Abstract

Background: The CONFIRM trial revealed potential harm with terlipressin in a subset of patients, who developed respiratory failure. It remains unclear to what degree concomitant albumin contributes to the undesirable outcomes of terlipressin treatment. Using ATTIRE trial data, we compared safety of serum targeted albumin infusions to standard-of-care in patients with cirrhosis receiving terlipressin.

Methods: ATTIRE was a randomized controlled trial of albumin infusions in 777 patients hospitalized with cirrhosis and hypoalbuminemia (<3.0 g/dL). Patients were randomized to serum targeted albumin (STA) infusions, aiming for a serum albumin level >3.0 g/dL, or standard-of-care (SoC), where albumin infusions was allowed as per clinical guidelines. At trial enrollment, 42 patients received terlipressin in the STA group (STA+TP) and 41 in SoC group (SoC+TP). Patients not receiving terlipressin at enrollment, served as controls (STA-TP, n=338 and SoC-TP, n=356). We studied mortality at day 15 and complications from trial SAE reporting. The primary outcome was a composite of 15-day complication-free survival (15-day mortality, respiratory failure, pulmonary edema and fluid overload).

Results: Terlipressin indications were variceal bleed (74%), hepatorenal syndrome (23%) and hypotension (3%). Patients in the STA+TP group received higher albumin doses compared to the SoC+TP group (mean+SD: 209+125 grams vs. 96+162 grams, p<0.001). Baseline disease severity was similar between the two groups (median MELD: STA+TP=19 [15-23] vs. SoC+TP=18 [14-24], p=0.520). The STA+TP group had a significantly lower 15-day complication-free survival than the SoC+TP group (Figure, p=0.006). Compared to patients without terlipressin use at enrollment, the prognosis was also worse for STA+TP vs. STA-TP (p<0.001), but similar between SoC+TP and SoC-TP (p=0.809). Mortality rate during the 15-day follow-up was 21% in STA+TP and 7% in SoC+TP. The risk of respiratory failure was 7% (STA+TP) and 2% (SoC+TP), despite similar renal function at baseline (median creatinine: STA+TP=1.0 mg/dL [0.7-1.6] vs. SoC+TP=0.9 mg/dL [0.7-1.5], p=0.752). Adjusting for disease severity, the increased risk of 15-day mortality and complications persisted in the STA+TP group (sHR=5.63, 95% CI: 1.60; 19.86, p=0.007), independently of baseline MELD (HR=1.05, 95% CI: 1.02; 1.08, p=0.002). A subgroup analysis of variceal bleed patients treated with terlipressin, showed a markedly higher risk of 15-day mortality and complications in the STA+TP group (19%) compared to the SoC+TP group (0%, p=0.011).

Conclusion: High albumin doses, due to serum targeted albumin infusions, is associated with an increased risk of mortality and complications in patients with cirrhosis receiving terlipressin, independently of disease severity. These findings suggest a cautious use of concomitant albumin to terlipressin, outside current dosing recommendations and indications.