Safety of direct oral anticoagulants in patients with hereditary hemorrhagic telangiectasia

C. L. Shovlin, C. M. Millar, F. Droege, A. Kjeldsen, G. Manfredi, P. Suppressa, S. Ugolini, N. Coote, A. D. Fialla, U. Geisthoff, G. M. Lenato, H. J. Mager, F. Pagella, M. C. Post, C. Sabbà, U. Sure, P. M. Torring, S. Dupuis-Girod, E. Buscarini

Research output: Contribution to journalArticle

Abstract

Background: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular dysplasia resulting in visceral arteriovenous malformations and smaller mucocutaneous telangiectasia. Most patients experience recurrent nosebleeds and become anemic without iron supplementation. However, thousands may require anticoagulation for conditions such as venous thromboembolism and/or atrial fibrillation. Over decades, tolerance data has been published for almost 200 HHT-affected users of warfarin and heparins, but there are no published data for the newer direct oral anticoagulants (DOACs) in HHT. Methods: To provide such data, a retrospective audit was conducted across the eight HHT centres of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), in Denmark, France, Germany, Italy, the Netherlands and the UK. Results: Although HHT Centres had not specifically recommended the use of DOACs, 32 treatment episodes had been initiated by other clinicians in 28 patients reviewed at the Centres, at median age 65 years (range 30-84). Indications were for atrial fibrillation (16 treatment episodes) and venous thromboembolism (16 episodes). The 32 treatment episodes used Apixaban (n = 15), Rivaroxaban (n = 14), and Dabigatran (n = 3). HHT nosebleeds increased in severity in 24/32 treatment episodes (75%), leading to treatment discontinuation in 11 (34.4%). Treatment discontinuation was required for 4/15 (26.7%) Apixaban episodes and 7/14 (50%) Rivaroxaban episodes. By a 4 point scale of increasing severity, there was a trend for Rivaroxaban to be associated with a greater bleeding risk both including and excluding patients who had used more than one agent (age-adjusted coefficients 0.61 (95% confidence intervals 0.11, 1.20) and 0.74 (95% confidence intervals 0.12, 1.36) respectively. Associations were maintained after adjustment for gender and treatment indication. Extreme hemorrhagic responses, worse than anything experienced previously, with individual nosebleeds lasting hours requiring hospital admissions, blood transfusions and in all cases treatment discontinuation, occurred in 5/14 (35.7%) Rivaroxaban episodes compared to 3/15 (20%) Apixaban episodes and published rates of ~ 5% for warfarin and heparin. Conclusions: Currently, conventional heparin and warfarin remain first choice anticoagulants in HHT. If newer anticoagulants are considered, although study numbers are small, at this stage Apixaban appears to be associated with lesser bleeding risk than Rivaroxaban.

Original languageEnglish
Article number210
JournalOrphanet Journal of Rare Diseases
Volume14
Issue number1
DOIs
Publication statusPublished - Aug 28 2019

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Hereditary Hemorrhagic Telangiectasia
Anticoagulants
Safety
Epistaxis
Warfarin
Heparin
Venous Thromboembolism
Therapeutics
Atrial Fibrillation
Confidence Intervals
Hemorrhage
Telangiectasis
Arteriovenous Malformations
Denmark
Vascular Diseases
Blood Transfusion
Netherlands
Italy
France
Germany

Keywords

  • Apixaban
  • Atrial fibrillation
  • Dabigatran
  • Epistaxis
  • Heparin
  • Pulmonary emboli
  • Rivaroxaban
  • Venous thromboemboli
  • Warfarin

ASJC Scopus subject areas

  • Genetics(clinical)
  • Pharmacology (medical)

Cite this

Safety of direct oral anticoagulants in patients with hereditary hemorrhagic telangiectasia. / Shovlin, C. L.; Millar, C. M.; Droege, F.; Kjeldsen, A.; Manfredi, G.; Suppressa, P.; Ugolini, S.; Coote, N.; Fialla, A. D.; Geisthoff, U.; Lenato, G. M.; Mager, H. J.; Pagella, F.; Post, M. C.; Sabbà, C.; Sure, U.; Torring, P. M.; Dupuis-Girod, S.; Buscarini, E.

In: Orphanet Journal of Rare Diseases, Vol. 14, No. 1, 210, 28.08.2019.

Research output: Contribution to journalArticle

Shovlin, CL, Millar, CM, Droege, F, Kjeldsen, A, Manfredi, G, Suppressa, P, Ugolini, S, Coote, N, Fialla, AD, Geisthoff, U, Lenato, GM, Mager, HJ, Pagella, F, Post, MC, Sabbà, C, Sure, U, Torring, PM, Dupuis-Girod, S & Buscarini, E 2019, 'Safety of direct oral anticoagulants in patients with hereditary hemorrhagic telangiectasia', Orphanet Journal of Rare Diseases, vol. 14, no. 1, 210. https://doi.org/10.1186/s13023-019-1179-1
Shovlin, C. L. ; Millar, C. M. ; Droege, F. ; Kjeldsen, A. ; Manfredi, G. ; Suppressa, P. ; Ugolini, S. ; Coote, N. ; Fialla, A. D. ; Geisthoff, U. ; Lenato, G. M. ; Mager, H. J. ; Pagella, F. ; Post, M. C. ; Sabbà, C. ; Sure, U. ; Torring, P. M. ; Dupuis-Girod, S. ; Buscarini, E. / Safety of direct oral anticoagulants in patients with hereditary hemorrhagic telangiectasia. In: Orphanet Journal of Rare Diseases. 2019 ; Vol. 14, No. 1.
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abstract = "Background: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular dysplasia resulting in visceral arteriovenous malformations and smaller mucocutaneous telangiectasia. Most patients experience recurrent nosebleeds and become anemic without iron supplementation. However, thousands may require anticoagulation for conditions such as venous thromboembolism and/or atrial fibrillation. Over decades, tolerance data has been published for almost 200 HHT-affected users of warfarin and heparins, but there are no published data for the newer direct oral anticoagulants (DOACs) in HHT. Methods: To provide such data, a retrospective audit was conducted across the eight HHT centres of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), in Denmark, France, Germany, Italy, the Netherlands and the UK. Results: Although HHT Centres had not specifically recommended the use of DOACs, 32 treatment episodes had been initiated by other clinicians in 28 patients reviewed at the Centres, at median age 65 years (range 30-84). Indications were for atrial fibrillation (16 treatment episodes) and venous thromboembolism (16 episodes). The 32 treatment episodes used Apixaban (n = 15), Rivaroxaban (n = 14), and Dabigatran (n = 3). HHT nosebleeds increased in severity in 24/32 treatment episodes (75{\%}), leading to treatment discontinuation in 11 (34.4{\%}). Treatment discontinuation was required for 4/15 (26.7{\%}) Apixaban episodes and 7/14 (50{\%}) Rivaroxaban episodes. By a 4 point scale of increasing severity, there was a trend for Rivaroxaban to be associated with a greater bleeding risk both including and excluding patients who had used more than one agent (age-adjusted coefficients 0.61 (95{\%} confidence intervals 0.11, 1.20) and 0.74 (95{\%} confidence intervals 0.12, 1.36) respectively. Associations were maintained after adjustment for gender and treatment indication. Extreme hemorrhagic responses, worse than anything experienced previously, with individual nosebleeds lasting hours requiring hospital admissions, blood transfusions and in all cases treatment discontinuation, occurred in 5/14 (35.7{\%}) Rivaroxaban episodes compared to 3/15 (20{\%}) Apixaban episodes and published rates of ~ 5{\%} for warfarin and heparin. Conclusions: Currently, conventional heparin and warfarin remain first choice anticoagulants in HHT. If newer anticoagulants are considered, although study numbers are small, at this stage Apixaban appears to be associated with lesser bleeding risk than Rivaroxaban.",
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TY - JOUR

T1 - Safety of direct oral anticoagulants in patients with hereditary hemorrhagic telangiectasia

AU - Shovlin, C. L.

AU - Millar, C. M.

AU - Droege, F.

AU - Kjeldsen, A.

AU - Manfredi, G.

AU - Suppressa, P.

AU - Ugolini, S.

AU - Coote, N.

AU - Fialla, A. D.

AU - Geisthoff, U.

AU - Lenato, G. M.

AU - Mager, H. J.

AU - Pagella, F.

AU - Post, M. C.

AU - Sabbà, C.

AU - Sure, U.

AU - Torring, P. M.

AU - Dupuis-Girod, S.

AU - Buscarini, E.

PY - 2019/8/28

Y1 - 2019/8/28

N2 - Background: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular dysplasia resulting in visceral arteriovenous malformations and smaller mucocutaneous telangiectasia. Most patients experience recurrent nosebleeds and become anemic without iron supplementation. However, thousands may require anticoagulation for conditions such as venous thromboembolism and/or atrial fibrillation. Over decades, tolerance data has been published for almost 200 HHT-affected users of warfarin and heparins, but there are no published data for the newer direct oral anticoagulants (DOACs) in HHT. Methods: To provide such data, a retrospective audit was conducted across the eight HHT centres of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), in Denmark, France, Germany, Italy, the Netherlands and the UK. Results: Although HHT Centres had not specifically recommended the use of DOACs, 32 treatment episodes had been initiated by other clinicians in 28 patients reviewed at the Centres, at median age 65 years (range 30-84). Indications were for atrial fibrillation (16 treatment episodes) and venous thromboembolism (16 episodes). The 32 treatment episodes used Apixaban (n = 15), Rivaroxaban (n = 14), and Dabigatran (n = 3). HHT nosebleeds increased in severity in 24/32 treatment episodes (75%), leading to treatment discontinuation in 11 (34.4%). Treatment discontinuation was required for 4/15 (26.7%) Apixaban episodes and 7/14 (50%) Rivaroxaban episodes. By a 4 point scale of increasing severity, there was a trend for Rivaroxaban to be associated with a greater bleeding risk both including and excluding patients who had used more than one agent (age-adjusted coefficients 0.61 (95% confidence intervals 0.11, 1.20) and 0.74 (95% confidence intervals 0.12, 1.36) respectively. Associations were maintained after adjustment for gender and treatment indication. Extreme hemorrhagic responses, worse than anything experienced previously, with individual nosebleeds lasting hours requiring hospital admissions, blood transfusions and in all cases treatment discontinuation, occurred in 5/14 (35.7%) Rivaroxaban episodes compared to 3/15 (20%) Apixaban episodes and published rates of ~ 5% for warfarin and heparin. Conclusions: Currently, conventional heparin and warfarin remain first choice anticoagulants in HHT. If newer anticoagulants are considered, although study numbers are small, at this stage Apixaban appears to be associated with lesser bleeding risk than Rivaroxaban.

AB - Background: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular dysplasia resulting in visceral arteriovenous malformations and smaller mucocutaneous telangiectasia. Most patients experience recurrent nosebleeds and become anemic without iron supplementation. However, thousands may require anticoagulation for conditions such as venous thromboembolism and/or atrial fibrillation. Over decades, tolerance data has been published for almost 200 HHT-affected users of warfarin and heparins, but there are no published data for the newer direct oral anticoagulants (DOACs) in HHT. Methods: To provide such data, a retrospective audit was conducted across the eight HHT centres of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), in Denmark, France, Germany, Italy, the Netherlands and the UK. Results: Although HHT Centres had not specifically recommended the use of DOACs, 32 treatment episodes had been initiated by other clinicians in 28 patients reviewed at the Centres, at median age 65 years (range 30-84). Indications were for atrial fibrillation (16 treatment episodes) and venous thromboembolism (16 episodes). The 32 treatment episodes used Apixaban (n = 15), Rivaroxaban (n = 14), and Dabigatran (n = 3). HHT nosebleeds increased in severity in 24/32 treatment episodes (75%), leading to treatment discontinuation in 11 (34.4%). Treatment discontinuation was required for 4/15 (26.7%) Apixaban episodes and 7/14 (50%) Rivaroxaban episodes. By a 4 point scale of increasing severity, there was a trend for Rivaroxaban to be associated with a greater bleeding risk both including and excluding patients who had used more than one agent (age-adjusted coefficients 0.61 (95% confidence intervals 0.11, 1.20) and 0.74 (95% confidence intervals 0.12, 1.36) respectively. Associations were maintained after adjustment for gender and treatment indication. Extreme hemorrhagic responses, worse than anything experienced previously, with individual nosebleeds lasting hours requiring hospital admissions, blood transfusions and in all cases treatment discontinuation, occurred in 5/14 (35.7%) Rivaroxaban episodes compared to 3/15 (20%) Apixaban episodes and published rates of ~ 5% for warfarin and heparin. Conclusions: Currently, conventional heparin and warfarin remain first choice anticoagulants in HHT. If newer anticoagulants are considered, although study numbers are small, at this stage Apixaban appears to be associated with lesser bleeding risk than Rivaroxaban.

KW - Apixaban

KW - Atrial fibrillation

KW - Dabigatran

KW - Epistaxis

KW - Heparin

KW - Pulmonary emboli

KW - Rivaroxaban

KW - Venous thromboemboli

KW - Warfarin

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