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Patent Foramen Ovale and the Risk of Stroke
Abstract & Commentary
By Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.
This article originally appeared in the April 2007 issue of Clinical Cardiology Alert. It was edited by Michael Crawford, MD, and peer reviewed by Rakesh Mishra, MD. Dr. Crawford is Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco, and Dr. Mishra is Assistant Professor of Medicine, Weill Medical College, Cornell University; Assistant Attending Physician, NewYork-Presbyterian Hospital. Dr. Crawford is on the speaker's bureau for Pfizer, and Dr. Mishra reports no financial relationships relevant to this field of study.
Synopsis: Compared with a lower dose, intensive treatment with atorvastatin in patients with stable coronary disease significantly reduces hospitalizations for HF.
Source: Di Tullio MR, et al. Patent foramen ovale and the risk of ischemic stroke in a multiethnic population. J Am Coll Cardiol. 2007;49:797-802.
A long-standing controversy exists regarding the importance of a patent foramen ovale (PFO) as a cause for TIA or stroke. This report is from NOMAS (Northern Manhattan Study), an epidemiologic study evaluating risk factors for, and the incidence of stroke in Northern Manhattan, New York City. The eligible study population had no history of a cerebral event. A total of 1100 subjects were recruited between 1993 and 1999. All had echocardiographic evaluation, a review of medical records, a physical/neurological exam, and standard blood work. Echo exams included agitated saline contrast, the Valsalva maneuver, and coughing, all employed to increase sensitivity for detection of a PFO.
A PFO was confirmed by microbubbles seen in the left heart within 3 cardiac cycles, following maximum right atrial opacification. An atrial septal aneurysm (ASA) was sought, diagnosed by more than 10 mm of septal protrusion behind the plane of the septum to the left or right. Telephone follow-up was done with little loss of study participants. Any possible neurologic, cardiac, or vascular event triggered an in-person interview and assessment. Subjects suspected to have a possible stroke were seen by a neurologist. Stroke was defined by the TOAST Criteria. Ischemic stroke was verified by 2 independent neurologists.
The primary study outcome was the occurrence of fatal or nonfatal ischemic stroke. Kaplan-Meier and COX proportional hazards survival models were utilized. Adjustments were made for other stroke risk factors, including hypertension, diabetes, elevated lipids, smoking, and atrial fibrillation. The cohort of 1100 patients included more women than men (640 vs 460), with a median age of 69. African Americans comprised 26%, Hispanics 50%, and Caucasians 25% of the population.
Results: PFO was detected in 15% of the subjects, and ASA in 2.5%; both a PFO and ASA were noted in 1.7%, or 19. Groups with and without an event were similar. Aspirin utilization was not different between the 2 groups. Overall follow-up was 80 ± 28 months. Ischemic stroke occurred in 6.2% of the subjects, with a stroke incidence of 12.2 per 1000 person years, compared to PFO-positive individuals, 8.9 per 1000 person years (P = 0.5). After adjusting for all stroke risk factors, the hazard ratio of a PFO for stroke was nonsignificant, 1.64 (95%; CI, 0.87 to 3.09). Frequency of embolic, as well as cryptogenic stroke was not different in patients with or without PFO. An isolated ASA was unrelated, although the numbers were small. The non-association between PFO and ischemic stroke was not influenced by gender, age, or ethnicity. Di Tullio and colleagues conclude "the study shows no significant increase in the risk of ischemic stroke from PFO in the general population during a mean follow up of 7 years."
Because of the concern that PFO increases stroke risk, there have been a number of trials evaluating PFO closure devices. The potential world-wide market for such devices is very large. Many believe that a significant number of strokes in the United States are cryptogenic and could be caused by a thromboembolic event related to a PFO. The prevalence of a PFO in patients who have had a stroke is somewhat higher than that of strokes of known cause. Heretofore, there have been an inadequate number of truly randomized trials, and outcomes are uncertain. Many non-randomized trials have been published, usually favorable for PFO closure devices.
The present study, as well as other data raise the issue as to whether the question of PFO and cryptogenic stroke has been resolved. A recent commentary in JAMA discusses in detail the scope of the problem, as well as focuses on the regulatory background for device approval, with particular focus in the PFO closure devices of which 2 have been widely used in the United States (Maisel WH, Laskey WK. JAMA. 2005;294:366-368.). Maisel and Laskey emphasize the many unresolved questions in regards to efficacy, device complications, the lack of randomized trials, and other aspects of this controversy. They state, "PFO closure device approval for a more widespread indication mandates a more rigorous, evidence-based evaluation." They point out that the American Academy of Neurology practice guidelines conclude that there is insufficient evidence to recommend routine device closure of PFO in individuals with cryptogenic strokes.
The Stroke Counsel of the American Heart Association "…has called for physicians to enroll their patients in randomized clinical trials." While the present study does not support the association between PFO and cerebral embolic event, the adjusted and unadjusted data all trend toward such a relationship, but do not come close to statistical significance. New data, and the perceptive analysis of the state of the art, as well as previous studies published, indicate that there is no final answer regarding efficacy and safety of routine PFO closure. Physicians need to carefully consider the therapeutic options available following the identification of a PFO in an individual who has not suffered a cerebral event, or in a population of patients who have had a cryptogenic stroke. Finally, the question remains related to devices: Is the horse already out of the barn?