Real-world effectiveness and safety of tolvaptan in liver cirrhosis patients with hepatic edema: results from a post-marketing surveillance study (START study)

Abstract

Background: This large-scale post-marketing surveillance study (START study) evaluated the effectiveness and safety of tolvaptan in Japanese liver cirrhosis patients with hepatic edema in real-world clinical settings. Here, we present the final analysis outcomes.

Methods: A prospective, multicenter, non-interventional study involving patients who received tolvaptan for the treatment of liver cirrhosis with hepatic edema with an insufficient response to conventional diuretics. The observation period was up to 6 months. Effectiveness evaluation included changes in body weight and clinical symptoms. Safety analysis included evaluation of adverse drug reactions (ADRs).

Results: Case reports of 1111 patients were collected. Of these, 1109 were included in the safety analysis and 1098 in the effectiveness analysis. The mean age was 69.4 ± 11.5 years and 695 (62.7%) patients were male. After tolvaptan treatment, a decrease in body weight from baseline was - 2.6 ± 2.7 kg on day 7 and - 3.8 ± 4.1 kg on day 14. Moreover, clinical symptoms significantly improved over the 14-day treatment. Frequently reported ADRs were thirst (6.6%), hepatic encephalopathy (2.3%), dehydration (1.5%), and hypernatremia (1.2%). A serum sodium level of ≥ 150 mEq/L was reported in five patients (0.5%). Multivariate analyses showed that the baseline blood urea nitrogen (BUN) level (cut-off value: 22.4 mg/dL) was the predictive factor for tolvaptan treatment response.

Conclusions: The results suggest that tolvaptan was effective and well-tolerated in liver cirrhosis patients with hepatic edema. In the real-world clinical setting, tolvaptan provides a useful option for the treatment of hepatic edema.

Keywords: Ascites; Cirrhosis; Edema; Fibrosis; Tolvaptan.

Fig. 1

Dose of loop diuretic at the initiation of tolvaptan by year (2014–2016). The figure shows the dose of loop diuretic at different doses for years 2014–2016. The Cochran–Armitage test (P < 0.0001) was used for trend analysis of the dose (≤ 20 mg) of loop diuretics

Fig. 2

Changes in body weight (a) and disappearance/improvement rates in clinical symptoms (b) from pretreatment levels. Mean (SD) changes in body weight during the course of the study are provided. Disappearance/improvement rates are provided and ascites, lower limb edema and pleural effusion were rated based on the physician’s discretion

Fig. 3

Responder rates of tolvaptan by BUN level at baseline. BUN blood urea nitrogen. Responders were defined as those whose body weight reduced by ≥ 1.5 kg within 1 week of initiating tolvaptan treatment. The figure shows percentage responders at different levels of BUN. Patients who had paracentesis from day 1 to 7 of administration were excluded. The Cochran–Armitage test (P < 0.0001) was used for trend analysis of the responder rates