of recurrent stroke (0.61 per 100 patient-years and 1.25 per 100 patient years in the device and MM groups, respectively) and a number needed to treat with the device of 27 to prevent one recurrent stroke at 5 years. An extended follow-up analysis (mean follow-up of 5.5 years in the device group and 4.9 years in the MM group) showed a 35% relative risk reduction in favor of the device group (recurrent stroke rate 0.65 per 100 patient-years vs per 100 patient years in the device and MM group, respectively) with a number needed to treat of 43 to prevent one recurrent stroke at 5 years
NNT = 27
NNT = 43

6. Medical Management (N=481)
For percutaneous transcatheter closure of a 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
RESPECT trial age exclusion criterion
Age <18 years to >60 years
RESPECT Enrollment
PFO Occluder (N=499)
Medical Management (N=481)
Age, years
45.7 (9.7)
46.2 (10.0)

7. RESPECT trial elements
For percutaneous transcatheter closure of a 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
RESPECT trial elements
Work-up guided by a neurologist and cardiology
Qualifying stroke confirmed by a neurologist
PFO confirmed by TEE
So in thinking about the utility of PFO closure to prevent recurrent stroke, one should appreciate that RESPECT subjects were evaluated by a neurologist …and were highly selected to exclude patients who had a potential underlying cause of stroke based on a planned comprehensive neurologic and cardiovascular evaluation

8. Non-PFO cardioembolic sources, aortic arch atheroma
For percutaneous transcatheter closure of a 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
Evaluation
Rule Out
TEE
Non-PFO cardioembolic sources, aortic arch atheroma
Prolonged heart rhythm monitoring
AFib
MRI/CT
Small vessel disease, lacunar infarct, non-stroke lesions
Intra and extracranial artery imaging (MRA, CTA or contrast angiography)
Atherosclerotic plaque, arterial dissection, other vascular diseases
Hematological evaluation
Hypercoagulable state
The Baseline Screening Tests for Cryptogenic Stroke Determination required a neurologist-investigator evaluating the qualifying stroke with testing that included a TEE…ECG or Holter monitor…Brain MRI or CT….Comprehensive Imaging of the intra- and extracranial arterial circulation via MRA, CTA, or contrast arterial angiography, transcranial Doppler, and/or carotid duplex ultrasound… and screening for an underlying Hypercoagulable state
RESPECT Baseline Screening Tests for Cryptogenic Stroke Determination
Patient Selection for Treatment section of the IFU

9. Ongoing and Future Pivotal Trials
PFO occluder vs. medical therapy
Test PFO occluder vs. approved PFO occluder
PFO closure “tool claim” studies not adequate to support use to reduce the risk of recurrent stroke

10. Ongoing and Future Pivotal Trials
Test Device
Control
PFO occluder
Medical therapy

11. Ongoing and Future Pivotal Trials
Test Device
Control
Endpoint (Statistical Testing)
PFO occluder
Medical therapy
Safety: Device, procedure, and medical therapy-associated SAEs Effectiveness 1: Recurrent stroke (superiority)
Effectiveness 2: PFO closure rate
Ongoing randomized trials
REDUCE (ClinicalTrials.gov Identifier: NCT )
CLOSE (ClinicalTrials.gov Identifier: NCT )

12. Ongoing and Future Pivotal Trials
Test Device
Control
PFO occluder
Approved PFO occluder

13. Ongoing and Future Pivotal Trials
Test Device
Control
Endpoint (Statistical Testing)
PFO occluder
Approved PFO occluder
Safety: Device and procedure-associated SAEs (superiority or non-inferiority)
Effectiveness 1: Recurrent stroke (superiority or non-inferiority)
Effectiveness 2: PFO closure rate (superiority or non-inferiority)

14. Ongoing and Future Pivotal Trials
Test Device
Control
Endpoint (Statistical Testing)
PFO occluder
Approved PFO occluder
Safety: Device and procedure-associated SAEs (superiority or non-inferiority)
Effectiveness 1: Recurrent stroke (superiority or non-inferiority)
Effectiveness 2: PFO closure rate (superiority or non-inferiority)
FDA not ready for PFO closure tool claim pivotal studies
Non-inferiority margin needs to avoid outcome drift such that a “win” for the new device allows for an event rate that is greater than a putative medical therapy control
Safety events of interest: AFib and venous thromboembolism

15. Parting Thoughts
A systematic assessment of underlying conditions and risks associated with ischemic stroke, guided by a neurologist and cardiologist, is needed in all patients who have a PFO.
When determining whether to pursue device closure of a PFO, clinicians should understand the strengths and limitations of available clinical trial data, and engage in benefit-risk discussions with their patients.
Interactions with FDA recommended to reach consensus on study designs to evaluate new PFO closure devices.

18. Outline
• RESPECT trial results in perspective • Crafting the label to guide the selection of appropriate patients • Neurology community views appreciated • Future trials: Device vs. device, device vs. OMT, S&E considerations