- Email: [email protected]
Amplatzer PFO Occluder Device may Prevent Recurrent Stroke in Patients with Patent Foramen Ovale and Cryptogenic Stroke: A Meta-Analysis of Randomised Trials
REVIEW
Heart, Lung and Circulation (2014) 23, 303–308 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2013.12.003
Amplatzer PFO Occluder Device may Prevent Recurrent Stroke in Patients with Patent Foramen Ovale and Cryptogenic Stroke: A Meta-Analysis of Randomised Trials Anil Pandit, MDa*, Madan Raj Aryal, MDb, Aashrayata Aryal Pandit, MDa, Leena Jalota, MDb, Sudheer Kantharajpur, MDc, Fayaz A. Hakim, MDa, Howard R. Lee, MDa a
Division of Cardiovascular Diseases, Mayo Clinic, Scottsdale, Arizona, USA Department of Internal Medicine, Reading Health System, West Reading, Pennsylvania, USA c Department of Medicine, Huntsville Hospital, Alabama, USA b
Received 13 November 2013; received in revised form 2 December 2013; accepted 6 December 2013; online published-ahead-of-print 17 December 2013
Objective
To review efficacy of percutaneous closure of patent foramen ovale compared with medical therapy in prevention of recurrent strokes in patients with cryptogenic stroke.
Methods and Results
Electronic databases; PUBMED, EMBASE, Cochrane registry and web of knowledge were searched for relevant studies. In three randomised clinical trials involving 2303 participants, risk of the recurrent strokes (pooled HR 0.62, 95% CI = 0.36-1.07, P = 0.09, I2 =10%) did not show benefit with device closure when compared with medical therapy group on meta-analysis of all three trials. However, on sensitivity analysis in trials using Amplatzer PFO occluder device, the closure of PFO was associated with significantly lower recurrent strokes (pooled HR = 0.44, 95% CI = 0.21-0.94, P = 0.03, I2 = 0%) compared with medical therapy.
Conclusion
The closure of PFO with Amplatzer PFO occluder device was associated with significant reduction in recurrent strokes in patients with cryptogenic stroke and patent foramen ovale. The better outcome in prevention of secondary stroke in patients with cryptogenic stroke and PFO may be associated with type of closure device used.
Keywords
Cryptogenic stroke device closure and meta-analysis
Introduction Stroke remains a major cause of morbidity and mortality in the United States. About one third of patients presenting with
stroke do not have identifiable aetiology for stroke [1]. About half of these patients have patent foramen ovale (PFO) giving rise to the suspicion that paradoxical embolism is a potential source of stroke in this patient population [1]. At present,
Abbreviations: CLOSURE, Evaluation of the STARFlex Septal Closure System in Patients with a Stroke and/or Transient Ischaemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale; PC Trial, Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism; RESPECT, Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment; PFO, Patent Foramen Ovale; TIA, Transient Ischaemic Attack; CI, Confidence Interval; HR, Hazard Ratio *Corresponding author. Mayo Clinic College of Medicine, 13400 E Shea Blvd, Scottsdale, AZ 85259, USA. Tel.: +480 301 8000; fax: +480 301 8018., Email: [email protected] © 2013 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
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PFO is closed by the closure device as an off label use. The American Heart Association/American Stroke Association and the American College of Cardiology Foundation have stated that more evidence is needed to advise for or against closing the PFO in patients with cryptogenic stroke. [2]. Off label use of the closure device is only supported by small, observational, non-randomised trials and a meta-analysis of observational studies [3–9]. There are three randomised trials published so far in the literature, which compared the closure device against standard medical therapy in patients with cryptogenic stroke [10–12]. All the three trials failed to show the superiority of the closure device over the standard medical therapy in the intention to treat cohort. However, all three trials were not sufficiently powered to show the difference in primary outcomes [10–12]. The third trial, RESPECT, showed the benefit of device closure in pre-specified per-protocol and as treated cohort [10,13]. A recently published meta-analysis and systematic review concluded the percutaneous closure was not superior to medical therapy. However, their cohort included randomised, non-randomised and observational cohort. [14] Another meta-analysis published recently suggested the beneficial role of trancatheter closure of PFO in
A. Pandit et al.
reducing the risk of recurrent vascular events when compared to medical therapy [15]. A randomised trial comparing three different devices for percutaneous closure of PFO showed lower recurrent neurological event rate with Amplatzer occluder device. [13] Therefore, we aimed to review the combined efficacy of the closure device, particularly Amplatzer device for stroke prevention in a randomised patient population with patent foramen ovale and cryptogenic stroke in this meta-analysis.
Methods Study Selection We searched PUBMED, Web of Knowledge, EMBASE and Cochrane library using search terms ‘‘Patent foramen ovale’’ and ‘‘Stroke’’. We followed PRISMA statement for reporting systematic reviews for conduct of this meta-analysis [16]. We included studies published up to June 2013. The search was limited to clinical trials. Hand searching of references was done until further references were found. Comparing same authors eliminated duplicate studies. Two authors
Figure 1 Flow diagram demonstrating search and selection strategy for meta-analysis.
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Closure of Patent Foramen Ovale in Cryptogenic Stroke
Table 1 Patient and study level characteristics of randomised controlled trials comparing PFO closure versus medical therapy. Data
CLOSURE I
PC
RESPECT
N = 909
N = 414
N = 980
Closure
Medical therapy
Closure
Medical
Closure
Medical
(447)
(462)
(204)
therapy
(499)
therapy
(210)
(481)
Mean Age in years
46.3 9.6
45.7 9.1
44.3 10.2
44.6 10.1
45.7 9.7
46.2 10.0
Male sex–no. of patients (%)
233
238
92
114
268
268
Closure device
(52.1) (51.5) STARFlex
(45.1) Amplatzer
(54.3)
(53.7) Amplatzer
(55.7)
Follow up period Mean WSD
2 years
2.6 W 2 years
Atrial septal aneurysm >= 10 mm
168
165
47
51
180
169
no.(%)
(37.6)
(35.7)
(23.0)
(24.3)
(36.1)
(35.1)
Grade1
NA
NA
55 (29.7)
72 (39.1)
108 (21.6)
114 (23.7)
Grade2
NA
NA
87
75
138
121
(47.0)
(40.8)
(27.7)
(25.2)
43
37
247
231
(23.2)
(20.1)
(49.5)
(48.0)
4 years
Interatrial right to left shunt no.(%)
NA
Grade3 Endpoints
NA
Composite of early
Composite of death,
Composite of early death
death, late neurologic
non-fatal stroke, TIA and
and non-fatal and fatal
death, stroke, and TIA
peripheral embolism
ischaemic stroke
No = number of patients, N= total number of patients, TIA= Transient ischaemic attack, DVT = Deep vein thrombosis, PE = Pulmonary embolism, NA = not available.
(MRA and AA) screened, retrieved and excluded the studies. Additional author (AP) participated in resolution process when uncertainty was encountered. We selected randomised clinical trials that compared device closure and medical therapy in patients with cryptogenic stroke and patent foramen ovale. The steps of literature search are summarised in Figure 1.
Outcomes The primary outcome for this meta-analysis was recurrent strokes. The primary outcome was also calculated for Amplatzer occluder device alone, as there was a call for pooling of results in meta-analysis in this cohort [17]. Since the PC and the RESPECT trial utilised Amplatzer occluder
device, we performed separate meta-analyses of these two trials.
Statistical Analysis The log hazard ratios with standard error were calculated (Table 2) for the outcome variable from intention to treat cohort and entered to RevMan version 5.2 (Cochrane Collaboration, Oxford, United Kingdom). The pooled hazard ratios and 95% confidence intervals were estimated using generic inverse variance method using fixed effect meta-analysis model. I2 statistics was calculated to evaluate heterogeneity among the studies. Publication bias was not assessed because of the small number of studies. A P value of < 0.05 was used as a level of significance. Sensitivity analysis was done by
Table 2 Outcomes and calculated log hazard ratios used for meta-analysis in all three RCTs. Closure
Medical therapy
Stroke CLOSURE
12/447
13/462
PC (Amplatzer)
1/204
5/210
RESPECT (Amplatzer)
9/499
16/481
Hazard ratio
Log (Hazard Ratio)
P value
0.9 (0.41-1.98)
-0.1054
0.79
0.2 (0.02-1.72)
-1.6
0.14
0.49 (0.22-1.11)
-0.71
0.08
306
A. Pandit et al.
Figure 2 The forests plot of all randomised trials comparing recurrent strokes in intention to treat cohort.
Figure 3 The forests plot of the randomised trials using Amplatzer PFO occluder in intention to treat cohort (recurrent strokes).
removing the data from the CLOSURE trial which used STARflex occluder device.
in strokes compared with medical therapy (pooled HR 0.62, 95% CI = 0.36-1.07, overall effect: z = 1.70, P = 0.09, I2 =10%).
Results
Recurrent strokes with Amplatzer device closure
Characteristics of included studies A total of 132 studies were assessed for eligibility. Of these, 129 studies were excluded for the following reasons; 114 did not meet the inclusion criteria, 14 were reviews and one was protocol. Only three trials met the inclusion criteria and were included in the meta-analysis (Figure 1). The baseline characteristics of the participants were similar in all three trials as shown in Table 1. The primary endpoints for each trial differed slightly as shown in Table 1. Specifically, the RESPECT trial differed from other trials in terms of primary end points by not including TIA as a component of primary end point. The RESPECT trial only included death and stroke as primary end points. Recurrent TIAs were included as secondary endpoints. A risk of bias assessment was done at study level for the included studies. All three trials had a ‘‘high’’ risk of bias at blinding of participants and personnel. It is understandable that blinding of participants is impossible and unethical in this situation. Similarly, there was also high risk of bias for all studies to blinding at outcome level for reasons explained above. The baseline characteristics and outcomes of the included studies are shown in Table 1 and Table 2.
Outcomes Recurrent Strokes in all three trials The recurrent strokes occurred in 23 of 1150 treated with device closure and 34 of 1153 treated with medical therapy (Figure 2). Device closure was not associated with reduction
The recurrent strokes occurred in 10 of 703 (1.4%) treated with Amplatzer device and in 21 of 691 (3.03%) treated with medical therapy. There was a significant reduction in recurrent strokes (Figure 3) (pooled HR = 0.44, 95% CI = 0.21-0.94, overall effect: z = 2.11, P = 0.03, I2 = 0%) in the Amplatzer device closure group compared with medical therapy alone.
Discussion Findings In this meta-analysis that included 2303 participants, the device closure was not associated with lower risk of recurrent strokes compared with medical therapy in patients with cryptogenic stroke and presence of patent foramen ovale. However, Amplatzer PFO occluder device was associated with significant reduction in recurrent strokes (pooled HR = 0.44, 95% CI = 0.21-0.94, overall effect: z = 2.11, P = 0.03, I2 = 0%) compared with medical therapy when we performed sensitivity analysis by excluding the CLOSURE trial, which used STARflex closure system. So far, all three randomised trials were deemed negative because none of the trials reached statistical significance in achieving their primary endpoints on intention to treat cohort. Particularly, the PC and the CLOSURE trials were underpowered to detect the difference in primary endpoints because of lower than expected event rates. [11,12] A metaanalysis of observational studies published earlier demonstrated the benefit of PFO closure in observation studies for recurrent neurological events. [7] To the best of our knowledge, this is the first meta-analysis demonstrating the benefit
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Closure of Patent Foramen Ovale in Cryptogenic Stroke
of Amplatzer device closure in preventing recurrent strokes in patients with cryptogenic stroke and PFO. Another metaanalysis and systematic review published recently, which included randomised, non-randomised and observational cohorts, did not demonstrate any benefit of prevention of stroke by percutaneous closure. Inclusion of non-randomised and observational cohort, which is heavily marred by selection biases, may have diluted the findings. We performed sensitivity analysis by excluding the CLOSURE trial (STARflex closure system) and performed meta-analysis of the PC and the RESPECT trial, which used Amplatzar occluder device. A recently published meta-analysis on the same topic found no benefit in risk of stroke with closure device (pooled odds ratio 0.65, 95% CI: 0.358-1.193). [13] This was true in our case too when we included all three trials, of which one used StarFlex closure device (CLOSURE trial) and Amplatzer occluder device (PC and the RESPECT trials). When we excluded CLOSURE trial and did pool analysis of the PC and the RESPECT trials, we found that trials using Amplatzer occluder device were associated with significant reduction in recurrent stroke (pooled HR = 0.44, 95% CI = 0.21-0.93, overall effect: z = 2.15, P = 0.03, I2 = 0%). Our finding is in agreement with findings from a recently published randomised clinical trial of three different devices: Amplatzer, Cardioseal-STARFlex and Helex implantation in cryptogenic stroke and PFO. The study found few neurological events in patients implanted with Amplatzer device. [14] However, this trial did not compare device therapy with medical therapy.
Understanding negative results of individual trials The CLOSURE trial was the first randomised clinical trial evaluating closure device and medical therapy in the treatment of cryptogenic stroke with patent foramen ovale. The trial did not show significant reduction in primary endpoint between device closure and medical therapy. The most likely explanation could have been the underpowered nature of the study [11]. The participants with stroke other than cryptogenic were also included in the study and would not have likely benefitted from the closure. [15] Off label use of PFO closure in cryptogenic stroke is common and the investigators may have had competition and difficulty enrolling the participants in study. Moreover, patients who were at higher risk of paradoxical embolism were most likely treated outside the trial. Likewise, PC trial also suffered from similar limitations as the CLOSURE trial. The enrollment process was very long and the study was also underpowered [12]. In the RESPECT trial the drop-out rate was higher in medical therapy, which could be due to availability of off label use of PFO closure device [10]. In PC trial, two out of seven primary events in device closure group were due to death unrelated to procedure or neurological events. One death was due to chronic obstructive pulmonary disease and another was due to glioma. Given no mortality related to procedure and neurological events was reported in the CLOSURE and RESPECT trials and two deaths unrelated to procedure
and neurological events were reported in the PC trial, we propose future studies on PFO closure and cryptogenic stroke should be conducted as recurrent neurological events or stroke alone as a primary endpoint. Particularly in the RESPECT trial, three out of the total nine primary events occurred in device closure group: one stroke occurred before the device closure was performed, the second stroke occurred in a patient who decided not to go through the procedure, and the third stroke occurred in a patient who underwent coronary artery bypass and patch closure of the patent foramen ovale. Pre-specified per-protocol analysis of the RESPECT trial did demonstrate the benefit of device closure in the primary endpoint. In our meta-analysis, we did not look for device related complications and incidence of atrial fibrillation because these outcomes have been evaluated in a recently published meta-analysis of these three randomised trials. [16] The meta-analysis found that new onset atrial fibrillation is higher in device closure of PFO and, when stratified with device type, Amplatzer device, is associated with non-significant increase in risk for developing atrial fibrillation. [17]
Limitations The potential limitation of this meta-analysis could be the small number of included randomised trials. However, it should be emphasised that there are only three randomised trials conducted to date on this subject while few others are underway. We followed rigorous steps in the conduct of meta-analysis as recommended by PRISMA statement [18] therefore, we believe that our findings are valid and robust. The major limitation of this meta-analysis is lack of patient level data, which precluded us from performing a co-variate adjusted analysis. We did not perform safety analysis as it was already performed by other meta-analyses involving the same three trials and found that device closure is found in a higher incidence of new onset atrial fibrillation in the closure group. [13,16,17]
Conclusion The closure of PFO with Amplatzer PFO occluder device was associated with a significant reduction in recurrent strokes in patients with cryptogenic stroke and patent foramen ovale. The better outcome in prevention of secondary stroke in patients with cryptogenic stroke and PFO may be associated with type of closure device used.
Financial Disclosures Authors have no financial disclosure to disclose
Funding There is no role of any funding agencies in the conduct of this meta-analysis.
308
Acknowledgements The authors have no relationships that might have an interest in the submitted work and have no financial or non-financial interests. There was no role of any funding agencies in the conduct of this meta-analysis.
References [1] Handke M, Harloff A, Olschewski M, Hetzel A, Geibel A. Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med 2007;357(22):2262–8. [2] O’Gara PT, Messe SR, Tuzcu EM, Catha G, Ring JC, American Heart Association, American Stroke Association, American College of Cardiology F. Percutaneous device closure of patent foramen ovale for secondary stroke prevention: a call for completion of randomized clinical trials. A science advisory from the American Heart Association/American Stroke Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2009;53(21):2014-8. [3] Amin Z, Hijazi ZM, Bass JL, Cheatham JP, Hellenbrand W, Kleinman CS. PFO closure complications from the AGA registry. Catheter Cardiovasc Interv 2008;72(1):74–9. [4] Anzai H, Child J, Natterson B, Krivokapich J, Fishbein MC, Chan VK, et al. Incidence of thrombus formation on the CardioSEAL and the Amplatzer interatrial closure devices. Am J Cardiol 2004;93(4): 426–31. [5] Krumsdorf U, Ostermayer S, Billinger K, Trepels T, Zadan E, Horvath K, et al. Incidence and clinical course of thrombus formation on atrial septal defect and patient foramen ovale closure devices in 1,000 consecutive patients. J Am Coll Cardiol 2004;43(2):302–9. [6] Staubach S, Steinberg DH, Zimmermann W, Wawra N, Wilson N, Wunderlich N, et al. New onset atrial fibrillation after patent foramen ovale closure. Catheter Cardiovasc Interv 2009;74(6):889–95. [7] Agarwal S, Bajaj NS, Kumbhani DJ, Tuzcu EM, Kapadia SR. Metaanalysis of transcatheter closure versus medical therapy for patent foramen ovale in prevention of recurrent neurological events after presumed paradoxical embolism. JACC Cardiovasc Interv 2012;5(7): 777–89.
A. Pandit et al.
[8] Hong TE, Thaler D, Brorson J, Heitschmidt M, Hijazi ZM, Amplatzer PFOI. Transcatheter closure of patent foramen ovale associated with paradoxical embolism using the amplatzer PFO occluder: initial and intermediate-term results of the U.S. multicenter clinical trial. Catheter Cardiovasc Interv 2003;60(4):524–8. [9] Ford MA, Reeder GS, Lennon RJ, Brown RD, Petty GW, Cabalka AK, et al. Percutaneous device closure of patent foramen ovale in patients with presumed cryptogenic stroke or transient ischemic attack: the Mayo Clinic experience. JACC Cardiovasc Interv 2009;2(5):404–11. [10] Carroll JD, Saver JL, Thaler DE, Smalling RW, Berry S, MacDonald LA, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med 2013;368(12):1092–100. [11] Furlan AJ, Reisman M, Massaro J, Mauri L, Adams H, Albers GW, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 2012;366(11):991–9. [12] Meier B, Kalesan B, Mattle HP, Khattab AA, Hildick-Smith D, Dudek D, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013;368(12):1083–91. [13] Nagaraja V, Raval J, Eslick GD, Burgess D, Denniss AR. Is transcatheter closure better than medical therapy for cryptogenic stroke with patent foramen ovale? A meta-analysis of randomized trials. Heart Lung Circ 2013;22:903–9. [14] Hornung M, Bertog SC, Franke J, Id D, Taaffe M, Wunderlich N, et al. Long-term results of a randomized trial comparing three different devices for percutaneous closure of a patent foramen ovale. European Heart Journal 2013;34(November (43)):3362–9. [15] Thaler DE, Wahl A. Critique of closure or medical therapy for cryptogenic stroke with patent foramen ovale: the hole truth. Stroke 2012;43(11):3147–9. [16] Wolfrum M, Froehlich GM, Knapp G, Casaubon LK, Dinicolantonio JJ, Lansky AJ, et al. Stroke prevention by percutaneous closure of patent foramen ovale: a systematic review and meta-analysis. Heart 2014;100 (March (5)):389–95. [17] Rengifo-Moreno P, Palacios IF, Junpaparp P, Witzke CF, Morris LD, Romero-Corral A. Patent foramen ovale transcatheter closure vs. medical therapy on recurrent vascular events: a systematic review and meta-analysis of randomized controlled trials. Eur Heart J 2013;34(November (43)): 3342–52. [18] Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009;6(7):e1000100.
Heart, Lung and Circulation (2014) 23, 303–308 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2013.12.003
Amplatzer PFO Occluder Device may Prevent Recurrent Stroke in Patients with Patent Foramen Ovale and Cryptogenic Stroke: A Meta-Analysis of Randomised Trials Anil Pandit, MDa*, Madan Raj Aryal, MDb, Aashrayata Aryal Pandit, MDa, Leena Jalota, MDb, Sudheer Kantharajpur, MDc, Fayaz A. Hakim, MDa, Howard R. Lee, MDa a
Division of Cardiovascular Diseases, Mayo Clinic, Scottsdale, Arizona, USA Department of Internal Medicine, Reading Health System, West Reading, Pennsylvania, USA c Department of Medicine, Huntsville Hospital, Alabama, USA b
Received 13 November 2013; received in revised form 2 December 2013; accepted 6 December 2013; online published-ahead-of-print 17 December 2013
Objective
To review efficacy of percutaneous closure of patent foramen ovale compared with medical therapy in prevention of recurrent strokes in patients with cryptogenic stroke.
Methods and Results
Electronic databases; PUBMED, EMBASE, Cochrane registry and web of knowledge were searched for relevant studies. In three randomised clinical trials involving 2303 participants, risk of the recurrent strokes (pooled HR 0.62, 95% CI = 0.36-1.07, P = 0.09, I2 =10%) did not show benefit with device closure when compared with medical therapy group on meta-analysis of all three trials. However, on sensitivity analysis in trials using Amplatzer PFO occluder device, the closure of PFO was associated with significantly lower recurrent strokes (pooled HR = 0.44, 95% CI = 0.21-0.94, P = 0.03, I2 = 0%) compared with medical therapy.
Conclusion
The closure of PFO with Amplatzer PFO occluder device was associated with significant reduction in recurrent strokes in patients with cryptogenic stroke and patent foramen ovale. The better outcome in prevention of secondary stroke in patients with cryptogenic stroke and PFO may be associated with type of closure device used.
Keywords
Cryptogenic stroke device closure and meta-analysis
Introduction Stroke remains a major cause of morbidity and mortality in the United States. About one third of patients presenting with
stroke do not have identifiable aetiology for stroke [1]. About half of these patients have patent foramen ovale (PFO) giving rise to the suspicion that paradoxical embolism is a potential source of stroke in this patient population [1]. At present,
Abbreviations: CLOSURE, Evaluation of the STARFlex Septal Closure System in Patients with a Stroke and/or Transient Ischaemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale; PC Trial, Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism; RESPECT, Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment; PFO, Patent Foramen Ovale; TIA, Transient Ischaemic Attack; CI, Confidence Interval; HR, Hazard Ratio *Corresponding author. Mayo Clinic College of Medicine, 13400 E Shea Blvd, Scottsdale, AZ 85259, USA. Tel.: +480 301 8000; fax: +480 301 8018., Email: [email protected] © 2013 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
304
PFO is closed by the closure device as an off label use. The American Heart Association/American Stroke Association and the American College of Cardiology Foundation have stated that more evidence is needed to advise for or against closing the PFO in patients with cryptogenic stroke. [2]. Off label use of the closure device is only supported by small, observational, non-randomised trials and a meta-analysis of observational studies [3–9]. There are three randomised trials published so far in the literature, which compared the closure device against standard medical therapy in patients with cryptogenic stroke [10–12]. All the three trials failed to show the superiority of the closure device over the standard medical therapy in the intention to treat cohort. However, all three trials were not sufficiently powered to show the difference in primary outcomes [10–12]. The third trial, RESPECT, showed the benefit of device closure in pre-specified per-protocol and as treated cohort [10,13]. A recently published meta-analysis and systematic review concluded the percutaneous closure was not superior to medical therapy. However, their cohort included randomised, non-randomised and observational cohort. [14] Another meta-analysis published recently suggested the beneficial role of trancatheter closure of PFO in
A. Pandit et al.
reducing the risk of recurrent vascular events when compared to medical therapy [15]. A randomised trial comparing three different devices for percutaneous closure of PFO showed lower recurrent neurological event rate with Amplatzer occluder device. [13] Therefore, we aimed to review the combined efficacy of the closure device, particularly Amplatzer device for stroke prevention in a randomised patient population with patent foramen ovale and cryptogenic stroke in this meta-analysis.
Methods Study Selection We searched PUBMED, Web of Knowledge, EMBASE and Cochrane library using search terms ‘‘Patent foramen ovale’’ and ‘‘Stroke’’. We followed PRISMA statement for reporting systematic reviews for conduct of this meta-analysis [16]. We included studies published up to June 2013. The search was limited to clinical trials. Hand searching of references was done until further references were found. Comparing same authors eliminated duplicate studies. Two authors
Figure 1 Flow diagram demonstrating search and selection strategy for meta-analysis.
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Closure of Patent Foramen Ovale in Cryptogenic Stroke
Table 1 Patient and study level characteristics of randomised controlled trials comparing PFO closure versus medical therapy. Data
CLOSURE I
PC
RESPECT
N = 909
N = 414
N = 980
Closure
Medical therapy
Closure
Medical
Closure
Medical
(447)
(462)
(204)
therapy
(499)
therapy
(210)
(481)
Mean Age in years
46.3 9.6
45.7 9.1
44.3 10.2
44.6 10.1
45.7 9.7
46.2 10.0
Male sex–no. of patients (%)
233
238
92
114
268
268
Closure device
(52.1) (51.5) STARFlex
(45.1) Amplatzer
(54.3)
(53.7) Amplatzer
(55.7)
Follow up period Mean WSD
2 years
2.6 W 2 years
Atrial septal aneurysm >= 10 mm
168
165
47
51
180
169
no.(%)
(37.6)
(35.7)
(23.0)
(24.3)
(36.1)
(35.1)
Grade1
NA
NA
55 (29.7)
72 (39.1)
108 (21.6)
114 (23.7)
Grade2
NA
NA
87
75
138
121
(47.0)
(40.8)
(27.7)
(25.2)
43
37
247
231
(23.2)
(20.1)
(49.5)
(48.0)
4 years
Interatrial right to left shunt no.(%)
NA
Grade3 Endpoints
NA
Composite of early
Composite of death,
Composite of early death
death, late neurologic
non-fatal stroke, TIA and
and non-fatal and fatal
death, stroke, and TIA
peripheral embolism
ischaemic stroke
No = number of patients, N= total number of patients, TIA= Transient ischaemic attack, DVT = Deep vein thrombosis, PE = Pulmonary embolism, NA = not available.
(MRA and AA) screened, retrieved and excluded the studies. Additional author (AP) participated in resolution process when uncertainty was encountered. We selected randomised clinical trials that compared device closure and medical therapy in patients with cryptogenic stroke and patent foramen ovale. The steps of literature search are summarised in Figure 1.
Outcomes The primary outcome for this meta-analysis was recurrent strokes. The primary outcome was also calculated for Amplatzer occluder device alone, as there was a call for pooling of results in meta-analysis in this cohort [17]. Since the PC and the RESPECT trial utilised Amplatzer occluder
device, we performed separate meta-analyses of these two trials.
Statistical Analysis The log hazard ratios with standard error were calculated (Table 2) for the outcome variable from intention to treat cohort and entered to RevMan version 5.2 (Cochrane Collaboration, Oxford, United Kingdom). The pooled hazard ratios and 95% confidence intervals were estimated using generic inverse variance method using fixed effect meta-analysis model. I2 statistics was calculated to evaluate heterogeneity among the studies. Publication bias was not assessed because of the small number of studies. A P value of < 0.05 was used as a level of significance. Sensitivity analysis was done by
Table 2 Outcomes and calculated log hazard ratios used for meta-analysis in all three RCTs. Closure
Medical therapy
Stroke CLOSURE
12/447
13/462
PC (Amplatzer)
1/204
5/210
RESPECT (Amplatzer)
9/499
16/481
Hazard ratio
Log (Hazard Ratio)
P value
0.9 (0.41-1.98)
-0.1054
0.79
0.2 (0.02-1.72)
-1.6
0.14
0.49 (0.22-1.11)
-0.71
0.08
306
A. Pandit et al.
Figure 2 The forests plot of all randomised trials comparing recurrent strokes in intention to treat cohort.
Figure 3 The forests plot of the randomised trials using Amplatzer PFO occluder in intention to treat cohort (recurrent strokes).
removing the data from the CLOSURE trial which used STARflex occluder device.
in strokes compared with medical therapy (pooled HR 0.62, 95% CI = 0.36-1.07, overall effect: z = 1.70, P = 0.09, I2 =10%).
Results
Recurrent strokes with Amplatzer device closure
Characteristics of included studies A total of 132 studies were assessed for eligibility. Of these, 129 studies were excluded for the following reasons; 114 did not meet the inclusion criteria, 14 were reviews and one was protocol. Only three trials met the inclusion criteria and were included in the meta-analysis (Figure 1). The baseline characteristics of the participants were similar in all three trials as shown in Table 1. The primary endpoints for each trial differed slightly as shown in Table 1. Specifically, the RESPECT trial differed from other trials in terms of primary end points by not including TIA as a component of primary end point. The RESPECT trial only included death and stroke as primary end points. Recurrent TIAs were included as secondary endpoints. A risk of bias assessment was done at study level for the included studies. All three trials had a ‘‘high’’ risk of bias at blinding of participants and personnel. It is understandable that blinding of participants is impossible and unethical in this situation. Similarly, there was also high risk of bias for all studies to blinding at outcome level for reasons explained above. The baseline characteristics and outcomes of the included studies are shown in Table 1 and Table 2.
Outcomes Recurrent Strokes in all three trials The recurrent strokes occurred in 23 of 1150 treated with device closure and 34 of 1153 treated with medical therapy (Figure 2). Device closure was not associated with reduction
The recurrent strokes occurred in 10 of 703 (1.4%) treated with Amplatzer device and in 21 of 691 (3.03%) treated with medical therapy. There was a significant reduction in recurrent strokes (Figure 3) (pooled HR = 0.44, 95% CI = 0.21-0.94, overall effect: z = 2.11, P = 0.03, I2 = 0%) in the Amplatzer device closure group compared with medical therapy alone.
Discussion Findings In this meta-analysis that included 2303 participants, the device closure was not associated with lower risk of recurrent strokes compared with medical therapy in patients with cryptogenic stroke and presence of patent foramen ovale. However, Amplatzer PFO occluder device was associated with significant reduction in recurrent strokes (pooled HR = 0.44, 95% CI = 0.21-0.94, overall effect: z = 2.11, P = 0.03, I2 = 0%) compared with medical therapy when we performed sensitivity analysis by excluding the CLOSURE trial, which used STARflex closure system. So far, all three randomised trials were deemed negative because none of the trials reached statistical significance in achieving their primary endpoints on intention to treat cohort. Particularly, the PC and the CLOSURE trials were underpowered to detect the difference in primary endpoints because of lower than expected event rates. [11,12] A metaanalysis of observational studies published earlier demonstrated the benefit of PFO closure in observation studies for recurrent neurological events. [7] To the best of our knowledge, this is the first meta-analysis demonstrating the benefit
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Closure of Patent Foramen Ovale in Cryptogenic Stroke
of Amplatzer device closure in preventing recurrent strokes in patients with cryptogenic stroke and PFO. Another metaanalysis and systematic review published recently, which included randomised, non-randomised and observational cohorts, did not demonstrate any benefit of prevention of stroke by percutaneous closure. Inclusion of non-randomised and observational cohort, which is heavily marred by selection biases, may have diluted the findings. We performed sensitivity analysis by excluding the CLOSURE trial (STARflex closure system) and performed meta-analysis of the PC and the RESPECT trial, which used Amplatzar occluder device. A recently published meta-analysis on the same topic found no benefit in risk of stroke with closure device (pooled odds ratio 0.65, 95% CI: 0.358-1.193). [13] This was true in our case too when we included all three trials, of which one used StarFlex closure device (CLOSURE trial) and Amplatzer occluder device (PC and the RESPECT trials). When we excluded CLOSURE trial and did pool analysis of the PC and the RESPECT trials, we found that trials using Amplatzer occluder device were associated with significant reduction in recurrent stroke (pooled HR = 0.44, 95% CI = 0.21-0.93, overall effect: z = 2.15, P = 0.03, I2 = 0%). Our finding is in agreement with findings from a recently published randomised clinical trial of three different devices: Amplatzer, Cardioseal-STARFlex and Helex implantation in cryptogenic stroke and PFO. The study found few neurological events in patients implanted with Amplatzer device. [14] However, this trial did not compare device therapy with medical therapy.
Understanding negative results of individual trials The CLOSURE trial was the first randomised clinical trial evaluating closure device and medical therapy in the treatment of cryptogenic stroke with patent foramen ovale. The trial did not show significant reduction in primary endpoint between device closure and medical therapy. The most likely explanation could have been the underpowered nature of the study [11]. The participants with stroke other than cryptogenic were also included in the study and would not have likely benefitted from the closure. [15] Off label use of PFO closure in cryptogenic stroke is common and the investigators may have had competition and difficulty enrolling the participants in study. Moreover, patients who were at higher risk of paradoxical embolism were most likely treated outside the trial. Likewise, PC trial also suffered from similar limitations as the CLOSURE trial. The enrollment process was very long and the study was also underpowered [12]. In the RESPECT trial the drop-out rate was higher in medical therapy, which could be due to availability of off label use of PFO closure device [10]. In PC trial, two out of seven primary events in device closure group were due to death unrelated to procedure or neurological events. One death was due to chronic obstructive pulmonary disease and another was due to glioma. Given no mortality related to procedure and neurological events was reported in the CLOSURE and RESPECT trials and two deaths unrelated to procedure
and neurological events were reported in the PC trial, we propose future studies on PFO closure and cryptogenic stroke should be conducted as recurrent neurological events or stroke alone as a primary endpoint. Particularly in the RESPECT trial, three out of the total nine primary events occurred in device closure group: one stroke occurred before the device closure was performed, the second stroke occurred in a patient who decided not to go through the procedure, and the third stroke occurred in a patient who underwent coronary artery bypass and patch closure of the patent foramen ovale. Pre-specified per-protocol analysis of the RESPECT trial did demonstrate the benefit of device closure in the primary endpoint. In our meta-analysis, we did not look for device related complications and incidence of atrial fibrillation because these outcomes have been evaluated in a recently published meta-analysis of these three randomised trials. [16] The meta-analysis found that new onset atrial fibrillation is higher in device closure of PFO and, when stratified with device type, Amplatzer device, is associated with non-significant increase in risk for developing atrial fibrillation. [17]
Limitations The potential limitation of this meta-analysis could be the small number of included randomised trials. However, it should be emphasised that there are only three randomised trials conducted to date on this subject while few others are underway. We followed rigorous steps in the conduct of meta-analysis as recommended by PRISMA statement [18] therefore, we believe that our findings are valid and robust. The major limitation of this meta-analysis is lack of patient level data, which precluded us from performing a co-variate adjusted analysis. We did not perform safety analysis as it was already performed by other meta-analyses involving the same three trials and found that device closure is found in a higher incidence of new onset atrial fibrillation in the closure group. [13,16,17]
Conclusion The closure of PFO with Amplatzer PFO occluder device was associated with a significant reduction in recurrent strokes in patients with cryptogenic stroke and patent foramen ovale. The better outcome in prevention of secondary stroke in patients with cryptogenic stroke and PFO may be associated with type of closure device used.
Financial Disclosures Authors have no financial disclosure to disclose
Funding There is no role of any funding agencies in the conduct of this meta-analysis.
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Acknowledgements The authors have no relationships that might have an interest in the submitted work and have no financial or non-financial interests. There was no role of any funding agencies in the conduct of this meta-analysis.
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