Safety of direct oral anticoagulants in patients with hereditary hemorrhagic telangiectasia

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. Electronic supplementary material The online version of this article (10.1186/s13023-019-1179-1) contains supplementary material, which is available to authorized users.

Antithrombotic Therapy in Hereditary Hemorrhagic Telangiectasia: Real-World Data from the Gemelli Hospital HHT Registry

“…As already mentioned in the Introduction section, two other studies have recently evaluated whether HHT subjects tolerate AT [ 11 , 12 ]. These studies and ours have many similarities.…”

“…First, they include a similar number of HHT patients: 28 in the study by Shovlin et al [ 11 ], 23 in the study by Riera-Mestre et al [ 12 ], and 26 in our study. Additionally, all these studies have a retrospective design: Shovlin et al utilized the databases of VASCERN-participating centers [ 11 ], Riera-Mestre et al analyzed the RIETE Registry [ 12 ], and we studied the database of the HHT Center of our University Hospital. However, there are also important differences between our study and the other two.…”

“…In contrast, in our study, all patients had a ‘definite’ diagnosis of HHT and a genetic confirmation of the disease was present in 24 out of 26 patients. Another difference is that Shovlin et al and Riera-Mestre et al only studied subjects treated with anticoagulants (and only with DOACs in the case of Shovlin et al) [ 11 , 12 ], while we included individuals treated with antiplatelet medications. Additionally, the indications to treatment were different between these three studies.…”

“…Additionally, the indications to treatment were different between these three studies. In Shovlin’s study, all patients were affected by either AF or VTE [ 11 ], while Riera-Mestre et al only evaluated subjects with VTE [ 12 ]. In contrast, the patients investigated in our study had more heterogeneous indications to AT, which included stroke, MI, thromboprophylaxis, and other diseases.…”

“…One of the most recent studies that evaluated the safety of AT in subjects with HHT was carried out by the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), which retrospectively analyzed 28 HHT subjects treated with direct oral anticoagulants (DOACs) for either AF or VTE [ 11 ]. The result was that epistaxis worsened in 24 cases and in 11 cases patients had to discontinue treatment.…”