Society: AASLD

Background: Hepatorenal syndrome (HRS) with rapidly deteriorating kidney function can be effectively reversed when treated with terlipressin, the US FDA-approved vasopressin analogue. The Phase III placebo-controlled CONFIRM study demonstrated that verified HRS reversal was achieved in significantly more patients in the terlipressin group versus placebo (29.1% vs 15.8%; P=.012). However, clinical outcomes in patients with HRS may be influenced by the presence of alcoholic hepatitis (AH), which further confounds treatment options and harbors a poor prognosis. This subgroup analysis of the CONFIRM study assessed the efficacy of terlipressin in patients with HRS and AH.

Methods: The CONFIRM study enrolled adult patients with cirrhosis, ascites, and HRS with rapidly progressing kidney failure, defined per protocol as a doubling of serum creatinine to ≥2.25 mg/dL within 14 days (d) of randomization. Patients were randomly assigned 2:1 to terlipressin (1 mg by intravenous bolus every 6 hours) or placebo; concomitant albumin was recommended (1 g/kg on Day 1 up to 100 g then 20–40 g/d as clinically indicated). Diagnosis of baseline AH was via investigator assessment. Data was retrospectively analyzed in patients with AH for verified HRS reversal (defined as the percentage of patients with 2 serum creatinine values of ≤1.5 mg/dL ≥2 hours apart, while on treatment up to 72 hours after the last dose of study drug), admission to the intensive care unit (ICU), length of ICU stay, transplant-free survival at Day 90, and incidence of renal replacement therapy (RRT) by Day 30.

Results: In CONFIRM (N=300), 41% (81/199) of patients in the terlipressin group and 39% (39/101) of patients in the placebo group had AH at baseline. In the subgroup of patients with AH (n=120), the median Maddrey discriminant function score was similar across treatment groups (terlipressin, 96.9; placebo, 97.9; P=.681). Verified HRS reversal was achieved in 30.9% (25/81) of patients in the terlipressin group versus 7.7% (3/39) in the placebo group (P=.005) (Figure 1). Median transplant-free survival was 28 d for the terlipressin group versus 15 d for placebo (P=0.207) (Figure 2). Admission to the ICU was similar for patients in the terlipressin and placebo groups (17.3% [14/81] and 17.9% [7/39]); whereas mean length of stay in the ICU was shorter for terlipressin (6.9 d) versus the placebo group (12.4 d). There was a numerical decrease in RRT by Day 30 in the terlipressin versus placebo group (21.0% [17/81] vs 25.6% [10/39]).

Conclusions: In this cohort of patients with HRS and AH from CONFIRM, significantly more patients achieved verified HRS reversal with terlipressin than placebo. Additionally, in the terlipressin group numerical improvements in clinical outcomes included shorter duration of ICU stay, longer transplant-free survival, and lower incidence of RRT compared to placebo.

Inpatients with cirrhosis are prone to multi-organ failures, including respiratory distress (RD). Albumin use in these pts is often not evidence-based & can increase fluid overload and RD. Terlipressin+albumin increased RD in the CONFIRM trial but the determinants of RD in those not exposed to terlipressin are unclear. Aim: Determine predisposing factors, including AKI & albumin use for RD in a multi-center inpatient cirrhosis cohort.
Methods: We created a consortium of 11 North American centers that enrolled up to 50 consecutive non-electively hospitalized cirrhosis pts/center, excluding prior transplant, & those unable to consent. We collected baseline & hospital course demographics, cirrhosis severity, AKI, organ failures, ICU, death, & transplant data. AKI was defined using IAC definitions & Rx (albumin, midodrine, octreotide, & noradrenaline) were collected. RD was defined as ventilation due to respiratory issues and/or Pa02/FiO2 ratio< 200/Sp02/FiO2 ratio< 214. Significant variables on univariate analysis were used to perform a multi-variable logistic regression for RD development. Albumin use details (dose, evidence-based indication vs not) and impact on RD were also evaluated.
Results: 511 patients from 12 sites (57 yrs, 58% men) with median MELD of 23 were enrolled. Prior history: 64% had prior hospitalizations, 77% had ascites, 43% had HE, 26% variceal bleed, 21% had prior LVP & 16% were listed.
Admission medications: 28% were on Beta-blockers, 37% on rifaximin, 56% on lactulose, 17% on SBP prophylaxis & 60% on PPI.
Hospital course: 46% developed AKI & 53% of those patients developed stage≥ 2, 15% developed bilirubin >12mg/dl, 11% each with high INR & grade 3-4 HE & 10% with shock. 42% of AKI pts received daily midodrine, 33% received octreotide & 6% Noradrenaline. 29% were transferred to ICU, 4% died & 9% were transplanted.
RD Development: 19% developed RD; higher percent of AKI pts developed RD. Albumin use was higher in patients with RD with a dose-response (p=0.005, OR/10 gm=1.02, 1.01-1.03,Table).
Multivariable analysis: Only AKI development (OR 2.18, 1.33-3.59, p=0.002) and IV albumin (OR 2.58, 1.43-4.66, p=0.001) were independently and significantly predictive of RD. Demographics, MELD, medications, or other factors were non-contributory.
Albumin indication: 62% received albumin; more AKI pts received albumin (82% vs 45%, p<0.0001). In those receiving albumin, 134(43%) were for evidence-based reasons. 22% given albumin for only evidence-based, 26% for other reasons & 28% for both reasons developed RD (p=0.56).
Conclusions: In a multi-center study of inpatients with cirrhosis, RD developed in almost a fifth of patients, which was independently associated with AKI & IV Albumin use even without terlipressin. Almost half of albumin use was for non-evidence-based indications and had a dose-response with respiratory distress development.

<b>Inpatients with Cirrhosis who did or did not develop Respiratory Distress </b>

Inpatients with Cirrhosis who did or did not develop Respiratory Distress

Rajender Reddy

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