Correspondence
Patent Foramen Ovale and Cryptogenic Stroke
N Engl J Med 2008; 358:1518-1521April 3, 2008
- Article
To the Editor:
It is hard to accept that a study of patent foramen ovale and cryptogenic stroke, reported by Handke et al. (Nov. 29, 2007, issue),1 would show that almost half of 596 consecutive patients admitted to a major university medical center for acute brain ischemia had a cryptogenic stroke, especially since 272 cases of stroke had no angiographic studies done (neither magnetic resonance nor digital-subtraction angiography). Without these critically important imaging studies, how can such a large group of cases of stroke be declared cryptogenic?
Table 1 of the article contains data on 276 stroke cases of known cause that are identical to data reported in the authors' earlier article on 503 cases examined by transesophageal echocardiography.2 However, Table 2 in this 2006 report revealed only 44 cases of patent foramen ovale among the 227 cases of stroke of unknown cause, in contrast to the much higher number of 77 reported in Table 1 of the current report on data from the same population of patients.
The size of patent foramen ovale increases with age.3 This condition has not been found by others to be a risk factor for stroke in the elderly.4
4 ReferencesMichael A. Meyer, M.D.
University at Buffalo, Buffalo, NY 14215
michaelandrewmeyer@yahoo.com 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;357:2262-2268
Full Text | Web of Science | Medline2
Harloff A ,Handke M ,Reinhard M ,Geibel A ,Hetzel A . Therapeutic strategies after examination by transesophageal echocardiography in 503 patients with ischemic stroke. Stroke 2006;37:859-864
CrossRef | Web of Science | Medline3
Hagen PT ,Scholz DG ,Edwards WD . Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc 1984;59:17-20
Web of Science | Medline4
Jones EF ,Calafiore P ,Donnan GA ,Tonkin AM . Evidence that patent foramen ovale is not a risk factor for cerebral ischemia in the elderly. Am J Cardiol 1994;74:596-599
CrossRef | Web of Science | Medline
To the Editor:
Handke et al. report on the association of patent foramen ovale with stroke of unknown cause. The sufficiency of the workup to determine the mechanism of stroke is always open to debate; however, the authors do not present a breakdown of the diagnostic tests performed in the two groups — that is, patients with cryptogenic stroke and patients with stroke of known cause. In addition, there is no mention of left ventricular function or type of heart rhythm in their data, which can also affect the comparison. Several population-based studies1,2 have established a prevalence of approximately 20% for patent foramen ovale; however, Handke et al. report only 11.9% in elderly patients with a known cause of stroke.
2 ReferencesChandra Kunavarapu, M.D.
Jeffrey A. Switzer, D.O.
Fenwick Nichols, III, M.D.
Medical College of Georgia, Augusta, GA 30912
ckunavarapu@mcg.edu 1
Meissner I ,Whisnant JP ,Khandheria BK , et al. Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study: Stroke Prevention: Assessment of Risk in a Community. Mayo Clin Proc 1999;74:862-869
CrossRef | Web of Science | Medline2
Hagen PT ,Scholz DG ,Edwards WD . Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc 1984;59:17-20
Web of Science | Medline
To the Editor:
In the study by Handke et al., the prevalence of patent foramen ovale among patients older than 55 years of age who had a known cause of stroke was 14.3%. In a group of patients with a mean age of 59 years, Homma et al. reported a 29.9% prevalence of patent foramen ovale among those with a known cause of stroke.1 In a population-based study of patients older than 45 years of age, Meissner et al. found a prevalence of patent foramen ovale of 24.3%.2
A prespecified substudy of the larger randomized trial reported by Homma et al. showed no significant difference in the time to recurrent stroke or death among patients with and those without a patent foramen ovale during a 2-year follow-up period. Furthermore, patent foramen ovale was not a significant independent predictor of stroke during a median follow-up period of 5.1 years in the study by Meissner et al. Given the substantially lower prevalence of patent foramen ovale in the retrospective study by Handke et al. and the absence of an increased risk of stroke in previous prospective studies, the conclusion that patent foramen ovale may be the source of stroke in older patients seems unwarranted at this time.
2 ReferencesBrian Silver, M.D.
Andrew Russman, D.O.
Henry Ford Hospital, Detroit, MI 48202
bsilver1@hfhs.org 1
Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP, PFO in Cryptogenic Stroke Study (PICSS) Investigators
CrossRef | Web of Science | Medline2
Meissner I ,Khandheria BK ,Heit JA , et al. Patent foramen ovale: innocent or guilty? Evidence from a prospective population-based study. J Am Coll Cardiol 2006;47:440-445
CrossRef | Web of Science | Medline
To the Editor:
Handke et al. found an increased prevalence of patent foramen ovale among both patients with cryptogenic stroke who were 55 years of age or older and those who were under the age of 55 years, but the authors do not directly address a clinically relevant question: What is the probability that the discovered patent foramen ovale is the culprit rather than an incidental finding?
However, assuming that the rate of incidental patent foramen ovale among patients with cryptogenic stroke is similar to the rate among controls, and assuming that cryptogenic strokes in patients without a detected patent foramen ovale are not caused by an undetected patent foramen ovale, the probability that a discovered patent foramen ovale in patients with cryptogenic stroke is incidental can be calculated with the use of Bayes' theorem (see the Supplementary Appendix, available with the full text of this letter at www.nejm.org). We calculated these probabilities for the subpopulations in the study by Handke et al.
These results (Table 1Table 1
Probability That Patent Foramen Ovale (PFO) Is an Incidental Finding in Patients with Cryptogenic Stroke.) suggest that in patients with otherwise cryptogenic strokes, about a third of discovered patent foramen ovales are likely to be incidental in patients over 55 years of age and a fifth are likely to be incidental in patients under the age of 55. These are average rates. However, as Handke et al. and others have shown, certain features may strengthen or weaken the association between patent foramen ovale and cryptogenic stroke. Thus, the probability that a patent foramen ovale is incidental is less likely when the patent foramen ovale is anatomically large or is associated with an atrial septal aneurysm or a high degree of shunting.1,2 Conversely, the probability that a patent foramen ovale is incidental is greater among patients with traditional risk factors for stroke (hypertension, hypercholesterolemia, current smoking, coronary artery disease, and aortic plaques).3 Deciding which patients are likely to benefit from closure of the patent foramen ovale depends both on the probability that the index stroke was related to the patent foramen ovale and on the risk of recurrent stroke, which has been estimated at approximately 2% annually.4 Predictive modeling and risk stratification by these joint probabilities may be useful in identifying patients most likely to benefit from an invasive procedure.David M. Kent, M.D., M.S.
Thomas A. Trikalinos, M.D.
David E. Thaler, M.D., Ph.D.
Tufts–New England Medical Center, Boston, MA 02111
dkent1@tufts-nemc.org Dr. Kent reports receiving research grants from Pfizer, and Dr. Thaler reports receiving consulting fees from AGA Medical. No other potential conflict of interest relevant to this letter was reported.
4 References1
Homma S ,Di Tullio MR ,Sacco RL ,Mihalatos D ,Li Mandri G ,Mohr JP . Characteristics of patent foramen ovale associated with cryptogenic stroke: a biplane transesophageal echocardiographic study. Stroke 1994;25:582-586
CrossRef | Web of Science | Medline2
Steiner MM ,Di Tullio MR ,Rundek T , et al. Patent foramen ovale size and embolic brain imaging findings among patients with ischemic stroke. Stroke 1998;29:944-948
CrossRef | Web of Science | Medline3
Mas J-L ,Arquizan C ,Lamy C , et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 2001;345:1740-1746
Full Text | Web of Science | Medline4
Homma S ,Sacco RL . Patent foramen ovale and stroke. Circulation 2005;112:1063-1072
CrossRef | Web of Science | Medline
Author/Editor Response
As stated by Meyer, angiography of the intracranial arteries was performed in only about half the patients. Although all patients underwent intracranial ultrasonography, the limitations of this technique prevent us from ruling out the possibility that some patients were erroneously assigned to the cryptogenic-stroke group. In addition, patients were categorized without consideration of the results of transesophageal echocardiography to allow comparison with earlier studies.1 We thank Meyer for making us aware of an erroneous presentation of the prevalence of patent foramen ovale in the table from a previously published article.2 The table is being corrected. We further regret not having cited this article to indicate an overlap in the data and in some of the findings between the two reports.
Kunavarapu et al. address the determination of the mechanism of stroke. Patients were classified according to the modified Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification into five major subtypes.3 The patients with stroke classified as one of the four known-cause subtypes were assigned to the known-cause group in our study. Patients with chronic or intermittent atrial fibrillation or flutter and patients with a reduction of left ventricular function were also assigned to the known-cause group. Kunavarapu et al. and Silver and Russman point out the higher prevalence of patent foramen ovale in some population-based studies and in a study including patients with stroke of known cause, as compared with our control group of older patients. In a meta-analysis, however, Overell et al. reported a mean prevalence of 14.0% among patients older than 55 years of age with stroke of known cause, which is in close agreement with our data.1 Di Tullio et al. found a similar prevalence (14.9%) using transthoracic echocardiography in a prospective population-based cohort study of patients with a mean age of 68.7 years.4 As stated by Silver and Russman, patent foramen ovale did not increase the risk of adverse events during follow-up in the study by Homma et al. These patients, however, were receiving treatment with aspirin or warfarin, which might have reduced the frequency of ischemic events.5 We agree with Kunavarapu et al. and with Silver and Russman that recent community-based studies have questioned the association between patent foramen ovale and stroke and that causality remains to be proved.
The analysis by Kent et al. is a promising approach to clarifying the causal link between patent foramen ovale and stroke. Most of the studies on patent foramen ovale rely on reporting associations. Therefore, the model-driven strategies of data evaluation proposed by Kent et al. are of high interest for the estimation of the underlying probability that patent foramen ovale is directly related to ischemic events. We agree that their proposal might be an important innovative step toward the identification of patients for whom patent foramen ovale is the cause of stroke.
5 ReferencesMichael Handke, M.D.
Andreas Harloff, M.D.
Annette Geibel, M.D.
University Hospital Freiburg, 79106 Freiburg, Germany
handkem@uhbs.ch 1
Overell JR ,Bone I ,Lees KR . Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000;55:1172-1179
Web of Science | Medline2
Harloff A ,Handke M ,Reinhard M ,Geibel A ,Hetzel A . Therapeutic strategies after examination by transesophageal echocardiography in 503 patients with ischemic stroke. Stroke 2006;37:859-864
CrossRef | Web of Science | Medline3
Adams HP Jr ,Bendixen BH ,Kappelle LJ , et al. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial: TOAST: Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24:35-41
CrossRef | Web of Science | Medline4
Di Tullio MR ,Sacco RL ,Sciacca RR ,Jin Z ,Homma S . Patent foramen ovale and the risk of ischemic stroke in a multiethnic population. J Am Coll Cardiol 2007;49:797-802
CrossRef | Web of Science | Medline5
Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP, PFO in Cryptogenic Stroke Study (PICSS) Investigators
CrossRef | Web of Science | Medline
