Stroke

BRIEF REPORT

Risk of Paradoxical Embolism (RoPE)–Estimated

Attributable Fraction Correlates With the Benefit
of Patent Foramen Ovale Closure
An Analysis of 3 Trials
David M. Kent , MD, MS; Jeffrey L. Saver , MD; Robin Ruthazer, MPH; Anthony J. Furlan, MD; Mark Reisman, MD;
John D. Carroll, MD; Richard W. Smalling, MD, PhD; Peter Jüni, MD; Heinrich P. Mattle , MD; Bernhard Meier, MD;
David E. Thaler, MD, PhD

BACKGROUND AND PURPOSE: In patients with cryptogenic stroke and patent foramen ovale (PFO), the Risk of Paradoxical Embolism
(RoPE) Score has been proposed as a method to estimate a patient-specific “PFO-attributable fraction”—the probability that a
documented PFO is causally-related to the stroke, rather than an incidental finding. The objective of this research is to examine
the relationship between this RoPE-estimated PFO-attributable fraction and the effect of closure in 3 randomized trials.

METHODS: We pooled data from the CLOSURE-I (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/
or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale), RESPECT (Randomized
Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment), and PC (Clinical Trial
Comparing Percutaneous Closure of Patent Foramen Ovale [PFO] Using the Amplatzer PFO Occluder With Medical Treatment in
Patients With Cryptogenic Embolism) trials. We examine the treatment effect of closure in high RoPE score (≥7) versus low RoPE
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score (<7) patients. We also estimated the relative risk reduction associated with PFO closure across each level of the RoPE score
using Cox proportional hazard analysis. We estimated a patient-specific attributable fraction using a PC trial–compatible (9-point)
RoPE equation (omitting the neuroradiology variable), as well as a 2-trial analysis using the original (10-point) RoPE equation. We
examined the Pearson correlation between the estimated attributable fraction and the relative risk reduction across RoPE strata.

RESULTS: In the low RoPE score group (<7, n=912), the rate of recurrent strokes per 100 person-years was 1.37 in the device
arm versus 1.68 in the medical arm (hazard ratio, 0.82 [0.42–1.59] P=0.56) compared with 0.30 versus 1.03 (hazard ratio,
0.31 [0.11–0.85] P=0.02) in the high RoPE score group (≥7, n=1221); treatment-by-RoPE score group interaction, P=0.12.
The RoPE score estimated attributable fraction anticipated the relative risk reduction across all levels of the RoPE score, in
both the 3-trial (r=0.95, P<0.001) and 2-trial (r=0.92, P<0.001) analyses.
CONCLUSIONS: The RoPE score estimated attributable fraction is highly correlated to the relative risk reduction of device
versus medical therapy. This observation suggests the RoPE score identifies patients with cryptogenic stroke who are likely
to have a PFO that is pathogenic rather than incidental.

Key Words:  embolism, paradoxical ◼ foramen ovale, patent ◼ patients ◼ prediction ◼ risk

A
pproximately 20% to 30% of ischemic strokes are cryp- foramen ovale (PFO), twice the prevalence in the general
togenic, an etiologically heterogeneous class including population.1,2 For these patients, the stroke mechanism may
many possible occult mechanisms. One-half of patients be paradoxical transcardiac embolism (ie, PFO-related) but
<60 years with cryptogenic stroke (CS) have a patent may still be another occult cause (ie, PFO-unrelated).
 
Correspondence to: David M. Kent, MD, MS, 800 Washington St, No. 63, Boston, MA 02111. Email dkent1@tuftsmedicalcenter.org
This manuscript was sent to Harold P. Adams, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.120.029350.
For Sources of Funding and Disclosures, see page 3122 and 3123.
© 2020 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str

Stroke. 2020;51:3119–3123. DOI: 10.1161/STROKEAHA.120.029350 October 2020   3119

 Kent et al
Nonstandard Abbreviation and Acronyms
Brief Report
CS cryptogenic stroke
HR hazard ratio
PFO patent foramen ovale
RoPE Risk of Paradoxical Embolism
RRR relative risk reduction
We previously developed the Risk of Paradoxical
Embolism (RoPE) score, which predicts the probability
of discovering a PFO in a patient with CS.3 Because
the probability of discovering a PFO in patients with CS
is directly related to the probability that the stroke is
caused by a PFO-related mechanism, we proposed that
this PFO propensity could be used to stratify patients
by the probability that a discovered PFO is pathogenic
versus incidental (ie, the attributable fraction). Although
the mathematical assumptions supporting this are well
accepted (ie, Bayes theorem), and the RoPE score per-
formance for predicting PFO was consistent across 9
component databases3 (and independently validated),4
the RoPE score has not yet been shown to predict the
degree of benefit from transcatheter PFO closure.
In theory, the attributable fraction—the proportion of
index events that are PFO-related—represents the theo-
retical maximal benefit of PFO closure. That is, if device
closure has a relative risk reduction (RRR) compared
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with medical therapy of 100% in patients with PFO-
related stroke, and if the RoPE score accurately esti-
mates attributable fraction, we would anticipate the RRR
in each RoPE stratum to reflect the RoPE-estimated
attributable fraction. Here, we examine the treatment
effect of closure in high RoPE Score versus low RoPE
score patients in 3 pooled trials and also examine the
correlation between the RoPE-estimated attributable
fraction and the RRR in recurrent stroke.
METHODS
The data that support the findings are aggregated across 12 dif-
ferent studies (9 in the RoPE study plus 3 clinical trials). The cor-
responding author has separate data use agreements for each of
the studies that do not include sharing the data with third parties.
The data are potentially available from the original study principal
investigators or the sponsoring companies. Proposals to the cor-
responding author can be considered by the RoPE Study team
and the individual study investigators. We used individual partici-
pant data from 3 randomized trials testing percutaneous mechan-
ical closure versus medical therapy: the CLOSURE-I (Evaluation
of the STARFlex Septal Closure System in Patients With a Stroke
and/or Transient Ischemic Attack due to Presumed Paradoxical
Embolism through a Patent Foramen Ovale),5 RESPECT
(Randomized Evaluation of Recurrent Stroke Comparing PFO
Closure to Established Current Standard of Care Treatment),6
and PC trials (Clinical Trial Comparing Percutaneous Closure of
Patent Foramen Ovale [PFO] Using the Amplatzer PFO Occluder
3120   October 2020
RoPE Score and Benefits of PFO Closure in 3 Trials
With Medical Treatment in Patients With Cryptogenic Embolism).7
Details of these trials were reported in their original reports, and
the 3-trial cohort used here is described in a prior individual patient
data meta-analysis.8 The primary outcome was stroke recurrence
and our primary analysis was intention-to-treat, in which random-
ized patients are analyzed according to their assigned treatment
groups. Ethics approval and consent were waived by the local
institutional review board.
Statistical Analysis
We used Cox proportional hazard regression to estimate the
hazard ratio associated with device versus medical therapy in
patients with high versus low RoPE score, dichotomizing the
RoPE score at < versus ≥7. We tested the significance of the
contrast in effect between the strata using a binary interac-
tion term in the regression equation. Patients who were miss-
ing neuroimaging data (ie, from the PC trial) were excluded
from this analysis only when the value of this variable may have
resulted in reclassification into different RoPE strata.
We then used Pearson correlation coefficient to characterize
the association between the RoPE-estimated attributable fraction
and the degree (ie, hazard ratio [HR]) of stroke recurrence reduc-
tion with PFO closure. To estimate the HR of recurrent stroke
for closure versus medical therapy across patients with different
RoPE scores, we again used Cox proportional hazard regression
including 3 terms: device closure versus medical therapy; RoPE
score as a continuous variable; and the interaction between RoPE
Score (as a continuous variable) and device closure. To include
the PC trial, for which no neuroradiological data were collected,
we used a 9-point RoPE score (ie, the originally reported RoPE
score without a point for neuroradiology). We also performed a
2-trial analysis (including only CLOSURE-I and RESPECT) using
the full 10-point RoPE Score. The 10-point RoPE score and
the RoPE logistic regression equation from which it was derived
are shown in the Data Supplement (Tables I and II in the Data
Supplement). We used cubic splines to examine potential nonlin-
earity in the effect of closure across RoPE scores, but these did
not improve model fit and are not shown. As a stability analysis,
we repeated the above correlation analyses using an as-treated
analysis, where patients who received the device are contrasted
with patients who did not, regardless of treatment assignment.
To estimate the attributable fraction, we used the RoPE
logistic regression equation, which predicts the prevalence of
a PFO among patients with CS, conditional on patient charac-
teristics.3 Although PFOs are a congenital defect distributed
randomly across the population, among patients diagnosed
with CS a correlation is induced between PFO and other risk
factors via index event (or collider) bias.9 Specifically, in patients
with CS, PFOs are associated with the absence of conventional
stroke risk factors (age, hypertension, hypercholesterolemia,
and diabetes mellitus), the absence of a prior stroke, and the
presence of a superficial infarct. The RoPE-estimated attribut-
able fraction can be calculated from the predicted PFO preva-
lence according to Bayes theorem, as follows:
Attributable fraction:
CR × (1 − ProbPFO )
1−
(1 − CR ) × (ProbPFO )
where ProbPFO is the probability of discovering a PFO based
on the RoPE logistic regression model conditioned on patient
characteristics, and CR represents the control rate (ie, the PFO
Stroke. 2020;51:3119–3123. DOI: 10.1161/STROKEAHA.120.029350
 Kent et al RoPE Score and Benefits of PFO Closure in 3 Trials

prevalence in the general population; here, we used 0.25). The treatment-by-RoPE score group interaction did not reach
attributable fraction is the probability that a CS is PFO-related statistical significance (P=0.12).
given that a CS patient has a PFO. Patients with CS but a very The Figure graphs both the RoPE-estimated attrib-

low RoPE score have a PFO prevalence near that in the gen-
eral population and so a near-zero attributable fraction (even
when a PFO is found). Patients with CS with a high RoPE score
have a high PFO prevalence and therefore a high attributable
fraction when a PFO is found. A PC trial–compatible equation
was derived excluding the neuroimaging variable for the 3-trial
analysis (Table III in the Data Supplement); the published RoPE
logistic regression model was used for the 2-trial analysis.
We graphically examined the RRR (1-HR) compared with the
attributable fraction estimated in each RoPE stratum.
Brief Report
utable fraction and the RRR (1-HR) across different
levels of the 9-point RoPE Score. The Pearson corre-
lation showed a strong association (r=0.95, P<0.001).
Similar results were obtained in the 2-trial analysis using
the 10-point RoPE score (Pearson correlation, 0.92,
P<0.001; Figure II in the Data Supplement) as well as
with an as-treated analysis (Pearson correlation, 0.94,
P<0.001; Figure III in the Data Supplement).

RESULTS
The pooled trials included 2303 randomized patients.
This analysis included 2289 patients with complete data
followed for 5926 person-years (Figure I in the Data
Supplement). There were 58 stroke outcomes. Dichoto-
mizing at a RoPE score of < 7 versus ≥7, the rate of
recurrent strokes per 100 person-years in the low RoPE
score group (n=912) was 1.37 in the device arm versus
1.68 in the medical therapy arm (HR, 0.82 [0.42–1.59]
P=0.56) and 0.30 versus 1.03 (HR, 0.31 [0.11–0.85]
P=0.02) in the high RoPE score group (n=1221). The
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DISCUSSION
In this 3-trial analysis, the estimated RRR was 69%
in patients with a RoPE score of ≥7, but only 18% in
those with a RoPE score of <7. Although this contrast
in effects did not reach statistical significance, we nev-
ertheless showed that the RRR for recurrent stroke
in patients treated with closure is highly correlated
to the calculated attributable fraction based on the
RoPE score. This observation adds important empiri-
cal support to the compelling theoretical claim that the
RoPE score identifies patients with CS likely to have
a PFO that is pathogenic versus incidental. We note

Figure. Risk of Paradoxical Embolism (RoPE)—estimated attributable fraction (AF) and relative risk reduction (RRR) across
different RoPE scores.
This Figure depicts the RoPE-estimated AF (open blue triangles) and the RRR as estimated from a Cox model (red squares) against different
RoPE scores. Higher RoPE scores are associated with much higher AFs and much higher RRR. The estimated RRR correlated highly with the
RoPE score estimated AF (r=0.88, P<0.001). Both the RoPE Equation and the 9-point RoPE score omit the neuroradiology variable to permit
inclusion of the PC trial (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale [PFO] Using the Amplatzer PFO Occluder With
Medical Treatment in Patients With Cryptogenic Embolism) data. HR indicates hazard ratio.

Stroke. 2020;51:3119–3123. DOI: 10.1161/STROKEAHA.120.029350 October 2020   3121

 Kent et al
that the magnitude of the effect of closure, and the
effect modification of the RoPE score on the relative
benefits of closure, is approximately what one might
Brief Report
expect based on theory—assuming PFO closure is a
near-perfect therapy to prevent recurrence in patients
whose index event is PFO-related. The gap between
the RoPE-estimated attributable fraction and the actual
benefit observed in the 3 trials may represent a combi-
nation of (1) closure is <100% effective in preventing
PFO-related stroke recurrence (eg, due to incomplete
closure in some patients10), (2) recurrent strokes in
patients with cryptogenic stroke and PFO may be from
other mechanisms,11 and (3) estimation error.
We acknowledge several limitations. Although differ-
ent devices were used across the trials and different clo-
sure rates were achieved, we considered the treatment
effect of closure as consistent across trials, in part due
to a lack of power to consider between-trial heterogene-
ity. We note our analysis applies only to patients meet-
ing trial enrollment criteria (eg, age ≤60). The potential
usefulness of the RoPE score for predicting effects in
patients not qualifying for the trials remains unknown.
Also, the methods used to derive the RoPE score do not
permit inclusion of anatomic features of the PFO (eg,
atrial septal aneurysm, shunt size), which might impact
recurrence risk and closure benefits.
Despite the highly significant correlation between the
RRR in recurrent stroke estimated from the Cox model
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and the RoPE-estimated attributable fraction, the RoPE
score-by-closure interaction did not reach conventional
thresholds of statistical significance. We attribute this
to the paucity of outcomes (only 58 recurrent strokes)
and that treatment interactions require substantial sta-
tistical power. We also note that, although RRR is the
appropriate scale to examine the influence of attribut-
able fraction, absolute risk reductions are often con-
sidered more important from a clinical decision making
perspective. Because the recurrence rate of strokes due
to PFOs appears to be low, and lower in patients with
high RoPE score,8 the score may identify large relative
reductions that translate to only low-to-moderate abso-
lute reductions. However, given that PFO-related stroke
is prevalent among young patients with stroke, small
absolute risk reductions may become magnified over
time. Furthermore, knowledge of the probable biological
mechanism for individual patients with stroke can be very
influential for mechanism-specific therapeutic decisions,
such as whether to close a PFO or treat with medication
alone. Additional studies (including recent trials12) are
necessary to better motivate decision rules for patient
selection.
In conclusion, the RoPE score estimated attribut-
able fraction is highly correlated to the RRR of device
therapy versus medical therapy. More thorough analysis
with more comprehensive databases may be needed to
3122   October 2020
RoPE Score and Benefits of PFO Closure in 3 Trials
better determine how this should influence clinical deci-
sion making.
ARTICLE INFORMATION
Received February 11, 2020; final revision received June 25, 2020; accepted
July 14, 2020.
Affiliations
Predictive Analytics and Comparative Effectiveness (PACE) Center, Institute for
Clinical Research and Health Policy Studies (D.M.K., R.R.) and Department of
Neurology (D.M.K., D.E.T.), Tufts Medical Center/Tufts University School of Medi-
cine, Boston, MA. Comprehensive Stroke Center and Department of Neurology,
David Geffen School of Medicine/University of California Los Angeles (J.L.S.).
Department of Neurology, Case Western Reserve University, Cleveland, OH
(A.J.F.). Division of Cardiology, University of Washington Medical Center, Seattle
(M.R.). Division of Cardiology, Department of Medicine, University of Colorado
Denver, Aurora (J.D.C.). Division of Cardiology, Department of Medicine, University
of Texas Medical School at Houston (R.W.S.). Applied Health Research Centre
(AHRC), Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Department
of Medicine and Institute of Health Policy, Management and Evaluation, University
of Toronto, ON, Canada (P.J.). Department of Neurology (H.P.M.) and Department
of Cardiology (B.M.), Bern University Hospital, Bern, Switzerland.
Acknowledgments
We would like to acknowledge the other investigators of the Risk of Paradoxical
Embolism (RoPE) Study for contributing the data and supporting the predictive
modeling on which this current analysis relies: Emanuele Di Angelantonio, MD,
MSc, Cambridge University; Marco DiTullio, MD, Columbia University; Mitchell S.
V. Elkind, MD, MS, Columbia University; Shunichi Homma, MD, FACC, Colum-
bia University; Cheryl Jaigobin, MD, FRCP, MSc, University of Toronto; Jean-
Louis Mas, MD, Hôpital Sainte-Anne, Paris-Descartes University; Patrik Michel,
MD, Centre Hospitalier Universitaire Vaudois; Marie-Luise Mono, MD, Triemli
Municipal Hospital, Zurich; Krassen Nedeltchev, MD, FESC, Triemli Municipal
Hospital, Zurich; Federica Papetti, MD, University of Rome; Joaquín Serena, MD,
PhD, Hospital Universitari Doctor Josep Trueta Institut d’Investigació Biomèdica
de Girona, Spain; Christian Weimar, MD, Professor of Neurology, University of
Duisburg-Essen.
Sources of Funding
This work was supported by 2 Patient-Centered Outcomes Research Institute (PCO-
RI) contracts (SA.Tufts.PARC.OCSO.2018.01.25) and (RS-SCOPE-2019-001).
Disclosures
Dr Saver is an employee of the University of California, Regents. Neither the
University of California, Regents nor Dr Saver received any direct support for
work on the current study. For topics broadly related to this study, the University
of California Regents received payments on the basis of clinical trial contracts
for the number of subjects enrolled in multicenter clinical trials from Abbott and
Boehringer Ingelheim; Dr Saver served as an unpaid site investigator under
these contracts. Dr Saver has received contracted hourly payments and travel
reimbursement for service as a scientific consultant advising on rigorous trial
design and conduct to Abbott and Boehringer Ingelheim. For topics completely
unrelated to the current study, the University of California Regents received pay-
ments on the basis of clinical trial contracts for the number of subjects enrolled
in multicenter clinical trials sponsored by Medtronic, Stryker, Cerenovus, NoNo
Inc, Diffusion Pharmaceuticals, and Rapid Medical. Dr Saver served as an un-
paid site investigator under these contracts. Dr Saver has received contracted
hourly payments and travel reimbursement for services as a scientific consultant
advising on rigorous trial design and conduct to Medtronic, Stryker, Cerenovus,
NoNo Inc, and Diffusion Pharmaceuticals. Dr Saver has received contracted stock
options for services as a scientific consultant advising on rigorous trial design
and conduct to Rapid Medical. Dr Saver has not participated as a medicolegal
expert in any litigation regarding stroke management. Dr Furlan was the princi-
pal investigator of CLOSURE NMT (Evaluation of the STARFlex Septal Closure
System in Patients With a Stroke and/or Transient Ischemic Attack due to Pre-
sumed Paradoxical Embolism Through a Patent Foramen Ovale, funded by NMT
Medical, Inc) Boston. Dr Carroll was a member of the Steering Committee for
the RESPECT trial sponsored by Abbott. He was a local site investigator for the
REDUCE trial (Randomized Evaluation of Recurrent Stroke Comparing PFO Clo-
sure to Established Current Standard of Care Treatment) sponsored by Gore. He
also served as a local site investigator in TRILUMINATE (Clinical Trial to Evalu-
Stroke. 2020;51:3119–3123. DOI: 10.1161/STROKEAHA.120.029350
 Kent et al
ate Cardiovascular Outcomes in Patients Treated With the Tricuspid Valve Repair
System Pivotal), COAPT (Cardiovascular Outcomes Assessment of the MitraClip
Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regur-
gitation), EVEREST 2 (Endovascular Valve Edge-to-Edge Repair Study), SUM-
MIT (Clinical Trial to Evaluate the Safety and Effectiveness of Using the Tendyne
Mitral Valve System for the Treatment of Symptomatic Mitral Regurgitation), and
EXPAND (A Contemporary, Prospective Study Evaluating Real-World Experience
of Performance and Safety for the Next Generation of MitraClip Devices) clinical
trials, on the Steering Committee for the AMULET IDE project (AMPLATZER
Amulet Left Atrial Appendage Occluder Randomized Controlled Trial), and as
Chair of the Data and Safety Monitoring Board for the TENDYNE EFS project
(Tendyne Early Feasibility Study), all associated with Abbott. Dr Carroll was also
a consultant for Holistick. Dr Smalling was a member of the Steering Commit-
tee for the RESPECT trial, sponsored by Abbott at St Jude’s Hospital and AGA
Medical Holdings, Inc. He has also served as a consultant for Proctor for patent
foramen ovale (PFO) closure. Dr Jüni serves as unpaid member of the steering
group of trials funded by Abbott Vascular, Astra Zeneca, Biotronik, Biosensors,
St. Jude Medical, Terumo and The Medicines Company, has received research
grants to the institution from Astra Zeneca, Biotronik, Biosensors International,
Eli Lilly, and The Medicines Company, and honoraria to the institution for partici-
pation in advisory boards and/or consulting from Amgen, Ava and Fresenius, but
has not received personal payments by any pharmaceutical company or device
manufacturer. Dr Mattle has been the Neurology principal investigator of the PC
trial (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale
[PFO] Using the Amplatzer PFO Occluder With Medical Treatment in Patients
With Cryptogenic Embolism) and has received honoraria for consulting from Co-
vidien/Medtronic, Neuravi/Cerenovus, Servier, and Bayer outside the submitted
work. Dr Meier has received speaker fees from Abbott. Dr Thaler was a member
of the Steering Committee for the RESPECT trial sponsored by Abbott. The other
authors report no conflicts.
Supplemental Material
Tables I–III
Figures I–III
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