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Proton pump inhibitors are widely used, and generally considered safe. In this clinical lesson two cases are presented with a strong suspicion of proton pump inhibitor induced decline of kidney function. This adverse event has only recently been identified in epidemiological studies. Our cases illustrate that chronic proton pump inhibitor nephrotoxicity can manifest subtle and may therefore be difficult to recognize. We discuss the current epidemiological evidence to support these observations, and the pathophysiology and clinical manifestations of proton pump inhibitor nephrotoxicity. In case a subject using a proton pump inhibitor shows kidney function decline, without a clear cause, withdrawal of this medication is advised. Although for an individual patient the risk may not be high, the large number of proton pump users makes that this adverse event is important on a population level.

Proton pump inhibitors are widely used, and generally considered safe. In this clinical lesson two cases are presented with a strong suspicion of proton pump inhibitor induced decline of kidney function. This adverse event has only recently been identified in epidemiological studies. Our cases illustrate that chronic proton pump inhibitor nephrotoxicity can manifest subtle and may therefore be difficult to recognize. We discuss the current epidemiological evidence to support these observations, and the pathophysiology and clinical manifestations of proton pump inhibitor nephrotoxicity. In case a subject using a proton pump inhibitor shows kidney function decline, without a clear cause, withdrawal of this medication is advised. Although for an individual patient the risk may not be high, the large number of proton pump users makes that this adverse event is important on a population level.

Background & Aims: Proton pump inhibitor (PPI) use has been associated with increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe outcomes. However, meta-analyses show unclear results, leading to uncertainty regarding the safety of PPI use during the ongoing coronavirus disease 2019 (COVID-19) pandemic. Methods: We conducted a nationwide observational study including all SARS-CoV-2 cases (n = 83,224) in Denmark as of December 1, 2020. The association of current PPI use with risk of infection was examined in a case-control design. We investigated the risk of severe outcomes, including mechanical ventilation, intensive care unit admission, or death, in current PPI users (n = 4473) compared with never users. Propensity score matching was applied to control for confounding. Finally, we performed an updated meta-analysis on risk of SARS-CoV-2 infection and COVID-19 mortality attributable to PPI use. Results: Current PPI use was associated with increased risk of infection; adjusted odds ratio, 1.08 (95% confidence interval [CI], 1.03–1.13). Among SARS-CoV-2 cases, PPI use was associated with increased risk of hospital admission; adjusted relative risk, 1.13 (1.03–1.24), but not with other severe outcomes. The updated meta-analysis showed no association between PPI use and risk of infection or mortality; pooled odds ratio, 1.00 (95% CI, 0.75–1.32) and relative risk, 1.33 (95% CI, 0.71–2.48). Conclusions: Current PPI use may be associated with an increased risk of SARS-CoV-2 infection and hospital admission, but these results with minimally elevated estimates are most likely subject to residual confounding. No association was found for severe outcomes. The results from the meta-analysis indicated no impact of current PPI use on COVID-19 outcomes.

The following article: Jung, R.E., Al-Nawas, B., Araujo, M., Avila-Ortiz, G., Barter, S., Brodala, N., ... Windisch, P. (2018). Group 1 ITI Consensus Report: The influence of implant length and design and medications on clinical and patient-reported outcomes. Clinical Oral Implants Research, 29(S16), 69-77, can be accessed at https://doi.org/10.1111/clr.13342. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Objectives: The aim of Working Group 1 was to address the influence of different local (implant length, diameter, and design) and systemic (medications) factors on clinical, radiographic, and patient‐reported outcomes in implant dentistry. Focused questions on (a) short posterior dental implants (≤6 mm), (b) narrow diameter implants, (c) implant design (tapered compared to a non‐tapered implant design), and (d) medication‐related dental implant failures were addressed. Materials and methods: Four systematic reviews were prepared in advance of the Consensus Conference and were discussed among the participants of Group 1. Consensus statements, clinical recommendations, and recommendations for future research were based on structured group discussions until consensus was reached among the entire expert Group 1. The statements were then presented and accepted following further discussion and modifications as required by the plenary. Results: Short implants (≤6 mm) revealed a survival rate ranging from 86.7% to 100%, whereas standard implant survival rate ranged from 95% to 100% with a follow‐up from 1 to 5 years. Short implants demonstrated a higher variability and a higher Risk Ratio [RR: 1.24 (95% CI: 0.63, 2.44, p = 0.54)] for failure compared to standard implants. Narrow diameter implants (NDI) have been classified into three categories: Category 1: Implants with a diameter of Tapered versus non‐tapered implants demonstrated only insignificant differences regarding clinical, radiographic, and patient‐reported outcomes. The intake of certain selective serotonin reuptake inhibitors and proton pump inhibitors is associated with a statistically significant increased implant failure rate. The intake of bisphosphonates related to the treatment of osteoporosis was not associated with an increased implant failure rate. Conclusions: It is concluded that short implants (≤6 mm) are a valid option in situations of reduced bone height to avoid possible morbidity associated with augmentation procedures; however, they reveal a higher variability and lower predictability in survival rates. Narrow diameter implants with diameters of 2.5 mm and more demonstrated no difference in implant survival rates compared to standard diameter implants. In contrast, it is concluded that narrow diameter implants with diameters of less than 2.5 mm exhibited lower survival rates compared to standard diameter implants. It is further concluded that there are no differences between tapered versus non‐tapered dental implants. Certain medications such as selective serotonin reuptake inhibitors and proton pump inhibitors showed an association with a higher implant failure rate.

Background\ud\udProphylaxis for gastrointestinal stress ulceration is frequently given to patients in the intensive care unit (ICU), but its risks and benefits are unclear.\udMethods\ud\udIn this European, multicenter, parallel-group, blinded trial, we randomly assigned adults who had been admitted to the ICU for an acute condition (i.e., an unplanned admission) and who were at risk for gastrointestinal bleeding to receive 40 mg of intravenous pantoprazole (a proton-pump inhibitor) or placebo daily during the ICU stay. The primary outcome was death by 90 days after randomization.\udResults\ud\udA total of 3298 patients were enrolled; 1645 were randomly assigned to the pantoprazole group and 1653 to the placebo group. Data on the primary outcome were available for 3282 patients (99.5%). At 90 days, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died (relative risk, 1.02; 95% confidence interval [CI], 0.91 to 1.13; P=0.76). During the ICU stay, at least one clinically important event (a composite of clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection, or myocardial ischemia) had occurred in 21.9% of patients assigned to pantoprazole and 22.6% of those assigned to placebo (relative risk, 0.96; 95% CI, 0.83 to 1.11). In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, as compared with 4.2% in the placebo group. The number of patients with infections or serious adverse reactions and the percentage of days alive without life support within 90 days were similar in the two groups.\udConclusions\ud\udAmong adult patients in the ICU who were at risk for gastrointestinal bleeding, mortality at 90 days and the number of clinically important events were similar in those assigned to pantoprazole and those assigned to placebo. (Funded by Innovation Fund Denmark and others; SUP-ICU ClinicalTrials.gov number, NCT02467621. opens in new tab.)

Proton pump inhibitors (PPIs) are a class of drugs that irreversibly inhibit the H(+)/K(+)-ATPase in gastric parietal cells. Since an association between PPI use and increased fracture risk has been found, the aim of this study was to detect potential adverse effects of pantoprazole, a representative of the PPIs, on primary human osteoblasts in vitro. The isolated cells were stimulated with pantoprazole concentrations ranging from 0 μg/ml to 10 μg/ml. Changes in proliferation, total cell number, viability, cytotoxicity, alkaline phosphatase activity, total protein synthesis and gene expression on mRNA level were determined over a period of 7 days. Pantoprazole stimulation resulted in increased viability and decreased cytotoxicity in the osteoblasts. The proliferation rate was stable and so was the relative cell number. Only at the highest pantoprazole concentration on day 7, a slight decrease of the cell number was detected. Alkaline phosphatase activity increased over the tested period under exposure to pantoprazole (p < 0.05 at 3 μg/ml and 10 μg/ml pantoprazole). Osteoblast-specific gene expression was increased through pantoprazole stimulation compared to the control on day 3. Towards day 7, gene expression returned to baseline levels or decreased slightly compared to unexposed cells. Interestingly, this in vitro experiment detected no evidence of adverse effects of PPIs on primary human osteoblasts. Osteoblasts were rather more viable with increased mitochondrial activity, gene expression and protein synthesis under pantoprazole stimulation. Therefore, these in vitro results do not suggest that impaired osteoblast function is the cause of an increased fracture risk in patients under PPI therapy.

Background. Recent studies suggest that proton pump inhibitors (PPIs) may increase the risk for listeriosis. We investigated a potential association in cases of nonpregnancy-associated listeriosis using registry data. Methods. We conducted a population-based, case-control study using Danish health registries. Cases (n = 721) were defined as patients aged ≥45 years notified with listeriosis from July 1994 to December 2012. We selected 34 800 controls using risk-set sampling. Controls were individually matched for age, sex, and municipality. Data on use of PPIs and other drugs and hospitalization diagnoses over a 5-year period were extracted from nationwide health registries. A comorbidity index (CMI) was constructed. We calculated the association between use of PPIs and related drugs within 30 days (current use) and other time windows before the index date. Using conditional logistic regression, matched odds ratios (ORs) adjusted for CMI and confounders were estimated. Results. The adjusted OR for current use of PPIs and development of listeriosis was 2.81 (95% confidence interval [CI], 2.14-3.69). PPI usage up to 90 days before the index date remained statistically significant. Subgroup analyses revealed increasing ORs with decreasing age and level of comorbidity and an increased OR for concurrent glucocorticoid treatment (OR, 4.61; 95% CI, 3.01-7.06). No significant association was found for current use of histamine-2-receptor antagonists (adjusted OR, 1.82; 95% CI, 0.89-3.71). Conclusions. Prescribed PPIs were associated with increased risk of listeriosis. The risk waned with time since last prescription redemption. PPIs may have unwanted side effects in vulnerable populations.

PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months and a discussion of these findings and how this has influenced our understanding of this association, the clinical impact and the underlying pathophysiology.RECENT FINDINGS: New studies have further strengthened existing evidence linking use of PPIs to osteoporosis. Short-term use does not appear to pose a lower risk than long-term use. There is a continued lack of conclusive studies identifying the pathogenesis. Direct effects on calcium absorption or on osteoblast or osteoclast action cannot at present plausibly explain the mechanism.SUMMARY: The use of PPIs is a risk factor for development of osteoporosis and osteoporotic fractures. However, as the direct pathogenesis remains unclear, specific points of intervention are lacking, other than being vigilant in regard to the indication for prescribing PPIs and to use the lowest effective dose where PPIs cannot be avoided.

Background: Proton pump inhibitors (PPIs) have been suggested to increase the effect of warfarin, and clinical guidelines recommend careful monitoring of international normalized ratio (INR) when initiating PPI among warfarin users. However, this drug–drug interaction is sparsely investigated in a clinical setting. The aim was to assess whether initiation of PPI treatment among users of warfarin leads to increased INR values. Methods: The study was an observational self-controlled study from 1998 to 2012 leveraging data on INR measurements on patients treated with warfarin from primary care and outpatient clinics and their use of prescription drugs. Data were analyzed in 2015. We assessed INR, warfarin dose, and dose/INR ratio before and after initiating PPI treatment using the paired student's t-test. Results: We identified 305 warfarin users initiating treatment with PPIs. The median age was 71 years (interquartile range 63–78 years), and 64% were men. The mean INR in the 70 days prior to PPI initiation was 2.6 (95%CI 2.5–2.8) and 2.6 (95%CI 2.5–2.7) in the period 1–3 weeks after PPI initiation (p = 0.67). Further, neither mean warfarin dose nor the dose/INR ratios were significantly different before and after PPI initiation. Sensitivity analyses revealed no differences among individual PPIs. Conclusions: We found no evidence of a clinically meaningful drug–drug interaction between PPIs and warfarin in a Northern European patient population of unselected patients from an everyday outpatient and primary care clinical setting. Thus, we do not support the recommendation to “cautiously monitor” users of warfarin initiating PPI treatment.

PURPOSE: To describe the prevalence of, risk factors for, and prognostic importance of gastrointestinal (GI) bleeding and use of acid suppressants in acutely ill adult intensive care patients.METHODS: We included adults without GI bleeding who were acutely admitted to the intensive care unit (ICU) during a 7-day period. The primary outcome was clinically important GI bleeding in ICU, and the analyses included estimations of baseline risk factors and potential associations with 90-day mortality.RESULTS: A total of 1,034 patients in 97 ICUs in 11 countries were included. Clinically important GI bleeding occurred in 2.6 % (95 % confidence interval 1.6-3.6 %) of patients. The following variables at ICU admission were independently associated with clinically important GI bleeding: three or more co-existing diseases (odds ratio 8.9, 2.7-28.8), co-existing liver disease (7.6, 3.3-17.6), use of renal replacement therapy (6.9, 2.7-17.5), co-existing coagulopathy (5.2, 2.3-11.8), acute coagulopathy (4.2, 1.7-10.2), use of acid suppressants (3.6, 1.3-10.2) and higher organ failure score (1.4, 1.2-1.5). In ICU, 73 % (71-76 %) of patients received acid suppressants; most received proton pump inhibitors. In patients with clinically important GI bleeding, crude and adjusted odds for mortality were 3.7 (1.7-8.0) and 1.7 (0.7-4.3), respectively.CONCLUSIONS: In ICU patients clinically important GI bleeding is rare, and acid suppressants are frequently used. Co-existing diseases, liver failure, coagulopathy and organ failures are the main risk factors for GI bleeding. Clinically important GI bleeding was not associated with increased adjusted 90-day mortality, which largely can be explained by severity of comorbidity, other organ failures and age.

BACKGROUND: Proton-pump inhibitors (PPIs) are among the most frequently prescribed medications. Community-acquired pneumonia (CAP) is a common cause of morbidity, mortality and healthcare spending. Some studies suggest an increased risk of CAP among PPI users. We conducted a systematic review and meta-analysis to determine the association between outpatient PPI therapy and risk of CAP in adults. METHODS: We conducted systematic searches of MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Scopus and Web of Science on February 3, 2014. Case-control studies, case-crossover, cohort studies and randomized controlled trials reporting outpatient PPI exposure and CAP diagnosis for patients >/=18 years old were eligible. Our primary outcome was the association between CAP and PPI therapy. A secondary outcome examined the risk of hospitalization for CAP and subgroup analyses evaluated the association between PPI use and CAP among patients of different age groups, by different PPI doses, and by different durations of PPI therapy. RESULTS: Systematic review of 33 studies was performed, of which 26 studies were included in the meta-analysis. These 26 studies included 226,769 cases of CAP among 6,351,656 participants. We observed a pooled risk of CAP with ambulatory PPI therapy of 1.49 (95% CI 1.16, 1.92; I2 99.2%). This risk was increased during the first month of therapy (OR 2.10; 95% CI 1.39, 3.16), regardless of PPI dose or patient age. PPI therapy also increased risk for hospitalization for CAP (OR 1.61; 95% CI: 1.12, 2.31). DISCUSSION: Outpatient PPI use is associated with a 1.5-fold increased risk of CAP, with the highest risk within the first 30 days after initiation of therapy. Providers should be aware of this risk when considering PPI use, especially in cases where alternative regimens may be available or the benefits of PPI use are uncertain.