Patent Foramen Ovale and Stroke

Learning objectives

Appropriate settings to look for Paradoxical Embolism Incidence of PFO Significance of PFO Treatment options

Introduction

• A Patent foramen ovale means that an embryological connection between the left and right atrium in the heart remains open in adult life.
• This hole exists in everyone before birth, but usually closes shortly after being born.
• The embryological persistence of a one-way flap valve (PFO) allows right to left blood flow

Aetiology

• A PFO is not pathological and studies show that up to 25% of the population have a PFO in adult life.
• A right to left shunt could allow clot to pass from right to left side i.e. from systemic venous drainage to the systemic arterial outflow pathway.
• Pathologically clot has been found in PFOs in post mortem patients.
• The pulmonary circulation provides a large filter for any thrombi returning from the systemic circulation.
• A small microthrombus to the lungs is probably insignificant but if the pulmonary circulation can be bypassed and shunted then there is a risk of thrombi entering the systemic arterial circulation and this can cause stroke.
• Systemic venous thrombosis crosses PFO when right atrial pressure exceeds that of the left.

DVT/PFO/Stroke Hypothesis

• There is an increased finding of PFO in those with otherwise unexplained stroke.
• This has led some to speculate that in these cases that the PFO is pathological and needs closure.
• Association does not equal causation and the PFO could be a marker of some other structural abnormality or risk of PAF.
• Make reasonable attempts to exclude all other stroke causes e.g. PAF before offering closure.

Arguments for closure

A history does not suggest another cause e.g. migraine There are multiple territory events if more than one The younger the patient the greater the possibly significance of the PFO and vice-versa A full work up shows no alternative cause. Prolonged possibly repeated 7 day or more tape shows no PAF. There is no other indication to anticoagulate - I would not do both PFO closure and anticoagulate More than one event which imaging suggests is embolic in different arterial territories with no local stenosis to blame No known temporary precipitant e.g. provoked DVT with suspected paradoxical embolism. A large PFO or Aneurysmal PFO Clear evidence of significant shunting on bubble study

Arguments against Closure

• A thrombophilia that can be reversed e.g. OCP/HRT increasing DVT risk
• A thombophilia that needs anticoagulated to prevent DVT/PE.
• AF that needs anticoagulated
• Age over 55 - patient has lived with PFO all life so why clot now ?
• A small PFO or non-Aneurysmal PFO

Clinical

• Valsalva at onset
• Multiterritory TIA symptoms
• Multiterritory Stroke symptoms
• Exclude stroke mimics

Factors that make a PFO more likely to have been the source

• Atrial septal aneurysm/Eustachian valves
• Large PFO and/or Large shunt > 50 bubbles
• Exclude stroke mimics
• Valsalva at onset
• Younger age
• Multiple territory events
• High risk DVT
• PE at time of episode
• Procoagulant state

Summary of PFO Trials

Reference	Outcome	N	Events in treatment arm	Events in Compared group	Significance
2017
Søndergaard L et al. PFO closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med 2017;377:1033-1042	Among patients with a PFO who had had a cryptogenic stroke, the risk of subsequent ischemic stroke was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone; however, PFO closure was associated with higher rates of device complications and atrial fibrillation.	N=664 (mean age, 45.2 years) of whom 81% had moderate or large interatrial shunts for 3.2 years	AIS 6 of 441 patients (1.4%) in PFO closure group over 3.2 years. New Brain infarction 22 patients [5.7%]	AIS in 12 of 223 patients (5.4%) in antiplatelet-only group over 3.2 years. New Brian infarction 20 patients [11.3%]	Significant reduction of stroke and new brain infarction. However silent brain infarction did not differ significantly. Increased risk of AF in 6.6% after PFO and some device related complications
Mas J-L et al. PFO closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med 2017;377:1011-1021	No stroke in 238 patients in the PFO closure group, vs 14/235 patients in the antiplatelet-only group (P<0.001). Procedural complications in 14 patients (5.9%). The rate of AF higher in the PFO closure group.	N= 663 patients for 5.3±2.0 years	Zero strokes/238 patients in PFO closure group. AF in 4.6%	Stroke in 14 of the 235 patients in antiplatelet-only group. AF in 0.9%	Significant reduction in stroke in those with PFO closure but an increase in AF and procedural complications
Saver JL et al. PFO closure or medical therapy after stroke. N Engl J Med 2017;377:1022-1032	Among adults who had had a cryptogenic ischaemic stroke, closure of a PFO was associated with a lower rate of recurrent ischaemic strokes than medical therapy alone during extended follow-up.	N= 980 patients x 5.9 years	AIS 18/3141 patient years (0.58 events/100 yrs) 10 patients	AIS 28/2669 patients years (1.07 events/100 yrs) 23 patients	Reduction in stroke in PFO group as p =0.046 by the log-rank test. VTE commoner in PFO group.

Comments on data seem to show that the risks of subsequent stroke in this population is actually very small and seems to be less than 1% per annum. It would not take many closure device AF related strokes to cancel out the benefits which are relatively significant but absolutely not massive.

Management

It is clear that patient selection is key. Do not assume that the only cause of a cryptogenic stroke is a found PFO. Make sure first that the pattern of stroke symptoms and findings does support a cardioembolic aetiology. The various PFO closure trials have shown mixed results. Some showed that PFO closure made no difference and others that stroke events were significantly reduced by closing a PFO. variable numbers of patients still had strokes after PFO closure but in several newer trials it was less than the small number who had strokes in the non closure groups. PFO closure reduces risk but does not eliminate it. However the ones who had further stroke either had another cause, had a PFO closure or they simply had undiagnosed PAF or some other cause. I have to say it is difficult to know what one would want for oneself and I suspect that as human nature likes doing things then most of us now would opt for closure once all other issues had been resolved. Doctors find it easier to justify action than inaction. The reality is the long term consequences of these devices is unknown and the aim of the device is to make a small absolute risk smaller. Whether the benefits continue later in life is unknown. There is no real long term data. We just don't know and we have to ensure that we discuss the uncertainties with the patient and lower expectation that this procedure possibly may or may not prevent further strokes. The risk of further stroke does seem to be small. Eliminating one possible cause of stroke also does not prevent the many others. The risks of the procedure need to be borne in mind. One should never operate on the heart without a clear understanding of future benefits.

Discussions with patients about PFO closure

I find this very challenging as one has to try and educate the patient about the uncertainty. I think everyone agrees that not all PFOs need closing but which specific ones to close and which to leave alone is difficult. The following points should be made to anyone who is being considered for PFO closure for cryptogenic stroke. There should hardly ever be the assumption that the presence of a PFO shows causation that is 100% strong. Remember there are other mechanism going on which can cause cryptogenic stroke such as PAF. Closing a PFO is unlikely to help PAF. A PFO may be a surrogate marker for PAF or something else we don’t fully understand and so closing the hole for many may be irrelevant. The discussion with the patient by stroke physician or cardiologist should cover these points. There should a clear discussion between both as to the merits and an agreed line with the acknowledgement of much uncertainty. Remember there are two parallel prongs to preventing PFO related stroke and these are A) Preventing venous thrombosis i.e. DVT and B) Occluding the Hole.

Having a PFO is normal. PFOs are very common - 12,500,000 people in the UK and even ones with shunts and the incidence of related stroke is very small indeed Your PFO may have nothing whatsoever to do with your stroke. Your PFO may have allowed a venous side clot to pass to the brain and caused your stroke No test will give a complete guarantee and answer which of these statements is true Strokes still occur in those with cryptogenic stroke following closure but in some trials are reduced in number. Cryptogenic strokes happen in patients with no PFO or a closed PFO so other silent causes occur which will also occur in those with a PFO It is not possible to say that the PFO did not case the stroke If the stroke was caused by a precipitant e.g. a provoked DVT then the DVT should be managed and ongoing Stroke risk reduced by avoiding the precipitant If the patient is on HRT or OCP then stopping these may reduce the risk of stroke to baseline without closure but there is no scientific proof but it is a logical argument. The PFO closure procedure is not without its own risks There are some patients who will feel happier if the hole is closed. There are others who will avoid procedures they feel are of dubious benefit The main message is to share the explanation and uncertainty. Never say that the PFO caused the stroke without qualification.

References

• CLOSE to the Heart: Patent Foramen Ovale Closure in Cryptogenic Stroke

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