High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis

Keith D. Lindor, Kris V. Kowdley, Velimir A C Luketic, M. Edwyn Harrison, Timothy McCashland, Alex S. Befeler, Denise Harnois, Roberta Jorgensen, Jan Petz, Jill Keach, Jody Mooney, Carol Sargeant, Tamara Bernard, Debra King, Ellen Miceli, Jeff Schmoll, Tanya Hoskin, Prabin Thapa, Felicity T Enders

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Abstract

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]). Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)808-814
Number of pages7
JournalHepatology
Volume50
Issue number3
DOIs
StatePublished - 2009

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Ursodeoxycholic Acid
Sclerosing Cholangitis
Placebos
Liver
Therapeutics
Aspartate Aminotransferases
Alkaline Phosphatase
Medical Futility
Cholangiocarcinoma
Cholangiography
Varicose Veins
Random Allocation
Serum
Liver Transplantation
Histology
Fibrosis
Transplantation
Outcome Assessment (Health Care)
Biopsy
Survival

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Lindor, K. D., Kowdley, K. V., Luketic, V. A. C., Harrison, M. E., McCashland, T., Befeler, A. S., ... Enders, F. T. (2009). High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology, 50(3), 808-814. https://doi.org/10.1002/hep.23082

High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. / Lindor, Keith D.; Kowdley, Kris V.; Luketic, Velimir A C; Harrison, M. Edwyn; McCashland, Timothy; Befeler, Alex S.; Harnois, Denise; Jorgensen, Roberta; Petz, Jan; Keach, Jill; Mooney, Jody; Sargeant, Carol; Bernard, Tamara; King, Debra; Miceli, Ellen; Schmoll, Jeff; Hoskin, Tanya; Thapa, Prabin; Enders, Felicity T.

In: Hepatology, Vol. 50, No. 3, 2009, p. 808-814.

Research output: Contribution to journalArticle

Lindor, KD, Kowdley, KV, Luketic, VAC, Harrison, ME, McCashland, T, Befeler, AS, Harnois, D, Jorgensen, R, Petz, J, Keach, J, Mooney, J, Sargeant, C, Bernard, T, King, D, Miceli, E, Schmoll, J, Hoskin, T, Thapa, P & Enders, FT 2009, 'High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis', Hepatology, vol. 50, no. 3, pp. 808-814. https://doi.org/10.1002/hep.23082
Lindor KD, Kowdley KV, Luketic VAC, Harrison ME, McCashland T, Befeler AS et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology. 2009;50(3):808-814. https://doi.org/10.1002/hep.23082
Lindor, Keith D. ; Kowdley, Kris V. ; Luketic, Velimir A C ; Harrison, M. Edwyn ; McCashland, Timothy ; Befeler, Alex S. ; Harnois, Denise ; Jorgensen, Roberta ; Petz, Jan ; Keach, Jill ; Mooney, Jody ; Sargeant, Carol ; Bernard, Tamara ; King, Debra ; Miceli, Ellen ; Schmoll, Jeff ; Hoskin, Tanya ; Thapa, Prabin ; Enders, Felicity T. / High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. In: Hepatology. 2009 ; Vol. 50, No. 3. pp. 808-814.
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AU - Lindor, Keith D.

AU - Kowdley, Kris V.

AU - Luketic, Velimir A C

AU - Harrison, M. Edwyn

AU - McCashland, Timothy

AU - Befeler, Alex S.

AU - Harnois, Denise

AU - Jorgensen, Roberta

AU - Petz, Jan

AU - Keach, Jill

AU - Mooney, Jody

AU - Sargeant, Carol

AU - Bernard, Tamara

AU - King, Debra

AU - Miceli, Ellen

AU - Schmoll, Jeff

AU - Hoskin, Tanya

AU - Thapa, Prabin

AU - Enders, Felicity T

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N2 - 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]). Conclusion: 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.

AB - 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]). Conclusion: 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.

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