title: Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial.
abstract: BACKGROUND
  Vascular Ehlers-Danlos syndrome is a rare severe disease that causes arterial dissections and ruptures that can lead to early death. No preventive treatment has yet been validated. Our aim was to assess the ability of celiprolol, a β(1)-adrenoceptor antagonist with a β(2)-adrenoceptor agonist action, to prevent arterial dissections and ruptures in vascular Ehlers-Danlos syndrome.
  
  
  METHODS
  Our study was a multicentre, randomised, open trial with blinded assessment of clinical events in eight centres in France and one in Belgium. Patients with clinical vascular Ehlers-Danlos syndrome were randomly assigned to 5 years of treatment with celiprolol or to no treatment. Randomisation was done from a centralised, previously established list of sealed envelopes with stratification by patients' age (≤32 years or >32 years). 33 patients were positive for mutation of collagen 3A1 (COL3A1). Celiprolol was administered twice daily and uptritrated by 100 mg steps every 6 months to a maximum of 400 mg per day. [DOSAGE ERROR CORRECTED]. The primary endpoints were arterial events (rupture or dissection, fatal or not). This study is registered with ClinicalTrials.gov, number NCT00190411.
  
  
  RESULTS
  53 patients were randomly assigned to celiprolol (25 patients) or control groups (28). Mean duration of follow-up was 47 (SD 5) months, with the trial stopped early for treatment benefit. The primary endpoints were reached by five (20%) in the celiprolol group and by 14 (50%) controls (hazard ratio [HR] 0·36; 95% CI 0·15-0·88; p=0·040). Adverse events were severe fatigue in one patient after starting 100 mg celiprolol and mild fatigue in two patients related to dose uptitration.
  
  
  CONCLUSIONS
  We suggest that celiprolol might be the treatment of choice for physicians aiming to prevent major complications in patients with vascular Ehlers-Danlos syndrome. Whether patients with similar clinical presentations and no mutation are also protected remains to be established.
  
  
  BACKGROUND
  French Ministry of Health, Programme Hospitalier de Recherche Clinique 2001.
authors.affiliation: Assistance Publique, Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Kim-Thanh
authors.initials: KT
authors.lastname: Ong
authors.forename: Jérôme
authors.initials: J
authors.lastname: Perdu
authors.forename: Julie
authors.initials: J
authors.lastname: De Backer
authors.forename: Erwan
authors.initials: E
authors.lastname: Bozec
authors.forename: Patrick
authors.initials: P
authors.lastname: Collignon
authors.forename: Joseph
authors.initials: J
authors.lastname: Emmerich
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Fauret
authors.forename: Jean-Noël
authors.initials: JN
authors.lastname: Fiessinger
authors.forename: Dominique P
authors.initials: DP
authors.lastname: Germain
authors.forename: Gabriella
authors.initials: G
authors.lastname: Georgesco
authors.forename: Jean-Sebastien
authors.initials: JS
authors.lastname: Hulot
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Henri
authors.initials: H
authors.lastname: Plauchu
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.forename: Stéphane
authors.initials: S
authors.lastname: Laurent
authors.forename: Pierre
authors.initials: P
authors.lastname: Boutouyrie
mesh_terms: D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000328:Adult; D000784:Aortic Dissection / Q000209:etiology / Q000517:prevention & control; D017542:Aneurysm, Ruptured / Q000209:etiology / Q000517:prevention & control; D017272:Celiprolol / Q000627:therapeutic use*; D024061:Collagen Type III / Q000235:genetics; D004535:Ehlers-Danlos Syndrome / Q000150:complications* / Q000175:diagnosis / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D014652:Vascular Diseases / Q000209:etiology / Q000517:prevention & control*; D055815:Young Adult
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; C439971:COL3A1 protein, human; D024061:Collagen Type III; D017272:Celiprolol