Combination of granulocyte colony-stimulating factor and erythropoietin improves outcomes of patients with decompensated cirrhosis.
OBJECTIVE
Patients with decompensated cirrhosis have significantly reduced survival without liver transplantation. Granulocyte colony-stimulating factor (G-CSF) has been shown to increase survival in patients with acute-on-chronic liver failure, and erythropoietin promoted hepatic regeneration in animal studies. We performed a double-blind, randomized, placebo-controlled trial to determine whether co-administration of these growth factors improved outcomes for patients with advanced cirrhosis.


METHODS
In a prospective study, consecutive patients with decompensated cirrhosis seen at the Institute of Liver and Biliary Sciences, New Delhi (from May 2011 through June 2012) were randomly assigned to groups given subcutaneous G-CSF (5 μg/kg/d) for 5 days and then every third day (12 total doses), along with subcutaneous darbopoietin α(40 mcg/wk) for 4 weeks (GDP group, n = 29), or only placebos (control group, n = 26). All patients also received standard medical therapy and were followed for 12 months. Histology was performed on liver biopsies. The primary end point was survival at 12 months.


RESULTS
Baseline characteristics of patients were comparable; alcohol intake was the most common etiology of cirrhosis. A higher proportion of patients in the GDP group than controls survived until 12 months (68.6% vs 26.9%; P = .003). At 12 months, Child-Turcotte Pugh scores were reduced by 48.6% in the GDP group and 39.1% in the control group, from baseline (P = .001); Model for End Stage Liver Disease scores were reduced by 40.4% and 33%, respectively (P = .03). The need for large-volume paracentesis was significantly reduced in GDP group, compared with controls (P < .05). A lower proportion of patients in the GDP group developed septic shock (6.9%) during follow-up compared with controls (38.5%; P = .005). No major adverse events were observed in either group.


CONCLUSIONS
In a single-center randomized trial, a significantly larger proportion of patients with decompensated cirrhosis given a combination of G-CSF and darbopoietin α survived for 12 months more than patients given only placebo. The combination therapy also reduced liver severity scores and sepsis to a greater extent than placebo. Clinicaltrials.gov ID: NCT01384565.
Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
Chandan Kumar
CK
Kedarisetty
Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
Lovkesh
L
Anand
Department of Biostatistics and Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India.
Ankit
A
Bhardwaj
Department of Biostatistics and Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India.
Ajeet Singh
AS
Bhadoria
Department of Biostatistics and Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India.
Guresh
G
Kumar
Department of Biostatistics and Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India.
Ashish Kumar
AK
Vyas
Department of Biostatistics and Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India.
Paul
P
David
Department of Biostatistics and Clinical Research, Institute of Liver and Biliary Sciences, New Delhi, India.
Nirupama
N
Trehanpati
Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India.
Archana
A
Rastogi
Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India.
Chhagan
C
Bihari
Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
Rakhi
R
Maiwall
Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
Hitendra Kumar
HK
Garg
Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
Chitranshu
C
Vashishtha
Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
Manoj
M
Kumar
Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
Vikram
V
Bhatia
Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India. Electronic address: sksarin@ilbs.in.
Shiv Kumar
SK
Sarin
D000328:Adult; D001706:Biopsy; D000068256:Darbepoetin alfa; D018450:Disease Progression; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004921:Erythropoietin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007194:India; D007279:Injections, Subcutaneous; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000503:physiopathology; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D019152:Paracentesis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000209:etiology / Q000517:prevention & control; D013997:Time Factors; D016896:Treatment Outcome
D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D000068256:Darbepoetin alfa
Chronic Liver Disease; Clinical Trial; DPO; Liver Regeneration