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PFO Closure in PFO-related Stroke

Last week, Gore REDUCE study, a randomized open-label trial with a median duration of follow-up of 5.0 years [4.8 to 5.2] demonstrated that 1.8% of patients with PFO closure had recurrent ischemic strokes (hazard ratio, 0.31; 95% confidence interval, 0.13 to 0.76), compared with 5.4% patients who treated with an antiplatelet-only group (Figure).1 A patent foramen ovale (PFO) is far and away from the most common congenital heart defect with an estimated prevalence of 1 in 4 adults.  The FDA has previously approved the Amplatzer PFO Occluder device in 2016, however initial trials such as the RESPECT, PC, and CLOSER I trials did not show any benefit for PFO closure in the reduction of recurrent embolic stroke, compared to medical therapy. Interestingly, more recent trials conducted within the last 5 years, such as the DEFENSE‐PFO, REDUCE, CLOSE and RESPECT trials, demonstrated that PFO closure had reduced incidence of stroke compared to medical therapy. Given this influx of new evidence from recent trials, it has been suggested that PFO closure be considered in patients 60 years or younger with a PFO-related stroke. However, other potential etiologies such as atrial fibrillation (AF, requires at least 30 days of cardiac monitoring based on recent trials), autoimmune disorders, uncontrolled diabetes or hypertension must first be ruled out.

Last year, the 2020 practice advisory update summary by the American Academy of Neurology suggested that PFO closure probably reduces the risk of stroke recurrence with an HR of 0.41 with acceptable heterogeneity (I2 = 12%) and an absolute risk reduction of 3.4% at 5 years for patients with cryptogenic stroke and presence of a PFO based on meta-analyses using fixed-effect.2 This was unsurprising to me given the trends seen in the RESPECT and CLOSE trials. Interestingly, the report suggested an increased risk of developing AF with RR 3.12 in participants who received closure compared with those receiving medical treatment. This raised an interesting causality dilemma similar to the story of the chicken and the egg. Did these trials capture paroxysmal AF using 30 days of ambulatory monitoring and exclude those with paroxysmal AF prior to PFO closure? If that is the case, what was the primary mechanism for the development of AF after PFO closure? Atrial stunning? If a patient were to develop AF following PFO closure would that increase their risk of recurrent stroke?  And if so, is the risk of recurrent stroke higher or lower with PFO closure compared to those without PFO closure? Indeed, it would be interesting see which echo parameters are independent predictors of developing AF in PFO closure (after adjustment for potential confounders). Moreover, the American Academy of Neurology recommends (level C) that aspirin or anticoagulation may be considered in patients who opt to receive medical therapy alone without PFO closure.2 In fact, the comparison between PFO closure and systemic anticoagulation (e.g., DOAC) to prevent recurrent ischemic stroke remains unknown.

Switching gears, let us look at post-PFO closure management. Again, very limited data currently exists on the optimal duration of DAPT (dual antiplatelet therapy) after PFO closure. RESPECT and CLOSE used DAPT for 1 and 3 months, respectively, while some experts recommend ranges DAPT anywhere from 1 to 6 months. A European position paper on the management of PFO, suggested that following PFO closure patients should be on DAPT for 1-6 months followed by antiplatelet monotherapy for ≥5 years.3

In a nutshell, PFO closure should be considered for patients 60 years or younger with PFO-related stroke patients without the comorbidities of the previously mentioned risk factors.  A multidisciplinary discussion between neurology, geriatrics, and interventional cardiology are key in decision-making regarding PFO management.  Further research should include a randomized controlled trial regarding DAPT duration and the use of DOACs (direct oral anticoagulants) following PFO closure in patients with PFO-related left circulation embolism.

Credit: Figure from the New England Journal of Medicine 2021; 384:970-971

Reference

  1. Kasner SE, Rhodes JF, Andersen G, Iversen HK, Nielsen-Kudsk JE, Settergren M, Sjöstrand C, Roine RO, Hildick-Smith D, Spence JD, Søndergaard L; Gore REDUCE Clinical Study Investigators. Five-Year Outcomes of PFO Closure or Antiplatelet Therapy for Cryptogenic Stroke. N Engl J Med. 2021 Mar 11;384(10):970-971. doi: 10.1056/NEJMc2033779.
  2. Messé SR, Gronseth GS, Kent DM, Kizer JR, Homma S, Rosterman L, Carroll JD, Ishida K, Sangha N, Kasner SE. Practice advisory update summary: Patent foramen ovale and secondary stroke prevention: Report of the Guideline Subcommittee of the American Academy of Neurology. Neurology. 2020 May 19;94(20):876-885. doi: 10.1212/WNL.0000000000009443. Epub 2020 Apr 29.
  3. Pristipino C, Sievert H, D’Ascenzo F, Louis Mas J, Meier B, Scacciatella P, Hildick-Smith D, Gaita F, Toni D, Kyrle P, Thomson J, Derumeaux G, Onorato E, Sibbing D, Germonpré P, Berti S, Chessa M, Bedogni F, Dudek D, Hornung M, Zamorano J; Evidence Synthesis Team; Eapci Scientific Documents and Initiatives Committee; International Experts. European position paper on the management of patients with patent foramen ovale. General approach and left circulation thromboembolism. Eur Heart J. 2019 Oct 7;40(38):3182-3195. doi: 10.1093/eurheartj/ehy649.
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Post-Stroke Cognitive Impairment And Dementia And Risk Factors and Prevention

Dr. Rebecca Gottesman presented on Thursday during the Stroke Conference of 2021. She addressed the past, present, and future related to vascular dementia, mixed dementia, early stroke recovery, and precision medicine.

https://pubmed.ncbi.nlm.nih.gov/30784556/

In the past, the definition of post-stroke dementia was not necessarily uniform. She explains this is related to the term vascular dementia being sort of “tricky”. When classifying dementia you should consider, when you look, where you look, and whom you are looking at?

Many people can have dementia prior to having the stroke, this important when reviewing the prevalence rates after the stroke. Nearly 10% has dementia prior to stroke onset (1).

Dr. Gottesman highlights the need to review mixed pathologies for vascular dementia. The trajectories of onset and recovery vary between people. There can be a decline in cognition, followed by a recovery, then a further decline or an improvement. The Individual-level risk is important in post-stroke dementia.

https://www.ahajournals.org/doi/epub/10.1161/STROKEAHA.117.017319

Dr. Gottesman shared that the same stroke does not affect the person the same way (not every stroke leads to the same outcome). The individual risk profile will help individualize treatments and allow for more precision in medicine. She acknowledges that it is difficult to identify everyone who may have a stroke before they have an actual stroke. The meta-analysis from Oberlin highlights leisure activity as a potential way to reduce post-stroke dementia (2). Near the end of the presentation, Dr. Gottesman suggests we consider the following questions:

1) How do you consider aphasia and other cognitive deficits from the stroke?

2) How much time should pass after the stroke before you call it “dementia”?

3) How do you characterize dementia?

4) How do you characterize the dementia subtype?

5) How might future studies improve post-stroke cognitive outcomes?

We should consider the different prevention approaches due to the number of the different pathologies related to post-stroke dementia.

References

  1. Pendlebury ST, Rothwell PM. Incidence and prevalence of dementia associated with transient ischaemic attack and stroke: analysis of the population-based Oxford Vascular Study. The Lancet Neurology. 2019 Mar 1;18(3):248–58.
  2. Oberlin LE, Waiwood AM, Cumming TB, Marsland AL, Bernhardt J, Erickson KI. Effects of Physical Activity on Poststroke Cognitive Function: A Meta-Analysis of Randomized Controlled Trials. Stroke. 2017 Nov;48(11):3093–100.

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

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The “PFO Headache”: PFO closer in severe and refractory migraine

Migraine headaches are a heterogeneous and recurrent condition with multiple potential phenotypes, making long-term management and preventive treatment extremely challenging on clinicians. In the general population, the prevalence of migraine headaches is approximately 15% with a female-to-male ratio of 3:1.  Once diagnosed, simple analgesics should be used in mild to moderate cases, while triptans, -ditans, or -gepants should be used in the treatment of severe migraines. Emerging evidence has suggested that patent foramen ovale (PFO) may be associated with the development of migraines.  Surprisingly, at least half of people who suffer from migraines, particularly those with aura, have a PFO.[1, 2] It is important to consider that the prevalence in the general population is quite high, with an estimated prevalence of 20-25%. Indeed, most individuals with a PFO do not develop related health issues and remain generally asymptomatic. My theory is that the pathogenesis of refractory migraines, particularly those with an associated aura, is multifactorial including activation of neurons in the central or peripheral nervous system, hormonal dysregulation, structural changes (e.g., PFO), and genetic heterogeneity. Echo screening for PFO in severe and refractory migraines may be useful.

There is emerging evidence regarding PFO closure in patients with severe, refractory migraines based on several recent clinical trials (MIST, MIST II, ESCAPE, EASTFORM, PRIMA, and PREMIUM trials). These RCTs assessed the effect of PFO closure on preventing migraines.  Although they did not demonstrate a significant benefit of PFO closure (e.g., a significant reduction in migraine attacks at 6, 9 months or 1 year), these RCTS shed some light on the potential benefits of PFO closure (e.g., migraine improvement) in this population, compared to medical therapy alone. Interestingly, in a recent study published in JACC: Cardiovascular Interventions with a median follow up 3.2 [2.1 to 4.9] years, investigators found that PFO closure was associated with a significant improvement in migraine burden (headaches both with and without aura) and, notably, the absence of residual right-to-left shunt was a predictor of a significant reduction in migraine burden.[3] Emerging evidence suggests that both presence of PFO and migraine headaches have a genetic predisposition. I believe that migraines and PFOs are primarily heterogeneous polygenic disorders (except familial hemiplegic migraine – monogenic) and that the triage and algorithmic approach should be similar to that taken for patients with hypertrophic cardiomyopathy (HCM).  HCM is a monogenic disorder with an autosomal dominant pattern of inheritance, and a recent study showed that PFO and Migraine may be inherited in an autosomal dominant pattern as well. Overall, there are still many lessons to be learned from the HCM in order to adapt this methodology to the treatment of patients with PFO and migraines. A good place to start might be to determine whether PFO closure in migraines using the -omic approach (e.g., GWAS and PheWAS) to identify markers (e.g., SNP, metabolites associated with atrial stunning) is needed. Ideally, testing common genetic mutations in individuals (e.g., endocardial and neuronal alteration-related genes) with both PFO and migraine may a good start before a genome-driven clinical trial of prophylactic PFO closure. I proposed the algorithm to use genetic-guided PFO-migraine management. (Figure)

In the future, PFO screening in Migraine patients with high-risk features (e.g., genetic mutations and deep-sea divers) may be needed and PFO closure in these populations may be beneficial. Currently, there is a significant lack of genetic data in this area, and future clinical trials are needed to determine the potential benefit from PFO closure in patients who suffer from migraine headaches.

REFERENCES

  1. Niessen, K. and A. Karsan, Notch signaling in the developing cardiovascular system. Am J Physiol Cell Physiol, 2007. 293(1): p. C1-11.
  2. Sadrameli, S.S., et al., Patent Foramen Ovale in Cryptogenic Stroke and Migraine with Aura: Does Size Matter? Cureus, 2018. 10(8): p. e3213.
  3. Ben-Assa, E., et al., Effect of Residual Interatrial Shunt on Migraine Burden After Transcatheter Closure of Patent Foramen Ovale. JACC: Cardiovascular Interventions, 2020. 13(3): p. 293-302.

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”