Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial.
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.
Ong
Kim-Thanh
KT
Assistance Publique, Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
Perdu
Jérôme
J
De Backer
Julie
J
Bozec
Erwan
E
Collignon
Patrick
P
Emmerich
Joseph
J
Fauret
Anne-Laure
AL
Fiessinger
Jean-Noël
JN
Germain
Dominique P
DP
Georgesco
Gabriella
G
Hulot
Jean-Sebastien
JS
De Paepe
Anne
A
Plauchu
Henri
H
Jeunemaitre
Xavier
X
Laurent
Stéphane
S
Boutouyrie
Pierre
P
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
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; C439971:COL3A1 protein, human; D024061:Collagen Type III; D017272:Celiprolol