Efficacy of Irbesartan in Celiprolol-Treated Patients With Vascular Ehlers-Danlos Syndrome
Abstract
BACKGROUND: Vascular Ehlers-Danlos syndrome is a rare genetic disorder characterized by defective type III collagen and a high risk of arterial morbidity and mortality. Several cardiovascular drugs are used for treatment, including celiprolol, but no controlled trial in this condition has been conducted to date. We hypothesized the benefit of the addition of an angiotensin II receptor blocker. METHODS: A multicenter, randomized, placebo-controlled trial was conducted to assess the efficacy and safety of the angiotensin II receptor blocker irbesartan in adults with vascular Ehlers-Danlos syndrome on stable background celiprolol therapy. Patients were randomized 1:1 to receive irbesartan (150 mg/day titrated to 300 mg/day) or placebo for 2 years. The composite primary outcome was defined as any vascular Ehlers-Danlos syndrome–related fatal or nonfatal arterial event or any new or worsening arterial lesions detected by systematic head-to-pelvis computed tomography angiography or peripheral arterial duplex ultrasound at different time points, using a time-to-first-event analysis. RESULTS: Twenty-nine participants (62% female; 40.3±11.3 years of age) were randomized to irbesartan, and 28 (64% female; 40.7±11.0 years of age) were randomized to placebo. The composite primary outcome occurred in 8 of 29 patients (27.6%) receiving irbesartan versus 15 of 28 patients (53.6%) receiving placebo (hazard ratio, 0.42 [95% CI, 0.17, 0.99]; P <0.05). The risk of recurrent symptomatic or nonsymptomatic arterial events was lower with irbesartan than with placebo (risk ratio, 0.37 [95% CI, 0.19, 0.68]; P =0.002). A reduction of progression of arterial lesions was observed at all sites. Irbesartan significantly reduced systolic blood pressure compared with placebo (baseline-adjusted difference of 5.4 mm Hg [ P <0.001]), but no relation was observed with the reduction of the primary composite outcome. Eleven episodes of irbesartan-related hypotension were recorded, leading to a downtitration in 4 patients. CONCLUSIONS: Compared with placebo, irbesartan reduced the risk of severe symptomatic and asymptomatic arterial events in patients with vascular Ehlers-Danlos syndrome on background celiprolol therapy. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02597361.
Article Details
Authors (26)
Xavier Jeunemaitre
PARCC (X.J., E.M., P.B., T.M., G.C.), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité, France.
Elie Mousseaux
PARCC (X.J., E.M., P.B., T.M., G.C.), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité, France.
Michael Frank
AP-HP, Hôpital Européen Georges-Pompidou, Service de Médecine Vasculaire et Centre de Référence des Maladies Artérielles Rares (M.F., S.A., M.E.H., N.D., T.M.), AP-HP, Hôpital Européen Georges-Pompidou, Paris, France.
Salma Adham
AP-HP, Hôpital Européen Georges-Pompidou, Service de Médecine Vasculaire et Centre de Référence des Maladies Artérielles Rares (M.F., S.A., M.E.H., N.D., T.M.), AP-HP, Hôpital Européen Georges-Pompidou, Paris, France.
Francesca Pitocco
AP-HP, Hôpital Européen Georges-Pompidou, Service de Radiologie Vasculaire (E.M., F.P.), AP-HP, Hôpital Européen Georges-Pompidou, Paris, France.
Clarisse Billon
AP-HP, Hôpital Européen Georges-Pompidou, Service de Médecine Génomique des Maladies Rares et DMU BioPhyGen (X.J., C. Billon, M.B.Y.), AP-HP, Hôpital Européen Georges-Pompidou, Paris, France.
Molka Ben Yakhlef
AP-HP, Hôpital Européen Georges-Pompidou, Service de Médecine Génomique des Maladies Rares et DMU BioPhyGen (X.J., C. Billon, M.B.Y.), AP-HP, Hôpital Européen Georges-Pompidou, Paris, France.
Mohamed El Hachmi
AP-HP, Hôpital Européen Georges-Pompidou, Service de Médecine Vasculaire et Centre de Référence des Maladies Artérielles Rares (M.F., S.A., M.E.H., N.D., T.M.), AP-HP, Hôpital Européen Georges-Pompidou, Paris, France.
Alessandra Bura-Rivière
Service de Médecine Vasculaire, CHU de Toulouse, Hôpital Rangueil, Toulouse, France (A.B.-R., F.-X.L.).
François-Xavier Lapébie
Service de Médecine Vasculaire, CHU de Toulouse, Hôpital Rangueil, Toulouse, France (A.B.-R., F.-X.L.).
Claire Le Hello
Departement de Médecine Vasculaire, CHU Caen Normandie, Caen, France (C.L.H.).
Damien Lanéelle
Christophe Seinturier
Service de Médecine Vasculaire, CHU Grenoble Alpes, Grenoble, France (C.S.).
Klaus Dieterich
Service de Génétique Médicale, CHU Grenoble, Université Grenoble Alpes, INSERM 1209, Institut pour l’Avancée des Biosciences, Grenoble University Hospital, France (K.D.).
Marc Lambert
Unité Médico Chirurgicale Vasculaire, Service de Médecine Interne, Hôpital Claude Huriez, CHRU Lille, France (M.L.).
Sophie Dupuis-Girod
Genetic Department, Hôpital Femme–Mère–Enfant, Hospices Civils de Lyon, Bron, France
Stéphane Zuily
Laurence Bal-Theoleyre
AP-HM, CHU La Timone, Centre de Référence Pour le Syndrome de Marfan et Apparentés, Centre Aorte Timone, Université Aix-Marseille, Marseille, France (L.B.-T.).
Carine Boulon
Hôpital Saint-André, CHU Bordeaux, France (C. Boulon).
Pierrick Henneton
INSERM, Biosanté Unit U1292, Université Grenoble Alpes, CEA, Grenoble, France (S.D.-G., P.H.).
Estelle Lu
Nicolas Denarié
AP-HP, Hôpital Européen Georges-Pompidou, Service de Médecine Vasculaire et Centre de Référence des Maladies Artérielles Rares (M.F., S.A., M.E.H., N.D., T.M.), AP-HP, Hôpital Européen Georges-Pompidou, Paris, France.
Pierre Boutouyrie
Tristan Mirault
PARCC (X.J., E.M., P.B., T.M., G.C.), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité, France.
Gilles Chatellier
Michel Azizi
Université Paris Cité, INSERM CIC1418, France (M.A.).