PFO Diagnosis Linked With Increased Risk of Perioperative Ischemic Stroke After Noncardiac Surgery

Not so fast, says one neurologist, who questioned the reliability of the data given the baseline differences between PFO and non-PFO patients.

PFO Diagnosis Linked With Increased Risk of Perioperative Ischemic Stroke After Noncardiac Surgery

Patients diagnosed with a patent foramen ovale (PFO) who are undergoing noncardiac surgery are at a greater risk of perioperative ischemic stroke within 30 days than patients without known PFOs, according to new retrospective data.

“The clarity and the level of clean data . . . really left no doubt for us that this is not just an association but something that allows us to almost draw causal inferences,” senior study author Matthias Eikermann, MD, PhD (Beth Israel Deaconess Medical Center, Boston, MA), told TCTMD. Whether changes need to be made in clinical practice to protect these patients from stroke by altering anticoagulation prescribing practices or even closing PFOs prior to surgery remains to be seen, he added.

Neurologist David Thaler, MD, PhD (Tufts Medical Center, Boston, MA), told TCTMD that the study’s conclusion “makes sense,” but added that he is “sufficiently concerned about the details of the methods of this study”—namely that the patient populations with and without known PFO are at different baseline risk—"that I'm not sure it's a reliable guide, certainly, to patient management.”

Published in the February 6, 2018, issue of JAMA and led by Pauline Ng, MD (Massachusetts General Hospital, Boston, MA), the retrospective cohort study included 150,198 patients undergoing noncardiac surgery at three Boston-area hospitals between 2007 and 2015. Overall, 1,540 patients had a confirmed diagnosis of PFO before surgery, and these patients had more comorbidities, including hypertension, diabetes, and A-fib; were older; were more likely to be on cardioprotective medications before surgery; and were undergoing higher-risk procedures.

A total of 850 perioperative strokes were recorded throughout the study period, with events occurring more frequently in those with PFO than in those without (3.2% vs 0.5%). After adjustment, a PFO diagnosis before surgery was associated with a greater risk of perioperative stroke within 30 days (OR 2.66; 95% CI 1.96-3.63).

Additionally, patients in the PFO cohort were at increased risk of large-vessel-territory ischemia (relative risk ratio 3.14; 95% CI 2.21-4.48), total anterior stroke (relative RR 3.66; 95% CI 2.20-6.08), and posterior circulation stroke (relative RR 3.14; 95% CI 1.75-5.63). PFO patients also reported more severe stroke-related neurological deficit. Neither 30-day readmission rates nor mortality were affected by a diagnosis of PFO before surgery.

While many studies have now examined the value of PFO closure among patients with cryptogenic stroke, “there are no guidelines for management of cases of patients undergoing surgery,” Ng and colleagues write. “In clinical practice, routine prophylactic antiplatelet or anticoagulation therapy is frequently withheld in the perioperative period.”

These results “identify a potentially actionable subgroup of patients,” they continue, and future studies should determine if they will benefit from additional perioperative preventive measures like “an individualized risk-benefit assessment with regards to timing and choice of perioperative antithrombotic therapy, modified transfusion thresholds, or preoperative PFO closure among select patients.”

What Should Be Done in Response?

In his role as a critical care physician, Eikermann said he plans to integrate these findings into his practice going forward by considering different anticoagulation practices in patients with known PFOs undergoing noncardiac operations. “I could, for example, start the aspirin or the anticoagulation a little bit earlier after surgery compared with my behavior in the past,” he said.

Acknowledging that “this is not a high-evidence study,” Eikermann said he remains “convinced . . . that there is a clear signal.”

In an editorial accompanying the study, Scott Kasner, MD, and Steven R. Messé, MD (University of Pennsylvania, Philadelphia), write that the major limitation of the study is “the question of why some patients had undergone prior echocardiography before surgery.” In other words, there had to be a reason why a patient had this test, inevitably introducing bias between patients in both study arms.

If you look at the table of patients with PFO and without PFO, they're completely different people. David Thaler

Eikermann admitted this is a limitation, but said the statistical adjustment methods used in the study were able to “eliminate or at least substantially mitigate the risk of bias.”

Thaler wasn’t convinced. He said he has kept a database of strokes reported by his PFO patients over the last decade, and about 10% of them occur within a few weeks after noncardiac surgeries. “It makes sense that if you have a surgical site somewhere, there are going to be veins in that site and some of those veins are going to have little blood clots in them,” he explained. These are “a risky circumstance for people who have a potential route of access for those thrombi into the arterial side.

“I just have a really hard time with the way they did this study believing that it actually tells us anything,” Thaler continued. “The reason I say that is because if you look at the table of patients with PFO and without PFO, they're completely different people.”

Echoing the concerns of Kasner and Messé, Thaler said the way patients were classified as having a PFO or not was highly selective. “How those patients ended up knowing they had a PFO means that they had some vascular disease or history of stroke or something, so it's just not a general population of PFO subjects, and it gives sort of the impression that it was because the numbers are so enormous,” said Thaler.

Given historical numbers on the prevalence of PFO in the general population, he guessed that “25% of that non-PFO group at least had PFOs, and we don't know who they were.”

To redesign this study with no bias, Thaler said he would either include only patients who had TEE scans with a bubble test and definitively know their PFO status or do a PFO screening on all patients before surgery. “You wouldn’t get a hundred and something thousand people in the sample, but you would at least be studying what you think you're studying,” he commented.

If PFO was definitively proven to be causally related to postoperative stroke, “a permanent intervention, such as prophylactic PFO closure, may not be broadly beneficial, but additional research may identify patients or procedures that are at particularly high risk of perioperative stoke, such as those associated with frequent venous thromboembolism,” Kasner and Messé say.

However, at this point, physicians “should not interpret the study findings as suggesting the need for diagnostic testing and aggressive treatment of PFO prior to noncardiac surgeries,” they add.

Thaler said he is “happy for this kind of question to be out there, though. If it gets people stimulated to think about how to approach these issues, I think that's great.”

  • Ng reports no relevant conflicts of interest.
  • Eikermann reports receiving grants from Merck, personal fees (honoraria) from Merck, and funding from Jeffrey and Judith Buzen, as well as holding equity in Calabash Bioscience.
  • Thaler reports serving on the steering committee for the RESPECT study.
  • Kasner reports receiving grants from WL Gore and Associates and Bayer and personal fees for consulting from Bristol-Myers Squibb, Boehringer Ingelheim, and Daiichi Sankyo.
  • Messé reports receiving grants for research support from WL Gore and Associates, the National Institutes of Health, the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, and GlaxoSmithKline; and personal fees from the Yale Cardiovascular Research Group for participation on a clinical event committee and from Claret Medical for consulting services.

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