Limited Progress in Hepatorenal Syndrome (HRS) Reversal and Survival 2002-2018: A Systematic Review and Meta-Analysis

Abstract

Introduction: Type 1 hepatorenal syndrome (HRS) is a fatal complication of cirrhosis. Treatments trend toward HRS reversal, but few show clear mortality benefit. We sought to quantify the progress-or lack thereof-in improving outcomes of type 1 HRS over time.

Methods: We performed a systematic review and meta-analysis for randomized controlled trials (RCTs) comparing type 1 HRS outcomes including (a) overall survival (liver transplant-free survival if reported) and (b) HRS reversal. Each study arm was analyzed separately to look at changes in outcomes over time. RCTs published comparing medical treatments for type 1 HRS were searched using several databases through July 31, 2019.

Results: Fourteen RCTs (28 arms) involving 778 participants enrolled between 2002 and 2018 were included. Twelve RCTs measured HRS reversal. In conjunction with albumin (or plasma expander), the most common medications used were terlipressin (13 arms), antibiotics (7), norepinephrine (6), dopamine (4), and midodrine/octreotide (3). Pooled survival rate was 34.6% (95% CI 26.4-43.8), and pooled HRS reversal rate was 42.8% (95% CI 34.2-51.9). Regression analyzing the incremental effect of the year the RCT was initiated showed that more recent studies were not associated with improved survival (OR 1.02, 95% CI 0.94-1.11, p = 0.66) or HRS reversal rates (OR 1.03, 95% CI 0.96-1.11, p = 0.41). There was no survival improvement when RCTs with endpoints assessed ≤ or > 1 month were analyzed separately with respective OR of 1.07 (95% CI 0.95-1.20, p = 0.26) and 0.97 (95% CI 0.85-1.12, p = 0.70).

Conclusion: Outcomes have not improved for patients with type 1 HRS since 2002. There is a need to improve prevention and treatment of type 1 HRS.

Keywords: Acute kidney injury; Albumin; Antibiotics; Cirrhosis; Hepatorenal syndrome; Hypertension; Liver cirrhosis; Portal; Renal failure; Vasopressors.

Figure 1:

The Process of Study Selection.

Figure 2:

Methodological Quality of Studies using the Cochrane Risk of Bias Tool.

Figure 3:. Pooled Survival of Patients with Type 1 HRS Over Time.

Survival as reported in published papers, assessed at varying time points. Pooled survival calculated with the addition of each arm. (A): Survival Measured at Any Time Point from Diagnosis (B): Survival Measured ≤ 1 Month from Diagnosis (C): Survival Measured > 1 Month from Diagnosis Key: Abx: Antibiotics, Alb: Albumin, DA: Dopamine, FFP: Fresh Frozen Plasma, Furos: Furosemide, Inf: Infusion, M/O: Midodrine/Octreotide, NE: Norepinephrine, Plc: Placebo, Symptom: DA + Furos + Abx + “Plasma Expander”, Terl: Terlipressin.

Figure 3:. Pooled Survival of Patients with Type 1 HRS Over Time.

Survival as reported in published papers, assessed at varying time points. Pooled survival calculated with the addition of each arm. (A): Survival Measured at Any Time Point from Diagnosis (B): Survival Measured ≤ 1 Month from Diagnosis (C): Survival Measured > 1 Month from Diagnosis Key: Abx: Antibiotics, Alb: Albumin, DA: Dopamine, FFP: Fresh Frozen Plasma, Furos: Furosemide, Inf: Infusion, M/O: Midodrine/Octreotide, NE: Norepinephrine, Plc: Placebo, Symptom: DA + Furos + Abx + “Plasma Expander”, Terl: Terlipressin.

Figure 3:. Pooled Survival of Patients with Type 1 HRS Over Time.

Survival as reported in published papers, assessed at varying time points. Pooled survival calculated with the addition of each arm. (A): Survival Measured at Any Time Point from Diagnosis (B): Survival Measured ≤ 1 Month from Diagnosis (C): Survival Measured > 1 Month from Diagnosis Key: Abx: Antibiotics, Alb: Albumin, DA: Dopamine, FFP: Fresh Frozen Plasma, Furos: Furosemide, Inf: Infusion, M/O: Midodrine/Octreotide, NE: Norepinephrine, Plc: Placebo, Symptom: DA + Furos + Abx + “Plasma Expander”, Terl: Terlipressin.

Figure 4:. Survival by Subgroup.

Mean survival with 95% Confidence Intervals.

Figure 5:. Pooled HRS Reversal with Type 1 HRS Over Time.

HRS Reversal as reported in published papers, assessed at varying time points. Pooled survival calculated with the addition of each arm. Key: Abx: Antibiotics, Alb: Albumin, DA: Dopamine, FFP: Fresh Frozen Plasma, Furos: Furosemide, Inf: Infusion, M/O: Midodrine/Octreotide, NE: Norepinephrine, Plc: Placebo, Symptom: DA + Furos + Abx + “Plasma Expander”, Terl: Terlipressin.

Figure 6:. HRS Reversal by Subgroup.

Mean survival with 95% Confidence Intervals.