Portal de Periódicos da CAPES

Are Patients with a Patent Foramen Ovale at Increased Risk of Stroke? A Billion Dollar Question

2007; Elsevier BV; Volume: 120; Issue: 6 Linguagem: Inglês

10.1016/j.amjmed.2006.03.021

1555-7162

James E. Dalen,

Traumatic Brain Injury and Neurovascular Disturbances

Approximately one third of the 600,000 ischemic strokes per year in the US are judged to be cryptogenic; that is, there is no evidence of cerebrovascular disease and no evidence of a cardiac source.1Meier B. Lock J.E. Contemporary management of patent foramen ovale.Circulation. 2003; 107: 5-9Crossref PubMed Scopus (228) Google Scholar, 2Maisel W.H. Laskey W.K. Patent foramen ovale closure devices.JAMA. 2005; 294: 366-369Crossref PubMed Scopus (50) Google ScholarIn 1988, Lechat et al3Lechat P. Mas J.L. Lascault G. et al.Prevalence of patent foramen ovale in patients with stroke.N Engl J Med. 1988; 318: 1148-1152Crossref PubMed Google Scholar reported an increased prevalence of patent foramen ovales (PFOs), as detected by transesophageal echocardiography (TEE), in 60 patients younger than age 55 years with an ischemic stroke who had a normal cardiac examination. Reports since then have shown that the prevalence of PFO is approximately 30% to 40% in patients with cryptogenic strokes1Meier B. Lock J.E. Contemporary management of patent foramen ovale.Circulation. 2003; 107: 5-9Crossref PubMed Scopus (228) Google Scholar, 4Homma S. Sacco R.L. DiTullio M.R. et al.Effect of medical treatment in stroke patients with patent foramen ovale.Circulation. 2002; 105: 2625-2631Crossref PubMed Scopus (894) Google Scholar compared with approximately 25% in the general population.5Hara H. Virmani R. Ladich E. et al.Patent foramen ovale: current pathology, pathophysiology, and clinical status.J Am Coll Cardiol. 2005; 46: 1768-1776Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar, 6Meissner I. Khandheria B.K. Heit J.A. et al.Patent foramen ovale: innocent or guilty?.J Am Coll Cardiol. 2006; 47: 440-445Abstract Full Text Full Text PDF PubMed Scopus (352) Google ScholarThese findings indicate that 60,000 to 80,000 cryptogenic ischemic strokes per year in the US occur in patients with a PFO.The increased prevalence of PFOs in patients with cryptogenic strokes has lead to the assumption that when a cryptogenic stroke occurs in a patient with a PFO, it is due to paradoxical embolism, ie, that a venous thrombus has passed through the PFO to enter the systemic circulation and then has embolized the cerebral circulation.The assumption that cryptogenic strokes in patients with PFO are due to paradoxical embolism led to reports of surgical closure of PFO to prevent recurrent strokes.7Homma S. DiTullio M.R. Sacco R.L. et al.Surgical closure of patent foramen ovale in cryptogenic stroke patients.Stroke. 1997; 28: 2376-2381Crossref PubMed Scopus (192) Google ScholarSurgical closure has been replaced by the introduction of catheter devices that permit transvenous closure of a PFO. At present there are at least 9 different transvenous devices available to close PFOs.5Hara H. Virmani R. Ladich E. et al.Patent foramen ovale: current pathology, pathophysiology, and clinical status.J Am Coll Cardiol. 2005; 46: 1768-1776Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar This procedure can be performed under local anesthesia with minimal serious complications.The Food and Drug Administration approves this procedure in patients who have recurrent unexplained ischemic strokes despite adequate anticoagulation with warfarin.8Blackshear J.L. Closure of patent foramen ovale in cryptogenic stroke.J Am Coll Cardiol. 2004; 44: 759-761PubMed Google Scholar However, the "off-label" use of this procedure is widespread and is accelerating. There are reports of the closure of up to 300 to 400 PFOs in patients who have had a cerebral ischemic event of unknown cause.9Wahl A. Krumsdorf U. Meier B. et al.Transcatheter treatment of atrial septal aneurysm associated with patent foramen ovale for prevention of recurrent paradoxical embolism in high risk patients.J Am Coll Cardiol. 2005; 45: 377-380Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 10Krumsdorf U. Ostermayer S. Billinger K. et al.Incidence and clinical course of thrombus formation on atrial septal defect and patent foramen ovale closure devices in 1,000 consecutive patients.J Am Coll Cardiol. 2004; 43: 302-309Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar None of these reports had controls, and the efficacy of this procedure is unproven.The financial implications of this unproven therapy are enormous. These devices cost $2800 to $5500; the total cost of the procedure is approximately $10,000 per patient.2Maisel W.H. Laskey W.K. Patent foramen ovale closure devices.JAMA. 2005; 294: 366-369Crossref PubMed Scopus (50) Google Scholar It is estimated that, worldwide, 500,000 cryptogenic strokes occur annually in patients with a PFO; the estimated potential world market for this procedure is approximately $2 billion per year.2Maisel W.H. Laskey W.K. Patent foramen ovale closure devices.JAMA. 2005; 294: 366-369Crossref PubMed Scopus (50) Google ScholarSeveral randomized clinical trials of transvenous closure of PFO are currently underway.11Thomson J.D.R. Percutaneous PFO closure, further data but so many unanswered questions.Eur Heart J. 2005; 27: 258-259Crossref PubMed Scopus (5) Google Scholar However, recruitment of patients to these trials has been slow because of a widespread belief that this treatment is effective in preventing recurrent stroke.11Thomson J.D.R. Percutaneous PFO closure, further data but so many unanswered questions.Eur Heart J. 2005; 27: 258-259Crossref PubMed Scopus (5) Google Scholar It appears that this procedure is following the path of the pulmonary artery catheter; widespread worldwide use without verification of efficacy by appropriately designed randomized clinical trials.12Dalen J.E. Bone R.C. Is it time to pull the pulmonary artery catheter?.JAMA. 1996; 276: 916-918Crossref PubMed Google ScholarWhat is the Evidence that Cryptogenic Strokes in Patients with a PFO Are Due to Paradoxical Embolism?Paradoxical embolism was first described by Cohnheim in 1877.13Cohnheim J. Thrombose und embolie.Vorlesungen uber allgemeine pathologie. 1877; 1: 134Google Scholar Originally, the diagnosis could only be made at postmortem by finding a venous thrombus straddling a patent foramen ovale or other intracardiac defect.Johnson, in 1951,14Johnson B.I. Paradoxical embolism.J Clin Pathol. 1951; 4: 316-332Crossref PubMed Scopus (143) Google Scholar proposed 3 criteria to make a presumptive clinical diagnosis of paradoxical embolism. These criteria are: systemic embolism without a cardiac source, the presence of venous thrombosis or pulmonary embolism, and an intracardiac defect that will permit a right-to-left shunt. In nearly all reported cases of paradoxical embolism, the intracardiac defect was a PFO. By 1970, only 8 cases of paradoxical embolism diagnosed during life had been reported in the medical literature.15Gazzaniga A.B. Dalen J.E. Paradoxical embolism: its pathophysiology and clinical recognition.Ann Surg. 1970; 171: 137-142Crossref PubMed Scopus (53) Google Scholar The paradoxical embolism caused a stroke in 3 of these 8 cases.Few of the reported cases of cryptogenic stroke in patients with PFO meet these criteria for the clinical diagnosis of paradoxical embolism.14Johnson B.I. Paradoxical embolism.J Clin Pathol. 1951; 4: 316-332Crossref PubMed Scopus (143) Google ScholarThe first criterion is the occurrence of unexplained systemic embolism. It is not certain that cryptogenic strokes are embolic; they could be thrombotic.The second criterion is the presence of venous thromboembolism. Few of the reported cases have noted the presence of venous thrombosis or pulmonary embolism.The third criterion is the presence of an intracardiac defect permitting a right-to-left shunt. It is clear that a patent foramen ovale can permit a right-to-left shunt. However, because left atrial (LA) pressure normally exceeds right atrial (RA) pressure, the increased pressure in the LA closes the flap-like opening in the PFO, preventing right-to-left shunting across the PFO.15Gazzaniga A.B. Dalen J.E. Paradoxical embolism: its pathophysiology and clinical recognition.Ann Surg. 1970; 171: 137-142Crossref PubMed Scopus (53) Google Scholar, 16Cheng T.O. The proper conduct of valsalva maneuver in the detection of patent foramen ovale.J Am Coll Cardiol. 2005; 45: 1145-1146Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar However, if right atrial pressure is increased, and exceeds left atrial pressure, right-to-left shunting can occur.15Gazzaniga A.B. Dalen J.E. Paradoxical embolism: its pathophysiology and clinical recognition.Ann Surg. 1970; 171: 137-142Crossref PubMed Scopus (53) Google Scholar, 16Cheng T.O. The proper conduct of valsalva maneuver in the detection of patent foramen ovale.J Am Coll Cardiol. 2005; 45: 1145-1146Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Most cases of paradoxical embolism occur in patients with major pulmonary embolism that has caused right heart failure with a resultant increase in RA pressure.17Meister S.M. Grossman W. Dexter L. Dalen J.E. Paradoxical embolism diagnosis during life.Am J Med. 1972; 53: 292-298Abstract Full Text PDF PubMed Scopus (152) Google Scholar A valsalva maneuver also can cause right atrial pressure to exceed LA pressure, thereby permitting right-to-left shunting across a PFO.15Gazzaniga A.B. Dalen J.E. Paradoxical embolism: its pathophysiology and clinical recognition.Ann Surg. 1970; 171: 137-142Crossref PubMed Scopus (53) Google Scholar, 16Cheng T.O. The proper conduct of valsalva maneuver in the detection of patent foramen ovale.J Am Coll Cardiol. 2005; 45: 1145-1146Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 18Banas J.S. Meister S.G. Gazzaniga A.B. et al.A simple technique for detecting small defects of the atrial septum.Am J Cardiol. 1971; 28: 467-471Abstract Full Text PDF PubMed Scopus (36) Google ScholarBanas et al18Banas J.S. Meister S.G. Gazzaniga A.B. et al.A simple technique for detecting small defects of the atrial septum.Am J Cardiol. 1971; 28: 467-471Abstract Full Text PDF PubMed Scopus (36) Google Scholar reported the use of dye curves to detect small (1 to 12 mm diameter) surgically created atrial septal defects in dogs. Right-to-left shunting across defects as small as 1.5 mm diameter was demonstrated if the injection was made during a simulated valsalva maneuver. At rest, without a valsalva maneuver, right-to-left shunts could be detected in only 3 of 8 defects.Right-to-left shunting across a PFO can be detected by echocardiography. When saline is injected intravenously, micro bubbles may be detected crossing the PFO from the RA to the LA.19De Castro S. Cartoni D. Fiorelli M. et al.Morphological and functional characteristics of patent foramen ovale and their embolic implications.Stroke. 2000; 31: 2407-2413Crossref PubMed Scopus (377) Google Scholar However, in many cases, right-to-left shunting can be demonstrated only if the injection is made while the patient is performing a valsalva maneuver to increase RA pressure. The demonstration by TEE that micro bubbles may cross a PFO and enter the left atrium in the absence of a valsalva maneuver does not establish that venous thrombi could cross a PFO when RA pressure is less than LA pressure.Few of the cryptogenic strokes in patients with a PFO have occurred in patients with major pulmonary embolism or other causes of right heart failure, or while patients were performing activities that simulate a valsalva maneuver, such as straining at the stool.In summary, the evidence that cryptogenic strokes in patients with a PFO are due to paradoxical embolism is less than compelling. The evidence that the strokes are due to embolism is uncertain. In the vast majority of cases, there is no evidence of venous thromboembolism. There is evidence of a PFO, but in most cases there is no evidence that right atrial pressure was elevated, permitting right-to-left shunting.Are Patients with PFO at Increase Risk of Ischemic Stroke?Even if cryptogenic strokes in patients with PFO are not due to paradoxical embolism, it is possible that patients with a PFO may be at increased risk of stroke by some mechanism other than paradoxical embolism. It has been suggested that other abnormalities associated with PFO, such as atrial septal aneurysms,20Mas J.L. Arouizan C. Lamy C. et al.Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal ameurysm or both.N Engl J Med. 2001; 345: 1740-1746Crossref PubMed Scopus (1207) Google Scholar, 21Overell J.R. Bone I. Lees K.R. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies.Neurology. 2000; 55: 1172-1179Crossref PubMed Scopus (824) Google Scholar Chiari networks,1Meier B. Lock J.E. Contemporary management of patent foramen ovale.Circulation. 2003; 107: 5-9Crossref PubMed Scopus (228) Google Scholar, 5Hara H. Virmani R. Ladich E. et al.Patent foramen ovale: current pathology, pathophysiology, and clinical status.J Am Coll Cardiol. 2005; 46: 1768-1776Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar or Eustachian valves,1Meier B. Lock J.E. Contemporary management of patent foramen ovale.Circulation. 2003; 107: 5-9Crossref PubMed Scopus (228) Google Scholar may predispose to strokes.The most accurate way to determine if patients with a PFO are at increased risk of ischemic strokes would be to perform an observational study of patients with and without a PFO as documented by TEE and follow them to determine the rate of ischemic stroke. If such a study found that patients with a PFO were not at increased risk of ischemic strokes, there would be no rationale for closure of PFO, and no reason to perform randomized clinical trials of closure of PFOs in patients with cryptogenic strokes and PFOs.A small prospective observational study of patients with and without PFO was recently reported by Meissner et al.6Meissner I. Khandheria B.K. Heit J.A. et al.Patent foramen ovale: innocent or guilty?.J Am Coll Cardiol. 2006; 47: 440-445Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar They determined the presence or absence of a PFO by TEE in 585 healthy people aged over 45 years. Over a 5-year follow-up, the incidence of transient ischemic attack, transient ischemic stroke, and cerebrovascular death was the same in the 24% who had PFO as those without a PFO. In a more recent study, DiTullio et al22Di Tullio M.R. Sacco R.L. Sciacca R.R. et al.Patent foramen ovale and the risk of ischemic stroke in a multiethnic population.J Am Coll Cardiol. 2007; 49: 797-802Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar found a prevalence of PFO of 14.9% in 1100 patients older than 39 without a history of stroke. During follow-up of more than 6 years, the incidence of ischemic stroke was the same in those with or without a PFO. Additional large studies are needed to determine if patients with a PFO are at increased risk of ischemic stroke.Several investigators have reported the recurrence rate of strokes in patients with cryptogenic strokes. Mas et al20Mas J.L. Arouizan C. Lamy C. et al.Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal ameurysm or both.N Engl J Med. 2001; 345: 1740-1746Crossref PubMed Scopus (1207) Google Scholar reported a prospective study of 581 patients with cryptogenic ischemic stroke. They were treated with aspirin, 300 mg/day, and followed for 4 years. The incidence of recurrent stroke was actually higher (4.2%) in 304 patients without a PFO than in 216 patients with a PFO (2.3%). They reported an increased incidence of 15.2% in 51 patients with a PFO who also had an atrial septal aneurysm.20Mas J.L. Arouizan C. Lamy C. et al.Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal ameurysm or both.N Engl J Med. 2001; 345: 1740-1746Crossref PubMed Scopus (1207) Google Scholar Homma et al4Homma S. Sacco R.L. DiTullio M.R. et al.Effect of medical treatment in stroke patients with patent foramen ovale.Circulation. 2002; 105: 2625-2631Crossref PubMed Scopus (894) Google Scholar randomized 265 patients with cryptogenic stroke to warfarin or to aspirin. The recurrence rate of stroke was the same in those with or without a PFO in those treated with either warfarin or aspirin. In contrast to the report of Mas et al,20Mas J.L. Arouizan C. Lamy C. et al.Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal ameurysm or both.N Engl J Med. 2001; 345: 1740-1746Crossref PubMed Scopus (1207) Google Scholar they found no difference in the incidence of recurrent stroke in patients with PFO with or without an associated atrial septal aneurysm.4Homma S. Sacco R.L. DiTullio M.R. et al.Effect of medical treatment in stroke patients with patent foramen ovale.Circulation. 2002; 105: 2625-2631Crossref PubMed Scopus (894) Google ScholarAn additional way to determine if there is an increased incidence of ischemic strokes in patients with PFO is to determine if the rate of recurrent stroke is decreased in patients who have had their PFO closed. Several such studies have been reported.9Wahl A. Krumsdorf U. Meier B. et al.Transcatheter treatment of atrial septal aneurysm associated with patent foramen ovale for prevention of recurrent paradoxical embolism in high risk patients.J Am Coll Cardiol. 2005; 45: 377-380Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 10Krumsdorf U. Ostermayer S. Billinger K. et al.Incidence and clinical course of thrombus formation on atrial septal defect and patent foramen ovale closure devices in 1,000 consecutive patients.J Am Coll Cardiol. 2004; 43: 302-309Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar, 23Windecker S. Wahl A. Nedetchev K. et al.Comparison of medical treatment with percutaneous closure of patent foramen ovale in patients with cryptogenic stroke.J Am Coll Cardiol. 2004; 44: 750-758Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar However, none of these studies has been randomized. There has been no blinding of the TEE readings and no blinding of the determination of end points.24Kizer J.R. Devereux R.B. Patent foramen ovale in young adults with unexplained stroke.N Engl J Med. 2005; 353: 2361-2372Crossref PubMed Scopus (166) Google Scholar In addition, because these studies were not randomized, there has been variability in associated conditions in those undergoing or not undergoing catheter closure. They are also difficult to assess because they used variable regimens of antiplatelet or anticoagulant therapy after the PFO had been closed.24Kizer J.R. Devereux R.B. Patent foramen ovale in young adults with unexplained stroke.N Engl J Med. 2005; 353: 2361-2372Crossref PubMed Scopus (166) Google ScholarA properly designed randomized clinical trial is required to determine if closure of PFOs decreases the rate of recurrent stroke.ConclusionThe observation that PFO are more prevalent in patients with cryptogenic strokes than in the general population has led to the conclusion that these strokes are due to paradoxical embolism, and therefore, these patients should undergo closure of their PFO.The evidence that these strokes are due to paradoxical embolism is minimal. It is uncertain that the strokes are due to embolism, and in most cases there is no evidence of co-existent venous thrombosis. In the absence of a cause for elevated right atrial pressure, it is uncertain if a right-to-left shunt has occurred.It has not been demonstrated that patients with PFO are at increased risk of recurrent stroke. There is currently no evidence that transvenous closure of PFOs decreases the risk of recurrent stroke. Given the costs associated with this procedure, it would be prudent to await the results of properly designed randomized clinical trials before recommending this unproven procedure. Until the results of a randomized clinical trial are known, it would be appropriate to treat patients with cryptogenic strokes and a PFO with antiplatelet agents as recommended by the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.25Albers G.W. Amarenco P. Easton J.D. et al.Antithrombotic and thrombolytic therapy for ischemic stroke: the seventh ACCP Conference on antithrombotic and thrombolytic therapy.Chest. 2004; 126: 483s-512sCrossref PubMed Scopus (476) Google Scholar Approximately one third of the 600,000 ischemic strokes per year in the US are judged to be cryptogenic; that is, there is no evidence of cerebrovascular disease and no evidence of a cardiac source.1Meier B. Lock J.E. Contemporary management of patent foramen ovale.Circulation. 2003; 107: 5-9Crossref PubMed Scopus (228) Google Scholar, 2Maisel W.H. Laskey W.K. Patent foramen ovale closure devices.JAMA. 2005; 294: 366-369Crossref PubMed Scopus (50) Google Scholar In 1988, Lechat et al3Lechat P. Mas J.L. Lascault G. et al.Prevalence of patent foramen ovale in patients with stroke.N Engl J Med. 1988; 318: 1148-1152Crossref PubMed Google Scholar reported an increased prevalence of patent foramen ovales (PFOs), as detected by transesophageal echocardiography (TEE), in 60 patients younger than age 55 years with an ischemic stroke who had a normal cardiac examination. Reports since then have shown that the prevalence of PFO is approximately 30% to 40% in patients with cryptogenic strokes1Meier B. Lock J.E. Contemporary management of patent foramen ovale.Circulation. 2003; 107: 5-9Crossref PubMed Scopus (228) Google Scholar, 4Homma S. Sacco R.L. DiTullio M.R. et al.Effect of medical treatment in stroke patients with patent foramen ovale.Circulation. 2002; 105: 2625-2631Crossref PubMed Scopus (894) Google Scholar compared with approximately 25% in the general population.5Hara H. Virmani R. Ladich E. et al.Patent foramen ovale: current pathology, pathophysiology, and clinical status.J Am Coll Cardiol. 2005; 46: 1768-1776Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar, 6Meissner I. Khandheria B.K. Heit J.A. et al.Patent foramen ovale: innocent or guilty?.J Am Coll Cardiol. 2006; 47: 440-445Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar These findings indicate that 60,000 to 80,000 cryptogenic ischemic strokes per year in the US occur in patients with a PFO. The increased prevalence of PFOs in patients with cryptogenic strokes has lead to the assumption that when a cryptogenic stroke occurs in a patient with a PFO, it is due to paradoxical embolism, ie, that a venous thrombus has passed through the PFO to enter the systemic circulation and then has embolized the cerebral circulation. The assumption that cryptogenic strokes in patients with PFO are due to paradoxical embolism led to reports of surgical closure of PFO to prevent recurrent strokes.7Homma S. DiTullio M.R. Sacco R.L. et al.Surgical closure of patent foramen ovale in cryptogenic stroke patients.Stroke. 1997; 28: 2376-2381Crossref PubMed Scopus (192) Google Scholar Surgical closure has been replaced by the introduction of catheter devices that permit transvenous closure of a PFO. At present there are at least 9 different transvenous devices available to close PFOs.5Hara H. Virmani R. Ladich E. et al.Patent foramen ovale: current pathology, pathophysiology, and clinical status.J Am Coll Cardiol. 2005; 46: 1768-1776Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar This procedure can be performed under local anesthesia with minimal serious complications. The Food and Drug Administration approves this procedure in patients who have recurrent unexplained ischemic strokes despite adequate anticoagulation with warfarin.8Blackshear J.L. Closure of patent foramen ovale in cryptogenic stroke.J Am Coll Cardiol. 2004; 44: 759-761PubMed Google Scholar However, the "off-label" use of this procedure is widespread and is accelerating. There are reports of the closure of up to 300 to 400 PFOs in patients who have had a cerebral ischemic event of unknown cause.9Wahl A. Krumsdorf U. Meier B. et al.Transcatheter treatment of atrial septal aneurysm associated with patent foramen ovale for prevention of recurrent paradoxical embolism in high risk patients.J Am Coll Cardiol. 2005; 45: 377-380Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 10Krumsdorf U. Ostermayer S. Billinger K. et al.Incidence and clinical course of thrombus formation on atrial septal defect and patent foramen ovale closure devices in 1,000 consecutive patients.J Am Coll Cardiol. 2004; 43: 302-309Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar None of these reports had controls, and the efficacy of this procedure is unproven. The financial implications of this unproven therapy are enormous. These devices cost $2800 to $5500; the total cost of the procedure is approximately $10,000 per patient.2Maisel W.H. Laskey W.K. Patent foramen ovale closure devices.JAMA. 2005; 294: 366-369Crossref PubMed Scopus (50) Google Scholar It is estimated that, worldwide, 500,000 cryptogenic strokes occur annually in patients with a PFO; the estimated potential world market for this procedure is approximately $2 billion per year.2Maisel W.H. Laskey W.K. Patent foramen ovale closure devices.JAMA. 2005; 294: 366-369Crossref PubMed Scopus (50) Google Scholar Several randomized clinical trials of transvenous closure of PFO are currently underway.11Thomson J.D.R. Percutaneous PFO closure, further data but so many unanswered questions.Eur Heart J. 2005; 27: 258-259Crossref PubMed Scopus (5) Google Scholar However, recruitment of patients to these trials has been slow because of a widespread belief that this treatment is effective in preventing recurrent stroke.11Thomson J.D.R. Percutaneous PFO closure, further data but so many unanswered questions.Eur Heart J. 2005; 27: 258-259Crossref PubMed Scopus (5) Google Scholar It appears that this procedure is following the path of the pulmonary artery catheter; widespread worldwide use without verification of efficacy by appropriately designed randomized clinical trials.12Dalen J.E. Bone R.C. Is it time to pull the pulmonary artery catheter?.JAMA. 1996; 276: 916-918Crossref PubMed Google Scholar What is the Evidence that Cryptogenic Strokes in Patients with a PFO Are Due to Paradoxical Embolism?Paradoxical embolism was first described by Cohnheim in 1877.13Cohnheim J. Thrombose und embolie.Vorlesungen uber allgemeine pathologie. 1877; 1: 134Google Scholar Originally, the diagnosis could only be made at postmortem by finding a venous thrombus straddling a patent foramen ovale or other intracardiac defect.Johnson, in 1951,14Johnson B.I. Paradoxical embolism.J Clin Pathol. 1951; 4: 316-332Crossref PubMed Scopus (143) Google Scholar proposed 3 criteria to make a presumptive clinical diagnosis of paradoxical embolism. These criteria are: systemic embolism without a cardiac source, the presence of venous thrombosis or pulmonary embolism, and an intracardiac defect that will permit a right-to-left shunt. In nearly all reported cases of paradoxical embolism, the intracardiac defect was a PFO. By 1970, only 8 cases of paradoxical embolism diagnosed during life had been reported in the medical literature.15Gazzaniga A.B. Dalen J.E. Paradoxical embolism: its pathophysiology and clinical recognition.Ann Surg. 1970; 171: 137-142Crossref PubMed Scopus (53) Google Scholar The paradoxical embolism caused a stroke in 3 of these 8 cases.Few of the reported cases of cryptogenic stroke in patients with PFO meet these criteria for the clinical diagnosis of paradoxical embolism.14Johnson B.I. Paradoxical embolism.J Clin Pathol. 1951; 4: 316-332Crossref PubMed Scopus (143) Google ScholarThe first criterion is the occurrence of unexplained systemic embolism. It is not certain that cryptogenic strokes are embolic; they could be thrombotic.The second criterion is the presence of venous thromboembolism. Few of the reported cases have noted the presence of venous thrombosis or pulmonary embolism.The third criterion is the presence of an intracardiac defect permitting a right-to-left shunt. It is clear that a patent foramen ovale can permit a right-to-left shunt. However, because left atrial (LA) pressure normally exceeds right atrial (RA) pressure, the increased pressure in the LA closes the flap-like opening in the PFO, preventing right-to-left shunting across the PFO.15Gazzaniga A.B. Dalen J.E. Paradoxical embolism: its pathophysiology and clinical recognition.Ann Surg. 1970; 171: 137-142Crossref PubMed Scopus (53) Google Scholar, 16Cheng T.O. The proper conduct of valsalva maneuver in the detection of patent foramen ovale.J Am Coll Cardiol. 2005; 45: 1145-1146Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar However, if right atrial pressure is increased, and exceeds left atrial pressure, right-to-left shunting can occur.15Gazzaniga A.B. Dalen J.E. Paradoxical embolism: its pathophysiology and clinical recognition.Ann Surg. 1970; 171: 137-142Crossref PubMed Scopus (53) Google Scholar, 16Cheng T.O. The proper conduct of valsalva maneuver in the detection of patent foramen ovale.J Am Coll Cardiol. 2005; 45: 1145-1146Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Most cases of paradoxical embolism occur in patients with major pulmonary embolism that has caused right heart failure with a resultant increase in RA pressure.17Meister S.M. Grossman W. Dexter L. Dalen J.E. Paradoxical embolism diagnosis during life.Am J Med. 1972; 53: 292-298Abstract Full Text PDF PubMed Scopus (152) Google Scholar A valsalva maneuver also can cause right atrial pressure to exceed LA pressure, thereby permitting right-to-left shunting across a PFO.15Gazzaniga A.B. Dalen J.E. Paradoxical embolism: its pathophysiology and clinical recognition.Ann Surg. 1970; 171: 137-142Crossref PubMed Scopus (53) Google Scholar, 16Cheng T.O. The proper conduct of valsalva maneuver in the detection of patent foramen ovale.J Am Coll Cardiol. 2005; 45: 1145-1146Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 18Banas J.S. Meister S.G. Gazzaniga A.B. et al.A simple technique for detecting small defects of the atrial septum.Am J Cardiol. 1971; 28: 467-471Abstract Full Text PDF PubMed Scopus (36) Google ScholarBanas et al18Banas J.S. Meister S.G. Gazzaniga A.B. et al.A simple technique for detecting small defects of the atrial septum.Am J Cardiol. 1971; 28: 467-471Abstract Full Text PDF PubMed Scopus (36) Google Scholar reported the use of dye curves to detect small (1 to 12 mm diameter) surgically created atrial septal defects in dogs. Right-to-left shunting across defects as small as 1.5 mm diameter was demonstrated if the injection was made during a simulated valsalva maneuver. At rest, without a valsalva maneuver, right-to-left shunts could be detected in only 3 of 8 defects.Right-to-left shunting across a PFO can be detected by echocardiography. When saline is injected intravenously, micro bubbles may be detected crossing the PFO from the RA to the LA.19De Castro S. Cartoni D. Fiorelli M. et al.Morphological and functional characteristics of patent foramen ovale and their embolic implications.Stroke. 2000; 31: 2407-2413Crossref PubMed Scopus (377) Google Scholar However, in many cases, right-to-left shunting can be demonstrated only if the injection is made while the patient is performing a valsalva maneuver to increase RA pressure. The demonstration by TEE that micro bubbles may cross a PFO and enter the left atrium in the absence of a valsalva maneuver does not establish that venous thrombi could cross a PFO when RA pressure is less than LA pressure.Few of the cryptogenic strokes in patients with a PFO have occurred in patients with major pulmonary embolism or other causes of right heart failure, or while patients were performing activities that simulate a valsalva maneuver, such as straining at the stool.In summary, the evidence that cryptogenic strokes in patients with a PFO are due to paradoxical embolism is less than compelling. The evidence that the strokes are due to embolism is uncertain. In the vast majority of cases, there is no evidence of venous thromboembolism. There is evidence of a PFO, but in most cases there is no evidence that right atrial pressure was elevated, permitting right-to-left shunting. Paradoxical embolism was first described by Cohnheim in 1877.13Cohnheim J. Thrombose und embolie.Vorlesungen uber allgemeine pathologie. 1877; 1: 134Google Scholar Originally, the diagnosis could only be made at postmortem by finding a venous thrombus straddling a patent foramen ovale or other intracardiac defect. Johnson, in 1951,14Johnson B.I. Paradoxical embolism.J Clin Pathol. 1951; 4: 316-332Crossref PubMed Scopus (143) Google Scholar proposed 3 criteria to make a presumptive clinical diagnosis of paradoxical embolism. These criteria are: systemic embolism without a cardiac source, the presence of venous thrombosis or pulmonary embolism, and an intracardiac defect that will permit a right-to-left shunt. In nearly all reported cases of paradoxical embolism, the intracardiac defect was a PFO. By 1970, only 8 cases of paradoxical embolism diagnosed during life had been reported in the medical literature.15Gazzaniga A.B. Dalen J.E. Paradoxical embolism: its pathophysiology and clinical recognition.Ann Surg. 1970; 171: 137-142Crossref PubMed Scopus (53) Google Scholar The paradoxical embolism caused a stroke in 3 of these 8 cases. Few of the reported cases of cryptogenic stroke in patients with PFO meet these criteria for the clinical diagnosis of paradoxical embolism.14Johnson B.I. Paradoxical embolism.J Clin Pathol. 1951; 4: 316-332Crossref PubMed Scopus (143) Google Scholar The first criterion is the occurrence of unexplained systemic embolism. It is not certain that cryptogenic strokes are embolic; they could be thrombotic. The second criterion is the presence of venous thromboembolism. Few of the reported cases have noted the presence of venous thrombosis or pulmonary embolism. The third criterion is the presence of an intracardiac defect permitting a right-to-left shunt. It is clear that a patent foramen ovale can permit a right-to-left shunt. However, because left atrial (LA) pressure normally exceeds right atrial (RA) pressure, the increased pressure in the LA closes the flap-like opening in the PFO, preventing right-to-left shunting across the PFO.15Gazzaniga A.B. Dalen J.E. Paradoxical embolism: its pathophysiology and clinical recognition.Ann Surg. 1970; 171: 137-142Crossref PubMed Scopus (53) Google Scholar, 16Cheng T.O. The proper conduct of valsalva maneuver in the detection of patent foramen ovale.J Am Coll Cardiol. 2005; 45: 1145-1146Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar However, if right atrial pressure is increased, and exceeds left atrial pressure, right-to-left shunting can occur.15Gazzaniga A.B. Dalen J.E. Paradoxical embolism: its pathophysiology and clinical recognition.Ann Surg. 1970; 171: 137-142Crossref PubMed Scopus (53) Google Scholar, 16Cheng T.O. The proper conduct of valsalva maneuver in the detection of patent foramen ovale.J Am Coll Cardiol. 2005; 45: 1145-1146Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Most cases of paradoxical embolism occur in patients with major pulmonary embolism that has caused right heart failure with a resultant increase in RA pressure.17Meister S.M. Grossman W. Dexter L. Dalen J.E. Paradoxical embolism diagnosis during life.Am J Med. 1972; 53: 292-298Abstract Full Text PDF PubMed Scopus (152) Google Scholar A valsalva maneuver also can cause right atrial pressure to exceed LA pressure, thereby permitting right-to-left shunting across a PFO.15Gazzaniga A.B. Dalen J.E. Paradoxical embolism: its pathophysiology and clinical recognition.Ann Surg. 1970; 171: 137-142Crossref PubMed Scopus (53) Google Scholar, 16Cheng T.O. The proper conduct of valsalva maneuver in the detection of patent foramen ovale.J Am Coll Cardiol. 2005; 45: 1145-1146Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 18Banas J.S. Meister S.G. Gazzaniga A.B. et al.A simple technique for detecting small defects of the atrial septum.Am J Cardiol. 1971; 28: 467-471Abstract Full Text PDF PubMed Scopus (36) Google Scholar Banas et al18Banas J.S. Meister S.G. Gazzaniga A.B. et al.A simple technique for detecting small defects of the atrial septum.Am J Cardiol. 1971; 28: 467-471Abstract Full Text PDF PubMed Scopus (36) Google Scholar reported the use of dye curves to detect small (1 to 12 mm diameter) surgically created atrial septal defects in dogs. Right-to-left shunting across defects as small as 1.5 mm diameter was demonstrated if the injection was made during a simulated valsalva maneuver. At rest, without a valsalva maneuver, right-to-left shunts could be detected in only 3 of 8 defects. Right-to-left shunting across a PFO can be detected by echocardiography. When saline is injected intravenously, micro bubbles may be detected crossing the PFO from the RA to the LA.19De Castro S. Cartoni D. Fiorelli M. et al.Morphological and functional characteristics of patent foramen ovale and their embolic implications.Stroke. 2000; 31: 2407-2413Crossref PubMed Scopus (377) Google Scholar However, in many cases, right-to-left shunting can be demonstrated only if the injection is made while the patient is performing a valsalva maneuver to increase RA pressure. The demonstration by TEE that micro bubbles may cross a PFO and enter the left atrium in the absence of a valsalva maneuver does not establish that venous thrombi could cross a PFO when RA pressure is less than LA pressure. Few of the cryptogenic strokes in patients with a PFO have occurred in patients with major pulmonary embolism or other causes of right heart failure, or while patients were performing activities that simulate a valsalva maneuver, such as straining at the stool. In summary, the evidence that cryptogenic strokes in patients with a PFO are due to paradoxical embolism is less than compelling. The evidence that the strokes are due to embolism is uncertain. In the vast majority of cases, there is no evidence of venous thromboembolism. There is evidence of a PFO, but in most cases there is no evidence that right atrial pressure was elevated, permitting right-to-left shunting. Are Patients with PFO at Increase Risk of Ischemic Stroke?Even if cryptogenic strokes in patients with PFO are not due to paradoxical embolism, it is possible that patients with a PFO may be at increased risk of stroke by some mechanism other than paradoxical embolism. It has been suggested that other abnormalities associated with PFO, such as atrial septal aneurysms,20Mas J.L. Arouizan C. Lamy C. et al.Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal ameurysm or both.N Engl J Med. 2001; 345: 1740-1746Crossref PubMed Scopus (1207) Google Scholar, 21Overell J.R. Bone I. Lees K.R. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies.Neurology. 2000; 55: 1172-1179Crossref PubMed Scopus (824) Google Scholar Chiari networks,1Meier B. Lock J.E. Contemporary management of patent foramen ovale.Circulation. 2003; 107: 5-9Crossref PubMed Scopus (228) Google Scholar, 5Hara H. Virmani R. Ladich E. et al.Patent foramen ovale: current pathology, pathophysiology, and clinical status.J Am Coll Cardiol. 2005; 46: 1768-1776Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar or Eustachian valves,1Meier B. Lock J.E. Contemporary management of patent foramen ovale.Circulation. 2003; 107: 5-9Crossref PubMed Scopus (228) Google Scholar may predispose to strokes.The most accurate way to determine if patients with a PFO are at increased risk of ischemic strokes would be to perform an observational study of patients with and without a PFO as documented by TEE and follow them to determine the rate of ischemic stroke. If such a study found that patients with a PFO were not at increased risk of ischemic strokes, there would be no rationale for closure of PFO, and no reason to perform randomized clinical trials of closure of PFOs in patients with cryptogenic strokes and PFOs.A small prospective observational study of patients with and without PFO was recently reported by Meissner et al.6Meissner I. Khandheria B.K. Heit J.A. et al.Patent foramen ovale: innocent or guilty?.J Am Coll Cardiol. 2006; 47: 440-445Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar They determined the presence or absence of a PFO by TEE in 585 healthy people aged over 45 years. Over a 5-year follow-up, the incidence of transient ischemic attack, transient ischemic stroke, and cerebrovascular death was the same in the 24% who had PFO as those without a PFO. In a more recent study, DiTullio et al22Di Tullio M.R. Sacco R.L. Sciacca R.R. et al.Patent foramen ovale and the risk of ischemic stroke in a multiethnic population.J Am Coll Cardiol. 2007; 49: 797-802Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar found a prevalence of PFO of 14.9% in 1100 patients older than 39 without a history of stroke. During follow-up of more than 6 years, the incidence of ischemic stroke was the same in those with or without a PFO. Additional large studies are needed to determine if patients with a PFO are at increased risk of ischemic stroke.Several investigators have reported the recurrence rate of strokes in patients with cryptogenic strokes. Mas et al20Mas J.L. Arouizan C. Lamy C. et al.Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal ameurysm or both.N Engl J Med. 2001; 345: 1740-1746Crossref PubMed Scopus (1207) Google Scholar reported a prospective study of 581 patients with cryptogenic ischemic stroke. They were treated with aspirin, 300 mg/day, and followed for 4 years. The incidence of recurrent stroke was actually higher (4.2%) in 304 patients without a PFO than in 216 patients with a PFO (2.3%). They reported an increased incidence of 15.2% in 51 patients with a PFO who also had an atrial septal aneurysm.20Mas J.L. Arouizan C. Lamy C. et al.Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal ameurysm or both.N Engl J Med. 2001; 345: 1740-1746Crossref PubMed Scopus (1207) Google Scholar Homma et al4Homma S. Sacco R.L. DiTullio M.R. et al.Effect of medical treatment in stroke patients with patent foramen ovale.Circulation. 2002; 105: 2625-2631Crossref PubMed Scopus (894) Google Scholar randomized 265 patients with cryptogenic stroke to warfarin or to aspirin. The recurrence rate of stroke was the same in those with or without a PFO in those treated with either warfarin or aspirin. In contrast to the report of Mas et al,20Mas J.L. Arouizan C. Lamy C. et al.Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal ameurysm or both.N Engl J Med. 2001; 345: 1740-1746Crossref PubMed Scopus (1207) Google Scholar they found no difference in the incidence of recurrent stroke in patients with PFO with or without an associated atrial septal aneurysm.4Homma S. Sacco R.L. DiTullio M.R. et al.Effect of medical treatment in stroke patients with patent foramen ovale.Circulation. 2002; 105: 2625-2631Crossref PubMed Scopus (894) Google ScholarAn additional way to determine if there is an increased incidence of ischemic strokes in patients with PFO is to determine if the rate of recurrent stroke is decreased in patients who have had their PFO closed. Several such studies have been reported.9Wahl A. Krumsdorf U. Meier B. et al.Transcatheter treatment of atrial septal aneurysm associated with patent foramen ovale for prevention of recurrent paradoxical embolism in high risk patients.J Am Coll Cardiol. 2005; 45: 377-380Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 10Krumsdorf U. Ostermayer S. Billinger K. et al.Incidence and clinical course of thrombus formation on atrial septal defect and patent foramen ovale closure devices in 1,000 consecutive patients.J Am Coll Cardiol. 2004; 43: 302-309Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar, 23Windecker S. Wahl A. Nedetchev K. et al.Comparison of medical treatment with percutaneous closure of patent foramen ovale in patients with cryptogenic stroke.J Am Coll Cardiol. 2004; 44: 750-758Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar However, none of these studies has been randomized. There has been no blinding of the TEE readings and no blinding of the determination of end points.24Kizer J.R. Devereux R.B. Patent foramen ovale in young adults with unexplained stroke.N Engl J Med. 2005; 353: 2361-2372Crossref PubMed Scopus (166) Google Scholar In addition, because these studies were not randomized, there has been variability in associated conditions in those undergoing or not undergoing catheter closure. They are also difficult to assess because they used variable regimens of antiplatelet or anticoagulant therapy after the PFO had been closed.24Kizer J.R. Devereux R.B. Patent foramen ovale in young adults with unexplained stroke.N Engl J Med. 2005; 353: 2361-2372Crossref PubMed Scopus (166) Google ScholarA properly designed randomized clinical trial is required to determine if closure of PFOs decreases the rate of recurrent stroke. Even if cryptogenic strokes in patients with PFO are not due to paradoxical embolism, it is possible that patients with a PFO may be at increased risk of stroke by some mechanism other than paradoxical embolism. It has been suggested that other abnormalities associated with PFO, such as atrial septal aneurysms,20Mas J.L. Arouizan C. Lamy C. et al.Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal ameurysm or both.N Engl J Med. 2001; 345: 1740-1746Crossref PubMed Scopus (1207) Google Scholar, 21Overell J.R. Bone I. Lees K.R. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies.Neurology. 2000; 55: 1172-1179Crossref PubMed Scopus (824) Google Scholar Chiari networks,1Meier B. Lock J.E. Contemporary management of patent foramen ovale.Circulation. 2003; 107: 5-9Crossref PubMed Scopus (228) Google Scholar, 5Hara H. Virmani R. Ladich E. et al.Patent foramen ovale: current pathology, pathophysiology, and clinical status.J Am Coll Cardiol. 2005; 46: 1768-1776Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar or Eustachian valves,1Meier B. Lock J.E. Contemporary management of patent foramen ovale.Circulation. 2003; 107: 5-9Crossref PubMed Scopus (228) Google Scholar may predispose to strokes. The most accurate way to determine if patients with a PFO are at increased risk of ischemic strokes would be to perform an observational study of patients with and without a PFO as documented by TEE and follow them to determine the rate of ischemic stroke. If such a study found that patients with a PFO were not at increased risk of ischemic strokes, there would be no rationale for closure of PFO, and no reason to perform randomized clinical trials of closure of PFOs in patients with cryptogenic strokes and PFOs. A small prospective observational study of patients with and without PFO was recently reported by Meissner et al.6Meissner I. Khandheria B.K. Heit J.A. et al.Patent foramen ovale: innocent or guilty?.J Am Coll Cardiol. 2006; 47: 440-445Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar They determined the presence or absence of a PFO by TEE in 585 healthy people aged over 45 years. Over a 5-year follow-up, the incidence of transient ischemic attack, transient ischemic stroke, and cerebrovascular death was the same in the 24% who had PFO as those without a PFO. In a more recent study, DiTullio et al22Di Tullio M.R. Sacco R.L. Sciacca R.R. et al.Patent foramen ovale and the risk of ischemic stroke in a multiethnic population.J Am Coll Cardiol. 2007; 49: 797-802Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar found a prevalence of PFO of 14.9% in 1100 patients older than 39 without a history of stroke. During follow-up of more than 6 years, the incidence of ischemic stroke was the same in those with or without a PFO. Additional large studies are needed to determine if patients with a PFO are at increased risk of ischemic stroke. Several investigators have reported the recurrence rate of strokes in patients with cryptogenic strokes. Mas et al20Mas J.L. Arouizan C. Lamy C. et al.Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal ameurysm or both.N Engl J Med. 2001; 345: 1740-1746Crossref PubMed Scopus (1207) Google Scholar reported a prospective study of 581 patients with cryptogenic ischemic stroke. They were treated with aspirin, 300 mg/day, and followed for 4 years. The incidence of recurrent stroke was actually higher (4.2%) in 304 patients without a PFO than in 216 patients with a PFO (2.3%). They reported an increased incidence of 15.2% in 51 patients with a PFO who also had an atrial septal aneurysm.20Mas J.L. Arouizan C. Lamy C. et al.Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal ameurysm or both.N Engl J Med. 2001; 345: 1740-1746Crossref PubMed Scopus (1207) Google Scholar Homma et al4Homma S. Sacco R.L. DiTullio M.R. et al.Effect of medical treatment in stroke patients with patent foramen ovale.Circulation. 2002; 105: 2625-2631Crossref PubMed Scopus (894) Google Scholar randomized 265 patients with cryptogenic stroke to warfarin or to aspirin. The recurrence rate of stroke was the same in those with or without a PFO in those treated with either warfarin or aspirin. In contrast to the report of Mas et al,20Mas J.L. Arouizan C. Lamy C. et al.Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal ameurysm or both.N Engl J Med. 2001; 345: 1740-1746Crossref PubMed Scopus (1207) Google Scholar they found no difference in the incidence of recurrent stroke in patients with PFO with or without an associated atrial septal aneurysm.4Homma S. Sacco R.L. DiTullio M.R. et al.Effect of medical treatment in stroke patients with patent foramen ovale.Circulation. 2002; 105: 2625-2631Crossref PubMed Scopus (894) Google Scholar An additional way to determine if there is an increased incidence of ischemic strokes in patients with PFO is to determine if the rate of recurrent stroke is decreased in patients who have had their PFO closed. Several such studies have been reported.9Wahl A. Krumsdorf U. Meier B. et al.Transcatheter treatment of atrial septal aneurysm associated with patent foramen ovale for prevention of recurrent paradoxical embolism in high risk patients.J Am Coll Cardiol. 2005; 45: 377-380Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 10Krumsdorf U. Ostermayer S. Billinger K. et al.Incidence and clinical course of thrombus formation on atrial septal defect and patent foramen ovale closure devices in 1,000 consecutive patients.J Am Coll Cardiol. 2004; 43: 302-309Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar, 23Windecker S. Wahl A. Nedetchev K. et al.Comparison of medical treatment with percutaneous closure of patent foramen ovale in patients with cryptogenic stroke.J Am Coll Cardiol. 2004; 44: 750-758Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar However, none of these studies has been randomized. There has been no blinding of the TEE readings and no blinding of the determination of end points.24Kizer J.R. Devereux R.B. Patent foramen ovale in young adults with unexplained stroke.N Engl J Med. 2005; 353: 2361-2372Crossref PubMed Scopus (166) Google Scholar In addition, because these studies were not randomized, there has been variability in associated conditions in those undergoing or not undergoing catheter closure. They are also difficult to assess because they used variable regimens of antiplatelet or anticoagulant therapy after the PFO had been closed.24Kizer J.R. Devereux R.B. Patent foramen ovale in young adults with unexplained stroke.N Engl J Med. 2005; 353: 2361-2372Crossref PubMed Scopus (166) Google Scholar A properly designed randomized clinical trial is required to determine if closure of PFOs decreases the rate of recurrent stroke. ConclusionThe observation that PFO are more prevalent in patients with cryptogenic strokes than in the general population has led to the conclusion that these strokes are due to paradoxical embolism, and therefore, these patients should undergo closure of their PFO.The evidence that these strokes are due to paradoxical embolism is minimal. It is uncertain that the strokes are due to embolism, and in most cases there is no evidence of co-existent venous thrombosis. In the absence of a cause for elevated right atrial pressure, it is uncertain if a right-to-left shunt has occurred.It has not been demonstrated that patients with PFO are at increased risk of recurrent stroke. There is currently no evidence that transvenous closure of PFOs decreases the risk of recurrent stroke. Given the costs associated with this procedure, it would be prudent to await the results of properly designed randomized clinical trials before recommending this unproven procedure. Until the results of a randomized clinical trial are known, it would be appropriate to treat patients with cryptogenic strokes and a PFO with antiplatelet agents as recommended by the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.25Albers G.W. Amarenco P. Easton J.D. et al.Antithrombotic and thrombolytic therapy for ischemic stroke: the seventh ACCP Conference on antithrombotic and thrombolytic therapy.Chest. 2004; 126: 483s-512sCrossref PubMed Scopus (476) Google Scholar The observation that PFO are more prevalent in patients with cryptogenic strokes than in the general population has led to the conclusion that these strokes are due to paradoxical embolism, and therefore, these patients should undergo closure of their PFO.