PFO closure with the Amplatzer device was found to be associated with a lower risk of recurrent ischemic stroke compared to medical therapy alone in patients aged 18-60 who experienced a cryptogenic stroke. Over a median follow up of 5.9 years, the rate of recurrent stroke was 0.58 events per 100 patient-years in the PFO closure group versus 1.07 events in the medical therapy group. However, PFO closure was also associated with a higher rate of venous thromboembolism such as pulmonary embolism and deep vein thrombosis compared to medical therapy.

1. LONG-TERM OUTCOMES OF PATENT FORAMEN
OVALE CLOSURE OR MEDICAL THERAPY AFTER
STROKE
Jeffrey L. Saver, M.D., John D. Carroll, M.D., David E. Thaler etc.
Article was published on September 14, 2017, at NEJM.org.
BY: DR.IMRAN KAMAL KHAN
(JR2 MEDICINE)
MODERATOR: DR.SAURABH AGARWAL
( MD MEDICINE )
ASSOCIATE PROFESSOR

2. INTRODUCTION
PATENT FORAMEN OVALE(PFO)

3. EMBRYOLOGIC DEVELOPMENT OF ATRIAL SEPTUM

4. FETAL CIRCULATION

5. NEONATAL SEPTAL DEVELOPMENT

6. • Ischemic strokes that occur without a well-defined etiology , are
labelled as cryptogenic.
• Between 20 and 30% of ischemic strokes are cryptogenic.
• Paradoxical embolism through a PFO may be one important cause of
otherwise unexplained infarct in patients of cryptogenic stroke who
were also having PFO.

7. CLINICAL SIGNIFICANCE OF PFO

8. CLINICAL SIGNIFICANCE OF PFO

10. PFO AND CRYPTOGENIC STROKE

11. TERMINOLOGIES
1.Patient Years
Statistic for expressing incidence rates.
The patient-year statistic is one way of dealing with the issue that in
many studies, the length of exposure to the treatment is different for
different subjects
Example: 100 patients are followed for 2 years. In this case, there are
200 patient-years of follow-up.
If there were 8 myocardial infarctions in the group, the rate would be 8
MIs per 200 patient years or 4 MIs per 100 patient-years.

12. • Patient years are calculated as follows: If 15 patients participated in a
study on heart attacks for 20 years, the study would have involved
300 patient years (15 x 20). This number can be divided by the
number of patients who have been affected by a certain condition or
event. For example, if six of the patients had heart attacks, that would
be equal to one heart attack for every 50 patient years in the study
(300 / 6 = 50
• Looking at data in this way can reveal trends and allows researchers
to communicate levels of risk.

13. Hazard Ratio
• measure of an effect of an intervention on an outcome of interest
over time
• Hazard Ratio (i.e. the ratio of hazards) = Hazard in the intervention
group ÷ Hazard in the control group
• instantaneous event rate, which means the probability that an
individual would experience an event (e.g. death/relapse) at a
particular given point in time after the intervention

14. Confidence Intervals:
• range of values likely to include the true population value.
• used to measure the precision of the study’s estimate .
• Narrower the confidence interval, the more precise the estimate.
• If the confidence interval includes 1, then the hazard ratio is not
significant.

15. For example …..hazard ratio with PFO closure vs. medical therapy, 0.55;
95% confidence interval [CI], 0.31 to 0.999; P = 0.046 means:
pfo closure group would be 45 % less likely to have recurrent ischemic
stroke than medical therapy group
And we are 95% confident that the true value is lying between 1% to
69% .

16. Purpose of this study
• To investigate whether percutaneous Patent Foramen Ovale (PFO) closure, using the
AMPLATZER PFO Occluder, is superior to current standard of care medical treatment in
the prevention of recurrent embolic stroke
• Three randomized trials individually did not show a significantly lower risk of recurrent
stroke with PFO closure than with medical therapy alone.
• However, in a pooled individual patient meta-analysis and a study level network meta-
analysis of randomized trials, closure of the PFO with the Amplatzer PFO Occluder was
found to result in a lower risk of recurrence of ischemic stroke than medical therapy

17. • The RESPECT trial sought to compare outcomes after PFO closure with
the Amplatzer PFO Occluder over medical therapy in patients with
cryptogenic stroke and evidence of a PFO.
• In the Randomized Evaluation of Recurrent Stroke Comparing PFO
Closure to Established Current Standard of Care Treatment (RESPECT)
trial, the results from the original trial period were reported with a
median of 2.1 years of follow up.
• To provide insight into the long-term effects of PFO closure, they now
report the results from the extended follow-up period.

18. METHODS
Trial Design
• multicentric
• randomized,
• open-label,
• controlled clinical trial.
• performed at 69 sites in the United States and Canada
• approved by the institutional review board at each site, and all the patients
provided written informed consent.
• designed by the sponsor (St. Jude Medical) and physician advisors, in
consultation with the Food and Drug Administration (FDA).

19. Patient Selection
Inclusion Criteria:
• cryptogenic ischemic stroke
• 18 to 60 years of age
• PFO confirmed by transesophageal echocardiography,
• and could undergo randomization within 270 days after the index
stroke.

20. Exclusion Criteria: Subjects with-
• large-vessel arteriopathy
• cardiac source of embolism
• intrinsic small-vessel disease
• an arterial hypercoagulable state (as indicated by the presence of
antiphospholipid antibodies or hyperhomocysteinemia).

21. RANDOMIZATION
1:1 ratio
Number of pt. enrolled: 980 (from aug 23 to dec
2011)
Duration of extended follow-up: 5.9 years (median)
Mean patient age: 46 years
PFO CLOSURE GROUP =499
MEDICAL THERAPY GROUP=481

22. Randomization
• Randomization was stratified according to
site,
planned antithrombotic medication regimen and
presence or absence of an atrial septal aneurysm
• PFO closure group patients underwent a procedure in which the
Amplatzer PFO Occluder was inserted under fluoroscopic and
echocardiographic guidance.

23. AMPLATZER PFO OCCLUDER

24. • procedure was performed within 21 days after randomization
• patients continued their prerandomization antithrombotic regimen
until the time of placement of the device
• After the device was implanted, patients received 81 to 325 mg of
aspirin plus clopidogrel daily for 1 month, followed by aspirin
monotherapy for 5 months.
• Four medical therapies were allowed throughout the trial in medical
therapy group: aspirin, warfarin, clopidogrel, and aspirin combined
with extended-release dipyridamole.

25. Trial End Points
• For ascertainment of trial outcomes, patients were evaluated at 1, 6,
12, 18, and 24 months and annually thereafter.
• Primary efficacy end point
1. recurrent nonfatal ischemic stroke,
2. fatal ischemic stroke, or
3. early death after randomization.

26. Early death after randomization was defined as :
PFO closure group:
death from any cause within 30 days after placement of the device
or
within 45 days after randomization, whichever occurred later;
Medical-therapy group:
death from any cause within 45 days after randomization

27. • Recurrent strokes were adjudicated as being of
“determined” or
“undetermined” mechanism based on:
ASCOD classification algorithm:
atherosclerosis [A],
small-vessel disease [S],
cardiac pathology [C],
other causes [O],
dissection [D]);
• .

28. • Events were adjudicated as being of
“cryptogenic” or “noncryptogenic” mechanism based on:
TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification algorithm, which
identifies five subtypes of ischemic stroke:
a) large-artery atherosclerosis (embolus / thrombosis)
b) cardioembolism
c) small-vessel occlusion (lacune)
d) stroke of other determined aetiology
e) stroke of undetermined aetiology

29. ADVANTAGES OF ASCOD OVER TOAST
• avoids conflation/merging of etiologic factors when more than one
defined etiologic factor is present
• gives clearer guidance on the use of recently developed diagnostic
tests
• provides useful mechanistic classification in patients who had less
stringent repeat etiologic workups as well as in patients who had
stringent repeat etiologic workups.

30. Clinical secondary efficacy end points :
a. the absence of recurrent symptomatic cryptogenic nonfatal
ischemic stroke or early cardiovascular death, and
b. the absence of transient ischemic attack

31. RESULTS
Trial Patients
• Extended follow-up of 5.9 years from original trial (uptill dec 28 2011)
onwards till may 31, 2016:
5688 patient-years of efficacy follow-up and
5810 patient-years of safety follow-up had accumulated
• Patients remained in follow up
At the end of the original trial period= 851 patients (86.8%)
After extended period =716 patients (73.1%)
• Dropout rate
medical therapy group :33.3% and
PFO closure group :20.8%

33. PFO closure group
499 patients
467 (93.6%) underwent the procedure
Amplatzer PFO Occluder was implanted in 465 of these patients
The medical-therapy group had greater intensity of antithrombotic
therapy during the course of the trial than the PFO closure group,
including more common use of anticoagulant agents.

34. Efficacy End Points
• Efficacy analyses : Total observation period : Recurrent ischemic
stroke
PFO closure group = 3080 patientyear : 18
Medical-therapy group = 2608 patient-years : 28
• Primary endpoints =46 patients overall :all nonfatal ischemic strokes.
• Yielding rates =0.58 events per 100 patient-years and
=1.07 events per 100 patient-years, respectively

39. Safety
• The safety analyses: total observation period
PFO closure group = 3141 patient-years
medical-therapy group = 2669 patient-years
• Overall rate of serious adverse events :
PFO closure group = 40.3%
medical-therapy group =36.0%
• The rate of pulmonary embolism:
PFO closure group = 0.41 per 100 patient-years and
medical-therapy group = 0.11 per 100 patient-years

40. • and the rate of deep-vein thrombosis was 0.16 per 100 patient-years
and 0.04 per 100 patient-years, respectively (hazard ratio, 4.44; 95%
CI, 0.52 to 38.05; P = 0.14).

41. PFO closure group
↓
• Patient with history of overt deep-vein thrombosis had a higher incidence of
venous thromboembolic events than did the subgroup of patients without such a
history.
• Deaths: PFO closure group = 7
medicaltherapy group= 11
• Deaths occurred after the early post-randomization period (which was defined in
the medical-therapy group as the 45day period after randomization and
as either the 45day period after randomization or the 30day period after
placement of the device IN PFO CLOSURE GROUP, whichever occurred later).
• were adjudicated as being unrelated to the trial.

43. DISCUSSION
• Closure of the PFO with the Amplatzer PFO Occluder was associated
with a lower rate of recurrent ischemic strokes than medical therapy.
• The association of PFO closure with lower rates of recurrent ischemic
strokes was particularly apparent in cases that involved strokes that
had no identified non-PFO mechanisms.

44. • The relative difference in the rate of recurrent ischemic stroke
between PFO closure and medical therapy alone was large (45% lower
with PFO closure), but the absolute difference was small (0.49 fewer
events per 100 patientyears with PFO closure).
• The cumulative absolute benefit had clinical relevance, since patients
in this trial were younger (18 to 60 years of age) than the general
population of patients who have strokes and thus faced a longer
period of risk for recurrent stroke.
• The rate of venous thromboembolism (which comprised events of
pulmonary embolism and deep vein thrombosis) was higher in the
PFO closure group than in the medical-therapy group

45. • persons who have had a cryptogenic stroke and also have a PFO have
a mildly elevated long-term risk of venous thrombo-emboli.
• the lower intensity of antithrombotic therapy, in the PFO closure
group than in the medical-therapy group may have contributed to the
higher rate of venous thromboembolism in the PFO closure group.
• Among the patients in the PFO closure group, the propensity to
venous thromboembolic events was particularly strong in the subgroup
of patients who had previous, clinically manifest, unprovoked deep-
vein thrombosis.

46. LIMITATIONS
• . The trial protocol did not require prolonged cardiac monitoring
before enrollment to exclude patients with occult, low-burden atrial
fibrillation.
• Workup of the etiologic factors of recurrent ischemic stroke was
performed in a clinically indicated manner rather than a protocol--
mandated manner.
• In clinical practice, causal workup for repeat strokes is sometimes not
as extensive as it is for first strokes.

47. CONCLUSION
• In an exploratory analysis, among patients with a PFO who were 18
to 60 years of age at the time of an index cryptogenic ischemic stroke,
PFO closure with the use of the Amplatzer PFO Occluder was
associated with a lower rate of recurrent ischemic strokes than
medical therapy alone during an extended follow-up period.
• PFO closure was associated with a higher rate of venous
thromboembolism than medical therapy alone.

48. THANK YOU