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J O U R N A L O F T H E AM 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 V O L . 6 7 , N O . 8 , 2 0 1 6

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Device Closure of Patent Foramen OvaleAfter Stroke

Pooled Analysis of Completed Randomized Trials

David M. Kent, MD,a,b Issa J. Dahabreh, MD,a,c,d,e Robin Ruthazer, MPH,a Anthony J. Furlan, MD,f

Mark Reisman, MD,g John D. Carroll, MD,h Jeffrey L. Saver, MD,i Richard W. Smalling, MD, PHD,j Peter Jüni, MD,k,l

Heinrich P. Mattle, MD,m Bernhard Meier, MD,n David E. Thaler, MDb

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BACKGROUND The comparative effectiveness of percutaneous closure of patent foramen ovale (PFO) plus medical

therapy versus medical therapy alone for cryptogenic stroke is uncertain.

OBJECTIVES The authors performed the first pooled analysis of individual participant data from completed randomized

trials comparing PFO closure versus medical therapy in patients with cryptogenic stroke.

METHODS The analysis included data on 2 devices (STARFlex [umbrella occluder] [NMT Medical, Inc., Boston, Massachu-

setts] and Amplatzer PFO Occluder [disc occluder] [AGAMedical/St. Jude Medical, St. Paul, Minnesota]) evaluated in 3 trials.

The primary composite outcome was stroke, transient ischemic attack, or death; the secondary outcome was stroke. We used

log-rank tests andunadjustedandcovariate-adjustedCox regressionmodels tocomparedeviceclosureversusmedical therapy.

RESULTS Among 2,303 patients, closure was not significantly associated with the primary composite outcome. The dif-

ference became significant after covariate adjustment (hazard ratio [HR]: 0.68; p ¼ 0.049). For the outcome of stroke, all

comparisons were statistically significant, with unadjusted and adjusted HRs of 0.58 (p ¼ 0.043) and 0.58 (p ¼ 0.044),

respectively. In analyses limited to the2disc occluder device trials, the effect of closurewasnot significant for the composite

outcome, but was for the stroke outcome (unadjusted HR: 0.39; p¼ 0.013). Subgroup analyses did not identify significant

heterogeneity of treatment effects. Atrial fibrillation was more common among closure patients.

CONCLUSIONS Among patients with PFO and cryptogenic stroke, closure reduced recurrent stroke and had a statis-

tically significant effect on the composite of stroke, transient ischemic attack, and death in adjusted but not unadjusted

analyses. (J Am Coll Cardiol 2016;67:907–17) © 2016 by the American College of Cardiology Foundation.

m the aPredictive Analytics and Comparative Effectiveness (PACE) Center, Institute for Clinical Research and Health Policy

dies, Tufts Medical Center/Tufts University School of Medicine, Boston, Massachusetts; bDepartment of Neurology, Tufts

dical Center/Tufts University School of Medicine, Boston, Massachusetts; cCenter for Evidence-based Medicine, School of

blic Health, Brown University, Providence, Rhode Island; dDepartment of Health Services, Policy & Practice, School of Public

alth, Brown University, Providence, Rhode Island; eDepartment of Epidemiology, School of Public Health, Brown University,

vidence, Rhode Island; fDepartment of Neurology, Case Western Reserve University, Cleveland, Ohio; gDivision of Cardiology,

iversity of Washington Medical Center, Seattle, Washington; hDivision of Cardiology, Department of Medicine, University of

lorado Denver, Aurora, Colorado; iComprehensive Stroke Center and Department of Neurology, David Geffen School of

dicine/University of California Los Angeles, Los Angeles, California; jDivision of Cardiology, Department of Medicine, The

iversity of Texas Medical School at Houston, Houston, Texas; kInstitute of Primary Health Care and Clinical Trials Unit Bern,

iversity of Bern, Switzerland; lApplied Health Research Centre (AHRC), Li Ka Shing Knowledge Institute of St. Michael’s

spital, University of Toronto, Ontario, Canada; mDepartment of Neurology, Bern University Hospital, Bern, Switzerland; and the

epartment of Cardiology, Bern University Hospital, Bern, Switzerland. This study was supported by the National Institutes of

alth (R01 NS062153, R21 NS079826), Patient-Centered Outcomes Research Institute (ME-1306-03758), and PACE Center Funds,

fts Medical Center. Dr. Furlan is Principal Investigator of the Closure I trial sponsored by NMT Medical Boston. Dr. Reisman

eives funding from St. Jude Medical and Coherex; and is a consultant on the advisory boards for Boston Scientific and Cordis.

iversity Physicians Incorporated of the University of Colorado School of Medicine receives funding from St. Jude Medical for Dr.

rroll’s services as a scientific consultant and RESPECT steering committee member. The University of California Regents receive

ding for Dr. Saver’s services as a scientific consultant regarding trial design and conduct to St. Jude Medical, Medtronic/

vidien, Stryker, Neuravi, BrainsGate, Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim (prevention only), and ZZ Biotech;

. Saver has served as an unpaid site investigator in multicenter trials run by St. Jude Medical and Gore, for which the UC Regents

ABBR EV I A T I ON S

AND ACRONYMS

ITT = intention to treat

PFO = patent foramen ovale

TIA = transient ischemic attack

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Kent et al. J A C C V O L . 6 7 , N O . 8 , 2 0 1 6

Pooled Analysis: PFO Closure in Stroke Trials M A R C H 1 , 2 0 1 6 : 9 0 7 – 1 7

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A pproximately 30% of ischemicstrokes are “cryptogenic,” an etiolog-ically heterogeneous class. Approxi-

mately one-half of patients <60 years of agewith cryptogenic stroke have a patent fora-men ovale (PFO), nearly double the preva-

SEE PAGE 918

lence in the general population. For these patients,cryptogenic stroke may be caused by paradoxicalembolism, in addition to other occult etiologies.

Controversy exists over the preferred managementstrategy for patients with cryptogenic stroke and PFO.Three randomized clinical trials investigating 2devices—STARFlex (umbrella occluder) (NMT Medi-cal, Inc., Boston, Massachusetts) in CLOSURE I (Eval-uation of the STARFlex Septal Closure System inPatients with a Stroke and/or Transient IschemicAttack due to Presumed Paradoxical Embolismthrough a Patent Foramen Ovale) (1), and AmplatzerPFO Occluder (disc occluder) (AGA Medical/St. JudeMedical, St. Paul, Minnesota) in the RESPECT (Ran-domized Evaluation of Recurrent Stroke ComparingPFO Closure to Established Current Standard of CareTreatment) (2) and PC (Percutaneous Closure of PatentForamen Ovale in Cryptogenic Embolism) (3) trials—have now been completed. The trials did not reportstatistically significant differences between deviceclosure and medical therapy. Meta-analyses usingpublished aggregate data have generally reported re-sults suggestive of a protective effect of closure onstroke or on the composite outcome of recurrentstroke, transient ischemic attack (TIA), or death, butthe data have been contradictory as to the statisticalsignificance of these associations (1–5). We performeda meta-analysis of individual participant data to bet-ter synthesize data from the 3 randomized trials (6–8).

Individual participant data meta-analysis holdsseveral advantages overmeta-analysis using aggregate

ayments on the basis of clinical trial contracts for the number

to Genentech advising on the design and conduct of the PRISMS t

y payments for this voluntary service). Dr. Smalling receives fu

mmittee or statistical executive committee member of trials fund

edtronic, The Medicines Company, and St. Jude Medical; has rec

tronik, Biosensors International, Eli Lilly, and The Medicines Com

s a staff policy of not accepting honoraria or consultancy fees but

ded by Abbott Vascular, Ablynx, Amgen, AstraZeneca, Biosenso

eron, Gilead Sciences, Nestlé, Novartis, Novo Nordisk, Padma, R

nologies. Dr. Mattle is supported by grants to his institution from

inger Ingelheim, Bristol-Myers Squibb, Covidien, Daiichi-Sankyo

a, St. Jude, and the Swiss Heart Foundation. Dr. Meier is supported

reau honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, B

e Medical. Dr. Thaler is a member of the national steering com

ACP Trial) and 1 trial sponsored by Coherex (WaveCrest). All

relevant to the contents of this paper to disclose.

received September 29, 2015; revised manuscript received Nove

results extracted from trial publications (9), includingthe ability to standardize outcome definitions andanalyses across studies without any reliance on nu-merical approximations, which are often necessarywhen extracting data from publications. Additionally,access to participant-level data allows the use of sta-tistical methods to address missing data, performcovariate-adjusted analyses (which often have greaterpower than unadjusted analyses for time-to-eventoutcomes [10–12]), and assess heterogeneity of treat-ment effects across subgroups.

METHODS

We pre-specified our analytical plan and registeredthe study protocol with PROSPERO, the inter-national prospective register of systematic reviews(CRD42014013895). The Tufts Medical Center Insti-tutional Review Board approved the study.

We used individual participant data from 3 ran-domized trials that, to our knowledge, represent thetotality of randomized evidence on percutaneouslyimplanted PFO closure devices versus medical ther-apy in patients with PFO and cryptogenic stroke. TheCLOSURE I trial (6) randomized 909 patients ages 18to 60 years between 2003 and 2008 with a plannedfollow-up of 2 years. The RESPECT trial (7) random-ized 980 patients in the same age range between2003 and 2011. The trial’s primary analysis was per-formed as planned after the 25th outcome event; themean duration of follow-up was 2.6 years (range 0 to8.1 years). The PC trial (8) randomized 414 patientsage <60 years between 2000 and 2009. The meanduration of follow-up was 4.1 years in the closuregroup and 4.0 years in the medical therapy group.

of subjects enrolled; and he serves as an unpaid

rial (neither the University of California nor Dr. Saver

nding from St. Jude Medical. Dr. Jüni is an unpaid

ed by AstraZeneca, Abbott Vascular, Biotronik, Bio-

eived research grants to his institution from Astra-

pany; and CTU Bern, which is part of the University

is involved in design, conduct, or analysis of clinical

rs, Biotronik, Boehringer Ingelheim, Eisai, Eli Lilly,

oche, Schering-Plough, St. Jude Medical, and Swiss

and served on the speakers bureau of Bayer, Biogen

, Genzyme, Merck-Serono, Neuravi, Novartis, Pfizer,

by research grants to his institution and by personal

oehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Pfizer,

mittees of 2 trials sponsored by St. Jude Medical

other authors have reported that they have no re-

mber 23, 2015, accepted December 1, 2015.

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TREATMENTS. The CLOSURE I trial (6) used theSTARFlex septal closure system (umbrella occluder).After closure, all device patients received an anti-platelet regimen of clopidogrel 75 mg daily for 6months and aspirin 81 or 325 mg daily for 2 years. Themedical therapy group received warfarin with a targetinternational normalized ratio of 2.0 to 3.0; aspirin325 mg daily (81 mg daily dose was allowed fordocumented gastrointestinal intolerance); or aspirin81 mg daily with warfarin. Clopidogrel, ticlopidine,and aspirin plus extended-release dipyridamole werenot allowed in the medical group.

The RESPECT trial (7) used the Amplatzer PFOOccluder (disc occluder). Patients assigned to closurealso received 81 to 325 mg of aspirin and clopidogrelfor 1 month after device placement, followed byaspirin monotherapy for 5 months, and thereafter atthe site investigator’s discretion. Patients in themedical therapy group received 1 of 4 permissiblemedical regimens: aspirin, warfarin, clopidogrel, oraspirin/extended-release dipyridamole. Aspirin withclopidogrel was originally permitted but was elimi-nated in 2006 following changes in the AmericanHeart Association (AHA)/American Stroke Association(ASA) practice guidelines (13).

The PC trial (8) also used the disc occluder.For patients randomized to closure, recommendedantithrombotic treatment included aspirin (100 to 325mg/day) for at least 5 to 6 months, plus ticlopidine(250 to 500 mg/day) or clopidogrel (75 to 150 mg/day)for 1 to 6 months. For patients with aspirin intoler-ance, ticlopidine or clopidogrel was recommended.Antithrombotic treatment in the medical group wasleft to physician discretion and could include anti-platelet or anticoagulation therapy.OUTCOME DEFINITIONS AND ASCERTAINMENT. Ourprimary outcome was the composite outcome ofischemic stroke, TIA, or death from any cause. Wedefined ischemic stroke events in accordance with theupdated AHA/ASA expert consensus definition (14): asudden-onset neurological deficit in a vascular terri-tory presumably due to focal ischemia; deficitslasting <24 h were TIAs unless accompanied by rele-vant acute infarcts on neuroimaging, in which casethey were classified as ischemic strokes. The PC trialhad originally used a stroke definition that requiredneurological deficits to persist for >24 h, regardless ofneuroimaging changes. For this analysis, we recodedoutcome data to conform to the updated stroke defi-nition (corresponding to a composite of PC trialprotocol-defined stroke plus TIA accompanied byneuroimaging changes, assessed blinded to treatmentassignment). Our secondary effectiveness outcomeswere stroke alone and the composite outcome of

ischemic stroke, TIA, or early death from any cause(within 45 days of randomization), similar to theprimary outcome definition in both RESPECT andCLOSURE I.

We considered the following safety outcomes,adopting the definitions used in the primary studies:major vascular procedural complication, atrial fibril-lation (AF), and major bleeding episode.STATISTICAL ANALYSIS. Summary descriptive sta-tistics (mean � SD and percentages) were generatedfor patient characteristics in the overall cohort andcompared between the 3 component studies. P valuestesting the null hypothesis of no difference betweenthe 3 studies were obtained either from an analysis ofvariance F-test (age, body mass index) or from achi-square test.

Our primary analyses of efficacy estimatedintention-to-treat (ITT) effects of PFO closure plusmedical therapy versus medical therapy alone. Inthese analyses, all randomized patients wereanalyzed according to their assigned treatmentgroups. We performed additional analyses estimating“as treated” effects by comparing outcomes amongpatients who underwent device closure (attempted orsuccessful, depending on the trial) compared withcontrol patients. Safety analyses (i.e., analyses ofadverse events) primarily estimated “as-treated” ef-fects; ITT safety effects are reported in the OnlineAppendix. For all analyses, data for patients whodiscontinued before study completion were includeduntil the time censored.

For time-to-event analyses, we obtained Kaplan-Meier estimates (15) and tested the equality of thesurvivor functions using the log-rank test stratifiedby trial. We obtained estimates of the hazard ratio(HR) comparing treatment groups using Cox propor-tional hazard regression stratified by trial withno covariate adjustment (16). In this analysis, weassumed that each study had a different baselinehazard and that the treatment effect was commonacross trials. We chose this model because thenumber of available studies was small, simulationstudies at the planning stage indicated that it hadreasonable statistical performance, and it is consis-tent with the statistical analyses performed withineach study.

We also performed Cox proportional hazardregression analyses adjusted for the following cova-riates: age, sex, coronary artery disease, diabetes,hypertension, hyperlipidemia, prior stroke, smokingstatus, hypermobile septum, and PFO shunt size(large vs. small). Covariates were selected on thebasis of prior work suggesting that they predictedstroke recurrence or a PFO-related mechanism in the

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RoPE (Risk of Paradoxical Embolism) score (17,18).We used multiple imputation to address missingdata in covariates used in adjusted and subgroupanalyses.

For safety outcomes, we reported procedural com-plications in the device arms and, for AF and bleedingevents, estimated unadjusted HRs comparing treat-ment groups using Cox regression stratified by trial.

We assessed heterogeneity of treatment effectsacross levels of baseline characteristics by repeatingthe efficacy analyses described in the previous text,including appropriate interactions in Cox regressions.Herein, we report pre-specified subgroups on the basisof age, sex, smoking status, and PFO anatomical fea-tures (shunt size and presence of atrial septal aneu-rysm). One additional subgroup analysis on the basis ofthe qualifying event (stroke vs. TIA) was added duringrevision. Planned subgroup analyses on the basis of theRoPE score and variations of the score that incorporaterecurrence risk will be described in a separate report.

We repeated the analyses described in the previoustext (stratified log-rank tests and unadjusted andadjusted stratified Cox regressions) using only datafrom the 2 disc occluder trials (i.e., excluding datafrom the CLOSURE I trial). We also performedstability analyses after excluding each of the othertrials in turn.

We defined 2-sided p values <0.05 as statisticallysignificant. All analyses were performed using SASversion 9.4 TS Level 1MI (SAS/Stat 13.1) (SAS Institute,Cary, North Carolina).

RESULTS

This patient-level pooled analysis included data from2,303 randomized patients followed for a total of5,849 person-years. Overall, 442 patients (263 in themedical therapy arm; 171 in the device arm) withdrewor were otherwise lost to follow-up before studytermination. Characteristics of patients are seenacross trials (Table 1) and treatments (Table 2). Therewere some minor differences across trials. The PCtrial had a higher prevalence of smoking and priorstroke, but a lower prevalence of other vascularrisk factors (i.e., diabetes, hypercholesterolemia, orhypertension). Qualifying infarcts in the RESPECTtrial were more frequently located superficially onneuroimaging than in CLOSURE I. (Infarct locationwas unavailable in the PC trial.) The PC trial hada higher proportion of patients receiving anti-coagulation (instead of antiplatelet) therapy in themedical arm and a lower prevalence of putative high-risk anatomic PFO features (i.e., large shunt orhypermobile interatrial septum) than the other trials.

Covariates were generally balanced across treatmentgroups, except that patients assigned to deviceclosure were slightly more likely to have large PFOs.

A total of 108 composite endpoint events (ischemicstroke/TIA/death) were observed, including 58ischemic strokes (56 as first events), 54 TIAs (48 asfirst events), and 7 deaths (4 as first events; 4 classi-fied as early deaths). The rate of stroke was 0.98 per100 person-years across both arms; the compositeevent rate was 1.8 per 100 person-years. Annualizedevent rates by treatment arm are shown in Table 3.Results from trial-specific analyses are shown inOnline Table 1.

The Central Illustration depicts Kaplan-Meiercurves for the primary composite outcome andstroke alone. As shown in Table 3, the effect of closureon the composite outcome narrowly missed statisticalsignificance in unadjusted analysis (stratified log-rank p ¼ 0.052; HR: 0.69; 95% confidence interval[CI]: 0.47 to 1.01; p ¼ 0.053). Yet, it was statisticallysignificant in adjusted analysis (HR: 0.68; 95% CI:0.46 to 1.00; p ¼ 0.049). Effects were similar for thesecondary composite outcome, including only earlydeaths, with the treatment effect being statisticallysignificant for the log-rank test and adjusted Coxregression analysis (p ¼ 0.049 and p ¼ 0.047,respectively), and borderline for the unadjusted Coxmodel (p ¼ 0.050) (Table 3).

As shown in Table 3, all analyses for the strokeoutcome showed that device closure plus medicaltherapy was significantly more effective than medicaltherapy alone, with the unadjusted and adjusted an-alyses producing identical HR estimates (HR: 0.58;95% CI: 0.34 to 0.98; p ¼ 0.043; and HR: 0.58; 95% CI:0.34 to 0.99; p ¼ 0.044, respectively).

When the 2 disc occluder trials were analyzed sepa-rately (i.e., excluding data from the CLOSURE I trial),the point estimates of the treatment effect for thecomposite outcome were lower (more favorable forclosure) than those in the overall analysis, but notstatistically significant in the smaller sample size ofthis subanalysis (1,394 patients; 54 events) (unad-justed HR: 0.63; 95% CI: 0.36 to 1.08; p ¼ 0.091). Theeffect on stroke outcome was stronger than in theoverall analysis (unadjusted HR: 0.39; 95% CI: 0.19to 0.82; p ¼ 0.013). The effect of closure on thesecondary composite outcomewas again stronger thanin the overall analysis and was statistically significantfor the log-rank test and the unadjusted Cox regressionanalysis (p¼0.045 andp¼0.048, respectively), but notfor the adjusted Cox regression analysis (p ¼ 0.065).

As-treated analyses produced point estimates morefavorable for closure compared with ITT analyses andwere statistically significant for all outcomes, both

TABLE 1 Patient Characteristics Across Individual Trials

Total(N ¼ 2,303)

CLOSURE(n ¼ 909)

PC Trial(n ¼ 414)

RESPECT(n ¼ 980)

p Value*†CLOSURE vs. PC Trial

vs. RESPECT

% of data in meta-analysis 100 39 18 43

Demographic variables

Age, yrs 45.3 � 9.7 (2,291) 45.5 � 9.3 (909) 44.5 � 10.2 (414) 45.4 � 9.8 (968) 0.1789

Male 52.7 (1,213/2,303) 51.8 (471/909) 49.8 (206/414) 54.7 (536/980) 0.1935

Body mass index, kg/m2 27.9 � 5.7 (1,305) 28.4 � 5.9 (834) 26.5 � 5.2 (391) 29.4 � 5.6 (80) <0.0001

Current smoker 15.9 (367/2,301) 15.2 (138/907) 23.9 (99/414) 13.3 (130/980) <0.0001

Medical history variables

Coronary artery disease 2.43 (56/2,303) 2.09 (19/909) 1.93 (8/414) 2.96 (29/980) 0.3622

Diabetes 6.73 (155/2,303) 7.81 (71/909) 2.66 (11/414) 7.45 (73/980) 0.0012

Hypercholesterolemia 39.1 (900/2,303) 44.1 (401/909) 27.1 (112/414) 39.5 (387/980) <0.0001

Hypertension 30.3 (697/2,303) 31.0 (282/909) 25.8 (107/414) 31.4 (308/980) 0.0950

Migraine 33.4 (770/2,303) 33.6 (305/909) 20.5 (85/414) 38.8 (380/980) <0.0001

Prior stroke/TIA 19.6 (451/2,303) 12.5 (114/909) 37.4 (155/414) 18.6 (182/980) <0.0001

Echocardiographic variables‡

Hypermobile septum 33.4 (758/2,267) 35.6 (311/873) 23.7 (98/414) 35.6 (349/980) <0.0001

Large PFO 61.1 (1,292/2,115) 61.1 (475/777) 21.7 (80/369) 76.1 (737/969) <0.0001

Index event variables

Index event of stroke 89.0 (2,047/2,303) 72.0 (653/907) 100 (414/414) 100 (980/980) <0.0001

Superficial stroke 56.5 (995/1,761) 37.0 (289/782) Not available 72.1 (706/979) <0.0001

Baseline NIHSS 0.7 � 1.5 (1,882) 0.6 � 1.2 (904) Not available 0.8 � 1.7 (978) <0.0100

Baseline Rankin 0.7 � 0.8 (1,882) 0.5 � 0.8 (902) Not available 0.8 � 0.8 (980) <0.0001

Treatment variables

Randomized to deviceclosure

49.9 (1,150/2,303) 49.2 (447/909) 49.3 (204/414) 50.9 (499/980) 0.7185

Treated withantiplatelets only†

85.2 (1,917/2,250) 84.7 (770/909) 80.0 (331/414) 88.0 (816/927) 0.0005

Values are mean � SD (n) or % (n/N) of patients with available data, unless otherwise indicated. *p values testing the null hypothesis of no difference between the 3 groups;obtained either from an analysis of variance F-test (age, body mass index) or from a chi-square test. †Among medical arm patients. ‡Findings on transesophagealechocardiography.

CLOSURE I ¼ Evaluation of the STARFlex Septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism through aPatent Foramen Ovale; NIHSS ¼ National Institutes of Health Stroke Scale; PC ¼ Percutaneous Closure of Patent Foramen Ovale in Cryptogenic Embolism; PFO ¼ patent foramenovale; RESPECT ¼ Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment; TIA ¼ transient ischemic attack.

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when all trials were pooled and when analyses werelimited to the 2 disc occluder trials (Table 4).

Subgroup analysis (Figure 1) did not reveal anystatistically significant heterogeneity of treatmenteffects. Subgroup effects for the ischemic strokeoutcome and for the analysis including just the discoccluder trials are shown in Online Figures 1 to 3.

Results for safety outcomes are summarized inTable 5. The hazard of AF among patients receivingclosure was 3 times as high as that among patientsreceiving medical therapy (HR: 3.22; 95% CI: 1.76 to5.90; p < 0.0002). In analyses restricted to the discoccluder trials, the HR for AF was 1.85 (95% CI: 0.86 to3.98; p ¼ 0.117). Bleeding rates were not statisticallydifferent between treatment groups. Online Table 2shows safety outcomes analyzed by ITT.

Finally, in stability analyses excluding either of thedisc occluder trials (i.e., pairing CLOSURE I with eitherRESPECT or the PC trial), treatment effects were nolonger statistically significant (Online Table 3).

DISCUSSION

Our study indicates that patients <60 years of agefound to have a PFO in the setting of a cryptogenicischemic stroke have relatively low stroke recurrencerates whether treated with percutaneous devicetherapy or with medical therapy. Outcome rates weregenerally lower with percutaneous closure plusmedical therapy than with medical therapy alone(Central Illustration); the difference between the 2treatments was consistently significant for the sec-ondary efficacy outcome of ischemic stroke and forthe primary composite outcome in adjusted but notunadjusted analyses.

We interpret these results, on the basis of the to-tality of available randomized data and all analysesperformed, as providing evidence that closure canprevent stroke recurrence in some patients withcryptogenic stroke found to have a PFO. However, AFis increased with closure, although less strongly with

TABLE 2 Patient Characteristics Across Treatment Strategies

Combined Dataset (N ¼ 2,303)

Device Closure(n ¼ 1,150)

Medical Therapy(n ¼ 1,153)

Source data

CLOSURE 38.9 (447) 40.1 (462)

PC trial 17.7 (204) 18.2 (210)

RESPECT 43.4 (499) 41.7 (481)

Clinical variables

Age 45.3 � 9.8 (1,143) 45.3 � 9.7 (1,148)

Male 51.6 (593/1,150) 53.8 (620/1,153)

Body mass index 28.0 � 5.6 (654) 27.8 � 5.8 (651)

Current smoker 17.0 (196/1,150) 14.9 (171/1,151)

Medical history

Coronary artery disease 3.1 (36/1,150) 1.7 (20/1,153)

Diabetes 6.9 (79/1,150) 6.6 (76/1,153)

Hypercholesterolemia 39.7 (456/1,150) 38.5 (444/1,153)

Hypertension 31.1 (358/1,150) 29.4 (339/1,153)

Migraine 34.3 (394/1,150) 32.6 (376/1,153)

Prior stroke/TIA 19.5 (224/1,150) 19.7 (227/1,153)

Echocardiographic variables*

Hypermobile septum 33.6 (380/1,130) 33.2 (378/1,137)

Large PFO 63.2 (672/1,063) 58.9 (620/1,052)

Index event variables

Index event of stroke 89.4 (1,027/1,149) 88.5 (1,020/1,152)

Superficial stroke 55.8 (484/867) 57.2 (511/894)

Baseline NIHSS 0.7 � 1.6 (942) 0.7 � 1.4 (940)

Baseline Rankin 0.7 � 0.8 (941) 0.6 � 0.8 (941)

Values are % (n), mean � SD (n), or % (n/N) of patients with available data. *Findings ontransesophageal echocardiography.

Abbreviations as in Table 1.

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the disc occluder device. These findings suggest thatclosure with the disc occluder is a reasonable thera-peutic option in the context of informed decisionmaking. Informally, for patients similar to those

TABLE 3 Composite Outcomes and Recurrent Ischemic Stroke (Intent

Outcome Rate

DeviceClosure

MedicalTherapy

Analyses Using Data From

Primary composite outcome 1.5 (45/3,057) 2.3 (63/2,792)

Recurrent ischemic stroke 0.7 (22/3,099) 1.3 (36/2,839)

Secondary composite outcome(ischemic stroke, TIA, early death)

1.4 (43/3,057) 2.2 (61/2,792)

Analyses Limited to Disc Occluder Device Tria

Primary composite outcome 1.0 (22/2,274) 1.6 (32/2,021)

Recurrent ischemic stroke 0.4 (10/2,301) 1.1 (23/2,044)

Secondary composite outcome(ischemic stroke, TIA, early death)

0.9 (20/2,274) 1.6 (32/2,021)

Values are % per person-year (events/total person-years) unless otherwise indicated. *Adjuprior stroke, smoking status, index event (stroke versus TIA), hypermobile septum, and PFcombined from 10 multiply imputed datasets. In meta-analyses, source study was include

CI ¼ confidence interval; HR ¼ hazard ratio; PH ¼ proportional hazards; other abbrev

enrolled in the trials, the annualized rate of ischemicstroke, if treated medically, is approximately 1%;device closure decreases this rate by one-half.Although there is uncertainty in the estimates, toavert 1 primary composite outcome event, the num-ber needed to treat over 2.5 years was 50, and to avert1 ischemic stroke, the number needed to treat was 67.A benefit of this magnitude may be clinically impor-tant to some patients and may continue beyond 2.5years among younger stroke patients with a long lifeexpectancy. We stress that our study results may notbe applicable to other devices, particularly non-PFOdevices that are being used off-label for PFO closure.

Although bleeding rates were similar betweendevice and medical therapy arms, rates of AFincreased with device closure in the overall analysis.The difference did not reach statistical significancefor the disc occluder device, for which point estimatesindicated a potential number needed to harm of 100by causing 1 additional patient to develop AF over 2.5years. These results emphasize the importance ofmeticulously ruling out occult AF as a cause of theindex event, close initial monitoring of the cardiacrhythm for patients treated with PFO closure, andappropriate management of documented AF.

Although the effects estimated in our analysis weresubstantial on the relative-risk scale, and the esti-mated reduction in absolute risk may be of clinicalimport, they were smaller than those anticipated inthe power calculation of the individual trials. Forexample, the RESPECT trial was powered to detect a75% relative risk reduction and the PC trial waspowered to detect an absolute effect of >2%/year.Research completed since the planning of these trials

ion-to-Treat Analyses)

Log-Rankp Value Cox PH Model

Covariate–AdjustedCox PH Model*

HR† (95% CI),p Value

HR† (95% CI),p Value

All 3 Trials (N ¼ 2,303)

0.0517 0.69 (0.47–1.01), 0.0531 0.68 (0.46–1.00), 0.0491

0.0407 0.58 (0.34–0.98), 0.0433 0.58 (0.34–0.99), 0.0443

0.0488 0.68 (0.46–1.00), 0.0502 0.67 (0.45–1.00), 0.0473

ls (i.e., RESPECT and PC Trial) (n ¼ 1,394)

0.0885 0.63 (0.36–1.08), 0.0914 0.64 (0.37–1.11), 0.1150

0.0103 0.39 (0.19–0.82), 0.0133 0.41 (0.20–0.88), 0.0213

0.0451 0.57 (0.33–1.00), 0.0480 0.59 (0.33–1.03), 0.0651

sted for age, sex, race, coronary artery disease, diabetes, hypertension, hyperlipidemia,O shunt size (large versus small). †Adjusted HRs were estimated using Cox PH modelsd in the model as a stratification term.

iations as in Table 1.

CENTRAL ILLUSTRATION Patent Foramen Ovale Closure in Stroke Trials: Kaplan-Meier Curves ComparingDevice Closure Versus Medical Therapy

Kent, D.M. et al. J Am Coll Cardiol. 2016; 67(8):907–17.

Kaplan-Meier curves comparing device closure (orange) versus medical therapy (blue). Results shown for all trials pooled (A, B) and for occluder device trials only

(RESPECT [Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (2)] and PC Trial [Percutaneous

Closure of Patent Foramen Ovale in Cryptogenic Embolism (3)]) (C, D), and for both the primary composite and ischemic stroke outcomes. Secondary composite outcome

(including only early death) was statistically significant for both the 3-trial (log-rank p ¼ 0.0488) and the disc occluder-only analysis (log-rank p ¼ 0.0451).

TIA ¼ transient ischemic attack.

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TABLE 4 Composite Outcomes and Recurrent Stroke (As-Treated Analyses)

Outcome RateLog-Rankp Value Cox PH Model

Covariate-AdjustedCox PH Model*

DeviceClosure

MedicalTherapy

HR† (95% CI),p Value

HR† (95% CI),p Value

Analyses Using Data From All 3 Trials (N ¼ 2,281)

Primary composite outcome 1.4 (40/2,948) 2.3 (66/2,877) 0.025 0.64 (0.43–0.95), 0.026 0.63 (0.43–0.94), 0.025

Recurrent ischemic stroke 0.6 (19/2,985) 1.3 (37/2,929) 0.023 0.53 (0.30–0.92), 0.025 0.53 (0.30–0.92), 0.025

Secondary composite outcome(ischemic stroke, TIA, early death)

1.3 (38/2,948) 2.2 (64/2,877) 0.022 0.63 (0.42–0.94), 0.023 0.63 (0.42–0.94), 0.023

Analyses Limited to Disc Occluder Device Trials (i.e., RESPECT and PC Trial) (n ¼ 1,372)

Primary composite outcome 0.8 (18/2,207) 1.7 (34/2,063) 0.018 0.51 (0.29–0.90), ¼ 0.020 0.51 (0.29–0.91), 0.022

Recurrent ischemic stroke 0.3 (7/2,230) 1.2 (24/2,091) 0.001 0.28 (0.12–0.64), 0.003 0.28 (0.12–0.66), 0.004

Secondary composite outcome(ischemic stroke, TIA, early death)

0.7 (16/2,207) 1.7 (34/2,063) 0.007 0.45 (0.25–0.82), 0.009 0.45 (0.25–0.83), 0.010

Values are % per person-year (events/total person-years) unless otherwise indicated. *Adjusted for age, sex, race, coronary artery disease, diabetes, hypertension, hyperlipidemia,prior stroke, smoking status, index event (stroke versus TIA), hypermobile septum, and PFO shunt size (large versus small). †Adjusted hazard ratios estimated using Cox PH modelscombined from 10 multiply imputed datasets. In meta-analyses, the source study was included in the model as a stratification term.

Abbreviations as in Tables 1 and 3.

FIGURE 1 Subgrou

Subgroup

Age

Sex

Smoking status

Shunt size (TEE)

ASA (TEE)

Index event

History of migraine

Radiology

Per unadjusted hazar

of treatment effect f

TEE ¼ transesophag

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Pooled Analysis: PFO Closure in Stroke Trials M A R C H 1 , 2 0 1 6 : 9 0 7 – 1 7

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has shown that a substantial proportion of indexcryptogenic strokes in patients with PFO may be dueto mechanisms unrelated to PFO (18,19). Studies haveadditionally suggested that paradoxical embolismmay be a mechanism with an especially low recur-rence risk; thus, even in patients with such PFO-related mechanisms, recurrent events may often beunrelated to PFO (6,20). Medical therapies, in theory,can have a protective effect on recurrent strokes for

p Analysis: Device Versus Medical Therapy

Stratum Ev/PT (closure) Ev/PT (medical)

Age < 45Age >= 45

MaleFemale

SmokerNon smoker

SubstantialNot substantial

ASA presentNo ASA

TIA Stroke

YesNo

Superficial strokeOthers

13 / 131732 / 1740

17 / 159328 / 1464

12 / 53333 / 2524

22 / 182723 / 1229

16 / 98729 / 2070

8 / 20737 / 2849

13 / 100232 / 2055

18 / 123315 / 864

25 / 120838 / 1584

36 / 151427 / 1278

15 / 38548 / 2407

32 / 156332 / 1229

24 / 89340 / 1899

15 / 21248 / 2580

26 / 81937 / 1974

23 / 115228 / 759

0.20Hazard

d ratios (HRs) for study-stratified Cox proportional hazards, pre-specified sub

or the primary composite outcome. ASA ¼ atrial septal aneurysm; CI ¼ confi

eal echocardiography; TIA ¼ transient ischemic attack.

both PFO-related and unrelated events, whereasdevice closure presumably protects only against theformer. Furthermore, our results do not suggest thatputative high-risk anatomical features, such as largePFO size or atrial septal aneurysm, are by themselvesvery useful at discriminating patients likely to benefitfrom closure from those unlikely to benefit. Thus,even though a consistent signal for an effect on strokerecurrence is seen in our study, the totality of results

HR (95% CI) p-val

0.52 (0.26, 1.01)0.79 (0.49, 1.26)

0.46 (0.26, 0.83)0.97 (0.57, 1.65)

0.65 (0.31, 1.40)0.68 (0.44, 1.06)

0.61 (0.35, 1.08)0.80 (0.46, 1.38)

0.65 (0.34, 1.23)0.71 (0.44, 1.14)

0.56 (0.24, 1.32)0.73 (0.47, 1.11)

0.44 (0.23, 0.85)0.87 (0.54, 1.39)

0.80 (0.43, 1.48)0.51 (0.27, 0.96)

0.313

0.064

0.937

0.525

0.845

0.601

0.103

0.328

0.5 0 2Ratio (Logarithmic Scale)

group analyses did not show any statistically significant heterogeneity

dence interval; Ev ¼ event; PT ¼ patient; p-val ¼ p value;

TABLE 5 Safety Outcomes (As-Treated Analyses)*

DeviceClosure

MedicalTherapy

HR* (95% CI),p Value†

Analyses using data fromall 3 trials (n ¼ 2,281)

1,067 1,214

Bleeding 3.7 (11/2,990) 3.7 (11/2,941) 1.11 (0.48–2.56), 0.81

Atrial fibrillation 1.44 (42/2,915) 0.48 (14/2,936) 3.22 (1.76–5.90), 0.0002

Analyses limited to disc occluderdevice trials (n ¼ 1,372)‡

663 709

Bleeding 0.09 (2/2,240) 0.14 (3/2,131) 0.68 (0.11–4.09), 0.67

Atrial fibrillation 0.87 (19/2,190) 0.47 (10/2,119) 1.85 (0.86–3.98), 0.12

Values are n or % per person-year (events/total person-years) unless otherwise indicated. *Unadjusted HRs and pvalues from Cox PH model; source study was included in the model as a stratification term. †See Table 3 for thedata included in as-treated analyses. Data for procedural complications were abstracted from the original studypublications (see Appendix) and not available for as-treated analysis. ‡Excludes data from the CLOSURE trial.

Abbreviations as in Table 3.

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reported over the last several years should providesome caution against overly simplistic assumptionsthat paradoxical embolism is the only importantmechanism of either index or recurrent stroke inthese patients.

Current AHA/ASA guidelines do not support theuse of PFO closure among patients with PFO andcryptogenic stroke (21). This recommendation was onthe basis of the null results of the 3 trials included inthis pooled analysis. Each of these trials was poweredto detect very large treatment effects only. In suchcircumstances, evidence synthesis across trials isappropriate and provides more powerful tests andmore precise estimates of the treatment effect thanseparate analyses of the individual trials (22). Ouranalysis of all available individual patient data fromrandomized trials generally suggests that closure plusmedical therapy improves outcomes compared withmedical therapy alone; however, CIs remained wide,and ongoing and future studies may yet revise theseeffect estimates.

Our results, particularly with respect to tests ofstatistical significance, depended on a number ofanalytic choices, such as using a composite outcome(stroke, TIA, or death) versus using stroke alone;relying on all trials to estimate an overall effectversus trials of different devices separately; andperforming an unadjusted versus adjusted analysis.Because the trials’ published results were knownbefore this pooled analysis was planned, our analyticchoices could not be made completely blinded tothose results. Thus, we sought to emulate pre-trialreasoning with respect to outcome selection,following widely accepted standard analysis prac-tices, reporting results from all analyses conducted,and interpreting findings on the basis of all availableinformation, including stability and sensitivityanalyses.

Our results were minimally affected by whetherthe composite outcome included all or (similar toRESPECT and CLOSURE I) only early deaths, but theseslight differences were of some interest because theyaffected whether p values were significant at the 0.05level or borderline nonstatistically significant. Ingeneral, clinically informative composite outcomesare those whose components are plausible targets ofthe intervention; for example, nonstroke fatal eventsoutside of the periprocedural period are unlikely to beaffected by closure versus medical therapy. Similarly,our results were minimally affected by whether ana-lyses were performed with or without adjustmentfor baseline covariates. Analyses adjusted for cova-riates generally have greater statistical power fortime-to-event outcomes compared with unadjusted

analyses. The interpretation of such analyses is typi-cally felt to be more relevant for the estimation ofpatient-level effects, and multivariate adjustment ofrandomized clinical trial results is a commonapproach (23). In this study, adjusted and crudeanalyses gave essentially identical results, despite thenominal significance of only the adjusted analysis forthe primary composite outcome.

Whether the endpoint analyzed was a compositeoutcome or ischemic stroke alone had a somewhatgreater effect on our analyses. By definition, com-posite outcomes have a higher incidence rate thantheir components and are generally presumed toprovide greater statistical power than componentoutcomes. Nonetheless, about one-half of the com-posite outcomes were TIA events, that is, transientneurological symptoms without objective neuro-imaging findings subject to diagnostic inaccuracy,and all-cause mortality was rare and was not patho-genically likely to be modifiable by PFO closure. Thus,ischemic stroke recurrence as a lone endpoint mayoffer a more reliable outcome with regard to treat-ment effect and is an endpoint with greater clinicalsignificance than when joined in a composite withTIA. In our pooled analysis, the benefits of deviceclosure for stroke alone were consistent across allanalytical approaches.

In a head-to-head trial comparing the disc occluderand the umbrella occluder, the umbrella occluder wasmore commonly associated with device-related com-plications such as AF and thrombus formation on thedevice (24); there was also some evidence that thedisc occluder device may more effectively preventcerebrovascular events (25). A network meta-analysisconcluded that the effectiveness of closure dependedon the type of device used (5). Thus, it is reasonableto consider the evidence on each device separately.Furthermore, analyses restricted to the disc occluder

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: Pa-

tients with PFO who develop cryptogenic ischemic

stroke face relatively low rates of recurrent cerebral

ischemic events during medical therapy with or without

device closure, but pooled results of randomized trials

show lower stroke rates with percutaneously implanted

device closure than with medical therapy alone.

TRANSLATIONAL OUTLOOK: Longer-term follow-

up of ongoing and completed trials will improve our

understanding of the comparative effectiveness of

closure versus medical therapy, but comparative

studies of various antithrombotic treatment regimens,

including those in patients undergoing PFO closure, are

needed to address important knowledge gaps.

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Pooled Analysis: PFO Closure in Stroke Trials M A R C H 1 , 2 0 1 6 : 9 0 7 – 1 7

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device trials are especially relevant to clinical de-cisions because, of the devices assessed, only the discoccluder device is available for clinical use (albeit notin the United States); the umbrella occluder device isno longer manufactured.

This analysis using individual participant dataoffered several advantages over prior study-levelmeta-analyses that were based on the publishedaggregate results. We were able to harmonizeoutcome definitions across trials and did not have torely on numerical approximations when extractingdata from trial publications; the availability ofperson-level data also permitted covariate adjust-ment, proper handling of missing data, and explora-tion of effect heterogeneity. These differencespresumably explained why our results for some ana-lyses were statistically significant where prior study-level meta-analyses were not (1–4,26–28).

STUDY LIMITATIONS. First, the pooled analysisinherited any limitations of the component studies.Crossover and loss to follow-up in the studies werehigh relative to the number of events and somewhatmore common in the medical arm. Although the ITTeffect is consistently estimated in the presence ofnoncompliance to assigned treatment, selection biasdue to loss to follow-up may have affected our ana-lyses. This analysis did not address questionsregarding the optimal antithrombotic regimen in pa-tients with PFO and cryptogenic stroke; medicalregimens—both for the comparison group and ascotreatments to device implantation—were hetero-geneous within and between the included studies.Observational comparative effectiveness research hasshown nonsignificant effects of oral anticoagulationover antiplatelet therapy in these patients (29).Newer agents are now under study in the cryptogenicstroke population (NCT02239120; NCT02313909).Additionally, the trials included in our analysis weredesigned as prospective, randomized, open, blindedendpoint studies, and it appears that this designmay have led to a slight imbalance in referralfor endpoint adjudication in the PC trial, althoughnot in CLOSURE I or RESPECT (30). Finally, mostpatients were followed for a short time frame of

around 2.5 years, and device implantation is essen-tially a permanent intervention. An observationalstudy comparing closure versus medical therapy us-ing propensity-score matching methods suggestedwidening benefits over time (31).

CONCLUSIONS

Patients with cryptogenic stroke and PFO have rela-tively low outcome rates with medical therapy with orwithout device closure; recurrent stroke rates arelower with percutaneously implanted device closurethan with medical therapy alone.

ACKNOWLEDGMENTS The authors thank theCLOSURE, RESPECT, and PC Trial Investigators, aswell as Jennifer S. Lutz, MA, PACE, Tufts MedicalCenter, for technical support and assistance withmanuscript preparation.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.David M. Kent, Tufts Medical Center, Predictive Analyticsand Comparative Effectiveness (PACE) Center, Institutefor Clinical Research & Health Policy Studies, 800 Wash-ington Street, Box 63, Boston, Massachusetts 02111.E-mail: dkent1@tuftsmedicalcenter.org.

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KEY WORDS cryptogenic stroke,meta-analysis, transient ischemic attack

APPENDIX For supplemental figures andtables, please see the online version of thispaper.