A patent foramen ovale is not an acquired but a congenital heart defect present from before birth and stays with us lifelong. Various autopsy studies have shown that they are prevalent in 25% of the population and it is suggested that they are a risk factor for ischaemic stroke in the young. They can be regarded as a normal variant in cardiac anatomy. However if we assume a UK population of 60 million of which 15 million have a PFO we are not seeing an epidemic of strokes due to PFO so in terms of having a PFO the subsequent risk of stroke is seemingly very small indeed. So what is the exact relationship between stroke and PFO and why the issue. In the past 15 years Cardiologist have become adept at closing these as they have developed tools and procedures and techniques that allow them to place devices across these PFOs and close them often with varying degrees of success. The procedure is not without risks and the question is whether it is merited. The real question is have they proved that closing these holes reduces recurrence rate. Sadly no and so we are left wondering how to proceed.
The Current evidence
The foramen ovale should close after birth but in some failure of closure of the foramen results in a persistent (or patent) foramen ovale that provides a potential route for blood borne material from the venous circulation to enter the
systemic circulation. Various case reports have identified clot lying across a PFO in the setting of systemic embolism providing circumstantial evidence of a theoretical stroke mechanism. However is the PFO a marker of increased risk of PAF and LA appendage clot rather than paradoxical embolism and so closing it changes little. The evidence is as follows.
- In series of ‘cryptogenic strokes – those with no cause indentified’ in those under 55 there is a greater incidence of PFO than would be expected. It has been shown that 46% of 202 patients under age 55 with cryptogenic stroke had PFOs, compared with 11% of controls (P < .05 in all studies) [Homma S et al. 2005]
- Another study looked at 1100 people with a PFO and no history of stroke and fund that over 11 years there stroek risk was no different to those without a PFO. This was repeated with the same finding in a study of 585 patient. [Di Tullio MR et al, 2007,2013 and Meissner I et al. 2006]
- One study in older patients has shown no difference in the incidence of stroke between those with and without a PFO. The incidence was approximately 1% per 100 patient years [Di Tullio MR 2007]. Perhaps this is different in younger patients.
- Several studies have in patients with stroke and patent were pooled in a meta-analysis and the combined rate of recurrent stroke in those managed medically was 1.6 events (95%confidence interval 1.1 to 2.1) per 100 person years.[Almekhlafi MA et al 2009]
- There is suggested that risk may be related to foramen ovale size, the presence of an atrial septal aneurysm (a bulge in the atrial septum often associated with increased septal mobility), or risk factors for venous thromboembolism,
but this has not been confirmed. [Stollberger C eta l 1993, Botto N et al. 2007, Homma S eta l. 2002]
- Treatments include antiplatelet therapy, anticoagulantion has been sued and placement of a sptal closre device transcutenously
- The use of a device to close the PFO has been suggested as a method to reduce stroke recurrence. One study has shown that in patients with patent foramen ovale when compared with medical management.13-16 In a recent systematic review of observational studies in patients with presumed systemic embolism through a patent foramen ovale, the incidence rate of recurrent stroke was 0.36 (95% confidence interval 0.24 to 0.56) per 100 person years after closure of the patent foramen ovale, but 2.53 (1.91 to 3.35) per 100 person years with medical therapy [Kitsios GD et al. 2012]
- However patent foramen ovale closure is associated with procedural and long term risks.[Abaci A et al.2013,Taggart NW et al ] and the author has seen a young diver who had a device placed who went on to have a large vessel stroke with no other underlying cause. Can closure devices cause stroke or be proarrhythmic.
Closure I Trial
n= 909 with PFO and cryptogenic stroke or transient ischaemic attack
- Starflex device combined with medical therapy (aspirin): successful closure in 81%
- Asprin + warfarin
- Primary endpoint (stroke, transient ischaemic attack, or death from neurological causes)
- At two years’ follow-up there was no significant difference in the rate of the primary endpoint between the treatment groups
- left atrial thrombus was detected in four (1.1%) of the 366 closure patients who underwent transoesophageal echocardiography within six months of the closure procedure, two of whom had a stroke
- major vascular complications occurred in 3.2% of the closure group but none of the medical therapy group, and atrial fibrillation itself a major stroke risk was significantly more common in the closure group than in the medical therapy group (5.7% v 0.7%) [Furlan AJ eta l. 2012]
- The lack of difference was regardless of shunt size or the presence of atrial septal aneurysm
RESPECT trial (NCT00465270) [Carroll JD et al. 2013]
n= 980 patients with patent foramen ovale and cryptogenic stroke to patent foramen ovale closure
- Amplatzer PFO occluder (St Jude Medical) successful closure in 92.6%
- Medical therapy alone (with anticoagulation or antiplatelet therapy).
Outcome over 2.6 years
- Primary endpoint (recurrent fatal or non-fatal ischaemic stroke or early death after randomisation)
- Seen in 1.8% of the closure group and 3.3% of the medical therapy group (hazard ratio 0.49 (0.22 to 1.11)).
- Some patients in the medical arm withdrew from the study and underwent non-assigned patent foramen ovale closure.
- Exploratory survival analyses by treatment received suggested that patent foramen ovale closure might have reduced the risk of recurrent stroke.
- The rate of serious adverse events did not differ between the two groups
- Showed percutaneous closure to be beneficial in patients with atrial septal aneurysm or large shunt however but not as clear for TIA
- Closure group showed a non-significant excess of new AF (3.0% v 1.5%) and PE (1.2% v 0.2%).21
The PC trial (NCT00166257)[Meier B et al. 2013]
n= 414 patients with patent foramen ovale and ischaemic stroke, TIA or extracranial peripheral thromboembolism
- Closure of the patent foramen ovale using the Amplatzer PFO occluder (St Jude Medical) – successfully implanted in 93.6%
- Standard medical care (antiplatelet therapy or anticoagulation)
- primary composite endpoint (death, non-fatal stroke, transient ischaemic attack, and peripheral embolism)
- Seen in 3.4% of the closure group and 5.2% of the medical care group (hazard ratio 0.63 (0.24 to 1.62)).
- There was a slightly higher rate of atrial fibrillation (2.9% v 1.0%) but thrombus was not seen
- Study found no statistically significant benefit of closure in those with atrial septal aneurysm.
Several recent articles have tried to address the issue and provided useful summaries. Henderson and Bath writing in the BMJ in 2013 have looked at the relevant trials and agreed that the data is insufficient to recommend close and make it clear that larger trials with longer follow up and carefully selected younger patients should be performed. [Henderson RA et al 2013]. Roth and Alli also look at the data in the Cleveland clinical Journal of medicine and state that there is still no definitive evidence that closure of PFO is better than medical therapy in all patients with PFO and cryptogenic stroke.
Summary – Difficulties
- The risk of stroke is small
- Were these patients representative of our patients
- Other patients were being recommended closure but not on a trial basis
- Short follow up times of less than 3 years
- The result is that we do not have definitive evidence
- Closure is associated with significant risk factors in 3%
Notes : An Atrial septal aneurysm is loosely defined as a septal excursion or bulging of at least 10 to 15 mm into the left and right atria during the cardiac cycle. It is suggested that an atrial septal aneurysm may be more of a risk
factor for stroke than PFO alone.
- Select high risk patient in whom the PFO is likely causative i.e. absence of alternative cause
- Ethically I think all patients should be offered to participate in a clinical of medical vs interventional but this means accepting that the data is unclear
- It is important that we do not overstate the old dictum of something – usually interventional should be done and remember primum non nocere
- Di Tullio MR, Sacco RL, Sciacca RR, Jin Z, Homma S. Patent foramen ovale and the risk of ischemic stroke in a multiethnic population. J Am Coll Cardiol 2007;49:797-802.
- Almekhlafi MA, Wilton SB, Rabi DM, Ghali WA, Lorenzetti DL, Hill MD. Recurrent cerebral ischemia in medically treated patent foramen ovale: a meta-analysis. Neurology 2009;73:89-97.
- Stollberger C, Slany J, Schuster I, Leitner H, Winkler WB, Karnik R. The prevalence of deep venous thrombosis in patients with suspected paradoxical embolism. Ann Intern Med 1993;119:461-5.
- Botto N, Spadoni I, Giusti S, Ait-Ali L, Sicari R, Andreassi MG. Prothrombotic mutations as risk factors for cryptogenic ischemic cerebrovascular events in young subjects with patent foramen ovale. Stroke 2007;38:2070-3
- Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP, for the PFO in Cryptogenic Stroke Study (PICSS) Investigators. Effect of medical treatment in stroke patients with patent foramen ovale: Patent Foramen Ovale in Cryptogenic Stroke Study. Circulation 2002;105:2625-31.
- Homma S, Sacco RL. Patent foramen ovale and stroke. Circulation 2005; 112:1063–1072.
- Kitsios GD, Dahabreh IJ, Abu Dabrh AM, Thaler DE, Kent DM. Patent foramen ovale closure and medical treatments for secondary stroke prevention: a systematic review of observational and randomized evidence. Stroke 2012;43:422-31.
- Abaci A, Unlu S, Alsancak Y, Kaya U, Sezenoz B. Short and long term complications of device closure of atrial septal defect and patent foramen ovale: meta-analysis of 28,142 patients from 203 studies. Cathet Cardiovasc Interv 2013, doi:10.1002/ccd.24875. [Epub ahead of print].
- Taggart NW, Dearani JA, Hagler DJ. Late erosion of an Amplatzer septal occluder device 6 years after placement. J Thorac Cardiovasc Surg 2011;142:221-2.
- Furlan AJ, Reisman M, Massaro J, Mauri L, Adams H, Albers GW, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 2012;366:991-9.
- Carroll JD, Saver JL, Thaler DE, Smalling RW, Berry S, MacDonald LA, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med 2013;368:1092-100.
- Meier B, Kalesan B, Mattle HP, Khattab AA, Hildick-Smith D, Dudek D, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013;368:1083-91.
- Henderson RA, Bath PMW BMJ 2013;347:f6193 doi: 10.1136/bmj.f6193
- Roth C, Alli O. CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 81 • NUMBER 7 JULY 2014
- Di Tullio MR, Sacco RL, Sciacca RR, Jin Z, Homma S. Patent foramen ovale and the risk of ischemic stroke in a multiethnic population. J Am Coll Cardiol 2007; 49:797–802.
- Di Tullio MR, Jin Z, Russo C, et al. Patent foramen ovale, subclinical cerebrovascular disease, and ischemic stroke in a population-based cohort. J Am Coll Cardiol 2013; 62:35–41
- Meissner I, Khandheria BK, Heit JA, et al. Patent foramen ovale: innocent or guilty? Evidence from a prospective population-based study. J Am Coll Cardiol 2006; 47:440–445.