Celiprolol Treatment in Patients with Vascular Ehlers-Danlos Syndrome

Hassan Baderkhan,Anders Wanhainen,Anna Stenborg,Eva-Lena Stattin,Martin Björck

doi:10.1016/j.ejvs.2020.10.020

Hassan Baderkhan, Anders Wanhainen + Show 3 more

Open Access

https://doi.org/10.1016/j.ejvs.2020.10.020

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Abstract

Vascular Ehlers-Danlos syndrome (vEDS) is a rare monogenetic disease caused by pathogenic variants in procollagen 3A1. Arterial rupture is the most serious clinical manifestation. A randomised controlled trial, the Beta-Blockers in Ehlers-Danlos Syndrome Treatment (BBEST) trial, reported a significant protective effect of the beta blocker celiprolol. The aim was to study the outcome of celiprolol treatment in a cohort of Swedish patients with vEDS. Uppsala is a national referral centre for patients with vEDS. They are assessed by vascular surgeons, angiologists, and clinical geneticists. Family history, previous and future clinical events, medication, and side effects are registered. Celiprolol was administered twice daily and titrated up to a maximum dose of 400mg daily. Logistic regression was used to analyse predictors of vascular events. Forty patients with pathogenic sequence variants in COL3A1 were offered treatment with celiprolol in the period 2011-2019. The median follow up was 22 months (range 1-98 months); total follow up was 106 patient years. In two patients, uptitration of the dose is ongoing. Of the remaining 38, 26 (65%) patients reached the target dose of 400mg daily. Dose uptitration was unsuccessful in six patients because of side effects; one died before reaching the maximum dose, and five terminated the treatment. Five major vascular events occurred; four were fatal (ruptured ascending aorta; aortic rupture after type B dissection; ruptured cerebral aneurysm; and ruptured pulmonary artery). One bled from a branch of the internal iliac artery, which was successfully coiled endovascularly. The annual risk of a major vascular event was 4.7% (n=5/106), similar to the treatment arm of the BBEST trial (5%) and lower than in the control arm of the same trial (12%). No significant predictor of vascular events was identified. Treatment with celiprolol is tolerated in most patients with vEDS. Despite fatal vascular events, these observations suggest that celiprolol may have a protective effect in vEDS.

Highlights

Ehlers-Danlos syndrome (EDS) is a heterogenous group of genetic connective tissue disorders, characterised by tissuePreliminary results on 33 patients were presented at the ESVS 33rd Annual Meeting, September 2019, in Hamburg, Germany.180%, have experienced at least one complication.[3,4] The most common cause of death is arterial rupture
The mean follow up index, measured from the initiation of celiprolol treatment to the last follow up date, divided by the time to 31 December 2019, was 0.83
Whole body magnetic resonance imaging (MRI) screening was performed in 19 patients and whole body computed tomography in two

Summary

Introduction

80%, have experienced at least one complication.[3,4] The most common cause of death is arterial rupture. The risks to pregnant women with vEDS is approximately 5% for pregnancy related death, which is mostly due to arterial complications.[5] In spite of this, it is not certain that avoiding pregnancy affects survival. Severe lacerations may be avoided.[6] Clinically, the disease is characterised by the presence of some of the Villefranche diagnostic criteria.[7] The diagnosis needs to be confirmed by molecular genetic analysis of COL3A1 or a biochemical test of the collagen (through tissue cultures of fibroblasts). Patients with vEDS have low intimae media thickness and high mechanical stress on the wall of elastic arteries, and an increased risk of arterial dissection and rupture.[8]

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