High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis.
Previous controlled trials are inconclusive regarding the efficacy of ursodeoxycholic acid (UDCA) for treating primary sclerosing cholangitis (PSC). One hundred fifty adult patients with PSC were enrolled in a long-term, randomized, double-blind controlled trial of high-dose UDCA (28-30 mg/kg/day) versus placebo. Liver biopsy and cholangiography were performed before randomization and after 5 years. The primary outcome measures were development of cirrhosis, varices, cholangiocarcinoma, liver transplantation, or death. The study was terminated after 6 years due to futility. At enrollment, the UDCA (n = 76) and placebo (n = 74) groups were similar with respect to sex, age, duration of disease, serum aspartate aminotransferase and alkaline phosphatase levels, liver histology, and Mayo risk score. During therapy, aspartate aminotransferase and alkaline phosphatase levels decreased more in the UDCA group than the placebo group (P < 0.01), but improvements in liver tests were not associated with decreased endpoints. By the end of the study, 30 patients in the UDCA group (39%) versus 19 patients in the placebo group (26%) had reached one of the pre-established clinical endpoints. After adjustment for baseline stratification characteristics, the risk of a primary endpoint was 2.3 times greater for patients on UDCA than for those on placebo (P < 0.01) and 2.1 times greater for death, transplantation, or minimal listing criteria (P = 0.038). Serious adverse events were more common in the UDCA group than the placebo group (63% versus 37% [P < 0.01]).


CONCLUSIONS
Long-term, high-dose UDCA therapy is associated with improvement in serum liver tests in PSC but does not improve survival and was associated with higher rates of serious adverse events.
Lindor
Keith D
KD
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA. lindor.keith@mayo.edu
Kowdley
Kris V
KV
Luketic
Velimir A C
VA
Harrison
M Edwyn
ME
McCashland
Timothy
T
Befeler
Alex S
AS
Harnois
Denise
D
Jorgensen
Roberta
R
Petz
Jan
J
Keach
Jill
J
Mooney
Jody
J
Sargeant
Carol
C
Braaten
Julie
J
Bernard
Tamara
T
King
Debra
D
Miceli
Ellen
E
Schmoll
Jeff
J
Hoskin
Tanya
T
Thapa
Prabin
P
Enders
Felicity
F
D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D002756:Cholagogues and Choleretics / Q000627:therapeutic use*; D015209:Cholangitis, Sclerosing / Q000188:drug therapy* / Q000401:mortality; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008111:Liver Function Tests; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid; D001219:Aspartate Aminotransferases; D000469:Alkaline Phosphatase; D001663:Bilirubin