Celiprolol Treatment of Patients With Vascular Ehlers-Danlos Syndrome

Abstract

Introduction: Vascular Ehlers-Danlos syndrome (vEDS) is a monogenetic disease caused by a mutation in procollagen 3A1. Clinical manifestations are arterial ruptures and dissections, as well as spontaneous ruptures of the colon, oesophagus and uterus. Expected survival is short, in historical cohorts approximately 50 years. In 2010 a French-Belgian randomized controlled trial (RCT), including 53 patients, reported a hazard ratio of only 0.36 of arterial events if patients were treated with the betablocker celiprolol [1], combining β1-adrenoceptor antagonist and β2-adrenoceptor agonist actions. The aim of this study is to report the feasibility and early outcome of celiprolol treatment in a cohort of patients with vEDS. Methods: This is a single centre series, although patients were referred from the entire country (with a population of 10 million) for assessment of a multidisciplinary team including vascular surgeons, angiologists and clinical geneticists. A prospective database was created with data on family history, previous and future clinical events, medication and side-effects. Celiprolol was administered twice daily, and titrated up by 100 mg steps every 6 months to a maximum of 400 mg per day, according to the same protocol as in the RCT. Logistic regression was used to analyse predictors of vascular events after the start of the treatment. Results: Thirty-three patients were offered treatment with celiprolol, 2011-2018. Median follow up time was 44 (range 1-78) months. Thirty-one patients had a verified mutation on COL3A1 gene. The treatment was initiated in 31 patients, while two patients abstained. Twelve patients have reached the target dose of 400 mg daily, during follow-up, and in seven patients dose uptitration is ongoing. Eleven patients experienced one or more side effects, preventing them from reaching the target dose, and two terminated the treatment for that reason. Five cases of major vascular events occurred during the time of the treatment. The following four were fatal: 1) Rupture of the ascending aorta with cardiac tamponade, 2) Aortic rupture after type B dissection, 3) Rupture of a cerebral aneurysm with subarachnoidal bleeding, and 4) Rupture of a pulmonary artery. The fifth patient (with a major vascular event) had a rupture of the splenic artery that was treated successfully with an endovascular Amplatzer plug. The two patients who were offered treatment but decided to wait, both developed severe complications: colonic perforation in one, and type B dissection in the other. The yearly risk of a major vascular event was 5% in this cohort, quite similar to that observed in the treatment-arm in the RCT (5%), but significantly lower than in the control-arm (12%). No significant predictor of vascular events was identified by logistic regression analysis. Conclusion: Treatment with celiprolol is tolerated in most vEDS patients, but less than half achieved the target dosage of 400 mg daily, during the observation period. Despite fatal vascular events, these observations suggest that celiprolol has a protective effect in vEDS. The number of patients in the cohort, and the length of follow up, is increasing. Thus, we will be able to report more definite results in the near future. Disclosure: Nothing to disclose