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Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk meta-analysis.
J Hepatol. 2022 10; 77(4):1014-1025.JH

Abstract

BACKGROUND & AIMS

Whether non-selective β-blockers can prevent decompensation of cirrhosis warrants clarification. Carvedilol might be particularly effective since its intrinsic vasodilatory activity may ameliorate hepatic vascular resistance, a major mechanism of portal hypertension in early cirrhosis. We assessed whether carvedilol may prevent decompensation and improve survival in patients with compensated cirrhosis and clinically significant portal hypertension (CSPH).

METHODS

By systematic review we identified randomized-controlled trials (RCTs) comparing carvedilol vs. control therapy (no-active treatment or endoscopic variceal ligation [EVL]) in patients with cirrhosis and CSPH without previous bleeding. We performed a competing-risk time-to-event meta-analysis using individual patient data (IPD) obtained from principal investigators of RCTs. Only compensated patients were included. Primary outcomes were prevention of decompensation (liver transplantation and death were competing events) and death (liver transplantation was a competing event). Models were adjusted using propensity scores for baseline covariates with the inverse probability of treatment weighting (IPTW) approach.

RESULTS

Among 125 full-text studies evaluated, 4 RCTs were eligible. The 4 provided IPD and were included, comprising 352 patients with compensated cirrhosis, 181 treated with carvedilol and 171 controls (79 received EVL and 92 placebo). Baseline characteristics were similar between groups. Standardized differences were <10% by IPTW. The risk of developing decompensation of cirrhosis was lower with carvedilol than in controls (subdistribution hazard ratio [SHR] 0.506; 95% CI 0.289-0.887; p = 0.017; I2 = 0.0%, Q-statistic-p = 0.880), mainly due to a reduced risk of ascites (SHR 0.491; 95% CI 0.247-0.974; p = 0.042; I2 = 0.0%, Q-statistic-p = 0.384). The risk of death was also lower with carvedilol (SHR 0.417; 95% CI 0.194-0.896; p = 0.025; I2 = 0.0%, Q-statistic-p = 0.989).

CONCLUSIONS

Long-term carvedilol therapy reduced decompensation of cirrhosis and significantly improved survival in compensated patients with CSPH. This suggests that screening patients with compensated cirrhosis for CSPH to enable the prompt initiation of carvedilol could improve outcomes.

PROSPERO REGISTRATION NUMBER

CRD42019144786.

LAY SUMMARY

The transition from compensated cirrhosis to decompensated cirrhosis is associated with markedly reduced life expectancy. Therefore, preventing decompensation in patients with compensated cirrhosis would be associated with greatly improved patient outcomes. There has been controversy regarding the use of non-selective β-blockers (portal pressure-lowering medications) in patients with cirrhosis and elevated portal blood pressure (portal hypertension). Herein, using a competing-risk meta-analysis to optimize sample size and properly investigate cirrhosis as a multistate disease and outcomes as time-dependent events, we show that carvedilol (a non-selective β-blocker) is associated with a reduced risk of decompensating events and improved survival in patients with cirrhosis and portal hypertension.

Authors+Show Affiliations

Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, 08025, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain. Electronic address: cvillanueva@santpau.cat.Medical Statistics Core Facility, IDIBAPS, Hospital Clinic, Barcelona, Spain; Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India.Section of Gastroenterology, Aga Khan University, Karachi, Pakistan.University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, UK; Department of Hepatology, Royal Infirmary of Edinburgh, Edinburgh, UK.Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, 08025, Spain.Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland; Department of BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland.Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India.National Institute of Liver & GI Diseases, Dow University of Health Sciences, Karachi, Pakistan.Department of Hepatology, Royal Infirmary of Edinburgh, Edinburgh, UK.Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India.Section of Gastroenterology, Aga Khan University, Karachi, Pakistan.Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, 08025, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain.Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Department of BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland.No affiliation info available

Pub Type(s)

Journal Article
Meta-Analysis
Systematic Review
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

35661713

Citation

Villanueva, Càndid, et al. "Carvedilol Reduces the Risk of Decompensation and Mortality in Patients With Compensated Cirrhosis in a Competing-risk Meta-analysis." Journal of Hepatology, vol. 77, no. 4, 2022, pp. 1014-1025.
Villanueva C, Torres F, Sarin SK, et al. Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk meta-analysis. J Hepatol. 2022;77(4):1014-1025.
Villanueva, C., Torres, F., Sarin, S. K., Shah, H. A., Tripathi, D., Brujats, A., Rodrigues, S. G., Bhardwaj, A., Azam, Z., Hayes, P. C., Jindal, A., Abid, S., Alvarado, E., & Bosch, J. (2022). Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk meta-analysis. Journal of Hepatology, 77(4), 1014-1025. https://doi.org/10.1016/j.jhep.2022.05.021
Villanueva C, et al. Carvedilol Reduces the Risk of Decompensation and Mortality in Patients With Compensated Cirrhosis in a Competing-risk Meta-analysis. J Hepatol. 2022;77(4):1014-1025. PubMed PMID: 35661713.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk meta-analysis. AU - Villanueva,Càndid, AU - Torres,Ferran, AU - Sarin,Shiv Kumar, AU - Shah,Hasnain Ali, AU - Tripathi,Dhiraj, AU - Brujats,Anna, AU - Rodrigues,Susana G, AU - Bhardwaj,Ankit, AU - Azam,Zahid, AU - Hayes,Peter C, AU - Jindal,Ankur, AU - Abid,Shahab, AU - Alvarado,Edilmar, AU - Bosch,Jaume, AU - ,, Y1 - 2022/05/31/ PY - 2021/12/17/received PY - 2022/04/25/revised PY - 2022/05/09/accepted PY - 2022/6/7/pubmed PY - 2022/9/21/medline PY - 2022/6/6/entrez KW - Carvedilol KW - Clinically significant portal hypertension KW - Compensated cirrhosis KW - Prevention of cirrhosis decompensation KW - Primary Prophylaxis KW - β-blockers SP - 1014 EP - 1025 JF - Journal of hepatology JO - J Hepatol VL - 77 IS - 4 N2 - BACKGROUND & AIMS: Whether non-selective β-blockers can prevent decompensation of cirrhosis warrants clarification. Carvedilol might be particularly effective since its intrinsic vasodilatory activity may ameliorate hepatic vascular resistance, a major mechanism of portal hypertension in early cirrhosis. We assessed whether carvedilol may prevent decompensation and improve survival in patients with compensated cirrhosis and clinically significant portal hypertension (CSPH). METHODS: By systematic review we identified randomized-controlled trials (RCTs) comparing carvedilol vs. control therapy (no-active treatment or endoscopic variceal ligation [EVL]) in patients with cirrhosis and CSPH without previous bleeding. We performed a competing-risk time-to-event meta-analysis using individual patient data (IPD) obtained from principal investigators of RCTs. Only compensated patients were included. Primary outcomes were prevention of decompensation (liver transplantation and death were competing events) and death (liver transplantation was a competing event). Models were adjusted using propensity scores for baseline covariates with the inverse probability of treatment weighting (IPTW) approach. RESULTS: Among 125 full-text studies evaluated, 4 RCTs were eligible. The 4 provided IPD and were included, comprising 352 patients with compensated cirrhosis, 181 treated with carvedilol and 171 controls (79 received EVL and 92 placebo). Baseline characteristics were similar between groups. Standardized differences were <10% by IPTW. The risk of developing decompensation of cirrhosis was lower with carvedilol than in controls (subdistribution hazard ratio [SHR] 0.506; 95% CI 0.289-0.887; p = 0.017; I2 = 0.0%, Q-statistic-p = 0.880), mainly due to a reduced risk of ascites (SHR 0.491; 95% CI 0.247-0.974; p = 0.042; I2 = 0.0%, Q-statistic-p = 0.384). The risk of death was also lower with carvedilol (SHR 0.417; 95% CI 0.194-0.896; p = 0.025; I2 = 0.0%, Q-statistic-p = 0.989). CONCLUSIONS: Long-term carvedilol therapy reduced decompensation of cirrhosis and significantly improved survival in compensated patients with CSPH. This suggests that screening patients with compensated cirrhosis for CSPH to enable the prompt initiation of carvedilol could improve outcomes. PROSPERO REGISTRATION NUMBER: CRD42019144786. LAY SUMMARY: The transition from compensated cirrhosis to decompensated cirrhosis is associated with markedly reduced life expectancy. Therefore, preventing decompensation in patients with compensated cirrhosis would be associated with greatly improved patient outcomes. There has been controversy regarding the use of non-selective β-blockers (portal pressure-lowering medications) in patients with cirrhosis and elevated portal blood pressure (portal hypertension). Herein, using a competing-risk meta-analysis to optimize sample size and properly investigate cirrhosis as a multistate disease and outcomes as time-dependent events, we show that carvedilol (a non-selective β-blocker) is associated with a reduced risk of decompensating events and improved survival in patients with cirrhosis and portal hypertension. SN - 1600-0641 UR - https://www.unboundmedicine.com/medline/citation/35661713/Carvedilol_reduces_the_risk_of_decompensation_and_mortality_in_patients_with_compensated_cirrhosis_in_a_competing_risk_meta_analysis_ DB - PRIME DP - Unbound Medicine ER -