Letter: proton pump inhibitors ‐ severity of liver disease and mortality in patients with cirrhosis – authors' reply

As mentioned by Lin and Dong patients taking PPIwere sicker, indicated by higher MELD and Child Pughscores, and are therefore considered to have a worseprognosis. However, there is little evidence whether PPIuse might be an additional risk factor for overall mortal-ity in cirrhotics in addition to well established prognosticparameters such as the MELD score or occurrence ofcomplication of cirrhosis. To consider the disease stage,MELD score and Child Pugh score were included in themultivariate analysis and PPI-usage turned out to be anindependent predictive factor for mortality.The lack of data concerning the relation of PPI use tooverall survival was the rationale for conducting thisstudy. We acknowledge the suggestions of Lin and Dong,and included additional parameters in the multivariateanalysis. We added hepatorenal syndrome (HRS), spon-taneous bacterial peritonitis (SBP) and the indication forPPI use (acute bleeding episode, reﬂux disease or currentvariceal band ligation) in the multivariate analysis.However, we did not have data concerning the durationof PPI treatment or about antibiotic regimens used inthe patients.In the extended analysis SBP [hazard ratio (HR)2.105, 95% conﬁdence interval (CI), 1.107–4.002,P = 0.023], PPI use (HR 1.926, 95% CI 1.010–3.675,P = 0.047), hepatocellular carcinoma (HCC; HR 5.117,95% CI 2.948–8.884, P < 0.001), MELD score (HR 1.111,95% CI 1.069–1.154, P < 0.001), hepatic decompensation(HR 1.865, 95% CI 1.009–3.448, P = 0.047) and indica-tion for PPI use (HR 1.867, 95% CI 1.166–2.990,P = 0.009) were independent prognostic parameters. Linand Dong proposed to exclude patients with short obser-vation times. We consider it inappropriate to excludepatients who fulﬁl inclusion criteria which may bias theresults of studies. Furthermore, the relation of risk andobservation time is valued in Cox survival models. Over-all survival was the primary objective of the study. Wedo not have complete follow-up data concerning bleed-ing events in patients according to their PPI use at theday of study inclusion.There are two central results of our study which areevident and should be emphasised once more. First, PPIuse was common among our cirrhotic patients, withmany patients taking PPI without an evidence-basedindication. Second, PPI use was associated with a higherrisk of death, independent from severity of liver diseaseand hepatic complications, which is evident and con-ﬁrmed by multivariate Cox regression analysis. However,although PPI use was a risk factor for death, HCC andMELD were stronger predictors of prognosis.Although Lin and Dong might have the impressionthat we claimed PPI use was the main risk factor formortality, we can only state that use of PPI was some-how associated with a higher risk of death. We cannotdraw further causative conclusions from a monocentricobservational study. PPI use comes along with anincreased risk of death. Whether the higher risk of deathcan be attributed to PPI therapy, or whether it is an epi-phenomenon, needs to be clariﬁed by further studies.Nonetheless, PPIs should be prescribed cautiously inpatients with cirrhosis, and the indication for a PPIshould be veriﬁed repeatedly in those on long-term treat-ment.ACKNOWLEDGEMENTThe authors’ declarations of personal and ﬁnancial inter-ests are unchanged from those in the original article.