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Infections in cirrhosis, especially those associated with intestinal bacterial overgrowth and translocation such as spontaneous bacterial peritonitis (SBP), are responsible for a substantial cost of care and can increase mortality up to four-fold.[1-4] These infections can impact patients directly by causing death or indirectly by precipitating hepatic encephalopathy and renal failure or reducing liver transplant eligibility.[4, 5] The leading pathogenic mechanism behind these infections in cirrhosis is small intestinal bacterial overgrowth (SIBO) leading to bacterial translocation, a process that is enhanced by acid suppression.[5-7] Efforts to reduce this tremendous burden in cirrhosis by potentially reducing the bacterial translocation and overgrowth are needed.
The association of acid-suppressive agents, such as proton pump inhibitors (PPI), with infections such as pneumonia, Clostridium difficile (C. difficile) and infectious gastroenteritis has been studied extensively in noncirrhotic patients.[9-13] The mechanism cited is related to the SIBO and a direct immunosuppressive effect making patients prone to bacterial translocation.[14, 15] PPI use is prevalent in the cirrhotic as well as noncirrhotic population.[16-19] There is also a growing body of evidence that PPIs are related to serious infections related to SIBO in cirrhosis such as SBP and C. difficile.[20-23] However, these were single-centre studies with limited sample sizes.
Our aim was to estimate the extent to which PPIs increase the rate of serious infections among decompensated cirrhotic patients in a national Veterans Health Administration (VHA) database. The a priori hypothesis was that PPI use is associated with a higher rate of serious infections, especially those related to acid suppression, in patients with decompensated cirrhosis.
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More than half of persons with decompensated cirrhosis were new users of gastric acid suppressants, with most using PPIs (45.6%) compared with H2RAs (5.9%). The majority of patients in the new PPI user group were on omeprazole (73%). The rest were on rabeprazole (23%), lansoprazole (2%) or pantoprazole (1%). Table 1 shows the distribution of socio-demographic and clinical characteristics by gastric acid suppressant use. The vast majority of patients with decompensated cirrhosis in the VA were men, and this did not vary by gastric acid suppressant use. Age and known race/ethnicity were also comparably distributed, although the proportion of missing data in the latter variable was very high. Cirrhosis aetiology was commonly alcoholic and slightly more so among H2RA new users (49.6% H2RA vs. 43.8% PPI users and 44.3% non-users). Hepatitis C infection was common with 52.4% of PPI new users and 46.0% of H2RA users and 46.3% non-users infected. The distribution of concomitant medications were similar between groups for antibiotics (and rare) and nonselective beta blockers (~12–14%). Although rifaximin use was relatively low, it was slightly more prevalent among PPI users than non-users (6.8% PPI; 1.6% H2RA; 2.4% in non-users); this was equalised in the matched samples. The PPI and H2RA users had a greater proportion of people with at least five comorbid conditions relative to the non-users (PPI: 41.7%; H2RA: 41.9%; non-user: 31.1%). The majority of the events that led to the inclusion of patients as decompensated cirrhosis were ascites (73%), followed by hepatic encephalopathy (18%), variceal bleeding (8%), hepato-renal syndrome (1%); only 9 patients had SBP as their primary decompensating event.
Table 1. Comparison of characteristics by gastric acid suppressant use
| ||Total sample (N = 4181)|
|PPI only users (N = 1905)||H2RA only users (N = 248)||Gastro suppressant non-users (N = 2028)|
|Drug use at baseline|
| Nonselective beta blocker||13.9||12.1||14.2|
|Out-patient visits in past year (median, IQR)||7 (14)||5 (13)||8 (16)|
Table 2 also shows the distribution of the potential confounders in the propensity-matched sample. The distributions of the potential confounders of the propensity-matched sample appear well-balanced. Relative to the matched non-users (32.1%), PPI users had five or more comorbid conditions (41.2%). Similar imbalance was observed between H2RA users (41.7%) and non-users (34.7%).
Table 2. Comparison of characteristics between propensity-matched samples
| ||PPI-matched sample (N = 2536)||H2RA-matched sample (N = 398)|
|PPI only users (N = 1268)||Non-users (N = 1268)||H2RA only users (N = 199)||Non-users (N = 199)|
|Drug use at baseline|
| Nonselective beta blocker||12.4||14.6||10.6||13.1|
|Out-patient visits in past year (median, IQR)||6 (13)||8 (15)||5 (13)||7 (14)|
Table 3 shows the association between gastric acid suppressant drug use and serious infections stratified by PPI and H2RA use. Among the propensity-matched PPI cohort, 25.3% developed serious infections. Acid suppression-associated infections were common (17.7%). Among the PPI users, acid suppression-related infections formed the bulk (75%) of all infections, whereas among nongastric acid suppressant users, 64% of serious infections were acid suppression-related. Among the propensity-matched H2RA cohort, 25.9% developed serious infections with 15% deemed acid suppressant-related. Although the bulk of serious infections in H2RA users were also acid suppression-related infections (64.7%) among non-users in this cohort, 51.9% were acid suppressant-related infections. There was no significant difference in the patterns of infection occurrence based on the initial decompensating event between the PPI and non-PPI groups. Leading serious infections were SBP/peritonitis (30%), pneumonia (25%), skin infections (23%), spontaneous bacteremia and septicemia (16%), C. difficile (5%) and UTI (1%). During the study period, liver transplant was uncommon.
Table 3. Effect of new user of PPIs and H2RAs on infections among propensity-matched samples
|PPI propensity-matched sample (N = 2536)||Number of cases||Person years||Incidence rate per 1000 person years||Crude hazard ratioa||Adjusted hazard ratiob|
| PPI users||320||474||675||1.08 (0.90–1.31)||1.66 (1.31–2.12)|
| Gastric suppressant non-users||321||459||700|
|Acid suppression-related infections|
| PPI users||241||346||696||1.22 (0.97–1.52)||1.75 (1.32–2.34)|
| Gastric suppressant non-users||207||290||714|
|H2RA propensity-matched sample (N = 398)|
| H2RA users||51||63||814||1.09 (0.68–1.73)||1.59 (0.80–3.18)|
| Gastric suppressant non-users||52||83||628|
|Acid suppression-related infections|
| H2RA users||33||39||844||1.10 (0.60–2.02)||0.92 (0.31–2.73)|
| Gastric suppressant non-users||27||37||730|
In the propensity-matched sample for PPI users, there was no association between PPI use and the rate of serious infections [crude propensity-matched hazard ratio (HR): 1.08; 95% CI: 0.90–1.31]. However, PPI users tended to develop serious acid suppression-related infections at a rate higher than nongastric acid suppressant users, although the confidence interval included unity (crude HR: 1.22; 95% CI: 0.97–1.52). As these estimates of effect are still prone to bias owing to the time-varying nature of PPI use, we estimated the effect of PPI use on serious infections and acid suppression-related infections accounting for time-varying PPI use. For serious infections, PPI users developed the outcome at a rate 1.66 times that of non-users (95% CI: 1.31–2.12). For acid suppression-related serious infections, PPI users developed the outcome at a rate 1.75 times faster than non-users (95% CI: 1.32–2.34).
In the propensity-matched H2RA analysis, no evidence of an association between H2RA use and infections was observed based on the crude analyses. Although the analyses adjusting for time-varying H2RA use revealed a hazard rate of 1.59 for H2RA use on all serious infections, the confidence interval was quite wide (95% CI: 0.80 and 3.18). No association between H2RA use and acid suppression-associated infections was noted (adjusted HR: 0.92; 95% CI: 0.31–2.73).
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We found PPI initiation to be prevalent among patients with decompensated cirrhosis. Furthermore, we documented that the initiation of PPI therapy accelerates the rate of infections associated with hospitalisation, especially those related to intestinal bacterial overgrowth and translocation, in decompensated cirrhotic patients. We also found that the use of H2-receptor antagonists do not appear to accelerate the rate of these infections in decompensated cirrhosis, although our sample size was limited and could have explained the negative findings.
Infections are one of the leading causes of mortality in cirrhosis, most of which have a presumed gut bacterial origin. The effect of PPIs has been studied in case series in cirrhotic patients showing that their use was associated with a significantly higher risk of gut-based infections such as SBP and C. difficile.[20-22] However, those studies were small in sample size and were unable to explore the time-varying nature of PPI use. Previous methodological research in pharmaco-epidemiology point to the bias introduced with treating drug exposures as fixed effects. Therefore, the results need to be expanded in a larger pool of patients who would otherwise be predisposed to develop infections. The AITC and PBM databases represent a large cross-section of veterans treated in the US that can be used to answer clinically relevant questions.
In our study, we chose to use decompensated cirrhotic patients defined stringently according to previously used ICD-9 criteria in which the mode of initial decompensation did not influence the risk of infections. The AITC and PBM databases do not include laboratory variables permitting adjustment for cirrhosis severity. Nevertheless, our findings are likely robust owing to several design features. First, we matched the time period of observation from the date of decompensation for gastric acid suppressant users to non-users. In doing so, we have likely created comparability in the natural history. Second, we conducted a propensity-matched analysis, which included key confounders, as well as emerging risk factors for infections. By matching via the greedy algorithm, our analyses included tight control for a variety of potential confounders (age, race, charlson score, alcoholic aetiology, year of entry, nonselective beta-blockers, rifaximin, antibiotics, number of out-patient and in-patient visits in last year), which were shown to have balance across the gastric acid suppressant categories. Third, the factors we adjusted for are likely highly correlated to Child and MELD scores and are related to the decompensating events. Fourth, we included analyses of H2RAs as a counter factual. Given the similarities in the distributions among H2RA and PPI users, it is highly unlikely that the PPI analyses would experience residual confounding by disease severity, but not the H2RA analyses. Lastly, we implemented a new user design, which also provides better control owing to prevalent use bias, which means the biases owing to relative length of the PPI or H2RA use would be removed. Given these design considerations, we believe that our findings are robust.
Our study specifically concentrated on decompensated cirrhotic patients who were first initiated on gastric acid suppression therapy (PPI or H2RA) after they developed decompensation defined by the complications of cirrhosis such as variceal bleeding, ascites or hepatic encephalopathy. This method ensured that the specific duration of PPI use was available for study as well as the refills and total dose during the follow-up period. It is also the appropriate method to eliminate prevalent use bias. Doing so, however, excluded patients with decompensated cirrhosis who had been on long-term PPI therapy before the decompensating event. This design, therefore, biased our results towards only showing an extreme effect of PPI use on the risk of infections; despite these restrictions, we were able to find that new PPI therapy significantly reduced the time to all infections, and especially time to gastric acid suppression-related infections.
To understand the extent to which PPIs as a class rather than simple acid suppression were associated with infections, we conducted a parallel study using identical methods on H2RA new users. We believed that if the mechanism was entirely through gastric acid suppression, we would find a lessened effect or no effect among H2RA users. Furthermore, this analysis helped evaluate the extent to which the findings may have been due to confounding by indication. Indeed, we found no specific effect of H2RAs on infection risk. This may be a testament to the specificity of PPIs as harbinger of infections in cirrhosis either due to a class effect or due to a higher potency of acid suppression. A key strength of this article was the study of time-varying on the days to infection rather than simply dividing patient groups into users and non-users. This also accounted for the days that the patients were not on PPIs. Indeed, we found that estimates of effect derived from the time-varying analyses were significantly higher than those created by fixed use of PPIs at study initiation.
The mechanisms behind the predisposition towards infections in cirrhotic patients initiated on PPI remain unclear. Studies have shown the appearance of SIBO after PPI therapy, to which cirrhotic patients are predisposed to given the abnormal intestinal motility and neuro-hormonal imbalance in the gut milieu. There is also evidence that PPIs have depressive effects on neutrophil action and innate immunity, adding a direct anti-inflammatory component to this predisposition. The presence of SIBO in cirrhosis is associated with peripheral bacterial DNA isolation signifying intestinal bacterial translocation, which worsens in decompensated patients.[7, 45] Interestingly, recent reports have shown that acid suppression can alter microbial flora even in the lower gastrointestinal tract.[10, 46] The finding that PPI therapy reduces the time to infections may be due to this effect, but mechanistic studies need to be performed to confirm this. However, it is clear that in this dataset, the co-administration of other studied drugs did not change the effect of PPI on rate of infections in cirrhosis. This comparatively rapid development of serious infections, especially in decompensated cirrhotics, can be significant in determining prognosis as determined by eligibility for liver transplantation and can modulate further decompensating events. In our group, indeed we found that patients who were newly initiated on PPIs after decompensation also had a faster progression to death and liver transplant, which is in essence organ death.
Although this study sample is one of the largest in which PPI therapy has been studied in cirrhosis, there are several caveats. Due to the lack of cirrhosis severity parameters, it may be possible that the patients started on PPI could have a worse cirrhosis severity and hence a higher infection, death and transplant rate. To mitigate this, we implemented a variety of robust techniques to ensure that they were comparable in the matched sample, but cannot rule out residual confounding entirely in a nonexperimental study. We used ICD-9 codes to define the population, as well as to define the outcomes of interest. However, the positive predictive values for these outcomes in VHA settings are quite high, indicating their usefulness for research purposes. We also excluded those followed for less than a year, meaning that if a patient died of sepsis within the first year, they would not be counted. This was done to ensure adequate follow-up in the VHA system. Although the study also could not account for the reason for PPI initiation, parallel analyses of H2RA helped rule out confounding by indication as an explanation of these findings. It may be that non-users of gastric acid suppressants filled prescriptions outside of the VA system as veterans may be eligible for more than one health-care system. In 2003, more than 50% of VA enrollees had Medicare coverage, including 22% of those under age 65. We reduced this source of bias by excluding Veterans who had not received at least one medication through the VA. Regardless, if present, this source of bias would have only attenuated the estimate of effect reported in our study.
We conclude that Veterans with decompensated cirrhosis who were started on PPI therapy after decompensation had a significantly higher risk of developing serious infections compared with those who were not initiated on gastric acid suppression. This increase in risk occurs in a time-varying fashion and is not explained by confounding by concomitant drug use, comorbid conditions or age. As patients with decompensated cirrhosis remain at a high risk of serious infections, clinicians should re-evaluate the reason for prescribing PPI and wherever possible, replace their acid suppressive needs with H2RAs. Further studies are required to prospectively analyse the value of PPI withdrawal in patients with decompensated cirrhosis.