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

We recommend PFO closure followed by antiplatelet therapy over antiplatelet therapy alone.This recommendation is for patients to whom anticoagulants are contraindicated, unacceptable, or unavailable.Key InfoRationaleWe issue a strong recommendation for PFO closure followed by antiplatelet therapy because we believe that the probable substantial benefit in stroke reduction, an outcome of very high importance to patients, clearly outweighs the undesirable consequences when compared to antiplatelet therapy alone, in patients to whom anticoagualants are contraindicated or unacceptable.Benefits and harmsThe panel agrees that PFO closure followed by antiplatelet therapy versus antiplatelet therapy alone probably has a large decrease in ischemic stroke (8.7% absolute risk reduction over 5 years, moderate quality evidence), carries a risk of device or procedure related adverse events (3.6% absolute risk, high quality evidence) and probably has an increase in persistent atrial fibrillation (1.8% absolute risk increase, moderate quality evidence) and transient atrial fibrillation (1.2% absolute risk increase, moderate quality evidence). There probably is little or no difference in death, major bleeding, pulmonary embolism, TIA and systemic embolism (moderate to high quality evidence).Substantial net benefits of the recommended alternativeQuality of evidenceWe had moderate certainty in a decrease in ischemic stroke, high certainty in an increase in device or procedure related adverse events and moderate certainty in an increase in persistent atrial fibrillation. We were moderate certainty that there were little or no difference in death, major bleeding, pulmonary embolism, recurrent TIA and systemic embolism.ModeratePreference and valuesOur strong recommendation for PFO closure reflects patients' high value on avoiding an ischemic stroke. The panel, including the patient representatives, felt that that the probable absolute reduction of stroke with PFO closure over 8.7% in 5 years is extremely important. We were concerned about the 3.6% incidence of serious device or procedure related adverse events following PFO closure. However, these events, in contrast to stroke, do not usually result in long term disability, and so, we felt, are much less important.We were also concerned about the 1,8% absolute increase in incidence of persistent atrial fibrillation following the PFO closure procedure. The main adverse consequence of atrial fibrillation is increased stroke risk, and stroke risk was substantially lower in patients randomized to PFO closure.No substantial variability expectedResources and other considerationsThe panel focused on the patient-perspective rather than that of society when formulating the recommendation. Implementation of this recommendation is likely to have an important impact on the costs for health funders which warrants cost-effectiveness data. Over the short term PFO closure is associated with higher costs related to the procedure; however in the long term PFO closure may reduce costs as a result of reduced stroke rates and reduction in the long-term costs of care for stroke patients. [1] No important issues with the recommended alternative Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group 8 of 28 Clinical Question/ PICO Population: Patients with cryptogenic stroke Intervention: PFO closure plus antiplatelet therapy Comparator: Antiplatelet therapy Weak RecommendationWe suggest PFO closure followed by antiplatelet therapy over anticoagulation therapy. Discuss both options with each patient.This recommendation is for patients to whom all options are acceptable.

## Summary
The panel agreed that PFO closure followed by antiplatelet therapy versus antiplatelet therapy alone:
- probably has a large decrease in ischemic stroke (8.7% absolute risk reduction over 5 years, moderate quality evidence) - carries a risk of device or procedure related adverse events (3.6% absolute risk, high quality evidence) - probably has an increase in persistent atrial fibrillation 

## Procedure and device
The PFO device will be implanted using a catheter (long, thin, flexible, hollow tube), inserted through a small cut made at the inner thigh (groin), with local anasthesia and moderate sedation or under general anaesthesia.
The procedure takes under 2 hours. In-hospital stay is usually one day.

## Recovery and adaptation
Most activities can be resumed within a few days, with full recovery within a few weeks.

## Costs and access
Most can take a low-cost medication available without a prescription.
Most can take a low-cost medication available without a prescription.
Exercise and activities Need to avoid strenuous activity during recovery.
Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group Work and education Time to return to work depends on speed of recovery.
Travel and driving Driving may be limited during recovery.

## Benefits and harms
The panel agreed that PFO closure followed by antiplatelet therapy versus anticoagulation may have little or no difference in ischaemic stroke (1.6% absolute risk reduction over 5 years, low quality evidence), probably decreases major bleeding (2.0% absolute risk reduction over 5 years, moderate quality evidence), has a risk of device or procedure related adverse events (3.6% absolute risk, high quality evidence) and probably has an increase in persistent atrial fibrillation (1.8% absolute risk increase, moderate quality evidence) and transient atrial fibrillation (1.2% absolute risk increase, moderate quality evidence). There probably is little or no Small net benefit, or little difference between alternatives Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group

## Rationale
We issue a weak recommendation for PFO closure versus anticoagulation because of the large uncertainty and possibly little or no difference in ischemic stroke between PFO closure and anticoagulation. In addition to the low certainty in the estimates of effect -that most panel members felt that whereas most serious complications of PFO closure are usually short-term, anticoagulation imposes a lifelong increased risk of major bleeding. The panel felt that the majority of fully informed patients would accept the mostly transient risk of major adverse events rather than the long-term bleeding risk, but that a substantial minority would choose anticoagulation.
difference in death, pulmonary embolism, TIA and systemic embolism (moderate quality evidence).

## Quality of evidence
There is low certainty that there is little or no difference in ischemic stroke, moderate certainty for a decrease in major bleeding and an increase in persistent atrial fibrillation. There is high certainty in a risk of device or procedure related adverse events. There is moderate certainty that there is little or no difference in death, recurrent TIA, systemic embolism, pulmonary embolism.

## Low

## Preference and values
The weak recommendation for PFO closure versus anticoagulation reflects -in addition to the low certainty in the estimates of effect -that most panel members felt that whereas most serious complications of PFO closure are usually short-term, anticoagulation imposes a lifelong increased risk of major bleeding. The panel felt that the majority of fully informed patients would accept the mostly transient risk of major adverse events rather than the long-term bleeding risk, but that a substantial minority would choose anticoagulation.
Substantial variability is expected or uncertain

## Resources and other considerations
The panel focused on the patient-perspective rather than that of society when formulating the recommendation. Implementation of this recommendation is likely to have an important impact on the costs for health funders which warrants cost-effectiveness data. Over the short term PFO closure is associated with higher costs related to the procedure; however in the long term PFO closure may reduce costs as a result of reduced stroke rates and reduction in the long-term costs of care for stroke patients. No important issues with the recommended alternative Medication routine One or two doses per day.

## Tests and visits
Initial frequent testing required to achieve appropriate dose. Periodic testing required while taking medication.
May include 1 or 2 visits to the cardiologist in the first 6 months followed by an appointment every 1-2 years.

## Procedure and device
The PFO device will be implanted using a catheter (long, thin, flexible, hollow tube), inserted through a small cut made at the inner thigh (groin), with local anasthesia and moderate sedation or under general anaesthesia.
The procedure takes under 2 hours. In-hospital stay is usually one day.

## Recovery and adaptation
Most activities can be resumed within a few days, with full recovery within a few weeks.

## Adverse effects, interactions and antidote
Certain medicines may increase one's risk of bleeding, and some may increase the risk of stroke, by reducing the effect of the anticoagulan.

## Pregnancy and nursing
Women who are pregnant or considering pregnancy may need to change their medication, and may face considerable complications of pregnancy and birth being on anticoagulation or heparine during pregnancy.
Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group

## Benefits and harms
The panel agreed that anticoagulation versus antiplatelet therapy may decrease ischaemic stroke (7.1% absolute risk reduction over 5 years, low quality evidence), probably increases major bleeding (1.2% absolute risk increase over 5 years, moderate quality evidence) and probably has little or no difference in death, pulmonary embolism, TIA and systemic embolism (moderate quality evidence).

## Small net benefit, or little difference between alternatives

## Quality of evidence
There is low certainty that there was a decrease in ischemic stroke, moderate certainty for an increase in major bleeding. There is moderate certainty that there is little or no difference in death, pulmonary embolism, TIA and systemic embolism.

## Low

## Preference and values
A typical patient places a high value in a possible absolute reduction of stroke with anticoagulation of 7.1% in 5 years and would therefore value the possible benefit in stroke reduction higher than the probable increased risk of major bleeding. A systematic review and a primary study regarding values and preferences on thromboprophylaxis treatment of patients with atrial fibrillation were highly variable, however both strongly suggest that patients value preventing strokes considerably more than they are concerned with increased risk of bleeding. However, there is substantial uncertainty in our estimates for stroke reduction -how this uncertainty would influence decisions is likely to vary substantially. Therefore we issue a weak recommendation for anticoagulation. Both options need to be discussed with the patients, ideally in a process of shared decision making.

## Substantial variability is expected or uncertain

## Resources and other considerations
The panel focused on the patient-perspective rather than that of society when formulating the recommendation. Implementation of this recommendation is likely to have an important impact on the costs for health funders which warrants cost-effectiveness data.
No important issues with the recommended alternative Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group benefit of anticoagulation on ischemic stroke, an outcome we feel a typical patient places a high value on. Another reason that drove this weak recommendation is anticoagulation probably increases major bleeding. Therefore we feel the possible benefit less clearly outweighs the undesirable consequences of antigoagulation versus antiplatelet therapy.

## Clinical question/ pico

## Population:
Patients with cryptogenic stroke

## Intervention: anticoagulation
Comparator: Antiplatelet

## Summary
The panel agreed that anticoagulation versus antiplatelet therapy:
- may decrease ischaemic stroke (7.1% absolute risk reduction over 5 years, low quality evidence) - probably increases major bleeding (

## Tests and visits
Initial frequent testing required to achieve appropriate dose. Periodic testing required while taking medication.

## Adverse effects, interactions and antidote
Certain medicines may increase one's risk of bleeding, and some may increase the risk of stroke, by reducing the effect of the anticoagulan.

## Pregnancy and nursing
Women who are pregnant or considering pregnancy may need to change their medication, and may face considerable complications of pregnancy and birth being on anticoagulation or heparine during pregnancy.

## Costs and access
Most can take a low-cost medication available without a prescription.
Newer medications cost more, but require less monitoring.
Food and drinks Dietary restrictions may apply.
Exercise and activities May need to limit activities with high injury risk.
Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group .

## -bmj rapid recommendations methods and process about bmj rapid recommendations
Translating research to clinical practice is challenging. Trustworthy clinical practice recommendations are one useful knowledge translation strategy. Organisations creating systematic reviews and guidelines often struggle to deliver timely and trustworthy recommendations in response to potentially practice-changing evidence. BMJ Rapid Recommendations aims to create trustworthy clinical practice recommendations based on the highest quality evidence in record time. The project is supported by an international network of systematic review and guideline methodologists, people with lived experience of the diseases or conditions, clinical specialists, and front-line clinicians. This overview is one of a package that includes recommendations and one or more systematic reviews published by the BMJ group and in MAGICapp (http://www.magicapp.org). The goal is to translate evidence into recommendations for clinical practice in a timely and transparent way, minimizing bias and centred around the experience of patients. BMJ Rapid Recommendations will consider both new and old evidence that might alter established clinical practice. The RapidRecs executive team and editors at The BMJ choose which clinical questions to pursue among the identified potentially-practice changing evidence, based on relevance to a wide audience, widespread interest, and likelihood to change practice. 3. We incorporate the evidence into the existing body of evidence and broader context of clinical practice via:

## Process overview
- A rapid and high-quality systematic review and meta-analysis on the benefits and harms with a focus on the outcomes that matter to patients
- Parallel rapid recommendations that meet the standards for trustworthy guidelines 1 by an international panel of people with relevant lived experience, front-line clinicians, clinical content experts, and methodologists.
- The systematic review and the recommendation panel will apply standards for trustworthy guidelines. 1,2 They use the GRADE approach, which has developed a transparent process to rate the quality (or certainty) of evidence and grade the strength of recommendations. - Further research may be conducted including:
Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group
- A systematic review of observational studies to identify baseline risk estimates that most closely represent the population at the heart of the clinical question, a key component when calculating the estimates of absolute effects of the intervention.
- A systematic review on the preferences and values of patients on the topic.

## Disseminate the rapid recommendations through: - publication of the research in bmj journals - short summary of recommendations for clinicians published in the bmj
- Press release and/or marketing to media outlets and relevant parties such as patient groups - Links to BMJ group's Best Practice point of care resource - MAGICapp which provides recommendations and all underlying content in digitally structured multilayered formats for clinicians and others who wish to re-examine or consider national or local adaptation of the recommendations.

## Who is involved?
Researchers, systematic review and guideline authors, clinicians, and patients often work in silos. Academic journals may publish work from any one or combinations of these groups of people and findings may also be published in the media. But it is rare that these groups work together to produce a comprehensive package. BMJ-RapidRecs circumvents organisational barriers in order to provide clinicians with guidance for potentially practice-changing evidence.
Our collaboration involves: 1. The RapidRecs group with a designated Executive team responsible for recruiting and coordinating the network of researchers who perform the systematic reviews and the recommendation panels.. The RapidRecs group is part of MAGIC (www.magicproject.org), a non for profit organization that provides MAGICapp (www.magicapp.org) an authoring and publication platform for evidence summaries, guidelines and decision aids, which are disseminated online for all devices. 2. The BMJ helps identifiying practice-changing evidence on key clinical questions, coordinates the editorial process and publishes the package of content linking to the MAGICapp that is presented in a user-friendly way.

## Methods for the rapid recommendations
The formation of these recommendations adheres to standards for trustworthy guidelines with an emphasis on patient involvement, strict management of conflicts of interests, as well as transparent and systematic processes for assessing the quality of evidence and for moving from evidence to recommendations. Guidance on how the panel is picked and how they contribute

## How the panel meets and works
Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group - The RapidRecs group will aim to include representation from most or every major geographic region in the world, with specific efforts made achieve gender-balance.
- We will facilitate patient and public involvement by including patient experience, via patient-representatives and systematic reviews addressing values and preferences to guide outcome choices and relative weights of each outcome, where available.
- Patient-representatives will be given priority during panel meetings and will have an explicit role in vetting the panel's judgements of values and preferences.

## Clinical practice guideline-systematic review
Intersection "CPG developers should use systematic reviews that meet standards set by the IOM. Guideline development group and systematic review team should interact regarding the scope, approach, and output of both processes."
- Each rapid recommendation will be based on one or more high-quality SRs either developed and published in parallel with our BMJ Rapid Recommendations or produced by other authors and available at the time of making the recommendaiton.
- The recommendation panel and SR teams will interact, with up to three members participating in both teams to facilitate communication and continuity in the process. - The GRADE approach will provide the framework for establishing evidence foundations and rating strength of recommendations. For each recommendation systematic and transparent assessments are made across the following key factors:

## Establishing evidence foundations for and rating strength of recommendations
- Absolute benefit and harms for all patient-important outcomes through structured evidence summaries (e.g. GRADE Summary of Findings tables) 4
- Quality of the evidence - Values and preferences of patients - Resources and other considerations (e.g. feasibility, applicability, equity)
- Each outcome will -if data are available through systematic reviews -include an effect estimate and confidence interval, with a measure of certainty in the evidence, as presented in Summary of Findings tables. If such data are not available narrative summaries will be provided.
- A summary of the underlying reasoning and all additional information (e.g. key factors, practical advice, references) will be available online in an interactive format at www.magicapp.org. This summary will include descriptions of how theory (e.g. pathophysiology) and clinical experience played into the evidence assessment and recommendation development.
- Recommendations will be rated either weak or strong, as defined by GRADE. [bib_ref] GRADE guidelines: 15. Going from evidence to recommendation-determinants of a recommendation's direction..., Andrews [/bib_ref] - If the panel members disagree regarding evidence assessment or strength of recommendations, we will follow a structured consensus proce customized to the GRADE system and report any final differences in opinion, with their rationale, in the online supplement and online at www.magicapp.org.

## Articulation of recommendations "recommendations should be articulated in a standardized form detailing precisely what the recommended action is, and under what circumstances it should be performed, and so that compliance with the recommendation(s) can be evaluated."
- Each recommendation will appear at the top of the guideline infographic, published in The BMJ, and will be available in standardised formats
MAGICapp, articulated to be actionable based on best current evidence on presentation formats of guidelines. [bib_ref] Development of a novel, multilayered presentation format for clinical practice guidelines, Kristiansen [/bib_ref] - There will be a statement included in each summary article in The BMJ and in the MAGICapp that these are recommendations to provide clinicians with guidance. They do not form a mandate of action and should be contextualised in the healthcare system a clinician's works in, and with an individual patient.

## 7.
External review "External reviewers should comprise a full spectrum of relevant stakeholders...., authorship should be kept confidential....., all reviewer comments Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy for management of cryptogenic stroke -WikiRecs group should be considered....a rationale for modifying or not should be recorded in writing.... a draft of the recommendation should be made available t general public for comment..."
- At least two external peer-reviewers and one patient reviewer will review the article for The BMJ and provide open peer review. Each will have access to all the information in the package. They will be asked for general feedback as well as to make an overall judgement on whether they view the guidelines as trustworthy.
- A BMJ series adviser with methodological and/or statistical expertise will review the BMJ Rapid Recommendations publication and the systematic reviews.
- The RapidRecs panel will be asked to read and respond to the peer review comments and make amendments where they judge reasonable.
- The BMJ and RapidRecs executive team may, on a case-by-case basis, choose to invite key organizations, agencies, or patient/public representatives to provide and submit public peer-review. - There will be post-publication public review process through which people can provide comments and feedback through MAGICapp (or through The BMJ). The Chair will, on behalf of panel authors, aim to respond to each publicly-available peer-review within 30 days, for a period o six months after publication.

## Updating
"The date for publication, systematic review and proposed date for future review should be documented, the literature should be monitored regularly and the recommendation should be updated when warranted by new evidence."
- The RapidRecs panel will, through monitoring of new research evidence for published BMJ Rapid Recommendations, aim to provide updates the recommendations in situations in which the evidence suggests a change in practice. These updates will be initially performed in MAGICapp and submitted to The BMJ for consideration of publication of a new Rapid Recommendation.
[fig] 1: On a daily basis, we monitor the literature for practice-changing evidence:  Formal monitoring through McMaster Premium LiteratUre Service (PLUS)  Informal monitoring the literature by BMJ Rapid Recommendations expert groups, including clinician specialists and patients 2. [/fig]
[fig] ": For each recommendation: explain underlying reasoning, including a clear description of potential benefits and harms, a summary of relevant available evidence and description of the quality., explain the part played by values, opinion, theory, and clinical experience in deriving the recommendation, provide rating of strength of recommendations. [/fig]