heterogeneity: p=0.64, I 2 =0%). PFO closure may be asso-ciated with six fewer TIAs over a period of 5 years (CI 15 fewer to 9 more, moderate con fi dence because of risk of bias ( fi gure 3, table 3).
Total mortality
There were seven deaths in the PFO closure arm vs 10 deaths in the medical treatment arm of the three studies (RD −0.00, 95% CI −0.01, 0.01; heterogeneity: p=0.23, I 2 =31%). None of the deaths were deemed secondary to treatment (PFO closure or antithrombotic therapy) or stroke. PFO closure may have no effect on mortality over a period of 5 years (CI 10 fewer to 10 more, low con fi -dence because of risk of bias and imprecision, table 3).
Adverse events
Pooling data from all three studies, bleeding occurred in 13 vs 7 patients in the PFO closure vs medical treatment arms (all were major bleeds except two bleeds from RESPECT study not classi fi ed) (RD 0.00, 95% CI − 0.01 to 0.02; heterogeneity p=0.12, I 2 =53%, see fi gure 4).
PFO closure may have no effect on major bleeding over a period of 5 years (CI 10 fewer to 20 more, moderate con fi dence because of risk of bias, table 3).
Atrial fi brillation occurred in 32 patients undergoing PFO closure vs 8 patients treated with medical therapy (RD 0.02, 95% − 0.02 to 0.06; heterogeneity: p<0.00001, I 2 =93%). PFO closure may be associated with 20 more cases of atrial fi brillation per 1000 treated compared with medical therapy over a period of 5 years (CI 20 fewer to 60 more, very low con fi dence because of risk of bias, inconsistency and imprecision, table 3). Of the 23 cases of atrial fi brillation reported after PFO closure in the CLOSURE I study six were deemed ‘ sustained ’—
atrial fi brillation in the medical group was not charac-terised. Of the eight cases of atrial fi brillation in the PC Trial occurring after PFO closure two were transient (in PFO closure arm) and six required cardioversion or were sustained. Atrial fi brillation was not characterised as transient or sustained in the RESPECT study.
We were unable to pool data regarding procedural or device-related complications given differences between studies in reporting styles. Serious procedural or device-related adverse events (in addition to bleeding, ischaemic stroke, atrial fi brillation which have already been captured in previous analyses) were reported in 15 patients in the RESPECT trial (3%). This included eight
procedural-related events. Major vascular events procedural-related to the
proced-ure occurred in 13 of the 402 patients (3.2%) in whom
PFO closure was attempted in CLOSURE I — these
included six major bleeding episodes already captured
above. The total number of serious procedural-related
adverse events was not speci fi cally reported in the PC Trial
although it was noted that no device-related thrombi
occurred.
Int J Cardiol. 2013;169:101.
Review
PFO closure vs. medical therapy in cryptogenic stroke or transient ischemic attack: A systematic review and meta-analysis
G. Ntaiosa,⁎, V. Papavasileioua, K. Makaritsisa, P. Michelb
aDepartment of Medicine & Research Lab, University of Thessaly, Larissa, Greece
b Neurology Service, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
a b s t r a c t a r t i c l e i n f o
Article history:
Received 18 June 2013
Received in revised form 12 August 2013 Accepted 18 August 2013
Available online 28 August 2013 Keywords:
Cryptogenic stroke Paradoxical embolism Patent foramen ovale PFO closure
AMPLATZER PFO Occluder STARFlex device
Background/objectives:This study aims to assess whether patent foramen ovale (PFO) closure is superior to med-ical therapy in preventing recurrence of cryptogenic ischemic stroke or transient ischemic attack (TIA).
Methods:We searched PubMed for randomized trials which compared PFO closure with medical therapy in cryp-togenic stroke/TIA using the items:“stroke or cerebrovascular accident or TIA”and“patent foramen ovale or par-adoxical embolism”and“trial or study”.
Results:Among 650 potentially eligible articles, 3 were included including 2303 patients. There was no statistical-ly significant difference between PFO-closure and medical therapy in ischemic stroke recurrence (1.91% vs. 2.94%
respectively, OR: 0.64, 95%CI: 0.37–1.10), TIA (2.08% vs. 2.42% respectively, OR: 0.87, 95%CI: 0.50–1.51) and death (0.60% vs. 0.86% respectively, OR: 0.71, 95%CI: 0.28–1.82). In subgroup analysis, there was significant reduction of ischemic strokes in the AMPLATZER PFO Occluder arm vs. medical therapy (1.4% vs. 3.04% respectively, OR: 0.46, 95%CI: 0.21–0.98, relative-risk-reduction: 53.2%, absolute-risk-reduction: 1.6%, number-needed-to-treat: 61.8) but not in the STARFlex device (2.7% vs. 2.8% with medical therapy, OR: 0.93, 95%CI: 0.45–2.11). Compared to medical therapy, the number of patients with new-onset atrialfibrillation (AF) was similar in the AMPLATZER PFO Occluder arm (0.72% vs. 1.28% respectively, OR: 1.81, 95%CI: 0.60–5.42) but higher in the STARFlex device (0.64% vs. 5.14% respectively, OR: 8.30, 95%CI: 2.47–27.84).
Conclusions:This meta-analysis does not support PFO closure for secondary prevention with unselected devices in cryptogenic stroke/TIA. In subgroup analysis, selected closure devices may be superior to medical therapy without increasing the risk of new-onset AF, however. This observation should be confirmed in further trials using inclusion criteria for patients with high likelihood of PFO-related stroke recurrence.
© 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Stroke etiology remains undetermined after a thorough work-up (“cryptogenic”) in a significant proportion of stroke patients even after multimodal imaging[1]. Patent foramen ovale (PFO), a frequentfinding in the general population[2,3], has been suggested as a possible etiolog-ic factor whetiolog-ich may allow venous emboli to bypass the pulmonary cir-culation and reach the systemic and cerebral circir-culation, thus allowing for paradoxical embolism [4]. Closure of PFO was introduced in 1992 as a means of preventing recurrent stroke in patients with cryptogenic stroke[5]. Meta-analyses of observational studies yielded inconsistent results showing on the one hand that PFO closure could be associated with reduction in the risk of stroke recurrence, however in the expense of adverse events like new-onset atrial fibrillation, which may offset the beneficial effect of PFO closure and set the need for long-term anticoagulation therapy[6–9].
Recently, three randomized controlled trials of PFO closure vs. med-ical therapy in patients with cryptogenic stroke individually did not show any benefit in favor of PFO closure[10–12]. A possible reason for this result may be the lack of a significant treatment effect of PFO clo-sure. However, it should be noticed that the rate of outcome events in these trials was lower than the expected, rendering the trials relatively underpowered[11–13].
In this study, we aimed to assess whether the meta-analysis of all randomized controlled trials of PFO closure vs. medical therapy in pa-tients with cryptogenic stroke or TIA identifies a significant benefit of PFO closure in preventing stroke recurrence, and whether the device used for PFO occlusion modifies the overall treatment effect.
2. Methods
2.1. Search strategy and inclusion criteria
We searched MEDLINE for related articles published until 18 April 2013 in the English language. Abstracts were not considered for inclusion. The search items were“stroke or cerebrovascular accident or transient ischemic attack” (TIA) and“patent foramen ovale or PFO or paradoxical embolism” and “trial or study”. In addition, we searched the International Journal of Cardiology 169 (2013) 101–105
⁎ Corresponding author at: Department of Medicine & Research Lab, University of Thessaly, Biopolis 41110, Larissa, Greece. Tel.: + 30 2413502888; fax: + 30 2413501557.
E-mail address:[email protected](G. Ntaios).
0167-5273/$–see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijcard.2013.08.058
Contents lists available atScienceDirect
International Journal of Cardiology
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / i j c a r d
references of related letters, reviews and editorials to identify potentially eligible studies.
To be eligible for the present analysis, the studies had to be randomized controlled trials of PFO closure vs. medical therapy in patients with cryptogenic stroke or TIA. This work was performed according to the PRISMA statement[14].
2.2. Data extraction and outcomes
The extraction of the data was performed independently by two authors (GN, VP).
Studies were screened to extract the number of patients in each treatment arm, the type of PFO closure device, the length of follow-up and the number of events for each outcome (ischemic stroke recurrence, death, TIA, new-onset atrial fibrillation and myocardial infarction). In the case that data were unavailable in the articles, these were sought by di-rect contact with and authorization by the trial investigators. Any discrepancy or uncer-tainty was resolved by consensus among the authors.
The primary endpoint of this meta-analysis was recurrence of ischemic stroke. Sec-ondary endpoints included transient ischemic attack, death, new-onset atrialfibrillation, and myocardial infarction.
2.3. Statistical analysis
Data were analyzed on an intention-to-treat basis. Odds-ratios (OR) and 95% confi -dence intervals (CI) were calculated for each outcome using the Petofixed-effects meth-od; although a random-effects model provides a larger scope of inference and would be more appropriate when combining trials with different treatments, random-effects models are not statistically suitable for combining a very small number of studies. Hetero-geneity between trials was assessed by measuring inconsistency using the I2index, which measures the proportion of the variability in effect estimates that can be attributed to het-erogeneity rather than chance. I2is calculated as follows: I2= 100%×(Q−df) /Q, where Qis Cochran's heterogeneity statistic and df is the degrees of freedom. A value of 0% indi-cates no observed heterogeneity and larger values show increasing heterogeneity[15].
In the case of statistically significant associations, absolute risk reduction (ARR) or in-crease (ARI) was calculated as (ME / MS)−(IE / IS), where ME is the number of events in the medical therapy group, MS is the number of patients randomized to medical thera-py, IE is the number of events in the PFO-closure (intervention) group and IE is the number of patients randomized to PFO closure; relative risk reduction (RRR) or increase (RRI) as [(ME / MS)−(IE / IS)] / (ME / MS); and number-needed-to-treat (NNT) to prevent/
cause one event as 1 / [(ME / MS)−(IE / IS)].
All analyses were performed with the Review Manager (RevMan) version 5.1 (Copen-hagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011).
3. Results
Among 605 potentially eligible articles, 3 fulfilled our criteria and were included in the analysis (Supplemental figure) [10–12]. The main characteristics of the trials included in the analysis are summa-rized in the table.
Among 2303 patients with cryptogenic stroke or TIA and PFO in these three trials, 1153 patients were allocated to medical therapy and 1150 to PFO closure (703 with the AMPLATZER PFO Occluder and 447 with the STARFlex device). The median follow-up ranged between 2.0 and 4.1 years.
Overall, there was no statistically significant difference in the end-points of ischemic stroke recurrence (1.91% vs. 2.94%, OR: 0.64, 95%CI:
0.37–1.10) (Fig. 1), transient ischemic attack (in 2.08% of patients vs.
in 2.42% of patients, OR: 0.87, 95%CI: 0.50–1.51) (Fig. 2) and death (0.60% vs. 0.86% respectively, OR: 0.71, 95%CI: 0.28–1.82) (Fig. 3) be-tween PFO closure and medical therapy arms respectively. Heterogene-ity was not significant in the analysis of the aforementioned end-points (I2was 11%, 4% and 0% for the endpoints of ischemic stroke, death, and TIA respectively).
In the subgroup analysis, there was a significant reduction of ische-mic strokes in the AMPLATZER PFO Occluder arm vs. medical therapy [1.4% vs. 3.04% respectively, OR: 0.46, 95%CI: 0.21–0.98, RRR: 53.2%, ARR: 1.6%, NNT: 61.8, without heterogeneity between the two trials (Fig. 1)] but not in the STARFlex device (2.7% vs. 2.8% in the medical therapy arm, OR: 0.93, 95%CI: 0.45–2.11). On the contrary, there was no statistically significant difference between patients randomized to the AMPLATZER PFO Occluder or medical therapy in the end-points of TIA and death (Figs. 2 and 3).
New-onset atrialfibrillation occurred more frequently in patients in the PFO-closure arm (2.78% of patients compared to 0.69% of patients in the medical therapy arm, OR: 4.15, 95%CI: 1.91–9.02, RRI: 75.1%, ARI:
2.1%, NNT: 47.8) (Fig. 4). There was a moderate level of heterogeneity in the analysis of new-onset atrial fibrillation (I2: 56%). As shown by the subgroup analysis, the difference in new-onset atrialfibrillation tween the two treatment arms was mainly driven by the difference be-tween the STARFlex device and the medical treatment arms: patients randomized to the STARFlex device had significantly more episodes of new-onset atrial fibrillation compared to the medical treatment arm (5.14% of patients in the PFO-closure arm vs. 0.64% of patients in the medical treatment arm, OR: 8.30, 95%CI: 2.47–27.84, RRI: 87.4%, ARI:
4.5%, NNT: 22.2) (Fig. 4). There was no difference in the rate of myocar-dial infarction between the PFO-closure and the medical treatment arms (0.43% vs. 0.26% respectively, OR: 1.68, 95%CI: 0.40–7.06) (Fig. 5).
4. Discussion
In this meta-analysis, we aimed to assess whether PFO closure is su-perior to medical therapy in preventing ischemic stroke recurrences in patients with cryptogenic stroke or TIA. The results do not support PFO closure with unselected devices for this purpose. These neutral re-sults were also found for other outcomes such as recurrence of any stroke, transient ischemic attack, and death. Explanations include low event rate, insufficient sample size, short follow-up, inappropriate
Fig. 1.Forest plot of the effects of PFO closure vs. medical therapy on ischemic stroke recurrence in patients with cryptogenic stroke and PFO. Two subgroups were analyzed according to the device used for PFO closure.
102 G. Ntaios et al. / International Journal of Cardiology 169 (2013) 101–105
-
①−③のRCTに関する２つ目のメタ解析⑤の
stroke
の発症率についての図．- PC trial
とRESCPECT trial
は、Amplatzer
というデバイスを用いている．- CLOSURE I trial
は、STARFLEX
というデバイスを用いている．-
前者２つのRCTの感度分析でPFO閉鎖術の再発予防効果あり（有意差あり．
※この
Amplatzer device
の優位性は、デバイスの種類による脳梗塞再発効果を検証した他のRCT
(Eur Heart Journal 2013;34:3362)
でも再現されている．Int J Cardiol. 2013;169:101.
may have different efficacy and safety profiles (as implied by the differ-ence in the endpoint of new-onset atrialfibrillation); we tried to over-come this by performing subgroup analyses according to the device used in each trial. Moreover, the primary endpoints were different across trials; we chose the recurrence of ischemic stroke as the primary endpoint in this meta-analysis as it is perhaps the clinically most rele-vant in this patient group. Also, there was a different rate of drop-outs between groups, which resulted in unequal exposure to the risk of stroke recurrence[10,13]. Furthermore, referral for adjudication of end-points was not blinded[13]. Also, high-risk patients with cryptogenic stroke were preferentially treated by PFO closure outside the trial which may have led to underrepresentation of these patients in the trial and hence, entry and retention biases [10,11,23,24]. Finally, we did not have individual patient data available to perform the overall and subgroup analyses, and could therefore not analyze the influence of the type of antithrombotic treatment that patients were receiving in the medical arms. A previous meta-analysis of nine randomized and non-randomized trials indeed suggested that oral anticoagulation may be a more effective secondary prevention than antiplatelet therapy[8].
Similarly, a subgroup analysis in RESPECT found PFO closure to be supe-rior to antiplatelet but not anticoagulant treatment[10].
Similar meta-analyses of PFO closure vs. medical therapy were recent-ly published with somewhat different results. The differences in reported results can be attributed to the statistical methodology used e.g.fixed vs.
random effects model, intention-to-treat vs. per-protocol analysis, and selection of end-points. Strengths of the present meta-analysis include that ARR, ARI and NNT are reported for significant associations, that it was performed according to the PRISMA guidelines [14], that it was performed on an intention-to-treat basis, and that subgroup analyses were also performed according to the device used for PFO closure.
Ongoing PFO-closure trials (like the REDUCE[25]and CLOSE[26] tri-als) and registries (like the RoPE study[27]), along with meta-analyses of pooled individual patient data from the CLOSURE-I, RESPECT and PC trials may provide further insight into the controversial issue of PFO clo-sure in patients with cryptogenic stroke or TIA and guide clinicians to the proper selection of patients who may benefit.
In conclusion, our meta-analysis does not support PFO closure for secondary prevention with unselected devices in patients with crypto-genic stroke or TIA. In the subgroup analysis, PFO closure using the AMPLATZER-PFO Occluder was superior to medical therapy without in-creasing the risk of new-onset atrialfibrillation, but thisfinding needs to be further confirmed before it can be incorporated in clinical practice.
Fig. 4.Forest plot of the effects of PFO closure vs. medical therapy on new-onset atrialfibrillation in patients with cryptogenic stroke and PFO. Two subgroups were analyzed according to the device used for PFO closure.
Fig. 5.Forest plot of the effects of PFO closure vs. medical therapy on myocardial infarction in patients with cryptogenic stroke and PFO. Two subgroups were analyzed according to the device used for PFO closure.
104 G. Ntaios et al. / International Journal of Cardiology 169 (2013) 101–105
- 同じく2つ目のメタ解析⑤．
- PFO 閉鎖術後の新規心房細動発症率に関する図．
- PFO 閉鎖術後、新規心房細動の発症が多くなることが示されている．
Review
PFO closure vs. medical therapy in cryptogenic stroke or transient ischemic attack: A systematic review and meta-analysis
G. Ntaiosa,⁎, V. Papavasileioua, K. Makaritsisa, P. Michelb
aDepartment of Medicine & Research Lab, University of Thessaly, Larissa, Greece
b Neurology Service, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
a b s t r a c t a r t i c l e i n f o
Article history:
Received 18 June 2013
Received in revised form 12 August 2013 Accepted 18 August 2013
Available online 28 August 2013 Keywords:
Cryptogenic stroke Paradoxical embolism Patent foramen ovale PFO closure
AMPLATZER PFO Occluder STARFlex device
Background/objectives:This study aims to assess whether patent foramen ovale (PFO) closure is superior to med-ical therapy in preventing recurrence of cryptogenic ischemic stroke or transient ischemic attack (TIA).
Methods:We searched PubMed for randomized trials which compared PFO closure with medical therapy in cryp-togenic stroke/TIA using the items:“stroke or cerebrovascular accident or TIA”and“patent foramen ovale or par-adoxical embolism”and“trial or study”.
Results:Among 650 potentially eligible articles, 3 were included including 2303 patients. There was no statistical-ly significant difference between PFO-closure and medical therapy in ischemic stroke recurrence (1.91% vs. 2.94%
respectively, OR: 0.64, 95%CI: 0.37–1.10), TIA (2.08% vs. 2.42% respectively, OR: 0.87, 95%CI: 0.50–1.51) and death (0.60% vs. 0.86% respectively, OR: 0.71, 95%CI: 0.28–1.82). In subgroup analysis, there was significant reduction of ischemic strokes in the AMPLATZER PFO Occluder arm vs. medical therapy (1.4% vs. 3.04% respectively, OR: 0.46, 95%CI: 0.21–0.98, relative-risk-reduction: 53.2%, absolute-risk-reduction: 1.6%, number-needed-to-treat: 61.8) but not in the STARFlex device (2.7% vs. 2.8% with medical therapy, OR: 0.93, 95%CI: 0.45–2.11). Compared to medical therapy, the number of patients with new-onset atrialfibrillation (AF) was similar in the AMPLATZER PFO Occluder arm (0.72% vs. 1.28% respectively, OR: 1.81, 95%CI: 0.60–5.42) but higher in the STARFlex device (0.64% vs. 5.14% respectively, OR: 8.30, 95%CI: 2.47–27.84).
Conclusions:This meta-analysis does not support PFO closure for secondary prevention with unselected devices in cryptogenic stroke/TIA. In subgroup analysis, selected closure devices may be superior to medical therapy without increasing the risk of new-onset AF, however. This observation should be confirmed in further trials using inclusion criteria for patients with high likelihood of PFO-related stroke recurrence.
© 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Stroke etiology remains undetermined after a thorough work-up (“cryptogenic”) in a significant proportion of stroke patients even after multimodal imaging[1]. Patent foramen ovale (PFO), a frequentfinding in the general population[2,3], has been suggested as a possible etiolog-ic factor whetiolog-ich may allow venous emboli to bypass the pulmonary cir-culation and reach the systemic and cerebral circir-culation, thus allowing for paradoxical embolism [4]. Closure of PFO was introduced in 1992 as a means of preventing recurrent stroke in patients with cryptogenic stroke[5]. Meta-analyses of observational studies yielded inconsistent results showing on the one hand that PFO closure could be associated with reduction in the risk of stroke recurrence, however in the expense of adverse events like new-onset atrial fibrillation, which may offset the beneficial effect of PFO closure and set the need for long-term anticoagulation therapy[6–9].
Recently, three randomized controlled trials of PFO closure vs. med-ical therapy in patients with cryptogenic stroke individually did not show any benefit in favor of PFO closure[10–12]. A possible reason for this result may be the lack of a significant treatment effect of PFO clo-sure. However, it should be noticed that the rate of outcome events in these trials was lower than the expected, rendering the trials relatively underpowered[11–13].
In this study, we aimed to assess whether the meta-analysis of all randomized controlled trials of PFO closure vs. medical therapy in pa-tients with cryptogenic stroke or TIA identifies a significant benefit of PFO closure in preventing stroke recurrence, and whether the device used for PFO occlusion modifies the overall treatment effect.
2. Methods
2.1. Search strategy and inclusion criteria
We searched MEDLINE for related articles published until 18 April 2013 in the English language. Abstracts were not considered for inclusion. The search items were“stroke or cerebrovascular accident or transient ischemic attack” (TIA) and“patent foramen ovale or PFO or paradoxical embolism” and “trial or study”. In addition, we searched the International Journal of Cardiology 169 (2013) 101–105
⁎ Corresponding author at: Department of Medicine & Research Lab, University of Thessaly, Biopolis 41110, Larissa, Greece. Tel.: + 30 2413502888; fax: + 30 2413501557.
E-mail address:[email protected](G. Ntaios).
0167-5273/$–see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijcard.2013.08.058
Contents lists available atScienceDirect
International Journal of Cardiology
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / i j c a r d
JACC Cardiovas Interven. 2013;6:1316.
-
①−③の
RCT
の３つ目のメタ解析⑥．-
脳梗塞再発率に関する図．
- ITT
解析とPer Protocol Analysis
のメタ解析が別個にされている．- ITT
解析を集めた感度分析ではギリギリ有意差がない．- PPA
を集めた感度分析ではPFO
閉鎖術で再発が少ない（有意差あり．Device Closure of Patent Foramen Ovale
Versus Medical Therapy in Cryptogenic Stroke
A Systematic Review and Meta-Analysis
Abdur R. Khan, MD,* Aref A. Bin Abdulhak, MD,y Mujeeb A. Sheikh, MD,*
Sobia Khan, MBBS,* Patricia J. Erwin, MLS,z Imad Tleyjeh, MD,xjj{ Sadik Khuder, PHD,#
Ehab A. Eltahawy, MD*
Toledo, Ohio; Kansas City, Missouri; Rochester, Minnesota; and Riyadh, Kingdom of Saudi Arabia
Objectives This study sought to perform a meta-analysis of randomized controlled trials comparing device closure with medical therapy in the prevention of recurrent neurological events in patients with cryptogenic stroke and patent foramen ovale.
Background The optimal strategy for secondary prevention of cryptogenic stroke with a patent foramen ovale is unclear.
Methods Several databases were searched from their inception to March 2013, which yielded 3 eligible studies. The results were pooled as per the different patient populations defined in the studies:dintention-to-treat, per-protocol, and as-treated cohorts. A generic inverse method was used based on time-to-event outcomes in afixed-effect model. A supplementary analysis pooled the results from only 2 trials (RESPECT [Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment] and PC Trial [Randomized Clinical Trial Comparing the Efficacy of Percutaneous Closure of Patent Foramen Ovale (PFO) With Medical Treatment in Patients With Cryptogenic Embolism]) as a similar device was used in them.
Results Our meta-analysis yielded effect-estimate hazard ratios of 0.67 (95% confidence interval [CI]:
0.44 to 1.00, I2 ¼ 0%) in the intention-to-treat cohort, 0.62 (95% CI: 0.40 to 0.95). I2 ¼ 0%) in the per-protocol cohort, and 0.61 (95% CI: 0.40 to 0.95, I2 ¼ 38%) in the as-treated cohort, showing beneficial effects of device closure. The results became more robust with pooled results from RESPECT and the PC Trial: The effect-estimate hazard ratios being 0.54 (95% CI: 0.29 to 1.01, I2 ¼ 0%), 0.48 (95% CI: 0.24 to 0.94, I2 ¼ 26%), and 0.42 (95% CI: 0.21 to 0.84, I2¼ 26%) in the intention-to-treat, per-protocol, and as-treated populations, respectively.
Conclusions Our meta-analysis suggests that PFO closure is beneficial as compared to medical therapy in the prevention of recurrent neurological events. This meta-analysis helps to further
strengthen the role of device closure in cryptogenic stroke. (J Am Coll Cardiol Intv 2013;6:1316–23) ª 2013 by the American College of Cardiology Foundation
From the *Division of Cardiovascular Medicine, Department of Internal Medicine, University of Toledo Medical Center, Toledo, Ohio;yDepartment of Internal Medicine, University of MissouridKansas City, Kansas City, Missouri; zMayo Medical Library, Mayo Clinic, Rochester, Minnesota; xDepartment of Medicine, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia;
jjDivision of Infectious Diseases, Mayo Clinic, Rochester, Minnesota; {Division of Epidemiology, Mayo Clinic, Rochester, Minnesota; and the #Department of Medicine and Public Health, University of Toledo Medical Center, Toledo, Ohio. All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Manuscript received April 16, 2013; revised manuscript received August 8, 2013, accepted August 14, 2013.
J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 6 , N O . 1 2 , 2 0 1 3
ª 2 0 1 3 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N I S S N 1 9 3 6 - 8 7 9 8 / $ 3 6 . 0 0
P U B L I S H E D B Y E L S E V I E R I N C . h t t p : / / d x . d o i . o r g / 1 0 . 1 0 1 6 / j . j c i n . 2 0 1 3 . 0 8 . 0 0 1
analyzed. If we include RESPECT and the PC Trial, using only the Amplatzer device, the bene fi t becomes more apparent, with a reduction of approximately 46% to 58%.
The safety of the device was comparable to medical therapy, with a low incidence of adverse events.
Not only did all the analyses have effect estimates in favor of device closure, the pooled results also con fi rmed a more signi fi cant bene fi cial effect. As mentioned, the trials most likely did not meet their expected outcome because of low numbers of enrolled patients, lower-than-expected event rates, and relatively short follow-up. All the reported studies had dif fi culty in enrollment. The trials were also performed in an environment of signi fi cant off-label closure (23). In addition to the total number of subjects enrolled, this likely led to a selection bias in which the enrolled population may not be representative of the groups most likely to bene fi t from PFO closure. This also may have diluted the actual bene fi cial effect of device closure in randomized patients.
Moreover, follow-up of study patients was likely too short to assess a signi fi cant difference in ef fi cacy between the 2 groups. Observational data has demonstrated that event rates in medical therapy versus device closure appeared to separate after 2 years of follow-up (10). Recently, a propensity-matched comparison cohort showed that mortality or stroke bene fi t becomes more apparent in long-term follow-up (11).
Data from RESPECT showed the same trend, with the curves continuing to diverge more after 2 years and continuing to diverge even at 5 years. The Kaplan-Meier curves in individual trials continued to diverge, suggesting that the postulated bene fi t may need more time to become signi fi cant.
Strengths of our analysis. To the best of our knowledge, this is the fi rst systematic review and meta-analysis of randomized controlled trials to compare the ef fi cacy and safety of device closure with medical therapy in cryptogenic stroke with PFO. Our results are consistent with a previous
Figure 2. Forest Plot Comparing the Efficacy of Device Closure Arm and Medical Therapy Arm
Stratified based on intention-to-treat, per-protocol, and as-treated cohorts. CI¼confidence interval; CLOSURE I¼Evaluation 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 (PFO)(16); df¼degrees of freedom;
PC Trial ¼ Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder With Medical Treatment in Patients With Cryptogenic Embolism(14);
RESPECT ¼ Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (15); SE ¼ standard error.
Khan et al. J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S , V O L . 6 , N O . 1 2 , 2 0 1 3
Role of PFO Closure in Cryptogenic Stroke D E C E M B E R 2 0 1 3 : 1 3 1 6–2 3
1320
PFO閉鎖術をしたほうがよいか？
３つのメタ解析のまとめ．
＜問題点＞
− 各RCTの
Lost to follow up
が多く、しかも群間で大きな差が生じている．− 信頼区間が幅広く、結果の正確性に疑問が残る．
− 薬物療法において抗血小板薬と抗凝固薬の区別を行っていない．
＜結果＞
-
統計学的有意差はないものの、
PFO
閉鎖術が薬物療法よりも再発率が低い という傾向や可能性が一貫してみられたともいえる．-
閉鎖術により新規心房細動が増える可能性が示された．
Cryptogenic Stroke
の再発予防において、PFO
閉鎖術が薬物療法より明らかに勝っているという根拠は現状は乏しいが、今後の研究次第では閉鎖術が第一選択となる可能性もあるのではないか．