1. Update on PFO Trials Michael S. Kim, MD, FACC, FSCAI
Assistant Professor of Medicine
Director, Structural Heart Disease Program
Division of Cardiology
University of Colorado Denver
July 11, 2012

2. Disclosures
None

3. Outline Status of PFO closure in 2012 Scope of the problem Data
Cryptogenic Stroke
Migraine Headache
Data
? Quantity vs. ? Quality
Conclusion

4. PFO Closure Before Randomized Trials
Devices were available, clinical expertise and experience developed, referral patterns formed, financial payment occurred, and highly motivated/engaged patients demanded treatment despite uncertainties
The Genie was out of the bottle

5. PFO Closure 2012
The field of PFO related medical disorders remains full of controversies, some contradictory findings, and underfunding of new research that could lead to greater clarity
For physicians: there are no professional society management standards for both evaluation and management of PFO related disorders
AHA/ASA guidelines for secondary stroke prevention
“PFO closure may be considered for patients with recurrent CS despite optimal medical therapy.” (Class IIb/LOE C)
For patients: widespread disparities in both recognition of their disorders as well as the quality of care received
O’Gara PT, et al. Circulation 2009

6. PFO and Cryptogenic Stroke

7. Scope of the Problem – Stroke View at 35,000 feet
Stroke = leading cause of disability worldwide
In United States
750,000 strokes/year
1/3 are recurrent
4th leading cause of death (as of 2009)
Leading cause of acquired disability
25% of strokes occur in patients < 65 years of age
~40% of all strokes are of unknown cause, despite thorough evaluation (i.e., “cryptogenic”)
“Dear Tedy, I went to Arizona State, and I always hated you. But I admire you for what you’ve overcome.”
- to Tedy Bruschi, former linebacker for NE Patriots, after he suffered a presumed cryptogenic stroke through a patent PFO.
Williams GR, et al. Stroke 1999
Sacco RL, et al. Ann Neurol 1989

8. PFO and Cryptogenic Stroke View at 10,000 feet
Prevalence of PFO in the general population
~25% based on autopsy studies
Prevalence of PFO in patients with CS
~40-50% in young (age < 55) patients
~20% in older patients
Possible causal relationship between PFO and CS
Relative risk of CS with PFO
+3-4 compared to patients without PFO
Homma S, et al. Circulation 2005

9. Paradoxical Embolism Definition
Arterial embolism without evidence of a left-sided source
Potential for RL shunting
“Fly by” theory
Thrombus in venous system transits the PFO
“Lurking clot” theory
Thrombus originates in PFO tunnel itself (in-situ propagation)
Rachko Angiology 2001;52:793
Falk V, et al., Thorac Cardiovasc Surg 1997

10. PFO and Paradoxical Embolism View at 1000 feet
PFO tunnel size and volume of RL shunt increases risk of paradoxical embolus
Presence of atrial septal aneurysm (ASA) also increases risk (PICCS Study)
Relative risk: +6 compared to patients without PFO

11. PFO and Cryptogenic Stroke Recurrence Rates
The Lausanne Study
Stroke recurrence: 2.4%/yr
Stroke + TIA recurrence: 3.8%/yr
Death: 1.2%/yr
Low incidence rate of CS recurrence = challenge of statistical power in RCT

12. Data? Observational vs. RCT
Quantity vs. quality?
Multiple observational studies; One RCT
Number of patients included in observational studies is nearly 10-fold higher than number of patients enrolled into CLOSURE I
Observational data cannot simply be ignored
Kitsios, GD, et al. Stroke. 2012

13. Data? Observational Data
Multitude of evidence suggesting efficacy of PFO closure in significantly reducing incidence of recurrent CS over medical therapy
Led to widespread adoption of “off label” use of closure devices for PFO closure
Kitsios, GD, et al. Stroke. 2012

14. Data? CLOSURE I

15. Data? CLOSURE I
Only RCT investigating PFO closure for secondary CS prevention with publically released data
RESPECT closed in January 2012 – data not yet released
Design
Patients with documented, definite TIA or stroke and a PFO with 6 months of randomization
1:1 randomization to PFO closure with STARFlex occluder (NMT Medical) or best medical therapy (ASA, warfarin, or both)
Primary endpoint: 2 year incidence of stroke or TIA, all-cause mortality for first 30 days, and neurologic mortality from ≥ 31 days
Results
909 patients randomized
No significant differences in primary endpoint of recurrent stroke (3.1% vs. 3.4%, p=0.77) or TIA (3.3 vs. 4.6%, p=0.39)
Increased incidence of major vascular complication (3.2% vs 0.0%, p<0.001) and atrial fibrillation (5.7% vs. 0.7%, p<0.001) with closure

16. CLOSURE I What went wrong?
CLOSURE I raises more questions than it answers
? Suboptimal device (86.7% closure rate) – 13.3% of patients were left with a residual shunt
? Inclusion of patients with TIA
Clinical description, diagnosis, and etiology of TIA is a mixed bag (even more so than stroke!)
Outcome rates in closure arm of study were nearly 4 times higher than event rate estimates based on previous nonrandomized data
Criticism of patient screening techniques
Clinical explanation other than paradoxical embolism could be found to explain recurrent TIA or stroke in close to 80% of patients studied
Kitsios, GD, et al. Stroke. 2012

17. CLOSURE I It’s not dogma.
CLOSURE I remains the only RCT investigating the safety/efficacy of PFO closure for recurrent CS
Data from RESPECT (and PC Trial) is imminent
CLOSURE I raises more questions than answers
CLOSURE I is not representative of the general population
The sheer volume of non RCT data CANNOT be ignored

18. Data? What is on the horizon?
Kim MS, Carroll JD. Cardiac Interventions Today 2012

19. PFO and Migraine

20. Scope of the Problem – Migraine View at 35,000 feet
Migraine prevalence
Worldwide
~18% of women, 6% of men
United States
~13% of general population between 20 and 64 years of age (~28 million people)
Affects women in a 3:1 ratio
Our understanding of migraine physiology and optimal therapy remains limited
Sharma A, et al. Echocardiography 2011
Lipton RB, et al. Headache 1998

21. Scope of the Problem – Migraine View from 10,000 feet
Migraine with aura (MA) – migraine variant characterized by transient neurological symptoms lasting from 5 to 60 min
Visual, sensory, or speech disturbance
Only 25-30% of migraineurs experience aura
Case controlled studies report PFO prevalence of 40% to 72% in patients with migraine
Highest reported prevalence in patients with MA

22. Scope of the Problem – Migraine View from 1000 feet
Is there a causal relationship? MOA remains unknown
Subclinical emboli, increased platelet activation & aggregation in response to serotonin, transient hypoxemia
Size of PFO, degree of shunting, prominent Eustachian valve and/or Chiari network, +/- ASA all may play a role
Genetic - ? Autosomal dominant inheritance of atrial shunts, Mendelian pattern inherence in rare forms of migraine, etc.
White matter changes and gray matter abnormalities?
Several non-randomized, case controlled studies have shown that closing a PFO in migraineurs for other reasons (i.e., stroke, decompression illness, etc.) reduced the frequency of migraine
Wilmshurst PT, et al. Lancet 2000
Wahl A, et al. Heart 2010
Reisman M, et al. Circ Cardiovasc Intervent 2009

23. Data? Different Indication – Same Story
Quantity vs. quality?
Multiple case controlled, non-randomized, retrospective studies
On average, PFO closure brought about complete resolution of migraine attacks in 57% (range, 29% to 84%) and improvement in 43% of patients (range, 8% to 83%)
Migraineurs with aura are ~4.5 times more likely to have > 50% reduction in migraine frequency after PFO closure than migraineurs without aura and nonmigraineurs
Placebo effect – 14% to 50%
Two RCT’s in US – MIST I (published), PREMIUM (ongoing)
Reisman M, et al. Circ Cardiovasc Intervent 2009

24. Data? MIST I

26. Data? MIST I Design Double-blind, prospective, randomized
History of migraine with aura
Frequent & disabling: ≥ 5 migraine headache days/month but at least 7 headache free days per month
Drug resistant: Reported having failed at least 2 classes of preventive medications
Primary endpoint: migraine headache cessation
Secondary endpoints: change in migraine severity/ frequency/ characteristics, quality of life, and safety
Dowson A, et al. NEJM 2008

27. Study Flow & Patient Disposition MIST I

28. Data? MIST I Results 432 migraine patients assessed for RLS by TTE
260 (60%) patients with RLS, 163 (38%) due to moderate or large PFO
147 patients divided into two study cohorts – device arm and control (sham procedure)
No significant difference in primary endpoint
No significant difference in secondary endpoints
Reportedly, exclusion of 2 outliers in treatment arm resulted in statistical significance (P = 0.027)
SAE in 16 patients in treatment arm; 3 patients in control arm
Residual shunts detected in 4 patients
Dowson A, et al. NEJM 2008

29. Exploratory Analysis MIST I
Given the failure to achieve predefined endpoints, an exploratory analysis was conducted to “aid hypothesis generation and future study design”
Two patients in the implant group were noted to account for > 1/3 of all migraine headache days throughout the study period and significantly differed from the rest of the population
When these patients were excluded from the per-protocol population, a significant 2.2 d/mo (37%) reduction was noted in median total migraine headache days for the implant group compared to 1.3 d/mo (26%) reduction in the sham group

30. Conclusions MIST I
Although a high frequency of R→L shunts in migraine with aura patients, no significant effect was found for the primary or secondary end points
The exploratory analysis supports further investigation

31. Critical Analysis of MIST Why was it not successful?
A completely negative study with regard to pre-defined primary and secondary efficacy endpoints
Overly demanding (and potentially unrealistic) primary endpoint of complete migraine cessation
Study was underpowered to adequately determine this endpoint
Although the exploratory analysis is hypothesis generating, it provides NO PROOF as to a causal relationship between PFO and migraine with aura

32. Critical Analysis of MIST Why was it not successful?
Was the follow-up period of 3-6 months adequate?
Early analysis of PFO closure may have been confounded by a hangover effect of clopidogrel, incomplete device closure, residual shunts etc.
Possible substandard quality of evaluation and treatment?
PFO unable to be crossed in 5 patients (? initial evaluation)  no core echocardiography lab used
4 patients with residual shunts following closure (? device performance)
Relatively high incidence of SAE’s - 16 patients (? quality of procedure execution)

33. Critical Analysis of MIST An “acceptable” risk-benefit ratio?
After exploratory analysis demonstrating a 2.2 d/mo (vs 1.3 d/mo) reduction in migraine frequency
Does an absolute reduction of 0.9 d/mo in migraine frequency justify the nearly 7% risk of major, potentially life-threatening procedural complication?
Although the true procedural complication rate of PFO closure is much lower (~1.5% or less), what is an acceptable risk for < 1 d/mo benefit?

34. MIST I Lessons learned – Is the answer near?
Kim MS, Carroll JD. Cardiac Intervntions Today 2012

35. PFO Closure – Beyond 2012 Will RCT’s bring us answers?
RCT’s have been crippled by slow enrollment and (perhaps) unrealistic expectations
Continued off-label use hampers enrollment
Are RCT’s the ideal method for shedding light on the clinical impact of PFO?
Creation of large, multicenter registries may be better suited to achieving “meaningful” answers

36. Food for thought

37. Two Middle Aged Patients with a CVA
Double Standards
Two Middle Aged Patients with a CVA
An immediate treatment recommendation, the availability of closure with an FDA approved device, and insurance coverage.
Hand-wringing by providers as to the best course of action, a prolonged informed consent process including discussions of off-label use of a device, and a potential insurance denial for an experimental procedure

38. Conclusions
The issue of PFO closure in preventing CS and/or reducing migraine frequency remains unresolved
No “reliable” data to suggest that PFO closure is NOT indicated
No “reliable” data to suggest that PFO closure is beneficial
Number of patients in observational data far outweighs number of patients in RCT’s
Can this large quantity of observational data simply be ignored?
Additional RCT data (RESPECT, PC Trial, REDUCE, PREMIUM) is pending and MAY shed additional light on the issue
Unknown as to how large, multicenter registry data may/may not be used to bring clarity
Until then, can we (in good conscience) deny patients a therapeutic option that is arguably just as safe and perhaps as effective as medical therapy?

39. Thank You