Current Patient Management Issues, Clinical Trial Design Challenges, and the Pathway Forward

  • John D. Carroll
  • Sharon Poisson
  • Michael S. Kim
Chapter

Abstract

Following the diagnosis and acute treatment of ischemic strokes, patients routinely undergo testing to classify the stroke in terms of potential causes. Ischemic strokes in the setting of a detected PFO may be differentiated into two major categories: (1) the negatively-defined cryptogenic category (i.e. the lack of a definitive cause with detection of a PFO) and (2) the cardio-embolic category where additional evidence supports a potential causal relationship with a paradoxical embolism related to PFO.

Uncertainty is common, both in determining the etiology of ischemic stroke and the management of patients with ischemic stroke who are found to have a PFO. Observational and some randomized clinical trial data provide supportive but not definitive data on the added benefits of PFO closure in secondary stroke prevention of select patients. Patients can be stratified as those most likely to benefit from PFO closure, those least likely, and those in whom uncertainty of the benefit of closure remains. The clinician must therefore provide an individualized approach to therapy in secondary stroke prevention strategies.

Clinical trials investigating the efficacy of PFO closure in the setting of secondary stroke prevention have faced numerous challenges, but the lessons learned have nonetheless been valuable. Additional focused research should lead to greater clarity as to the role of PFO closure.

Keywords

Patent foramen ovale Ischemic stroke Device closure Secondary prevention Paradoxical embolism TIA Venous thrombo-embolic disease 

References

  1. 1.
    Hankey GJ. Secondary stroke prevention. Lancet Neurol. 2014;13:178–94.PubMedCrossRefGoogle Scholar
  2. 2.
    Adams Jr HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, 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.PubMedCrossRefGoogle Scholar
  3. 3.
    Amarenco P, Bogousslavsky J, Caplan LR, Donnan GA, Wolf ME, Hennerici MG. The A-S-C-O-D phenotyping of ischemic stroke (updated ASCO phenotyping). Cerebrovasc Dis. 2013;36:1–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Cotter PE, Belham M, Martin PJ. Towards understanding the cause of stroke in young adults utilising a new stroke classification system (A-S-C-O). Cerebrovasc Dis. 2012;33:123–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Wolf ME, Sauer T, Alonso A, Hennerici MG. Comparison of the new ASCO classification with the TOAST classification in a population with acute ischemic stroke. J Neurol. 2012;259:1284–9.PubMedCrossRefGoogle Scholar
  6. 6.
    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;62:35–41. 9.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Stroke Risk in Atrial Fibrillation Working Group. Comparison of 12 risk stratification schemes to predict stroke in patients with nonvalvular atrial fibrillation. Stroke. 2008;39:1901–10.CrossRefGoogle Scholar
  8. 8.
    January CT, Wann LS, Alpert JS, Calkins H, Cleveland JC, Cigarroa JE, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. [Epub March 28, 2014].Google Scholar
  9. 9.
    Thaler DE, Ruthazer R, Weimar C. Recurrent stroke predictors differ in medically treated patients with pathogenic vs. other PFOs. Neurology. 2014;83:221–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology. 2013;81:619–25.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Thaler DE, Di Angelantonio E, Di Tullio MR, et al. The Risk of Paradoxical Embolism (RoPE) Study: initial description of the completed database. Int J Stroke. 2013;8:612–9.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Howick J, Glasziou P, Aronson JK. The evolution of evidence hierarchies: what can Bradford Hill’s ‘guidelines for causation’ contribute? J R Soc Med. 2009;102:186–94.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Carroll JD, Fuller CJ. RoPE: a safety line but tangles remain. Neurology. 2014;83:204–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Pristipino C, Anzola GP, Ballerini L, et al. Management of patients with patent foramen ovale and cryptogenic stroke: a collaborative, multidisciplinary position paper. Catheter Cardiovasc Interv. 2013;82:122–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Thaler DE, Kimmelstiel C. Do we know, or do we believe? Catheter Cardiovasc Interv. 2013;82:130–1.PubMedCrossRefGoogle Scholar
  16. 16.
    Carroll JD, Saver JL, Thaler DE, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med. 2013;368:1092–100.PubMedCrossRefGoogle Scholar
  17. 17.
    Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med. 2013;368:1083–91.PubMedCrossRefGoogle Scholar
  18. 18.
    Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012;366:991–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Pilgrim T, Meier B, Khattab AA. Death by patent foramen ovale in a soccer player. J Invasive Cardiol. 2013;25(3):162–4.PubMedGoogle Scholar
  20. 20.
    Stollberger C, Slany J, Schuster I, et al. The prevalence of deep venous thrombosis in patients with suspected paradoxical embolism. Ann Intern Med. 1993;119:461–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Lethen H, et al. Frequency of deep vein thrombosis in patients with patent foramen ovale and ischemic stroke or transient ischemic attack. Am J Cardiol. 1997;80:1066–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Ahn D, Brickner ME, Dowell J. Embolic stroke secondary to an indwelling catheter in a patient with a patent foramen ovale: a case report and review of the literature. http://www.hematologyandoncology.net/files/2013/05/ho0512_ahn3.pdf. Accessed 24 Mar 2014.
  23. 23.
    Michaels AD, Burlew BS. Pacemaker lead thrombus causing cryptogenic stroke in a patient referred for percutaneous patent foramen ovale closure. J Invasive Cardiol. 2009;21:224–5.Google Scholar
  24. 24.
    Desimone CV, Desimone DC, Hagler DJ, et al. Cardioembolic stroke in patients with patent foramen ovale and implanted cardiac leads. Pacing Clin Electrophysiol. 2013;36(1):50–4.PubMedCrossRefGoogle Scholar
  25. 25.
    DeSimone CV, Friedman PA, Noheria A, et al. Stroke or transient ischemic attack in patients with transvenous pacemaker or defibrillator and echocardiographically detected patent foramen ovale. Circulation. 2013;128:1433–41.PubMedCrossRefGoogle Scholar
  26. 26.
    Goodman LR. Small pulmonary emboli: what do we know? Radiology. 2005;23:654–8.CrossRefGoogle Scholar
  27. 27.
    Wiener RS, Schwartz LM, Woloshin S. When a test is too good: how CT pulmonary angiograms find pulmonary emboli that do not need to be found. BMJ. 2013;347:3368–75.CrossRefGoogle Scholar
  28. 28.
    Clergeau MR, et al. Silent cerebral infarcts in patients with pulmonary embolism and a patent foramen ovale: a prospective diffusion-weighted MRI study. Stroke. 2009;40:3758–62.PubMedCrossRefGoogle Scholar
  29. 29.
    Hassell MEC, Nijveldt R, Roos YBW, Majoi CBL, Hamon M, Piek JJ, Delewi R. Silent cerebral infarcts associated with cardiac disease and procedures. Nat Rev Cardiol. 2013;10:696–706.PubMedCrossRefGoogle Scholar
  30. 30.
    Windecker S, Meier B. Is closure recommended for patent foramen ovale and cryptogenic stroke? Circulation. 2008;118:1989–98.PubMedCrossRefGoogle Scholar
  31. 31.
    Schuchlenz HW, Sauerer G, Weihs W. Patent foramen ovale, atrial septal aneurysm, and recurrent stroke. N Engl J Med. 2002;346:1331–2.PubMedCrossRefGoogle Scholar
  32. 32.
    Hara H, Virmani R, Ladich E, et al. Patent foramen ovale: current pathology, pathophysiology, and clinical status. J Am Coll Cardiol. 2005;46(9):1768–76.PubMedCrossRefGoogle Scholar
  33. 33.
    Bang OY, Ovbiagele B, Kim JS. Evaluation of cryptogenic stroke with advanced diagnostic techniques. Stroke. 2014;45(4):1186–94.PubMedCrossRefGoogle Scholar
  34. 34.
    Jauss M, Wessels T, Trittmacher S, Allendörfer J, Kaps M. Embolic lesion pattern in stroke patients with patent foramen ovale compared with patients lacking an embolic source. Stroke. 2006;37(8):2159–61.PubMedCrossRefGoogle Scholar
  35. 35.
    Thaler DE, Ruthazer R, Di Angelantonio E, Di Tullio MR, Donovan JS, Elkind MSV, Griffith J, Homma S, Jaigobin C, Mas J-L, Mattle HP, Michel P, Mono M-L, Nedeltchev K, Papetti F, Serena J, Weimar C, Kent DM. Neuroimaging findings in cryptogenic stroke patients with and without patent foramen ovale. Stroke. 2013;44:675–80.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Etgen T, Hochreiter M, Mundel M, et al. Insertable cardiac event recorder in detection of atrial fibrillation after cryptogenic stroke. Stroke. 2013;44:2007–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Culebras A, Messé SR, Chaturvedi S, et al. Summary of evidence-based guideline update: prevention of stroke in nonvalvular atrial fibrillation: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014;82:716–24.PubMedCrossRefGoogle Scholar
  38. 38.
    Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, et al. American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Interdisciplinary Council on Quality of Care and Outcomes Research. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:227–76.Google Scholar
  39. 39.
    National institute for health and care excellence. http://www.nice.org.uk/nicemedia/live/14345/66095/66095.pdf. Accessed 24 Mar 2014.
  40. 40.
    Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, Dearani JA, del Nido P, Fasules JW, Graham Jr TP, Hijazi ZM, Hunt SA, King ME, Landzberg MJ, Miner PD, Radford MJ, Walsh EP, Webb GD. ACC/AHA 2008 guidelines for the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to develop guidelines for the management of adults with congenital heart disease). Circulation. 2008;118:2395–452.PubMedCrossRefGoogle Scholar
  41. 41.
    Carroll JD. Double standards in the world of ASD and PFO management: closure for paradoxical embolism. Catheter Cardiovasc Interv. 2009;74:1070–1.PubMedCrossRefGoogle Scholar
  42. 42.
    Cohen PR, Day D, De Lisio J, et al. Management of uncertainty in medicine. Int J Approx Reason. 1987;1:103–16.CrossRefGoogle Scholar
  43. 43.
    Hackam DG, Spence JD. Combining multiple approaches for the secondary prevention of vascular events after stroke: a quantitative modeling study. Stroke. 2007;38:1881–5.PubMedCrossRefGoogle Scholar
  44. 44.
    Carroll JD, Patrick-Lake B. Design of patent foramen ovale closure trials: the importance of patient-reported outcomes. Clin Invest. 2011;1(9):1251–5.CrossRefGoogle Scholar
  45. 45.
    FDA approval expands access to artificial heart valve for inoperable patients. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm369510.htm. Accessed 6 Apr 2014.
  46. 46.
    Mojadidi MK, Roberts SC, Winoker JS, Romero J, Goodman-Meza D, Gevorgyan R, Tobis JM. Accuracy of transcranial doppler for the diagnosis of intracardiac right-to-left shunt: a bivariate meta-analysis of prospective studies. J Am Coll Cardiol Img. 2014;7(3):236–50.CrossRefGoogle Scholar
  47. 47.
    Zoghby WA. Patent foramen ovale: going beyond the bubbles. JACC Cardiovasc Imaging. 2014;7(3):251–3.CrossRefGoogle Scholar
  48. 48.
    Alexandrov AV, Sloan MA, Tegeler CH, et al. American Society of Neuroimaging Practice Guidelines Committee. Practice standards for transcranial Doppler (TCD) ultrasound. Part II. Clinical indications and expected outcomes. J Neuroimaging. 2012;22:215–24.Google Scholar
  49. 49.
    Carroll JD, Edwards F, Marinac-Dabic D, Brindis R, Grover F, Peterson E, Tuczu M, Sahian D, Rumsfeld JS, Shewan C, Hewitt K, Holmes D, Mack M. The STS-ACC transcatheter valve therapy national registry: a new partnership and infrastructure for the introduction and surveillance of medical devices and therapies. J Am Coll Cardiol. 2013;62:1026–34.PubMedCrossRefGoogle Scholar
  50. 50.
    National cardiovascular data registry. https://www.ncdr.com/webncdr/. Accessed 6 Apr 2014.
  51. 51.
    Wöhrle J, Kochs M, Hombach V, Merkle N. Prevalence of myocardial scar in patients with cryptogenic cerebral ischemic events and patent foramen ovale. J Am Coll Cardiol Img. 2010;3:833–9.CrossRefGoogle Scholar
  52. 52.
    Kirk EP, Hyun C, Thomson PC, Lai D, Castro ML, Biben C, et al. Quantitative trait loci modifying cardiac atrial septal morphology and risk of patent foramen ovale in the mouse. Circ Res. 2006;98:651–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Belvís R, Tizzano EF, Martí-Fàbregas J, Leta RG, Manel Baena M, Carreras F, Pons-Lladó G, Baiget M, Martí-Vilalta JL. Mutations in the NKX2-5 gene in patients with stroke and patent foramen ovale. Clin Neurol Neurosurg. 2009;111:574–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Ning M, et al. The brain’s heart—therapeutic opportunities for patent foramen ovale (PFO) and neurovascular disease. Pharmacol Ther. 2013;139:111–23.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2015

Authors and Affiliations

  • John D. Carroll
    • 1
  • Sharon Poisson
    • 2
  • Michael S. Kim
    • 1
  1. 1.Division of CardiologyUniversity of Colorado DenverAuroraUSA
  2. 2.Division of Cardiology, Department of NeurologyUniversity of Colorado DenverAuroraUSA

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