Chayakrit Krittanawong, MD is a clinician-scientist at Baylor College of Medicine, Houston, Texas. His primary research interests include precision medicine, bioinformatics, multi-omics, artificial intelligence (AI), deep learning, digital health, wearable technology, and preventive cardiology. Dr. Krittanawong serves on a member of an abstract review committee for the American Heart Association Scientific Sessions and he is extensively involved for the Council on Genomic and Precision Medicine (GPM) and the Council on Peripheral Vascular Disease (PVD). He is also serving on an editorial board for Journal of the American Heart Association (JAHA) and the European Heart Journal Digital health, as an advisory board of the Lancet Digital Health, and as the associate editor for the Journal of Scientific Innovation in Medicine.
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PFO Closure in PFO-related Stroke

Chayakrit Krittanawong, MD

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

Chayakrit Krittanawong, MD

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.”
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Big Data: The Double-Edged Sword

Chayakrit Krittanawong, MD

In today’s climate, industries often talk about the new buzz word of this era, Big data. In this case, Big data refers to data on the macro scale (mostly unorganized and unstructured). The utilization of Big data has tremendous potential for various industries, healthcare included. Facebook, Amazon, Netflix, for example, incorporate big data for their digital structures, creating algorithms to match customers with their interests. Some experts in discussing big data have described it as the three or four Vs; Volume rereferring to a large amount of data; Velocity referring to the timely generation of data; Variety rereferring to the multiple forms of data (e.g., genetics, emails, numbers, surveys); Veracity referring to the quality of the data. I recently discussed the potential of big data in medicine in my expert review article (https://www.tandfonline.com/doi/abs/10.1080/23808993.2018.1528871).

For example, Big data can be utilized to improve decision-making when combined with other emerging technology such as artificial intelligence or quantum internet. It is possible that Big data can combine clinical characteristics (e.g., high HbA1C, high cholesterol, hypertension), multi-omics (e.g., genes, protein, metabolites), lifestyle (e.g., smoking cigarettes, exercise, physical activities, sleep hygiene), and environmental factors (e.g., air pollution, PM2.5, traffic noises) with artificial intelligence in future clinical trials. (Figure) As Dr. Jacqueline Tamis-Holland discussed in the AHA meeting today, current clinical trials do not confirm the genotype-guided antiplatelet therapy. However, this remains just a pipe dream at the present moment. So far, all Big data techniques are primarily descriptive and retrospective. In the future, with advanced computational power (aka quantum computing), leveraging Big data in medicine is promising.

Source: Krittanawong et al. JACC 2017

Big data also has its limitations, and there are several lessons we must learn before implementing it effectively. First, big data is never well-curated and comes with a large degree of heterogeneity. Thus, selecting the correct technology with human power to curate Big data is crucial. Second, analytic companies can misinterpret big data by using incorrect research questions to test their hypothesis or using the wrong tool to analyze the associated data, resulting in delivering false messages. Surgisphere is a prime example of what can go wrong through the analysis of big data. Surgisphere claimed to collect data from over 1000 hospitals worldwide. Although this is possible and emerging technology can accomplish this task with minimal human resources, it is unlikely that this data can also be well-curated. In addition, healthcare data is challenging to work with, as the integration of electronic medical records (EHRs) and data privacy are primary barriers. Another example is the Cambridge Analytica case, where data obtained from Facebook was used without consent.

When appropriately utilized, Big data can be a game-changer for various industries, including the healthcare industry. This requires well-curated data, pertinent research questions, transparency, appropriate analytic tools, and advanced computational powers. In the wrong hands, Big data can be a potent threat that can disrupt industries as a whole.