Closure or Medical Therapy for Cryptogenic Stroke with Patent Foramen Ovale

Furlan, Anthony J.; Reisman, Mark; Massaro, Joseph M.; Mauri, Laura; Adams, Harold P.; Albers, Gregory W.; Felberg, Robert A.; Herrmann, Howard C.; Kar, Saibal; Landzberg, Michael J.; Raizner, Albert E.; Wechsler, Lawrence R.

doi:10.1056/nejmoa1009639

Cited by 914 publications

(724 citation statements)

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“…We identified 9 articles reporting the results of 8 different RCTs meeting the inclusion criteria 7, 8, 9, 10, 11, 12, 30, 31. Four studies (CLOSURE I,7 PC trial,8 RESPECT,10 and DEFENSE‐PFO13) compared PFO closure with antithrombotic therapy (oral anticoagulation or antiplatelet therapy at the discretion of the investigator). Two studies (Gore REDUCE11 and CLOSE12) compared PFO closure with antiplatelet therapy.…”

Section: Resultsmentioning

confidence: 99%

“…The meta‐analysis of PFO closure versus antithrombotic therapy comprised a total of 3560 patients from 6 studies 7, 8, 10, 11, 12, 13. Key features of the design of included trials are summarized in Table.…”

Section: Resultsmentioning

confidence: 99%

“…The upper age limit for enrollment was 60 years in all trials except DEFENSE‐PFO, and median follow‐up duration ranged from 2 to 5.9 years (Table S2). Three trials (PC Trial,8 RESPECT,10 and DEFENSE‐PFO13) used the Amplatzer occluder device, the CLOSURE I study used the Starflex device,7 the Gore REDUCE study used the Cardioform or Helex device,11 and choice of the device was left to the discretion of the investigator in the CLOSE trial 12. For this analysis, the comparator was the one used in the design of each study: antiplatelet therapy or/and anticoagulation at the discretion of the investigator in CLOSURE I, PC Trial, RESPECT, and DEFENSE‐PFO; antiplatelet therapy in CLOSE and Gore REDUCE.…”

Section: Resultsmentioning

confidence: 99%

“…In the trial sequential analysis (Figure 2), the cumulative Z score curve crossed the monitoring boundary, suggesting a “true‐positive” result regarding the superiority of PFO closure over medical therapy (Figure S1). 26 The HR for stroke recurrence was provided in 5 out of 6 RCTs (pooled HR 0.40, 95% CI, 0.20–0.82, P =0.01; I 2 =54%; Figure 1B) 7, 8, 10, 11, 12. The random‐effects pooled incidence of stroke recurrence per 100 person‐years was 0.29 (95% CI, 0.02–0.76; I 2 =83%) in the PFO closure group (Figure S4) and 1.27 (95% CI, 0.84–1.78; I 2 =53%) in the antithrombotic therapy group (Figure S5).…”

Section: Resultsmentioning

confidence: 99%

“…Observational studies have demonstrated a strong association between patent foramen ovale (PFO) and cryptogenic stroke,3, 4 suggesting that paradoxical embolism through a PFO may be an important cause of otherwise unexplained ischemic strokes, notably in younger patients 5, 6. Three randomized controlled trials (RCTs) published in 2012 and 2013 (CLOSURE I (STARFlex Septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale),7 PC Trial (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism),8 and RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment)9) failed to demonstrate the superiority of PFO closure over antithrombotic therapy (antiplatelet therapy or anticoagulants) to prevent recurrent stroke. Recently, the long‐term analysis of the RESPECT trial10 and 3 other RCTs (Gore REDUCE (Gore Helex septal occluder and antiplatelet medical management for reduction of recurrent stroke or imaging‐confirmed transient ischemic attack in patients with patent foramen ovale),11 CLOSE (Patent Foramen Ovale Closure or Anticoagulants versus Antiplatelet Therapy to Prevent Stroke Recurrence),12 and DEFENSE‐PFO (Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High Risk Patent Foramen Ovale)13) reported a lower incidence rate of recurrent stroke in patients randomized to PFO closure compared with controls.…”

Section: Introductionmentioning

confidence: 99%

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Closure, Anticoagulation, or Antiplatelet Therapy for Cryptogenic Stroke With Patent Foramen Ovale: Systematic Review of Randomized Trials, Sequential Meta‐Analysis, and New Insights From the CLOSE Study

Turc

Calvet

Guérin

et al. 2018

JAHA

123

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BackgroundWe conducted a systematic review and meta‐analysis of randomized controlled trials (RCTs) comparing patent foramen ovale (PFO) closure, anticoagulation, and antiplatelet therapy to prevent stroke recurrence in patients with PFO‐associated cryptogenic stroke.Methods and ResultsWe searched Medline, Cochrane Library, and EMBASE through March 2018. The primary outcome was stroke recurrence. Pooled incidences, hazard ratios, and risk ratios (RRs) were calculated in random‐effects meta‐analyses. PFO closure was associated with a lower risk of recurrent stroke compared with antithrombotic therapy (antiplatelet therapy or anticoagulation: 3560 patients from 6 RCTs; RR=0.36, 95% CI: 0.17–0.79; I2=59%). The effect of PFO closure on stroke recurrence was larger in patients with atrial septal aneurysm or large shunt (RR=0.27, 95% CI, 0.11–0.70; I2=42%) compared with patients without these anatomical features (RR=0.80, 95% CI, 0.43–1.47; I2=12%). Major complications occurred in 2.40% (95% CI, 1.03–4.25; I2=77%) of procedures. New‐onset atrial fibrillation was more frequent in patients randomized to PFO closure versus antithrombotic therapy (RR=4.33, 95% CI, 2.37–7.89; I2=14%). One RCT compared PFO closure versus anticoagulation (353 patients; hazard ratio=0.14, 95% CI, 0.00–1.45) and 2 RCTs compared PFO closure versus antiplatelet therapy (1137 patients; hazard ratio=0.18, 95% CI, 0.05–0.63; I2=12%). Three RCTs compared anticoagulation versus antiplatelet therapy, with none showing a significant difference.Conclusions PFO closure is superior to antithrombotic therapy to prevent stroke recurrence after cryptogenic stroke. The annual absolute risk reduction of stroke was low, but it has to be tempered by a substantial time at risk (at least 5 years) in young and middle‐aged patients. PFO closure was associated with an increased risk of atrial fibrillation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Closure, Anticoagulation, or Antiplatelet Therapy for Cryptogenic Stroke With Patent Foramen Ovale: Systematic Review of Randomized Trials, Sequential Meta‐Analysis, and New Insights From the CLOSE Study

Turc

Calvet

Guérin

et al. 2018

JAHA

123

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Is Patent Foramen Ovale a Risk Factor for Perioperative Stroke?

Kasner

Messé

2018

JAMA

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Heterogeneity of Treatment Effects in an Analysis of Pooled Individual Patient Data From Randomized Trials of Device Closure of Patent Foramen Ovale After Stroke

Kent

Saver

Kasner

et al. 2021

JAMA

Self Cite

103

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IMPORTANCEPatent foramen ovale (PFO)-associated strokes comprise approximately 10% of ischemic strokes in adults aged 18 to 60 years. While device closure decreases stroke recurrence risk overall, the best treatment for any individual is often unclear.OBJECTIVE To evaluate heterogeneity of treatment effect of PFO closure on stroke recurrence based on previously developed scoring systems.DESIGN, SETTING, AND PARTICIPANTS Investigators for the Systematic, Collaborative, PFO Closure Evaluation (SCOPE) Consortium pooled individual patient data from all 6 randomized clinical trials that compared PFO closure plus medical therapy vs medical therapy alone in patients with PFO-associated stroke, and included a total of 3740 participants. The trials were conducted worldwide from 2000 to 2017.EXPOSURES PFO closure plus medical therapy vs medical therapy alone. Subgroup analyses used the Risk of Paradoxical Embolism (RoPE) Score (a 10-point scoring system in which higher scores reflect younger age and the absence of vascular risk factors) and the PFO-Associated Stroke Causal Likelihood (PASCAL) Classification System, which combines the RoPE Score with high-risk PFO features (either an atrial septal aneurysm or a large-sized shunt) to classify patients into 3 categories of causal relatedness: unlikely, possible, and probable. MAIN OUTCOMES AND MEASURES Ischemic stroke.RESULTS Over a median follow-up of 57 months (IQR, 24-64), 121 outcomes occurred in 3740 patients. The annualized incidence of stroke with medical therapy was 1.09% (95% CI, 0.88%-1.36%) and with device closure was 0.47% (95% CI, 0.35%-0.65%) (adjusted hazard ratio [HR], 0.41 [95% CI, 0.28-0.60]). The subgroup analyses showed statistically significant interaction effects. Patients with low vs high RoPE Score had HRs of 0.61 (95% CI, 0.37-1.00) and 0.21 (95% CI, 0.11-0.42), respectively (P for interaction = .02). Patients classified as unlikely, possible, and probable using the PASCAL Classification System had HRs of 1.14 (95% CI, 0.53-2.46), 0.38 (95% CI, 0.22-0.65), and 0.10 (95% CI, 0.03-0.35), respectively (P for interaction = .003). The 2-year absolute risk reduction was −0.7% (95% CI, −4.0% to 2.6%), 2.1% (95% CI, 0.6%-3.6%), and 2.1% (95% CI, 0.9%-3.4%) in the unlikely, possible, and probable PASCAL categories, respectively. Device-associated adverse events were generally higher among patients classified as unlikely; the absolute risk increases in atrial fibrillation beyond day 45 after randomization with a device were 4.41% (95% CI, 1.02% to 7.80%), 1.53% (95% CI, 0.33% to 2.72%), and 0.65% (95% CI, −0.41% to 1.71%) in the unlikely, possible, and probable PASCAL categories, respectively.CONCLUSIONS AND RELEVANCE Among patients aged 18 to 60 years with PFO-associated stroke, risk reduction for recurrent stroke with device closure varied across groups classified by their probabilities that the stroke was causally related to the PFO. Application of this classification system has the potential to guide individualized decision-making.

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Closure or Medical Therapy for Cryptogenic Stroke with Patent Foramen Ovale

Abstract: In patients with cryptogenic stroke or TIA who had a patent foramen ovale, closure with a device did not offer a greater benefit than medical therapy alone for the prevention of recurrent stroke or TIA. (Funded by NMT Medical; ClinicalTrials.gov number, NCT00201461.).

Cited by 914 publications

References 35 publications

Closure, Anticoagulation, or Antiplatelet Therapy for Cryptogenic Stroke With Patent Foramen Ovale: Systematic Review of Randomized Trials, Sequential Meta‐Analysis, and New Insights From the CLOSE Study

Closure, Anticoagulation, or Antiplatelet Therapy for Cryptogenic Stroke With Patent Foramen Ovale: Systematic Review of Randomized Trials, Sequential Meta‐Analysis, and New Insights From the CLOSE Study

Is Patent Foramen Ovale a Risk Factor for Perioperative Stroke?

Heterogeneity of Treatment Effects in an Analysis of Pooled Individual Patient Data From Randomized Trials of Device Closure of Patent Foramen Ovale After Stroke

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