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β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.
Lancet. 2019 Apr 20; 393(10181):1597-1608.Lct

Abstract

BACKGROUND

Clinical decompensation of cirrhosis is associated with poor prognosis. Clinically significant portal hypertension (CSPH), defined by a hepatic venous pressure gradient (HVPG) ≥10 mm Hg, is the strongest predictor of decompensation. This study aimed at assessing whether lowering HVPG with β blockers could decrease the risk of decompensation or death in compensated cirrhosis with CSPH.

METHODS

This study on β blockers to prevent decompensation of cirrhosis with portal hypertension (PREDESCI) was an investigator-initiated, double-blind, randomised controlled trial done in eight hospitals in Spain. We enrolled patients with compensated cirrhosis and CSPH without high-risk varices. All participants had HVPG measurements with assessment of acute HVPG-response to intravenous propranolol. Responders (HVPG-decrease ≥10%) were randomly assigned to propranolol (up to 160 mg twice a day) versus placebo and non-responders to carvedilol (≤25 mg/day) versus placebo. Doses were individually determined during an open-label titration period after which randomisation was done with 1:1 allocation by a centralised web-based system. The primary endpoint was incidence of cirrhosis decompensation (defined as development of ascites, bleeding, or overt encephalopathy) or death. Since death in compensated cirrhosis is usually unrelated to the liver, an intention-to-treat analysis considering deaths unrelated to the liver as competing events was done. This study is registered with ClinicalTrials.gov, number NCT01059396. The trial is now completed.

FINDINGS

Between Jan 18, 2010, and July 31, 2013, 631 patients were evaluated and 201 were randomly assigned. 101 patients received placebo and 100 received active treatment (67 propranolol and 33 carvedilol). The primary endpoint occurred in 16 (16%) of 100 patients in the β blockers group versus 27 (27%) of 101 in the placebo group (hazard ratio [HR] 0·51, 95% CI 0·26-0·97, p=0·041). The difference was due to a reduced incidence of ascites (HR=0·44, 95%CI=0·20-0·97, p=0·0297). The overall incidence of adverse events was similar in both groups. Six patients (four in the β blockers group) had severe adverse events.

INTERPRETATION

Long-term treatment with β blockers could increase decompensation-free survival in patients with compensated cirrhosis and CSPH, mainly by reducing the incidence of ascites.

FUNDING

Spanish Ministries of Health and Economy.

Authors+Show Affiliations

Hospital of Santa Creu and Sant Pau, Autonomous University of Barcelona, Hospital Sant Pau Biomedical Research Institute (IIB Sant Pau) Barcelona, Spain; Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), University of Alcalá, Madrid, Spain. Electronic address: cvillanueva@santpau.cat.Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), University of Alcalá, Madrid, Spain; Ramón y Cajal University Hospital, Ramón y Cajal Institute of Health Research (IRYCIS), University of Alcalá, Madrid, Spain.Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), University of Alcalá, Madrid, Spain; Liver Unit, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute (VHRI), Autonomous University of Barcelona, Barcelona, Spain.Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), University of Alcalá, Madrid, Spain; Barcelona Hepatic Haemodynamic Laboratory, Liver Unit, Institute of Digestive and Metabolic Diseases, August Pi i Sunyer Institute of Biomedical Research, Hospital Clínic, Barcelona, Spain.Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), University of Alcalá, Madrid, Spain; Puerta de Hierro University Hospital, Puerta de Hierro Hospital Research Institute, Autonomous University of Madrid, Madrid, Spain.Institute of Biomedical Research, Arnau de Vilanova University Hospital (IRBLleida), Lleida, Spain.Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), University of Alcalá, Madrid, Spain; Gregorio Marañón University General Hospital, Gregorio Marañón Sanitary Research Institute, Faculty of Medicine, Complutense University of Madrid, Spain.Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), University of Alcalá, Madrid, Spain; University Hospital Germans Trias i Pujol, Badalona, Spain.Hospital of Santa Creu and Sant Pau, Autonomous University of Barcelona, Hospital Sant Pau Biomedical Research Institute (IIB Sant Pau) Barcelona, Spain; Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), University of Alcalá, Madrid, Spain.Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), University of Alcalá, Madrid, Spain; Ramón y Cajal University Hospital, Ramón y Cajal Institute of Health Research (IRYCIS), University of Alcalá, Madrid, Spain.Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), University of Alcalá, Madrid, Spain; Liver Unit, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute (VHRI), Autonomous University of Barcelona, Barcelona, Spain.Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), University of Alcalá, Madrid, Spain; Barcelona Hepatic Haemodynamic Laboratory, Liver Unit, Institute of Digestive and Metabolic Diseases, August Pi i Sunyer Institute of Biomedical Research, Hospital Clínic, Barcelona, Spain; University of Alberta, Edmonton, Canada.Hospital of Santa Creu and Sant Pau, Autonomous University of Barcelona, Hospital Sant Pau Biomedical Research Institute (IIB Sant Pau) Barcelona, Spain; Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), University of Alcalá, Madrid, Spain.Medical Statistics Core Facility, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic, Barcelona; Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, Barcelona, Spain.Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), University of Alcalá, Madrid, Spain; Barcelona Hepatic Haemodynamic Laboratory, Liver Unit, Institute of Digestive and Metabolic Diseases, August Pi i Sunyer Institute of Biomedical Research, Hospital Clínic, Barcelona, Spain; Inselspital, Bern University, Switzerland.

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial

Language

eng

PubMed ID

30910320

Citation

Villanueva, Càndid, et al. "Β Blockers to Prevent Decompensation of Cirrhosis in Patients With Clinically Significant Portal Hypertension (PREDESCI): a Randomised, Double-blind, Placebo-controlled, Multicentre Trial." Lancet (London, England), vol. 393, no. 10181, 2019, pp. 1597-1608.
Villanueva C, Albillos A, Genescà J, et al. Β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2019;393(10181):1597-1608.
Villanueva, C., Albillos, A., Genescà, J., Garcia-Pagan, J. C., Calleja, J. L., Aracil, C., Bañares, R., Morillas, R. M., Poca, M., Peñas, B., Augustin, S., Abraldes, J. G., Alvarado, E., Torres, F., & Bosch, J. (2019). Β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet (London, England), 393(10181), 1597-1608. https://doi.org/10.1016/S0140-6736(18)31875-0
Villanueva C, et al. Β Blockers to Prevent Decompensation of Cirrhosis in Patients With Clinically Significant Portal Hypertension (PREDESCI): a Randomised, Double-blind, Placebo-controlled, Multicentre Trial. Lancet. 2019 Apr 20;393(10181):1597-1608. PubMed PMID: 30910320.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial. AU - Villanueva,Càndid, AU - Albillos,Agustín, AU - Genescà,Joan, AU - Garcia-Pagan,Joan C, AU - Calleja,José L, AU - Aracil,Carles, AU - Bañares,Rafael, AU - Morillas,Rosa M, AU - Poca,María, AU - Peñas,Beatriz, AU - Augustin,Salvador, AU - Abraldes,Juan G, AU - Alvarado,Edilmar, AU - Torres,Ferran, AU - Bosch,Jaume, Y1 - 2019/03/22/ PY - 2018/05/10/received PY - 2018/08/03/revised PY - 2018/08/07/accepted PY - 2019/3/27/pubmed PY - 2019/5/2/medline PY - 2019/3/27/entrez SP - 1597 EP - 1608 JF - Lancet (London, England) JO - Lancet VL - 393 IS - 10181 N2 - BACKGROUND: Clinical decompensation of cirrhosis is associated with poor prognosis. Clinically significant portal hypertension (CSPH), defined by a hepatic venous pressure gradient (HVPG) ≥10 mm Hg, is the strongest predictor of decompensation. This study aimed at assessing whether lowering HVPG with β blockers could decrease the risk of decompensation or death in compensated cirrhosis with CSPH. METHODS: This study on β blockers to prevent decompensation of cirrhosis with portal hypertension (PREDESCI) was an investigator-initiated, double-blind, randomised controlled trial done in eight hospitals in Spain. We enrolled patients with compensated cirrhosis and CSPH without high-risk varices. All participants had HVPG measurements with assessment of acute HVPG-response to intravenous propranolol. Responders (HVPG-decrease ≥10%) were randomly assigned to propranolol (up to 160 mg twice a day) versus placebo and non-responders to carvedilol (≤25 mg/day) versus placebo. Doses were individually determined during an open-label titration period after which randomisation was done with 1:1 allocation by a centralised web-based system. The primary endpoint was incidence of cirrhosis decompensation (defined as development of ascites, bleeding, or overt encephalopathy) or death. Since death in compensated cirrhosis is usually unrelated to the liver, an intention-to-treat analysis considering deaths unrelated to the liver as competing events was done. This study is registered with ClinicalTrials.gov, number NCT01059396. The trial is now completed. FINDINGS: Between Jan 18, 2010, and July 31, 2013, 631 patients were evaluated and 201 were randomly assigned. 101 patients received placebo and 100 received active treatment (67 propranolol and 33 carvedilol). The primary endpoint occurred in 16 (16%) of 100 patients in the β blockers group versus 27 (27%) of 101 in the placebo group (hazard ratio [HR] 0·51, 95% CI 0·26-0·97, p=0·041). The difference was due to a reduced incidence of ascites (HR=0·44, 95%CI=0·20-0·97, p=0·0297). The overall incidence of adverse events was similar in both groups. Six patients (four in the β blockers group) had severe adverse events. INTERPRETATION: Long-term treatment with β blockers could increase decompensation-free survival in patients with compensated cirrhosis and CSPH, mainly by reducing the incidence of ascites. FUNDING: Spanish Ministries of Health and Economy. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/30910320/β_blockers_to_prevent_decompensation_of_cirrhosis_in_patients_with_clinically_significant_portal_hypertension__PREDESCI_:_a_randomised_double_blind_placebo_controlled_multicentre_trial_ DB - PRIME DP - Unbound Medicine ER -