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Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy alone for management of cryptogenic stroke? A clinical practice guideline

BMJ 2018; 362 doi: https://doi.org/10.1136/bmj.k2515 (Published 25 July 2018) Cite this as: BMJ 2018;362:k2515

Population

Comparison 2 PFO closure Anticoagulants or Are all options acceptable? Treatment options: PFO closure Anticoagulants Antiplatelets Yes Comparison 1 Comparison 3 PFO closure Antiplatelets or Anticoagulants Antiplatelets or Anticoagulants Anticoagulants contraindicated, unacceptable, or unavailable PFO closure PFO closure contraindicated, unacceptable, or unavailable Peoplewith: Patent foramen ovale (PFO) Cryptogenicstroke + No atrial fibrillation No aortic disease No cerebrovascular disease No left sided heart disease

Comparison 1

or Antiplatelets Antiplatelet therapy alone APL PFO closure Percutaneous closure of PFO followed by antiplatelet therapy APL + PFO closure Antiplatelets

We recommend PFO closure followed by antiplatelet therapy over antiplatelet therapy alone. More details Strong Benefits outweigh harms for almost everyone. All or nearly all informed patients would likely want this option. Weak Benefits outweigh harms for the majority, but not for everyone. The majority of patients would likely want this option. Weak Benefits outweigh harms for the majority, but not for everyone. The majority of patients would likely want this option. Strong Benefits outweigh harms for almost everyone. All or nearly all informed patients would likely want this option.

Comparison of benefits and harms

Within 5 years Favours PFO closure Favours antiplatelets Evidence quality Events per 1000 people No important difference The panel found that these differences were not important for most patients, because the intervention effects were negligible and/or very imprecise (such as statistically not significant)

Ischaemic stroke Moderate More 100 87 fewer 13

Risk of Bias No serious concerns Imprecision Serious Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns PFO closure plus antiplatelet therapy probably results in a large decrease in ischemic stroke

No important difference Death Moderate More 3 9

Risk of Bias No serious concerns Imprecision Serious Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns There is probably little or no difference in death

No important difference Major bleeding Moderate More 14 7

Risk of Bias No serious concerns Imprecision Serious Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns There is probably little or no difference in major bleeding
Within 1 year Evidence quality Events per 1000 people

18 fewer Persistent AF or flutter Moderate More 5 23 AF = Atrial fibrillation

Risk of Bias Serious Imprecision No serious concerns Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns PFO closure plus antiplatelet therapy probably increases persistent atrial fibrillation or flutter

36 fewer Device-related adverse events High More 0 36

Risk of Bias No serious concerns Imprecision No serious concerns Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns PFO closure can lead to device- or procedure-related adverse events
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The panel believes that there is probably substantial benefit in stroke reduction after PFO closure, which will be very important to all or almost all patients. This is likely to outweigh important undesirable consequences, like procedure or device related events and persistent atrial fibrillation Preferences and values Applicability The applicability of these findings to patients over 60 and those with traditional cerebrovascular risk factors (e.g. diabetes, hypertension, and hyperlipidemia) is more uncertain. In older patients, fewer cryptogenic strokes are caused by paradoxical emboli, so we expect the benefits of PFO closure would be smaller and the harms greater No key practical issues Procedure takes under 2 hours In-hospital stay is usually one day Most activities can be resumed within a few days Full recovery within a few weeks Key practical issues PFO closure Antiplatelets

Comparison 2

or PFO closure Anticoagulants Anticoagulation therapy Percutaneous closure of PFO followed by antiplatelet therapy PFO closure Anticoagulants OAC APL +

We suggest PFO closure followed by antiplatelet therapy over anticoagulation therapy. Discuss both options with each patient. More details Strong Benefits outweigh harms for almost everyone. All or nearly all informed patients would likely want this option. Weak Benefits outweigh harms for the majority, but not for everyone. The majority of patients would likely want this option. Weak Benefits outweigh harms for the majority, but not for everyone. The majority of patients would likely want this option. Strong Benefits outweigh harms for almost everyone. All or nearly all informed patients would likely want this option.

Comparison of benefits and harms

Favours PFO closure Favours anticoagulants Within 5 years Evidence quality Events per 1000 people No important difference The panel found that these differences were not important for most patients, because the intervention effects were negligible and/or very imprecise (such as statistically not significant)

Ischaemic stroke Low More 29 No important difference 13

Risk of Bias No serious concerns Imprecision Very serious Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns There may be little or no difference in ischaemic stroke

No important difference Death Moderate More 13 9

Risk of Bias No serious concerns Imprecision Serious Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns There is probably little or no difference in death

Major bleeding Moderate More 27 7 20 fewer

Risk of Bias No serious concerns Imprecision Serious Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns PFO closure plus antiplatelet therapy probably decreases major bleeding
Within 1 year Evidence quality Events per 1000 people

18 fewer Moderate More 5 23 Persistent AF or flutter AF = Atrial fibrillation

Risk of Bias Serious Imprecision No serious concerns Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns PFO closure plus antiplatelet therapy probably increases persistent atrial fibrillation

36 fewer Device-related adverse events High More 0 36

Risk of Bias No serious concerns Imprecision No serious concerns Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns PFO closure can lead to device- or procedure-related adverse events
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Key practical issues The panel felt that many patients would not want the long-term bleeding risk from anticoagulation therapy, which will usually outweigh the probable risk of procedure or device related events and persistent atrial fibrillation with PFO closure Preferences and values Applicability The applicability of these findings to patients over 60 and those with traditional cerebrovascular risk factors (e.g. diabetes, hypertension, and hyperlipidemia) is more uncertain. In older patients, fewer cryptogenic strokes are caused by paradoxical emboli, so we expect the benefits of PFO closure would be smaller and the harms greater PFO closure Anticoagulants Procedure takes under 2 hours In-hospital stay is usually one day Most activities can be resumed within a few days Full recovery within a few weeks Initial frequent testing required to achieve appropriate dose Periodic testing required while taking medication

Comparison 3

or Anticoagulants Antiplatelets Antiplatelet therapy Anticoagulation therapy Anticoagulants Antiplatelets APL OAC

We suggest anticoagulation over antiplatelet therapy. Discuss both options with each patient. More details Strong Benefits outweigh harms for almost everyone. All or nearly all informed patients would likely want this option. Weak Benefits outweigh harms for the majority, but not for everyone. The majority of patients would likely want this option. Weak Benefits outweigh harms for the majority, but not for everyone. The majority of patients would likely want this option. Strong Benefits outweigh harms for almost everyone. All or nearly all informed patients would likely want this option.

Comparison of benefits and harms

Within 5 years Favours anticoagulants Favours antiplatelets Evidence quality Events per 1000 people No important difference The panel found that these differences were not important for most patients, because the intervention effects were negligible and/or very imprecise (such as statistically not significant)

Ischaemic stroke Low More 100 71 fewer 29

Risk of Bias No serious concerns Imprecision Very serious Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Anticoagulation may decrease ischaemic stroke

No important difference Death Low More 3 13

Risk of Bias No serious concerns Imprecision Very serious Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns There may be little or no difference in death

Major bleeding Moderate More 26 12 fewer 14

Risk of Bias No serious concerns Imprecision Serious Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Anticoagulation probably increases major bleeding

Pulmonary embolism Moderate More 5 1 No important difference Modelling data from VTE literature

Risk of Bias No serious concerns Imprecision No serious concerns Indirectness Serious Inconsistency No serious concerns Publication bias No serious concerns There is probably little or no difference in pulmonary embolism.
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The panel felt that the possible decrease in ischemic stroke with anticoagulants would be more important to most patients than the probable increase in major bleeding. We expect variability in how patients might value these outcomes. Shared decision making may help establish what matters most to each patient Preferences and values Key practical issues Anticoagulants Antiplatelets Initial frequent testing required to achieve appropriate dose Periodic testing required while taking medication No key practical issues

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