A recent randomized, blinded study (M Krag et al. NEJM 2018; 379: 2199-2208, editorial 2263-4) describes the use of proton pump inhibitor (PPI) therapy in adults (n=3298) in the ICU at high risk for gastrointestinal bleeding. High risk features included liver disease, coagulopathy, shock, anticoagulant therapy, renal replacement treatment, and mechanical ventilation.
Stress-ulcer bleeding may be less prevalent than in the past, perhaps due to improved ICU care. GI bleeding occurred in 4.2% of placebo-treated patients compared to 2.5% of pantoprazole-treated patients
Overall outcomes were essentially identical. At 90 days, 510 patients (31.1%) in the pantoprazole group and 49 (30.4%) in the placebo group had died (RR 1.02).
Using a composite event score to weight potential good and adverse effects (eg C diff infection, myocardial infarction, bleeding, pneumonia) of PPI therapy, the authors found that this occurred in 21.9% of pantoprazole group compared with 22.6% of placebo group (22.6%).
Reduction in GI bleeding could be related in part to the more frequent use of enteral feedings. And, the combination of enteral feeding with the use of PPI treatment may increase the risk of pneumonia.
In the associated commentary, the authors note that “prophylaxis with a PPI, if initiated, should be reserved for seriously ill patients who are at high risk for this complication.” They acknowledge a lack of a uniform definition of high risk and the “admittedly small (1.7%) difference in bleeding rates.”
This article provides a thorough review of EoE -including clinical features, differential diagnosis, diagnostic criteria, and treatments.
Key point: “The evidence suggests that PPIs are better classified as a treatment for esophageal eosinophilia that may be due to EoE than as a diagnostic criterion, and we have developed updated consensus criteria for EoE that reflect this change.”
A recent study (DY Graham, A Tansel. Clin Gastroenterol Hepatol 2018; 16: 800-808) analyzed 56 randomized trials to determine relative potency of proton pump inhibitors (PPIs) based on time in which intragastric pH was 4 or less (pH4time).
Pantoprazole 20 mg was equivalent to 4.5 mg of omeprazole
Lansoprazole 15 mg was equivalent to 13.5 mg of omeprazole
Esomeprazole 20 mg was equivalent to 32 mg of omeprazole
Rabeprazole 20 mg was equivalent to 36 mg of omeprazole
The authors note that peak effectiveness for PPIs was at ‘approximately 70 mg of omeprazole equivalents’. In addition, they state that twice a day dosing was more effective than increasing once a day dosing; however, three times a day dosing was not more effective than twice a day. “Dexlansoprazole, a quasi-twice-a-day formulation produced similar acid suppression to the lowest twice-daily PPI regimen and 20 mg vonoprazan once daily provided similar efficacy aas high-dose twice-daily PPI.” The authors also compare costs; generics of pantoprazole, omeprazole, and esomeprazole cost as little as $0.02-0.04 per omeprazole equivalent. Thus, 20 mg of omeprazole would be as little as 40 cents.
My take: Using the lowest effective dose of a PPI is recommended. In patients needing higher dosing or with suboptimal response to acid suppression, this data can be very helpful.
In a prospective study (M Wod et al. Clin Gastroenterol Hepatol 2018; 16: 681-89), data on middle-aged (n=2346, 46-67 yrs) and older individuals (n=2475) were collected in the Longitudinal Study of Aging Danish Twins. This study showed that there was no difference in cognitive decline between PPI users and non-users.
The second study (SN Landi et al. Gastroenterol 2018; 154: 861-73) used a large administrative database and reviewed more than 5 million new users of prescription PPIs and prescription H2RAs. The authors found no significant difference in myocardial infarctions (MIs) between PPIs and H2RAs over a 12 month period.
A recent study (P Manzoni et al. J Pediatr 2018; 193: 62-7) provide more data on the detrimental effects of gastric acid inhibitors (eg. proton pump inhibitors, histamine-2 receptor antagonists). This study was a secondary analysis using prospectively collected data from 235 preterm very low birth weight infants. Key findings:
“After multivariate analysis, exposure to inhibitors of gastric acidity remained significantly and independently associated with LOS [late-onset sepsis] (OR 1.03); each day of inhibitors of gastric acidity exposure conferred an additional 3.7% odds of developing LOS.”
Acid suppression therapy was associated with gram-negative (P<.001) and fungal pathogens (P=.001)
The study showed an association between acid blockers and with necrotizing enterocolitis, which was mitigated in those who received bovine lactoferrin
My take (borrowed, in part, from authors): This data “confirm, strengthen, and expand on previous reports describing an association between inhibitors of gastric acidity and infections.” Thus, the risks of these medications is likely greater than the benefits in the majority of preterm infants.
The blog post reviews a recent article on PPIs and potential complications.
A review article from Michael F. Vaezi et al discusses potential adverse consequences of proton-pump inhibitor (PPI) therapy in the July issue of Gastroenterology…(2017; 153: 35-48). The authors discuss overzealous conclusions based on weak associations that have caused widespread alarm, leading to inappropriate discontinuation of a medicine that is needed for an established disease process. They present absolute and relative risks for adverse effects associated with long-term use of PPIs…
Vaezi et al review the consistency of proposed associations with PPI use and the time period between the PPI exposure and outcome, and the effects of different doses. They provide guidance for methodologies of future studies.
The review article concludes that PPIs have revolutionized the management of patients with GERD and patients at risk of upper gastrointestinal ulceration and bleeding from aspirin or NSAIDs. However, many patients receive PPIs unnecessarily for conditions or symptoms for which they would not have been expected to provide benefit… Vaezi et al state that, as always, PPIs should be given in the lowest effective dose, for the shortest possible time.
They add that much of the evidence linking PPI use to serious long-term adverse consequences is weak and insubstantial. It should not deter prescribers from using appropriate doses of PPIs for appropriate indications.
Table 6 lists the strengths of the findings along with other Hill Criteria to assess all of the proposed complications. The vast majority of potential complications have “weak” proof; the exceptions include bacterieal enteric infections/Clostridium difficile infection which have moderate strength of evidence and and fundic gland polyps which have high strength of evidence.
My take: This study and the associated AGA Journals blog post indicate that most of the reports of complications associated with PPI remain unproven and are based on weak evidence.