Population-Based Study Fails to Link PFOs to Increased Risk of CV Events

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A large, population-based study that followed people with and without patent foramen ovale (PFO) for more than decade found no substantive evidence that having the defect increases the risk of stroke or cerebrovascular events. The study is scheduled to be published online April 30, 2013, ahead of print in the Journal of the American College of Cardiology.

Marco R. Di Tullio, MD, of Columbia University College of Physicians and Surgeons (New York, NY), and colleagues evaluated 1,100 stroke-free patients older than 39 years who were enrolled as part of the Northern Manhattan Study (NOMAS). All underwent baseline transthoracic echocardiography and annual protocol-required neurological follow-up and 32.7% (n = 360) of patients also underwent brain MRI to look for silent brain infarcts potentially related to PFO.

No Difference in Total Stroke or Stroke Types

The rate of PFO was 14.9% in the total population and 16.7% in the MRI subcohort.

Over a mean follow-up of 11.0 ± 4.5 years (range, 0.04-18.6 years), there were 111 ischemic strokes (10.1%), with rates of 9.2% in the PFO group and 10.3% in the non-PFO group. The 12.5-year cumulative risk was 10.1% in the PFO group and 10.4% in the non-PFO group (P = 0.46).

PFO status did not affect stroke type. No disparities were seen between the PFO and non-PFO groups for either cryptogenic stroke (21.4% vs. 17.9%; P = 0.75) or embolic stroke (21.4% vs. 34.5%; P = 0.33).

Silent brain infarcts occurred in the total MRI cohort at a rate of 14.4%; there again was no difference between subjects with and without PFO (16.7% vs. 14.0%; P = 0.59). Those with infarcts were older (68.0 ± 8.0 years vs. 63.4 ± 8.1 years; P = 0.0002), more frequently male (P = 0.01), less frequently Hispanic (P = 0.05), and more likely to have hypertension (P = 0.01) and use aspirin (P = 0.02).

PFO also was not a predictor of silent brain infarcts or log-white matter hyperintensity volume in either unadjusted or adjusted analysis.

In individuals with coexisting PFO and atrial septal aneurysm (ASA), no increased risk of stroke or combined cerebrovascular events was observed in multivariable adjusted analysis (table 1). These observations were consistent across age, sex, and race-ethnicity subgroups.

Table 1. Risk by PFO/ASA Status

 

Ischemic Stroke
HR (95% CI)

CV Events
HR (95% CI)

PFO

1.10 (0.64-1.91)

1.13 (0.81-1.57)

PFO + ASA

0.48 (0.07-3.50)

0.87 (0.38-1.98)

ASA Alone

2.10 (0.51-8.65)

1.09 (0.35-3.42)


General Population Not at Risk

According to the study authors, the role of PFO as a risk factor for ischemic stroke has mainly been demonstrated in case-control studies, with an approximately 4-fold increase in PFO prevalence seen in patients younger than 55 and an approximately twofold increase in older patients vs. controls of similar age.

However, the lack of an association between PFO status and CV events in this study, together with no apparent effect on potential sequelae of cardiac embolism, such as silent brain infarcts or white matter hyperintensities, “suggest that PFO should not be considered a significant risk factor for cerebrovascular events in the general population,” they conclude.

Younger Patients Needed for Study

But in an editorial accompanying the study, Deeb N. Salem, MD, and David E. Thaler, MD, both of Tufts Medical Center (Boston, MA), say the data, while of high quality, do little to settle the ongoing PFO controversy.

“If a population at risk from their PFOs is going to be identified before their first stroke, it needs to be done in people who are in their 20s and 30s (and perhaps 40s), with PFO status defined by transesophageal echo or transcranial Doppler and perhaps also described in detail beyond present/absent, and with or without atrial septal aneurysm,” they write, adding that future studies should focus on asymptomatic subpopulations that may be at higher risk of a first-ever stroke including those with migraine with aura, obstructive sleep apnea, and silent infarcts.

“Age of the patients is absolutely the biggest issue I have with this paper,” agreed Robert J. Sommer, MD, of Columbia University Medical Center (New York, NY), in a telephone interview with TCTMD. “Most of the time we’re dealing with a young population with PFOs, so we want to be able to figure out who among them is going to stroke.”

Dr. Sommer said the paper provides reassurance that patients who have never had a stroke are not likely to have one related to their PFO. On the other hand, he added, it does not help clinicians decide on how to proceed with treatment for such patients.

“I think now we recognize that we shouldn’t be automatically treating patients who have PFOs and who have never had an event because they are at extremely low risk, but we still need to get to a level of understanding about which patients we should be treating to prevent their chance of having an event,” he added.

Dr. Sommer noted that the 14.9% rate of PFOs in the NOMAS study is extremely low considering that larger studies of the general population have found rates of 20 to 25%. One explanation for the low rate may be the use of transthoracic echo as the screening tool, he said. But another may be that as people age, PFOs are less commonly detected.

“Nobody really knows why,” Dr. Sommer said. “[PFOs] don’t spontaneously close and the joke has always been ‘What would Darwin say?’ But I think the older age of this population probably explains why they didn’t find as many PFOs as we would expect in a large group like this.”

Study Details

In the overall cohort, hypertension was less frequent in participants with a PFO (60.4% vs. 68.5%; P = 0.04). However, in the MRI subcohort, there were no differences in demographics or stroke risk factors between subjects with and without PFO. ASA was more frequent among subjects with PFO in both cohorts.

 


Sources:
1. Di Tullio MR, Jin Z, Russo C, et al. Patent foramen ovale, subclinical cerebrovascular disease and ischemic stroke in a population-based cohort. J Am Coll Cardiol. 2013;Epub ahead of print.

2. Salem DN, Thaler DE. Patent foramen ovale science: Keeping the horse in front of the cart. J Am Coll Cardiol. 2013;Epub ahead of print.

 

  • Dr. Sommer reports serving as a physician trainer for AGA Medical and WL Gore and Associates as well as serving on the medical advisory board for Coherex.

 

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Disclosures
  • Dr. Di Tullio reports no relevant conflicts of interest.
  • The editorial contains no statement on potential conflicts of interest for Drs. Salem or Thaler.

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