TY - JOUR
T1 - Effects of sapropterin on endothelium-dependent vasodilation in patients with CADASIL
T2 - A randomized controlled trial
AU - De Maria, Renata
AU - Campolo, Jonica
AU - Frontali, Marina
AU - Taroni, Franco
AU - Federico, Antonio
AU - Inzitari, Domenico
AU - Tavani, Alessandra
AU - Romano, Silvia
AU - Puca, Emanuele
AU - Orzi, Francesco
AU - Francia, Ada
AU - Mariotti, Caterina
AU - Tomasello, Chiara
AU - Dotti, Maria Teresa
AU - Stromillo, Maria Laura
AU - Pantoni, Leonardo
AU - Pescini, Francesca
AU - Valenti, Raffaella
AU - Pelucchi, Claudio
AU - Parolini, Marina
AU - Parodi, Oberdan
PY - 2014/10/12
Y1 - 2014/10/12
N2 - BACKGROUND AND PURPOSE -: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare autosomal dominant disorder caused by NOTCH3 mutations, is characterized by vascular smooth muscle and endothelial cells abnormalities, altered vasoreactivity, and recurrent lacunar infarcts. Vasomotor function may represent a key factor for disease progression. Tetrahydrobiopterin, essential cofactor for nitric oxide synthesis in endothelial cells, ameliorates endothelial function. We assessed whether supplementation with sapropterin, a synthetic tetrahydrobiopterin analog, improves endothelium-dependent vasodilation in CADASIL patients. METHODS -: In a 24-month, multicenter randomized, double-blind, placebo-controlled trial, CADASIL patients aged 30 to 65 years were randomly assigned to receive placebo or sapropterin 200 to 400 mg BID. The primary end point was change in the reactive hyperemia index by peripheral arterial tonometry at 24 months. We also assessed the safety and tolerability of sapropterin. Analysis was done by intention-to-treat. RESULTS -: The intention-to-treat population included 61 patients. We found no significant difference between sapropterin (n=32) and placebo (n=29) in the primary end point (mean difference in reactive hyperemia index by peripheral arterial tonometry changes 0.19 [95% confidence interval, -0.18, 0.56]). Reactive hyperemia index by peripheral arterial tonometry increased after 24 months in 37% of patients on sapropterin and in 28% on placebo; however, after adjustment for age, sex, and clinical characteristics, improvement was not associated with treatment arm. The proportion of patients with adverse events was similar on sapropterin and on placebo (50% versus 48.3%); serious adverse events occurred in 6.3% versus 13.8%, respectively. CONCLUSIONS -: Sapropterin was safe and well-tolerated at the average dose of 5 mg/kg/day, but did not affect endothelium-dependent vasodilation in CADASIL patients. CLINICAL TRIAL REGISTRATION -: URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2007-004370-55.
AB - BACKGROUND AND PURPOSE -: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare autosomal dominant disorder caused by NOTCH3 mutations, is characterized by vascular smooth muscle and endothelial cells abnormalities, altered vasoreactivity, and recurrent lacunar infarcts. Vasomotor function may represent a key factor for disease progression. Tetrahydrobiopterin, essential cofactor for nitric oxide synthesis in endothelial cells, ameliorates endothelial function. We assessed whether supplementation with sapropterin, a synthetic tetrahydrobiopterin analog, improves endothelium-dependent vasodilation in CADASIL patients. METHODS -: In a 24-month, multicenter randomized, double-blind, placebo-controlled trial, CADASIL patients aged 30 to 65 years were randomly assigned to receive placebo or sapropterin 200 to 400 mg BID. The primary end point was change in the reactive hyperemia index by peripheral arterial tonometry at 24 months. We also assessed the safety and tolerability of sapropterin. Analysis was done by intention-to-treat. RESULTS -: The intention-to-treat population included 61 patients. We found no significant difference between sapropterin (n=32) and placebo (n=29) in the primary end point (mean difference in reactive hyperemia index by peripheral arterial tonometry changes 0.19 [95% confidence interval, -0.18, 0.56]). Reactive hyperemia index by peripheral arterial tonometry increased after 24 months in 37% of patients on sapropterin and in 28% on placebo; however, after adjustment for age, sex, and clinical characteristics, improvement was not associated with treatment arm. The proportion of patients with adverse events was similar on sapropterin and on placebo (50% versus 48.3%); serious adverse events occurred in 6.3% versus 13.8%, respectively. CONCLUSIONS -: Sapropterin was safe and well-tolerated at the average dose of 5 mg/kg/day, but did not affect endothelium-dependent vasodilation in CADASIL patients. CLINICAL TRIAL REGISTRATION -: URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2007-004370-55.
KW - CADASIL
KW - endothelium
KW - nitric oxide
KW - randomized controlled trial
KW - tetrahydrobiopterin
KW - vascular
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U2 - 10.1161/STROKEAHA.114.005937
DO - 10.1161/STROKEAHA.114.005937
M3 - Article
C2 - 25184356
AN - SCOPUS:84922480870
VL - 45
SP - 2959
EP - 2966
JO - Stroke
JF - Stroke
SN - 0039-2499
IS - 10
ER -