Objectives : Concerns regarding the real efficacy of transcatheter patent foramen ovale (PFO) closure versus medical therapy in patients with cryptogenic stroke remained unresolved. We performed a meta-analysis using the randomized controlled trials on the efficacy and safety of transcatheter PFO closure in patients with cryptogenic stroke. Methods : Web of Science, EMBASE, PubMed, and the Cochrane Library were searched for relevant randomized controlled trials (RCTs). The primary outcome was recurrent stroke and transient-ischemic attack (TIA). Original data, hazard ratio (HR) with 95% confidence interval (95% CI) were abstracted to calculate a pooled effect size. Results: Our meta-analysis showed benefit with device closure when compared with medical therapy with an HR of 0.54 (95% CI: 0.39 - 0.74, P = 0.108) in the intention-to-treat cohort, 0.44 (95% CI: 0.24 - 0.82, P = 0.103) in the per-protocol populations, and 0.43 (95% CI: 0.31 - 0.60, P = 0.019 ) in the as-treated populations. There was a significantly higher incidence of new-onset atrial fibrillation in PFO closure patients (OR = 4.53, 95% CI: 2.58 - 7.97, P = 0.094). PFO Patients with an atrial septal aneurysm benefit from device closure (OR = 0.39, 95% CI: 0.22 - 0.69, P = 0.053). Patients with a substantial PFO shunt benefit the greatest with device closure with a pooled OR of 0.27 (95% CI: 0.14 - 0.56, P = 0.525). Conclusions: The meta-analysis concluded that PFO closure was associated with significantly lower risk of recurrent stroke in PFO patients with cryptogenic stroke than with medical therapy alone. The benefit of PFO closure was greater in patients with a substantial shunt and atrial septal aneurysm. PFO closure was associated with higher rates of new-onset atrial fibrillation.
The patent foramen ovale (PFO) is a critical communication of the normal fetal circulation; however, it continues to remain patent after birth in up to 25% of adults [
We performed a systematic literature search of PubMed, Embase, Web of Science, and Cochrane Library from inception to October 4, 2017. The meta-analysis was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [
A study was included in the meta-analysis if it met the following criteria: 1) Original studies reported the population of PFO patients with cryptogenic stroke/TIA; 2) Study results focused on comparison of medical therapy versus transcatheter PFO closure in patients with cryptogenic stroke; and 3) The design of clinical trial is based on randomized controlled trial. Two experience reviewers independently performed the data extraction according to a pre-defined data extraction form and any disagreements were resolved by discussion among all authors. Extracted data included the following: first author’s name, study acronym, year of study, the total sample size, the place of study, type of medical therapy or device used, hazard ratio and 95% confidence intervals in each study of stroke/TIA, primary endpoint, and secondary endpoint.
The primary outcome was a composite of recurrent stroke, TIA or adverse event, including new-onset atrial fibrillation, major bleeding episode, during the follow up period. Sub-group analysis was performed with respect to the Amplatzer occluder device alone, atrial septal aneurysm, and shunt size. All investigators independently evaluated methodological quality of the included studies using the Cochrane Collaboration’s tool of risk of bias for RCTs [
All statistical analyses were carried out with Stata version 11.0 software (StataCorp, College Station, TX). Hazard Ratio (HR) or Odds Ratio (OR) with 95% confidence interval (95% CI) was used to estimate the effect sizes. I-squared (I2) statistical tests were used to explore the statistical heterogeneity among studies. There was no statistical heterogeneity when I2 < 50%, and a fixed-effects model was used; otherwise, statistical heterogeneity was existed, and a random-effects model was adopted [
Our literature search initially yielded 117 citations. After removing the duplicates records and further screening the titles and the abstracts, 32 papers remained for full text evaluation. 26 of them were excluded by reading full texts. Finally, 6 RCTs were included in this meta-analysis (
A total of 4370 PFO patients with a prior history of cryptogenic stroke were randomized divided into device closure group (2278 participants) and medical therapy group (2092 participants). The meta-analysis found that device closure was superior to medical treatment in the prevention of strokes and/or TIA in PFO patients according to intention to treat population (HR = 0.54, 95% CI: 0.39 - 0.74, I2 = 44.7%, P = 0.108). The pooled HR was 0.52 (95% CI: 0.35 - 0.77, I2 =
First author | Study acronym | Publication year | Country | Participants | Follow-up | HR (95% CI) | Device closure | Medical therapy | Primary endpoint | Secondary endpoint |
---|---|---|---|---|---|---|---|---|---|---|
Carroll et al. | RESPECT | 2013 | USA and Canada | 980 | 2.6 ± 2.0 years | 0.49 (0.22 - 1.11) | Amplatzer PFO Occluder | Aspirin, warfarin, clopidogrel, aspirin with dipyridamole, or aspirin with clopidogrel | Recurrence of fatal or nonfatal ischemic stroke, all-cause mortality | Complete closure rate, absence of recurrent cryptogenic, nonfatal TIA/stroke or cardiovascular death |
Meier et al. | PC | 2013 | Europe, Canada, Brazil, and Australia | 414 | 4.1 years in the closure group and 4.0 years in the medical-therapy group | 0.63 (0.24 - 1.62) | Amplatzer PFO Occluder | Antiplatelet therapy or oral anticoagulation | Nonfatal stroke, TIA, peripheral embolism, and all-cause mortality | Cardiovascular death, new arrhythmias, myocardial infarction, device-related problems, and bleeding |
Furlan et al. | CLOSURE I | 2012 | USA and Canada | 909 | 2 years | 0.78 (0.45 - 1.35) | STARFlex septal closure system | Warfarin, aspirin or both | Stroke or TIA, all-cause mortality, and death from neurologic causes | Major bleeding, death from any cause, stroke, TIA, and transient neurologic events of uncertain cause |
Mas et al. | CLOSE | 2017 | France and Germany | 663 | 5.3 ± 2.0 years | 0.55 (0.31 - 0.999) | Eleven different devices | aspirin, clopidogrel, or aspirin with dipyridamole | Recurrence of fatal or nonfatal stroke | Ischemic stroke, TIA systemic embolism, disabling stroke; ischemic stroke, all-cause mortality, cardiovascular death |
Saver et al. | RESPECT | 2017 | USA and Canada | 980 | Median of 5.9 years | 0.23 (0.09 - 0.62) | Amplatzer PFO Occluder | Aspirin, warfarin, clopidogrel, or aspirin combined with dipyridamole | Recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death | Absence of recurrent cryptogenic, early cardiovascular death, absence of transient ischemic attack |
Søndergaard et al. | Gore REDUCE | 2017 | Canada, Denmark, Finland, Norway, Sweden, the UK, and the US | 664 | Median of 3.2 years | 0.03 (0 - 0.26) | Helex Septal Occluder and Cardioform Septal Occluder | Aspirin, aspirin with dipyridamole, clopidogrel, or clopidogrel | Recurrent ischemic stroke, all-cause mortality | New brain infarction, success of PFO closure |
HR = hazard ratio; TIA = transient-ischemic attack; PFO = patent foramen ovale; RESPECT = randomized evaluation of recurrent stroke comparing PFO closure to established current standard of care treatment; PC Trial = clinical trial comparing percutaneous closure of patent foramen ovale (PFO) using the Amplatzer PFO occluder with medical treatment in patients with cryptogenic embolism; CLOSURE I = evaluation of the STARFlex septal closure system in patients with a stroke and/or transient ischemic attack due to presumed paradoxical embolism through a patent foramen ovale; CLOSE = patent foramen ovale closure or anticoagulants versus antiplatelet therapy to prevent stroke recurrence; Gore REDUCE = comparing antiplatelet medical management plus percutaneous patent foramen ovale device closure to antiplatelet medical management alone.
Study | Sequence generation | Allocation concealment | Blinding of participants and personnel and outcome assessors | Incomplete outcome data | Selective outcome reporting | Other sources of bias |
---|---|---|---|---|---|---|
Carroll et al. 2013 | Low | Low | Highb | Highc | Low | Uncertaind |
Meier et al. 2013 | Low | Low | Highb | Highc | Low | Uncertaind |
Furlan et al. 2012 | Low | Low | Highb | Highc | Low | Uncertaind |
Saver et al. 2017 | Low | Low | Highb | Highc | Low | Uncertaind |
Søndergaard et al. 2017 | Low | Low | Highb | Low | Low | Uncertaind |
Mas et al. 2017 | Low | Low | Highb | Highc | Low | Uncertaind |
aEach study has been evaluated as being “High”, “Low”, or “Unclear” according to the Cochrane Collaboration’s tool of risk of bias for RCTs. “Low” indicates a study with “Low Risk of Bias”; “High” indicates “High Risk of Bias”; “Unclear” indicates “Unclear Risk of Bias”. bUn-blinded, open-labeled. cDrop-off rate > 10%. dConflict of interest, financial supports.
48.0%, P = 0.103) using the per-protocol population and was 0.43 (95% CI: 0.31 - 0.60, I2 = 69.9%, P = 0.019) using the as-treated population, which also presenting a beneficial effect of device closure (
New-onset atrial fibrillation/flutter (AF) was observed in 78 of 2282 patients treated with the device closure and in 15 of 2088 patients treated with standard medical therapy. The risk of new-set AF was higher in the device closure group when compared with medical therapy (pooled OR = 4.53, 95% CI: 2.58 - 7.97, I2 = 46.8%, P = 0.094) (
We conducted subgroup analyses to assess whether “high-risk PFO” patients benefited from device closure when compared with medical therapy. Four studies reported substantial right-to-left shunt (RLS) both in device closure group and medical therapy group [
in recurrent cryptogenic strokes (combined HR = 0.55, 95% CI = 0.36 - 0.84, I2 = 0%, P = 0.925) in the Amplatzer PFO closure group compared with medical therapy alone.
Sensitivity analysis was performed by removing a single study on the overall HR/OR at a time. The result of sensitivity analysis for total HR/OR in this meta-analysis was not affected by removing the single study which indicated the results had a good stability. To evaluate potential publication bias across six studies, Egger’s test with funnel plot asymmetry was used to identify small study effects in this study. The Result for Egger test indicated a low potential publication bias (P = 0.462).
In this update meta-analysis of six RCTs, we concluded that the PFO device closure was associated with lower risk of recurrent strokes/TIA when compared to standard medical therapy in patients with PFO and cryptogenic stroke. In pooled analyses, the meta-analysis demonstrated that transcatheter PFO device closure is superior to medical therapy in patients with a substantial shunt and patients with PFO concomitant with an atrial septal aneurysm for secondary prevention of cryptogenic stroke. The pooled results also demonstrated a benefit effect of Amplatzer PFO device closure in preventing recurrent strokes in PFO patients with cryptogenic stroke.
Previous three randomized controlled trials failed to show the superiority of device closure over standard medical therapy in the prevention of recurrence cryptogenic stroke in patients with PFO [
Two recently completed pivotal randomized controlled trials also demonstrated reduced a risk of recurrent stroke after PFO device closure when compared to medical therapy in patients with cryptogenic stroke [
The study concluded that transcatheter device closure is superior to medical therapy for secondary prevention of stroke in patients with cryptogenic stroke and a PFO. However, in fact, current guidelines from the American Heart Association do not disapprove PFO device closure in prevention of cryptogenic stroke or TIA only when a deep venous thrombosis is confirmed [
Our meta-analysis of six randomized studies indicates that PFO device closure is associated with significantly lower risk of recurrent stroke in patients with cryptogenic stroke and PFO when compared with medical treatment alone. The benefit of device closure is greater in patients with a large degree of shunt and atrial septal aneurysm. However, the incidence of new-onset atrial fibrillation is relatively high as indicated by this study.
No financial assistance was required for this study.
Yajuan Du conceived and designed the study; Xiaohui Luo collected the data; Hui Shao and Dandan Yan analyzed the data; Yajuan Du and Xiaohui Luo contributed to the writing of the manuscript.
We declare no conflicts of interest.
Luo, X.H., Yan, D.D., Shao, H. and Du, Y.J. (2018) Percutaneous Patent Foramen Ovale Closure versus Medical Therapy in Cryptogenic Stroke: An Update Meta-Analysis of Randomized Controlled Trials. World Journal of Cardiovascular Diseases, 8, 411-423. http://dx.doi.org/10.4236/wjcd.2018.88040