PPIs tied to elevated mortality risk in decompensated cirrhosis

Extended exposure to proton pump inhibitors (PPIs) may raise mortality risk in individuals with decompensated cirrhosis, according to a Singapore study.

“In our study of patients with decompensated liver cirrhosis, PPI users had twice the risk of mortality … compared to non-users … and were 61 percent more likely to have hospitalization for hepatic decompensation than non-users,” said the researchers.

The study was conducted using data of 295 adults who had been hospitalized at Changi General Hospital, Singapore, between January 2013 and June 2017 for decompensated liver cirrhosis. Of these, 238 used PPIs (mean age 63.3 years, 68.1 percent male), defined in this study as a cumulative defined daily dose (cDDD)of ≥28 between 3 months prior and 6 months following the hospitalization for hepatic decompensation. Fifty-seven patients were not using PPIs (mean age 60 years, 68.4 percent male).

Landmark analysis at 6 months showed that PPI users had a higher overall mortality (death or liver transplant*) risk than non-users (42.9 percent vs 22.8 percent; adjusted hazard ratio [adjHR], 2.10, 95 percent confidence interval [CI], 1.20–3.67; p=0.009), with the risk persistent at the 9-month landmark analysis (adjHR, 3.44, 95 percent CI, 1.50–7.85; p=0.003). [World J Gastroenterol 2019;25:4933-4944]

Mortality risk among PPI users was also elevated with a longer duration of use at the 6-month analysis (adjHR, 2.27, 95 percent CI, 1.10–5.14; p=0.038 for cDDD 91–180 and adjHR, 2.08, 95 percent CI, 1.17–3.61; p=0.011 for cDDD >180) and at 9 months (adjHR, 3.52, 95 percent CI, 1.53–8.09; p=0.003 for cDDD >180).

There were 835 and 231 subsequent hospitalizations for hepatic decompensation** among 335 and 116 PPI users and non-users, respectively. The incidence of hospitalization for hepatic decompensation was also increased among PPI users compared with non-users (adjusted relative risk [adjRR], 1.61, 95 percent CI, 1.30–2.11; p<0.001), with a higher risk among PPI users with longer exposure (cDDD >180) compared with non-users (adjRR, 1.91, 95 percent CI, 1.49–2.45; p<0.001).

Previous studies on the effect of PPI on mortality risk in patients with cirrhosis have produced conflicting results, with some showing an increased mortality risk and others suggesting no effect on survival. [Aliment Pharmacol Ther 2015;41:459-466; Aliment Pharmacol Ther 2016;44:1213-1223] Reasons for these contradictory findings include varying durations of PPI exposure and potential lack of adjustment for cardiovascular comorbidities and their treatments, said the researchers.

“Our study showed that after correcting for these different potential biases and 43 relevant confounders for mortality, decompensated cirrhotic patients with PPI use, particularly with prolonged duration, have an increased risk of mortality,” they noted.

Gut dysbiosis may play a key role in these elevated risks, said the researchers. “Patients with decompensated liver cirrhosis have increased intestinal permeability and decreased hepatic clearance of PPIs, which predispose to gut dysbiosis and increase the risk of severe hepatic decompensation and ultimately mortality. Higher dose exposure to PPI worsens this,” they said.

“PPIs [also] inhibit the bactericidal effect of gastric hydrochloric acid and predispose to gut dysbiosis. When used in patients with decompensated liver cirrhosis who have decreased hepatic clearance of PPI, there is increased dose exposure that can potentially cause more harm,” they said, calling for research to conclusively establish these mechanisms.

“[All in all, these results suggest that] PPI use should be reviewed regularly especially in patients with liver cirrhosis. It should be stopped when there are no indications. If PPIs are indicated, dosage should be reduced to the lowest possible dose,” said the researchers.