Jamil, Khurram

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is associated with significant morbidity and mortality. While liver transplantation is the definitive treatment, continuous terlipressin infusion for HRS-AKI may provide benefit and, as such, was assessed in a population composed of candidates for liver transplant (LT). Fifty hospitalized LT-eligible patients with HRS-AKI received a single bolus followed by continuous terlipressin infusion. Acute-on-chronic liver failure grade 3, serum creatinine (SCr)>5.0 mg/dL, or Model for End-Stage Liver Disease (MELD) ≥35 were exclusions. Fifty hospitalized patients who received midodrine and octreotide or norepinephrine for HRS-AKI served as a historical comparator cohort. Complete response (CR) was defined as a ≥30% decrease in SCr with end-of-treatment (EOT) SCr≤1.5, partial response as a ≥30% decrease in SCr with EOT SCr>1.5, and nonresponse as a <30% decrease in SCr. CR rate was significantly higher in the terlipressin cohort compared to the historical cohort (64% vs. 16%, p<0.001). Survival, while numerically higher in those who received terlipressin, was statistically similar (D30: 94% vs. 82%, p=0.12; D90: 78% vs. 68%, p=0.37). Renal replacement therapy (RRT) was more common among terlipressin NR than CR and PR (70% vs. 3% vs. 13%, p < 0.001). EOT MELD and SCr were significantly lower within terlipressin cohort (MELD: 19 vs. 25, SCr: 1.4 vs. 2.1 mg/dL, p<0.001). Sixteen of 40 terlipressin-treated patients received LT-alone (terlipressin CR in 10/16). One patient on terlipressin had a hypoxic respiratory failure that responded to diuretics; one possibly had drug-related rash. With continuous terlipressin infusion, a CR rate of 64% was observed with a favorable safety profile. Terlipressin use was associated with lower EOT MELD and SCr than the historical midodrine and octreotide/norepinephrine cohort; LT-alone was accomplished in a high proportion of complete terlipressin responders.

Hepatorenal syndrome-acute kidney injury (HRS-AKI), a serious complication of decompensated cirrhosis, has limited therapeutic options and significant morbidity and mortality. Terlipressin improves renal function in some patients with HRS-1, while liver transplantation (LT) is a curative treatment for advanced chronic liver disease. Renal failure post-LT requiring renal replacement therapy (RRT) is a major risk factor for graft and patient survival. A post hoc analysis with a 12-month follow-up of LT recipients from a placebo-controlled trial of terlipressin (CONFIRM; NCT02770716) was conducted to evaluate the need for RRT and overall survival. Patients with HRS-1 were treated with terlipressin plus albumin or placebo plus albumin for up to 14 days. RRT was defined as any type of procedure that replaced kidney function. Outcomes compared between groups included the incidence of HRS-1 reversal, the need for RRT (pretransplant and posttransplant), and overall survival. Of the 300 patients in CONFIRM (terlipressin n = 199; placebo, n = 101), 70 (23%) underwent LT alone (terlipressin, n = 43; placebo, n = 27) and 5 had simultaneous liver-kidney transplant (terlipressin, n = 3, placebo, n = 2). The rate of HRS reversal was significantly higher in the terlipressin group compared with the placebo group (37%, n = 16 vs. 15%, n = 4; p = 0.033). The pretransplant need for RRT was significantly lower among those who received terlipressin (p = 0.007). The posttransplant need for RRT, at 12 months, was significantly lower among those patients who received terlipressin and were alive at Day 365, compared to placebo (p = 0.009). Pretransplant treatment with terlipressin plus albumin in patients with HRS-1 decreased the need for RRT pretransplant and posttransplant.

INTRODUCTION: Evidence on the comparison of treatments for hepatorenal syndrome-acute kidney injury (HRS-AKI) in a US population is limited. An indirect comparison of terlipressin plus albumin vs midodrine and octreotide plus albumin (MO) may provide further insight into treatment efficacy. METHODS: Cohorts of patients treated for HRS-AKI characterized by inclusion of patients with serum creatinine (SCr) <5 mg/dL and baseline acute-on-chronic liver failure grades 0–2 and exclusion of patients listed for transplant if model for end-stage liver disease scores ≥35 were pooled from (i) the CONFIRM and REVERSE randomized controlled trials (N = 159 meeting eligibility criteria from N = 216 overall, treated with terlipressin) and (ii) a retrospective review of medical records from 10 US tertiary hospitals (2016–2019; N = 55 treated with MO meeting eligibility criteria from N = 200 overall). The primary end point comparing the 2 cohorts was HRS reversal defined as achieving SCr ≤1.5 mg/dL at least once during the treatment. Covariate balancing propensity scoring was used to adjust for differences in baseline characteristics. RESULTS: HRS-AKI reversal was achieved in 52.35% of terlipressin-treated patients compared with 20% of MO-treated patients (adjusted mean difference 32.35%, 95% confidence interval [CI] 17.40–47.30, P < 0.0001). Terlipressin-treated patients had increased overall survival (adjusted hazard ratio 0.57, 95% CI 0.35–0.93, P = 0.02) but similar transplant-free survival (adjusted hazard ratio 0.79, 95% CI 0.53–1.17, P = 0.24). Achievement of HRS-AKI reversal was associated with increased OS and TFS regardless of treatment ( P < 0.001). DISCUSSION: Consistent with prior reports, terlipressin plus albumin is more effective in improving kidney function and achieving HRS-AKI reversal than MO plus albumin based on indirect comparison in a US population.

Key Points Hepatorenal syndrome type 1 (HRS-1) is an often fatal, but potentially reversible, kidney failure in patients with decompensated cirrhosis. Treatment with terlipressin in patients with HRS-1 is associated with a reduction in the need for RRT. Background Hepatorenal syndrome type 1 (HRS-1)—also known as hepatorenal syndrome-AKI (HRS-AKI)—is a rapidly progressing and usually fatal, but potentially reversible, kidney failure occurring in patients with decompensated cirrhosis. A large proportion of patients with HRS-1 require renal replacement therapy (RRT). Terlipressin demonstrated efficacy in reversing HRS and improving renal function in patients with HRS-1 in three phase III, randomized, clinical trials (RCTs; i.e. , OT-0401, REVERSE, and CONFIRM). However, these RCTs were not designed to evaluate the effect of terlipressin on the requirement of RRT. In this study, the effect of terlipressin on RRT requirements in the pooled phase III patient population was assessed. Methods For this retrospective analysis, data from patients who participated in the OT-0401, REVERSE, and CONFIRM studies were integrated in the largest-to-date randomized database ( N =608). Results The need for RRT was significantly decreased in patients in the terlipressin group versus the placebo group by day 30 (28.1% versus 35.9%, respectively; P = 0.040) and day 60 (30.1% versus 37.9%, respectively; P = 0.045) in the pooled population and also postliver transplantation (LT) at day 60 (20.5% versus 40.3%, respectively; P = 0.008) and day 90 (25.3% versus 43.1%, respectively; P = 0.018). More patients were alive and RRT-free by day 90 in the overall population (36.9% versus 28.5%; P = 0.030) and among patients who received an LT (60.0% versus 39.7%; P = 0.010). Random assignment to receive terlipressin was an independent positive predictor of avoidance of RRT ( P = 0.042); while higher baseline serum creatinine (sCr) level and Child-Pugh scores were negatively associated with RRT avoidance ( P < 0.001 and P = 0.040, respectively). Conclusions Terlipressin decreased the requirement of RRT compared with placebo among patients with HRS-1, including those receiving LT. A lower sCr level at the beginning of therapy was associated with avoidance of RRT.

Hepatorenal syndrome type 1 (HRS-1) is a serious complication of advanced cirrhosis and a potentially reversible form of acute kidney injury that is associated with rapidly deteriorating kidney function. Liver transplantation remains the only curative treatment for decompensated cirrhosis. However, terlipressin, a vasopressin analog, successfully reverses HRS-1, and may improve patient survival while awaiting liver transplantation. Patients with higher baseline serum creatinine have a reduced response to treatment with terlipressin. These post hoc analyses examined pooled data from 352 patients with HRS-1 treated with terlipressin in 3 North American-centric, Phase III, placebo-controlled clinical studies (i.e. OT-0401, REVERSE, and CONFIRM)—across 3 serum creatinine subgroups (i.e. <3, ≥3–<5, and ≥5 mg/dL)—to further delineate their correlation with HRS reversal, renal replacement therapy-free survival, and overall survival. Serum creatinine was significantly associated with HRS reversal in univariate and multivariate logistic regression analyses (P<0.001). The incidence of HRS reversal inversely correlated with serum creatinine subgroup (<3 mg/dL, 49.2%; ≥3–<5 mg/dL, 28.0%; ≥5 mg/dL, 9.1%). At Day 30 follow-up, renal replacement therapy-free survival was significantly higher for patients with HRS-1 in the lower serum creatinine subgroups than in the higher subgroup (<5 vs. >5 mg/dL; p=0.01). Terlipressin-treated patients with HRS-1, with a lower baseline serum creatinine level, had a higher overall survival (p<0.001) and higher transplant-free survival at Day 90 (p=0.04). Patients with HRS-1 and lower serum creatinine levels who were treated with terlipressin had higher HRS reversal and survival outcomes, highlighting the significant need to identify and treat patients with HRS-1 early when they often have lower serum creatinine levels, and likely a greater response to terlipressin.

Summary Background Previous studies suggested increased mortality in patients with hepatorenal syndrome type 1 (HRS1) and advanced acute‐on‐chronic liver failure (ACLF). Aim To assess mortality and respiratory failure (RF) in patients with HRS1 and ACLF treated with terlipressin. Methods In the CONFIRM study, we randomised 299 patients with HRS1 2:1 to terlipressin or placebo, both with albumin. At enrolment, all patients were assessed for organ failure (OF) using a validated ACLF grading system. Post hoc analyses assessed the effects of terlipressin vs. placebo on the incidence of RF and 90‐day mortality. Results The incidence of RF with terlipressin ( n = 200) was 9.4% in patients with grades 1–2 ACLF, and 30% with grade 3 ACLF ( p = 0.0002); no such difference was observed in placebo‐treated patients ( n = 99) (6.2% grades 1–2 vs. 0% grade 3 ACLF, p > 0.05). RF incidence between terlipressin and placebo in patients with grade 3 ACLF was significant ( p = 0.01). Baseline predictors of RF with terlipressin were INR ( p = 0.011), mean arterial pressure ( p = 0.037), and SpO 2 ( p = 0.014). Prior albumin as a continuous variable was not a predictor of RF. 90‐day survival between terlipressin and placebo arms was similar for grades 1–2 ACLF (55.5% and 56.6%, respectively), but lower for grade 3 ACLF (27.55% vs. 50.0%) ( p = 0.122), mainly related to RF. Conclusion Terlipressin should be used with caution in patients with HRS1 and grade 3 ACLF. Patients with hypoxaemia are at increased risk of RF and mortality.