Author + information
- Received September 29, 2015
- Revision received November 23, 2015
- Accepted December 1, 2015
- Published online March 1, 2016.
- David M. Kent, MDa,b,∗ (, )
- Issa J. Dahabreh, MDa,c,d,e,
- Robin Ruthazer, MPHa,
- Anthony J. Furlan, MDf,
- Mark Reisman, MDg,
- John D. Carroll, MDh,
- Jeffrey L. Saver, MDi,
- Richard W. Smalling, MD, PhDj,
- Peter Jüni, MDk,l,
- Heinrich P. Mattle, MDm,
- Bernhard Meier, MDn and
- David E. Thaler, MDb
- aPredictive Analytics and Comparative Effectiveness (PACE) Center, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center/Tufts University School of Medicine, Boston, Massachusetts
- bDepartment of Neurology, Tufts Medical Center/Tufts University School of Medicine, Boston, Massachusetts
- cCenter for Evidence-based Medicine, School of Public Health, Brown University, Providence, Rhode Island
- dDepartment of Health Services, Policy & Practice, School of Public Health, Brown University, Providence, Rhode Island
- eDepartment of Epidemiology, School of Public Health, Brown University, Providence, Rhode Island
- fDepartment of Neurology, Case Western Reserve University, Cleveland, Ohio
- gDivision of Cardiology, University of Washington Medical Center, Seattle, Washington
- hDivision of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado
- iComprehensive Stroke Center and Department of Neurology, David Geffen School of Medicine/University of California Los Angeles, Los Angeles, California
- jDivision of Cardiology, Department of Medicine, The University of Texas Medical School at Houston, Houston, Texas
- kInstitute of Primary Health Care and Clinical Trials Unit Bern, University of Bern, Switzerland
- lApplied Health Research Centre (AHRC), Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Ontario, Canada
- mDepartment of Neurology, Bern University Hospital, Bern, Switzerland
- nDepartment of Cardiology, Bern University Hospital, Bern, Switzerland
- ↵∗Reprint requests and correspondence:
Dr. David M. Kent, Tufts Medical Center, Predictive Analytics and Comparative Effectiveness (PACE) Center, Institute for Clinical Research & Health Policy Studies, 800 Washington Street, Box 63, Boston, Massachusetts 02111.
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, Massachusetts] and Amplatzer PFO Occluder [disc occluder] [AGA Medical/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 and unadjusted and covariate-adjusted Cox regression models to compare device closure versus medical therapy.
Results Among 2,303 patients, closure was not significantly associated with the primary composite outcome. The difference became significant after covariate adjustment (hazard ratio [HR]: 0.68; p = 0.049). For the outcome of stroke, all comparisons were statistically significant, with unadjusted and adjusted HRs of 0.58 (p = 0.043) and 0.58 (p = 0.044), respectively. In analyses limited to the 2 disc occluder device trials, the effect of closure was not significant for the composite outcome, but was for the stroke outcome (unadjusted HR: 0.39; p = 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 statistically significant effect on the composite of stroke, transient ischemic attack, and death in adjusted but not unadjusted analyses.
This study was supported by the National Institutes of Health (R01 NS062153, R21 NS079826), Patient-Centered Outcomes Research Institute (ME-1306-03758), and PACE Center Funds, Tufts Medical Center. Dr. Furlan is Principal Investigator of the Closure I trial sponsored by NMT Medical Boston. Dr. Reisman receives funding from St. Jude Medical and Coherex; and is a consultant on the advisory boards for Boston Scientific and Cordis. University Physicians Incorporated of the University of Colorado School of Medicine receives funding from St. Jude Medical for Dr. Carroll’s services as a scientific consultant and RESPECT steering committee member. The University of California Regents receive funding for Dr. Saver’s services as a scientific consultant regarding trial design and conduct to St. Jude Medical, Medtronic/Covidien, Stryker, Neuravi, BrainsGate, Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim (prevention only), and ZZ Biotech; Dr. Saver has served as an unpaid site investigator in multicenter trials run by St. Jude Medical and Gore, for which the UC Regents received payments on the basis of clinical trial contracts for the number of subjects enrolled; and he serves as an unpaid consultant to Genentech advising on the design and conduct of the PRISMS trial (neither the University of California nor Dr. Saver received any payments for this voluntary service). Dr. Smalling receives funding from St. Jude Medical. Dr. Jüni is an unpaid steering committee or statistical executive committee member of trials funded by AstraZeneca, Abbott Vascular, Biotronik, Biosensors, Medtronic, The Medicines Company, and St. Jude Medical; has received research grants to his institution from AstraZeneca, Biotronik, Biosensors International, Eli Lilly, and The Medicines Company; and CTU Bern, which is part of the University of Bern, has a staff policy of not accepting honoraria or consultancy fees but is involved in design, conduct, or analysis of clinical studies funded by Abbott Vascular, Ablynx, Amgen, AstraZeneca, Biosensors, Biotronik, Boehringer Ingelheim, Eisai, Eli Lilly, Exelixis, Geron, Gilead Sciences, Nestlé, Novartis, Novo Nordisk, Padma, Roche, Schering-Plough, St. Jude Medical, and Swiss Cardio Technologies. Dr. Mattle is supported by grants to his institution from and served on the speakers bureau of Bayer, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Covidien, Daiichi-Sankyo, Genzyme, Merck-Serono, Neuravi, Novartis, Pfizer, Sanofi, Teva, St. Jude, and the Swiss Heart Foundation. Dr. Meier is supported by research grants to his institution and by personal speakers bureau honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Pfizer, and St. Jude Medical. Dr. Thaler is a member of the national steering committees of 2 trials sponsored by St. Jude Medical (RESPECT, ACP Trial) and 1 trial sponsored by Coherex (WaveCrest). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received September 29, 2015.
- Revision received November 23, 2015.
- Accepted December 1, 2015.
- American College of Cardiology Foundation