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  1. 1. Professor Bernhard Meier, Department of Cardiology, University Hospital Bern, 3010 Bern, Switzerland;
  2. 2. A patent foramen ovale (PFO) is present in 25% of the population with decreasing prevalence with age.  A PFO with ominous anatomical features such as atrial septal aneurysm or Eustachian valve is present in about 4% of the population. Stroke and PFO have a proven and migraine and PFO a suspected causal relationship. To call a stroke in a patient with a PFO cryptogenic is an historical oxymoron. Catheter based PFO closure is the safest and most simple therapeutic intervention in cardiology. The protective power against paradoxical stroke of PFO closure is probably better than that of oral anticoagulation and certainly better than that of antiplatelet therapy. First results of randomised studies comparing PFO closure in patients with stroke or migraine cannot be expected before 2010, and first positive results may take even longer.
  3. 3. Transthoracic echocardiography depicting a highly mobile septum primum (arrows), a sign making a patent foramen ovale highly probable. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
  4. 4.  A field study in northern Manhatten found no difference in the incidence of ischaemic stroke among 1100 subjects (with an average age of about 70 years) during an observation period of about 7 years with respect to their PFO status; 15% were diagnosed by non-specialised transthoracic echocardiography to have a PFO and 3% to also have an associated ASA(Atrial Septal Aneurysm)
  5. 5.  A meta-analysis on individuals below 55 years of age identified a threefold risk of a PFO carrier suffering a stroke (16-fold if an ASA was also present) compared to controls.  The respective risk of suffering a cryptogenic stroke was estimated at fivefold and 24-fold, respectively.
  6. 6.  Using standard means for detection, a PFO is found in about 50% of patients with a cryptogenic stroke.  This is most likely an underestimation due to many missed PFOs with the somewhat crude screening techniques used.
  7. 7.  Even when most of the so-called cryptogenic strokes are put on the account of the PFO, its risk may still be underestimated. It appears logical that the potential of a PFO to mediate stroke is independent of associated problems.  Venous thrombosis, a sine qua non of paradoxical embolism, is exquisitely rare in children (although PFO mediated juvenile strokes have been observed), but starts to rise steeply after the age of 50 years to reach about 600 afflicted people per year among 100 000 octogenarians.
  8. 8.  A sub-analysis of WARSS (Warfarin Aspirin Recurrent Stroke Study) found a positive correlation between the 2 year ischaemic stroke recurrence rate in patients with an initial cryptogenic stroke only in those 65 years or older.  A much smaller Spanish study on about 500 patients with cryptogenic stroke and 2 years of follow-up did not find any increased hazard with the presence of a PFO, not even in younger patients with a massive right-to-left shunt.
  9. 9.  A 20 year population based field study on middle-aged people with venous thromboembolism proved a high concomitant incidence of stroke and myocardial infarction.  Over the subsequent 20 years the risk never completely returned to normal.  The authors hypothesised about general pro-coagulant factors begetting simultaneous venous thrombosis and arterial plaque rupture. They did not even mention the PFO,
  10. 10.  Patients (average age 60 years) presenting with a clinically significant pulmonary embolism had a mortality of 33% if they had a PFO and 14% if they had none.  The respective risks of a simultaneous peripheral embolism such as a stroke were 28% and 2%, respectively.  This conspicuous display of danger posed by the PFO published 10 years ago has all but fallen into obscurity.
  11. 11. Situations where preventive PFO closure can be considered Embolism prone surgery:  major orthopaedic surgery  brain surgery in sitting position   Planned pregnancy  Vocational or recreational hazards: deep sea divers  brass musicians  glass blowers  professions requiring squatting position  military jet pilots  astronauts  commercial drivers or pilots 
  12. 12. Diseases putatively blamed on the PFO among other causes  Ischaemic stroke Transient ischaemic attacks Transitory (global) amnesia Retinal infarction Myocardial infarction Visceral infarction Limb ischaemia Economy class stroke syndrome Migraine (with and without aura) Decompression illness in deep sea divers High altitude pulmonary oedema Platypnoea orthodeoxia Sleep apnoea syndrome Excessive snoring
  13. 13.  A study reported an improvement after PFO closure only in patients with migraine and aura or with migraine and documented embolic brain defects, but not in patients with migraine alone.  The correlation with migraine was shown to be more conspicuous in females than in males and in people with a PFO and an ASA, as opposed to people with a simple PFO.
  14. 14.  To confound the issue further, an analysis of the cross sectional Northern Manhatten Study (NOMAS) found absolutely no correlation between PFO and migraine,  and another study found the closest correlation between PFO and migraine in patients with an ASA but no PFO
  15. 15.  Lastly, a study in 75 adults on device closure of an ASD showed that migraine disappeared in 12 (16%)and newly appeared in 10 (13%). Migraine without aura was reduced from 19 to 12 patients but migraine with aura increased from 11 to 15 patients.
  16. 16. Before PFO Devise Closure No echocardiographic guidance required Local anaesthesia Access: right femoral vein Heparin bolus 5000 units 0.0035 inch (exchange) wire Multipurpose catheter to pass defect unless wire crossed spontaneously No balloon gauging 9 French sheath fits most PFO occluder sizes Right atrial dye injections for position control (with device in perfect profile) Antibiotics (1–3 doses)
  17. 17. After PFO Devise treatment  Unrestricted physical activity after a few hours  Aspirin 100 mg for 5 months  Clopidogrel 75 mg for 1 month  Prophylaxis against endocarditis (for 3–6 months)  Transoesophageal echocardiography at about 6 months (1 month after stopping platelet inhibitors)
  18. 18. Recurrent ischaemic events in patients treated for patent foramen ovale (PFO) with three different modalities at a centre for 4 years (top panel)and another centre for 10 years(bottom panel). The numbers in parenthesis
  19. 19. conclusion of a panel of the US Food and Drug Administration on 2 March 2007  Advocating patients abstain from percutaneous PFO closures except for those willing to participate in randomised trials
  20. 20.  Another View
  21. 21. Increased prevalence of PFO in cryptogenic stroke?  SPARC – Olmsted County Study (JACC 2006;47:440-5): Prospektive (5,1years) population based study of 585 randomly sampled persons age 45+ yrs with TEE: PFO not a risk factor for stroke or TIA (hazard ratio 1,28 (0,65-2,50), after adjustment for comorbidity HR1,46 (0,74- 2,88) , both non significant
  22. 22. Increased prevalence of PFO in Cryptogenic Stroke?  NOMAS-study: Prospektive study (6,5 yrs) of incidence, risk factors and clinical outcome of stroke in 1.100 individuals (39+ yrs) without previous stroke, evaluated by TTE (JACC 2007;49:797-802): Stroke incidence 12,2 (+PFO) vs 8,9 (no PFO) pr 1.000 person yrs (p= 0,5). Hazard Ratio after risk-factor adjustment 1,46 (CI 0.87-3.09)
  23. 23. PFO and Cryptogenic Stroke Present knowledge  Retrospektive case control studies show a significantly increased prevalence of PFO with cryptogenic stroke, and a reduced recurrence rate following PFO closure  Newer prospektive population based sudies report a minor and non-significantly higher prevalence of PFO in individuals who subsequently had a stroke.  The stroke recurrence rate on antithrombotics is independent of PFO
  24. 24. Stroke undergo Catheter Closure?  A low risk procedure, but small risk of: Periprocedure stroke, arrhytmias,catheter perforation or occluder erosion with pericardial tamponade, infection, thrombus formation on atrial discs, occluder embolisation (open heart surgery). Catheter Cardiovasc Interv 2004;62:512-16: 272 PFO-closures, 8 centers Complication frequency 6,6% ! (?) Long term (15+ yrs) side effects of implant unknown Estimated Costs: USD 10.000, in DK 5.000
  25. 25. USA FDA 2000 humanitarian device exemption ” is indicated for closure of PFO in patients with recurrent cryptogenic stroke due to presumed embolism through a PFO and who have failed conventional drug therapy” (warfarin) This exemption withdrawn in 2006 . Since then only available at selected institutions with institutional protocols
  26. 26. Guidelines for Prevention of Stroke in Patients with Ischemic Stroke or TIA. A Statement for Healthcare Professionals from AHA, Am Stroke Ass Council on Stroke, Co-sponsored by Council of Cardiovasc Rad. and Interv. and affirmed by Am Ac of Neurol: Circulation 2006;113:409-49  ”Insufficient data exist to make a recommendation about PFO closure in patients with a first stroke and a PFO. PFO closure may be considered for patients with recurrent cryptogenic stroke despite optimal medical treatment (Class IIb, Level of Evidence C)”
  27. 27. Conclusions  For patients with an ischemic stroke or TIA and a PFO antiplatelet therapy is reasonably to prevent a recurrent event  Warfarin is reasonable for high-risk patients who have other indications for oral anticoagulation  It is truely unknown whether patients benefit from catheter closure of PFO, which therefore can only be recommended in controlled clinical trials