Effect of Celiprolol on Prevention of Cardiovascular Events in Vascular Ehlers-Danlos Syndrome: A Prospective Randomised, Open, Blinded-Endpoints Trial

Lancet. 2010 Oct 30;376(9751):1476-84. doi: 10.1016/S0140-6736(10)60960-9. Epub 2010 Sep 7.

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.

Findings: 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.

Interpretation: 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.

Funding: French Ministry of Health, Programme Hospitalier de Recherche Clinique 2001.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenergic beta-Agonists / therapeutic use*
  • Adrenergic beta-Antagonists / therapeutic use*
  • Adult
  • Aneurysm, Dissecting / etiology
  • Aneurysm, Dissecting / prevention & control
  • Aneurysm, Ruptured / etiology
  • Aneurysm, Ruptured / prevention & control
  • Celiprolol / therapeutic use*
  • Collagen Type III / genetics
  • Ehlers-Danlos Syndrome / complications*
  • Ehlers-Danlos Syndrome / diagnosis
  • Ehlers-Danlos Syndrome / genetics
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Vascular Diseases / etiology
  • Vascular Diseases / prevention & control*
  • Young Adult

Substances

  • Adrenergic beta-Agonists
  • Adrenergic beta-Antagonists
  • COL3A1 protein, human
  • Collagen Type III
  • Celiprolol

Associated data

  • ClinicalTrials.gov/NCT00190411