Nonvariceal upper gastrointestinal bleeding in COVID-19 patients: insights from the National Inpatient Sample.

BACKGROUND: This retrospective study, conducted using the U.S. National Inpatient Sample (NIS), examines the outcomes and management of nonvariceal upper gastrointestinal bleeding (NVUGIB) in COVID-19 patients and identifies predictive factors to enhance patient prognosis. METHODS: We analyzed the 2020 U.S. NIS data involving adult patients (≥18 years) admitted with NVUGIB and categorized them based on the presence of COVID-19. Primary and secondary outcomes, NVUGIB-related procedures, and predictive factors were evaluated. RESULTS: Of 184,885 adult patients admitted with NVUGIB, 1.6% (2990) had COVID-19. Patients with NVUGIB and COVID-19 showed higher inpatient mortality, acute kidney injury, need for intensive care, and resource utilization metrics. Notably, there was a lower rate of early esophagogastroduodenoscopy (EGD). Multivariate logistic regression revealed conditions like peptic ulcer disease, mechanical ventilation, and alcohol abuse as significant positive predictors for NVUGIB in COVID-19 patients, whereas female gender and smoking were negative predictors. CONCLUSION: Our findings suggest that COVID-19 significantly increases the risk of mortality and complications in NVUGIB patients. The observed decrease in early EGD interventions, potentially contributing to higher mortality rates, calls for a review of treatment strategies. Further multicenter, prospective studies are needed to validate these results and improve patient care strategies.

Pharmacokinetic/pharmacodynamic assessment of a novel, pharmaceutical lipid-aspirin complex: results of a randomized, crossover, bioequivalence study.

Aspirin (acetylsalicylic acid, ASA) can lead to gastrointestinal mucosal injury through disruption of its protective phospholipid bilayer. A liquid formulation of a novel pharmaceutical lipid-aspirin complex (PL-ASA) was designed to prevent this disruption. We sought to determine the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of PL-ASA compared with immediate release aspirin (IR-ASA). In this active-control crossover study, 32 healthy volunteers were randomized to receive 1 of 2 dose levels (a single dose of 325 mg or 650 mg) of either PL-ASA or IR-ASA. After a 2-week washout period between treatment assignments, subjects received a single dose of the alternative treatment, at the same dose level. The primary objectives of the study were to assess, for PL-ASA and IR-ASA at 325 mg and 650 mg dose levels, PK and PD bioequivalence, and safety, over a 24-h period after administration of both drugs. PK parameters were similar for PL-ASA and IR-ASA, and met FDA-criteria for bioequivalence. Regarding PD, both drugs also showed Cmin TxB2 values below 3.1 ng/mL (cut-off associated with decreased cardiovascular events) and > 99% inhibition of serum TxB2 ( ≥ 95% inhibition represents the cut-off for aspirin responders) along with similar results in several secondary PK/PD parameters. There were no serious adverse events or changes from baseline in vital signs or laboratory values in either of the 2 treatment groups. PL-ASA's novel liquid formulation has similar PK and PD performance compared with IR-ASA, supporting functional and clinical equivalence. These data coupled with the improved gastric safety of PL-ASA suggest that this novel formulation may exhibit an improved benefit-risk profile, warranting evaluation in future trials.Clinical trial registration: http://www.clinicaltrials.gov . Unique Identifier: NCT04008979.

Efficacy and Safety of Lubiprostone in Patients with Opioid-Induced Constipation: Phase 3 Study Results and Pooled Analysis of the Effect of Concomitant Methadone Use on Clinical Outcomes.

Objective: The efficacy and safety of oral lubiprostone for relieving symptoms of opioid-induced constipation (OIC) in patients with chronic noncancer pain were evaluated in a randomized, double-blind, placebo-controlled study. These data were also pooled with those from two similar phase 3 studies to explore the effects of methadone on treatment response. Methods: In the primary study, adults with OIC (fewer than three spontaneous bowel movements [SBMs] per week) were randomized to receive lubiprostone 24 mcg or placebo twice daily for 12 weeks. The primary end point was a change from baseline in the frequency of SBMs at week 8 in patients without a prior dose reduction. For the pooled analysis, the efficacy of lubiprostone was compared with placebo in patients receiving methadone or nonmethadone opioids. Responders were defined as patients with nine or more weeks of nonmissing SBM data who had one or more additional SBMs per week from baseline for each week that data were available and three or more SBMs per week for nine or more weeks. Results: In the primary study, the change from baseline at week 8 in SBM frequency was similar in the lubiprostone and placebo groups (P = 0.842). In the pooled analysis, the response rate was significantly higher with lubiprostone treatment vs placebo for patients receiving nonmethadone opioids (P = 0.002) but was similar between lubiprostone treatment and placebo in patients receiving methadone (P = 0.692). The safety profile of lubiprostone was unaffected by methadone use. Conclusions: The phase 3 study did not meet its primary efficacy end point. However, analysis of pooled data from all phase 3 studies in the OIC clinical development program, stratified by methadone opioid usage, confirmed that lubiprostone is effective for treatment of OIC in patients taking nonmethadone opioids; no safety concerns were identified based on the type of opioid used.

Accuracy of Referring Provider and Endoscopist Impressions of Colonoscopy Indication.

Background: Referring provider and endoscopist impressions of colonoscopy indication are used for clinical care, reimbursement, and quality reporting decisions; however, the accuracy of these impressions is unknown. This study assessed the sensitivity, specificity, positive and negative predictive value, and overall accuracy of methods to classify colonoscopy indication, including referring provider impression, endoscopist impression, and administrative algorithm compared with gold standard chart review. Methods: We randomly sampled 400 patients undergoing a colonoscopy at a Veterans Affairs health system between January 2010 and December 2010. Referring provider and endoscopist impressions of colonoscopy indication were compared with gold-standard chart review. Indications were classified into 4 mutually exclusive categories: diagnostic, surveillance, high-risk screening, or average-risk screening. Results: Of 400 colonoscopies, 26% were performed for average-risk screening, 7% for high-risk screening, 26% for surveillance, and 41% for diagnostic indications. Accuracy of referring provider and endoscopist impressions of colonoscopy indication were 87% and 84%, respectively, which were significantly higher than that of the administrative algorithm (45%; P<.001 for both). There was substantial agreement between endoscopist and referring provider impressions (κ=0.76). All 3 methods showed high sensitivity (>90%) for determining screening (vs nonscreening) indication, but specificity of the administrative algorithm was lower (40.3%) compared with referring provider (93.7%) and endoscopist (84.0%) impressions. Accuracy of endoscopist, but not referring provider, impression was lower in patients with a family history of colon cancer than in those without (65% vs 84%; P=.001). Conclusions: Referring provider and endoscopist impressions of colonoscopy indication are both accurate and may be useful data to incorporate into algorithms classifying colonoscopy indication.

Analysis of Nausea in Clinical Studies of Lubiprostone for the Treatment of Constipation Disorders.

BACKGROUND: Lubiprostone is a ClC-2 chloride channel activator approved for the treatment of chronic idiopathic constipation (CIC) and opioid-induced constipation (OIC) in adults and irritable bowel syndrome with constipation (IBS-C) in women. Lubiprostone is generally well tolerated, with nausea being the most common adverse event. AIMS: To characterize nausea with lubiprostone using pooled results from clinical studies in patients with CIC, OIC, or IBS-C. METHODS: Data from three 3- and 4-week placebo-controlled studies and three long-term open-label studies were pooled for the CIC analysis. The OIC and IBS-C analyses each used pooled data from three 12-week placebo-controlled studies and one 36-week open-label extension study. RESULTS: The populations included the following numbers of patients: CIC, 316 (placebo) and 1113 (lubiprostone 24 mcg twice daily [BID]); OIC, 652 (placebo) and 889 (lubiprostone 24 mcg BID); and IBS-C, 435 (placebo) and 1011 (lubiprostone 8 mcg BID). The incidence of nausea in lubiprostone-treated patients ranged from 11.4 to 31.1%, with the highest incidence in patients with CIC. Among patients with any nausea, most reported only mild or moderate severity (96.5-99.1% across indications) and only one event (83.6-88.7%); most events occurred within the first 5 days of treatment. CONCLUSIONS: Nausea was the most common adverse event following the treatment with lubiprostone. Event rates varied by indication and dose, and the majority of nausea adverse events were mild to moderate in severity. Nausea events predominantly occurred early in the treatment period in all of the pooled study populations.

Helicobacter pylori Clarithromycin Resistance and Treatment Failure Are Common in the USA.

BACKGROUND: Helicobacter pylori antibiotic resistance leads to frequent treatment failure. However, the current US prevalence of H. pylori clarithromycin resistance and treatment failure is unknown. AIMS: To determine the prevalence of clarithromycin-resistant H. pylori and its impact on treatment failure in the USA. METHODS: A multicenter, retrospective, cohort study for clarithromycin-resistant H. pylori was conducted over four academic medical centers in different geographic regions of the USA. Gastric biopsy material, residual from standard clinical pathologic examination, was examined for clarithromycin resistance by DNA sequencing of H. pylori 23S rRNA. RESULTS: One hundred and twenty-four cases of H. pylori gastritis were examined from medical centers in four different geographic regions of the USA. The overall prevalence of clarithromycin resistance was 32.3 % (range 23.1-45.8 %). There was no significant difference in the prevalence of clarithromycin resistance by study site, gender, age, or race/ethnicity. In a subset of 67 patients that had clinical follow-up data, the overall prevalence of clarithromycin resistance was 31.3 %. There was a 2.9-fold increase (p = 0.002) in treatment failure for cases with clarithromycin resistance (57.1 %) compared to wildtype H. pylori (19.6 %). CONCLUSIONS: H. pylori clarithromycin resistance in the USA exceeds the estimated 20 % prevalence compatible with successful empiric antibiotic therapy. This resistance resulted in a significant rate of treatment failure in all sites surveyed. Empiric therapy in the USA should be used with caution until there is better regional or local determination of H. pylori antibiotic resistance.

Evolving therapeutic strategies to improve nonsteroidal anti-inflammatory drug safety.

Nonsteroidal anti-inflammatory drugs (NSAIDs) possess potent anti-inflammatory and analgesic properties through inhibition of cyclooxygenase enzymes (COX-1 and COX-2), which are responsible for synthesis of proinflammatory mediators. NSAIDs are frequently used for treatment of acute and chronic pain conditions. However, their use is associated with serious dose-dependent gastrointestinal (GI), cardiovascular, renal, and hepatic adverse effects, which pose a serious clinical concern for both patients and physicians. During the past 2 decades, approaches to improving the tolerability of NSAIDs were mainly directed toward discovery of COX-2 selective NSAIDs (coxibs), which were expected to minimize the risk of GI injury. Unfortunately, the results from multiple clinical studies have shown that treatment with coxibs may increase the risk for cardiovascular complications. This review summarizes current strategies used to reduce the toxicity of NSAIDs and outlines novel therapeutic approaches still in preclinical development. To minimize the risk of GI ulcerations and bleeding, combination therapies with gastroprotective agents are currently recommended. The new therapeutic agents anticipated to have similar effects include nitric oxide- and hydrogen sulfide-releasing NSAIDs. Novel manufacturing technologies enhance dissolution and absorption of NSAID products, allowing for their administration at low doses, which could lead to improved drug tolerability without diminishing the analgesic and anti-inflammatory efficacy of NSAIDs. This principle is in line with the current recommendation by the US Food and Drug Administration that NSAIDs should be used at the lowest effective dosage. Finally, NSAID formulations targeted directly to the site of inflammation are expected to reduce systemic drug exposure and thus decrease the risk of systemic adverse effects.

PA32540 (a coordinated-delivery tablet of enteric-coated aspirin 325 mg and immediate-release omeprazole 40 mg) versus enteric-coated aspirin 325 mg alone in subjects at risk for aspirin-associated gastric ulcers: results of two 6-month, phase 3 studies.

BACKGROUND: Discontinuations and/or interruptions in aspirin therapy for secondary cardioprotection due to upper gastrointestinal (UGI) complications or symptoms have been shown to increase the risk for subsequent cardiovascular events. PA32540 is a coordinated-delivery, combination tablet consisting of enteric-coated aspirin (EC-ASA) 325 mg and immediate-release (IR) omeprazole 40 mg. METHODS: Two identically-designed, 6-month, randomized, double-blind trials evaluated PA32540 vs. EC-ASA 325 mg in a secondary cardiovascular disease prevention population taking aspirin 325 mg daily for ≥3 months and at risk for ASA-associated gastric ulcers (GUs). The combined study population was 1049 subjects (524 randomized to PA32540, 525 to EC-ASA 325 mg). The primary endpoint was the occurrence of endoscopically-determined gastric ulceration over 6 months. Safety outcomes included the rates of major adverse cardiovascular events (MACE) and UGI symptoms. RESULTS: Significantly fewer PA32540-treated subjects (3.2%) developed endoscopic GUs vs. EC-ASA 325 mg-treated subjects (8.6%) (P < .001). Overall occurrence of MACE was low (2.1%), with no significant differences between treatments in types or incidence of MACE. PA32540-treated subjects had significantly fewer UGI symptoms (P < .001) and significantly fewer discontinuations due to pre-specified UGI adverse events (1.5% vs. 8.2%, respectively; P < .001). CONCLUSIONS: PA32540 reduced the incidence of endoscopic GUs compared to EC-ASA 325 mg, but with a similar cardiovascular event profile. Due to fewer UGI symptoms, continuation on aspirin therapy was greater in the PA32540 treatment arm.

A randomized study of lubiprostone for opioid-induced constipation in patients with chronic noncancer pain.

OBJECTIVE: To evaluate the efficacy and safety of oral lubiprostone for relieving symptoms of opioid-induced constipation (OIC) in patients with chronic noncancer pain. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Seventy-nine US and Canadian centers. SUBJECTS: Patients aged ≥ 18 years with OIC, defined as <3 spontaneous bowel movements (SBMs) per week. METHODS: Patients received lubiprostone 24 mcg or placebo twice daily for 12 weeks. The primary endpoint was change from baseline in SBM frequency at week 8. RESULTS: Among randomized patients (N=418; lubiprostone, N=210; placebo, N=208), most completed the study (lubiprostone, 67.1%; placebo, 69.7%). The safety and efficacy (intent-to-treat) populations included 414 (lubiprostone, N=208; placebo, N=206) and 413 (lubiprostone, N=209; placebo, N=204) patients, respectively. The mean (standard deviation) age was 50.4 (10.9) years; most patients were female (64.4%) and white (77.7%). Changes from baseline in SBM frequency rates were significantly higher at week 8 (P=0.005) and overall (P=0.004) in patients treated with lubiprostone compared with placebo. Pairwise comparisons showed significantly greater overall improvement for abdominal discomfort (P=0.047), straining (P<0.001), constipation severity (P=0.007), and stool consistency (P<0.001) with lubiprostone compared with placebo. Moreover, patients rated the effectiveness of lubiprostone as significantly (P<0.05) better than placebo for 11 of 12 weeks. The most common treatment-related adverse events (AEs) with lubiprostone and placebo were nausea (16.8% vs 5.8%, respectively), diarrhea (9.6% vs 2.9%), and abdominal distention (8.2% vs 2.4%). No lubiprostone-related serious AEs occurred. CONCLUSION: Lubiprostone effectively relieved OIC and associated signs and symptoms and was well tolerated in patients with chronic noncancer pain (http://clinicaltrials.gov/ct2/show/NCT00595946).

Increasing Diversity in Academic Medicine Via a Strategic Intermural Housestaff Leadership Development Program.

PROBLEM: By 2055, the United States will no longer have a single race or ethnic majority. As the nation's demographics change, the field of medicine must also change to meet the needs of diverse patients. APPROACH: In 2013, UT Southwestern Medical Center implemented the Housestaff Emerging Academy of Leaders (HEAL) program, which provides leadership development skills and training to underrepresented in medicine physician residents in preparation for academic medicine careers. Program leaders hypothesized that by providing housestaff with structured mentorship, career coaching, and individualized development plans, HEAL would increase interest in pursuing academic careers and prepare residents for faculty positions. HEAL has since expanded to graduate medical education programs nationwide. OUTCOMES: From 2013 to 2018, HEAL included housestaff at UT Southwestern and other Texas medical centers, totaling 392 enrollees. In 2019, the program increased to include housestaff from around the country. The first HEAL USA program had 39 housestaff, which increased to 173 in 2019, including 60 faculty from 31 U.S. academic medical centers. The 2019 HEAL USA preassessment survey (32 trainee responses) revealed that 10 (31%) of the housestaff were "extremely interested" in academic medicine, but only 1 (3%) felt "extremely confident" to pursue an academic medicine career. Postassessment responses to these same items (5 trainee responses) were 3 (60%) and 1 (20%), respectively, with 3 (60%) also feeling "extremely prepared" (1 [20%]) or "very prepared" (2 [40%]) to pursue an academic medicine career. Of 70 evaluable participants who attended at least 2 sessions and have graduated from residency, 47 (67%) have attained academic faculty positions, whereas 23 (33%) have pursued positions at nonacademic centers. NEXT STEPS: The next steps for HEAL USA will be continued expansion to additional medical centers and effective delivery of career development and leadership training to encourage participants to pursue academic medical careers.

Clopidogrel with or without omeprazole in coronary artery disease.

BACKGROUND: Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel. METHODS: We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing. RESULTS: We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole. CONCLUSIONS: Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.).

Low rate of postpolypectomy bleeding among patients who continue thienopyridine therapy during colonoscopy.

BACKGROUND & AIMS: It is not clear whether the cardiovascular risk of discontinuing treatment with antiplatelet agents, specifically the thienopyridines, before elective colonoscopy outweighs the risks of postpolypectomy bleeding (PPB). We studied the rate of PPB in patients who continue thienopyridine therapy during colonoscopy. METHODS: We performed a prospective study of 516 patients not taking warfarin who received polypectomies during elective colonoscopies; 219 were receiving thienopyridines, and 297 were not (controls). The occurrence of immediate PPB and delayed PPB was recorded. Delayed PPB was categorized as clinically important if it resulted in repeat colonoscopy, hospitalization, or blood transfusion. RESULTS: Patients receiving thienopyridines were older and had significantly more comorbid diseases than controls; the mean number of polyps removed per patient was significantly higher (3.9 vs 2.9) in the thienopyridine group. Immediate PPB developed in 16 patients in the thienopyridine group (7.3%) and in 14 in the control group (4.7%, P = .25). Among patients who completed a 30-day follow-up analysis (96% of patients enrolled), clinically important, delayed bleeding occurred in 2.4% of patients receiving thienopyridines and in none of the controls (P = .01). All PPB events in both groups were resolved without surgery, angiography, or death. CONCLUSIONS: Although a significantly higher percentage of patients who continue thienopyridine therapy during colonoscopy and polypectomy develop clinically important delayed PPB than patients who discontinue therapy, the rate of PPB events is low (2.4%), and all are resolved without sequelae. The risk for catastrophic cardiovascular risks among patients who discontinue thienopyridine therapy before elective colonoscopies could therefore exceed the risks of PPB. ClinicalTrials.gov, Number NCT01647568.

GI-REASONS: a novel 6-month, prospective, randomized, open-label, blinded endpoint (PROBE) trial.

OBJECTIVES: Because of the limitations of randomized controlled trials (RCTs) and observational studies, a prospective, randomized, open-label, blinded endpoint (PROBE) study may be an appropriate alternative, as the design allows the assessment of clinical outcomes in clinical practice settings. The Gastrointestinal (GI) Randomized Event and Safety Open-Label Nonsteroidal Anti-inflammatory Drug (NSAID) Study (GI-REASONS) was designed to reflect standard clinical practice while including endpoints rigorously evaluated by a blinded adjudication committee. The objective of this study was to assess if celecoxib is associated with a lower incidence of clinically significant upper and/or lower GI events than nonselective NSAIDs (nsNSAIDs) in standard clinical practice. METHODS: This was a PROBE study carried out at 783 centers in the United States, where a total of 8,067 individuals aged ≥ 55 years, requiring daily NSAIDs to treat osteoarthritis, participated. The participants were randomized to celecoxib or nsNSAIDs (1:1) for 6 months and stratified by Helicobacter pylori status. Treatment doses could be adjusted as per the United States prescribing information; patients randomized to nsNSAIDs could switch between nsNSAIDs; crossover between treatment arms was not allowed, and patients requiring aspirin at baseline were excluded. The primary outcome was the incidence of clinically significant upper and/or lower GI events. RESULTS: Significantly more nsNSAID users met the primary endpoint (2.4% (98/4,032) nsNSAID patients and 1.3% (54/4,035) celecoxib patients; odds ratio, 1.82 (95% confidence interval, 1.31-2.55); P = 0.0003). Moderate to severe abdominal symptoms were experienced by 94 (2.3%) celecoxib and 138 (3.4%) nsNSAID patients (P=0.0035). Other non-GI adverse events were similar between treatment groups. One limitation is the open-label design, which presents the possibility of interpretive bias. CONCLUSIONS: Celecoxib was associated with a lower risk of clinically significant upper and/or lower GI events than nsNSAIDs. Furthermore, this trial represents a successful execution of a PROBE study, where therapeutic options and management strategies available in clinical practice were incorporated into the rigor of a prospective RCT.

Prone positioning of obese patients for colonoscopy results in shortened cecal intubation times: a randomized trial.

BACKGROUND: Obesity is a risk factor for colorectal cancer, and colonoscopy can be technically challenging in obese patients. It has been proposed (with little supporting data) that prone positioning of obese patients might facilitate a difficult colonoscopy. AIM: The aim of this study was to determine if starting colonoscopy in the prone position for obese patients decreases cecal intubation times. METHODS: This was a prospective, randomized study conducted at the North Texas VA Medical Center. Patients with a body mass index of ≥30 kg/m(2) undergoing elective colonoscopy were randomized 1:1 to either initial prone positioning or standard, left-lateral positioning. The outcome measurements were cecal intubation time, frequency of repositioning, sedative medications used, reports of pain, complications, and procedure tolerability. RESULTS: Fifty patients were randomized to have colonoscopy starting in the standard, left-lateral decubitus position, and 51 to the prone position. The average cecal intubation time for the standard group was 550 vs. 424 s in the prone group (p = 0.03). Patient repositioning was used in 28 % of patients in the standard group versus 8 % in the prone group (p = 0.009). There was no difference in subjective reports of pain between groups (p = 0.95) or in average pain scores (p = 0.79). Follow-up interviews were conducted in 93 % of patients, all of whom said that they would be willing to have repeat colonoscopy in the same position. CONCLUSIONS: Performance of colonoscopy in the prone position for obese patients results in significantly shorter cecal intubation times and decreased need for patient repositioning. Prone positioning is well accepted and does not significantly increase procedure-related discomfort.

Proton pump inhibitors increase the incidence of bone fractures in hepatitis C patients.

BACKGROUND: While proton pump inhibitors (PPI) may increase the risk of bone fractures, the incidence of new bone fractures in a chronic hepatitis C virus (HCV) infected cohort, with or without PPI exposure, has not been explored. METHODS: A retrospective cohort study of the incidence of bone fractures over 10 years in 9,437 HCV antibody positive patients in the Dallas VA Hepatitis C Registry was performed. The study endpoint was the incidence of verified new bone fractures per patient-years (pt-yrs) in PPI users compared to non-PPI users. PPI use was defined as those taking a PPI for ≥360 days. Pt-yrs of exposure for PPI users began on the first PPI prescription date, and pt-yrs of exposure for non-PPI users began with first date of any non-PPI prescription. For both HCV groups, the final date of patients' study duration was defined by end of PPI exposure, bone fracture occurrence, death or end of study evaluation period. Exclusion criteria included use of bone health modifying medications ≥30 days. Statistical differences in fracture incidence between groups were determined by multivariate regression analysis. RESULTS: Among the total study population analyzed (n = 2,573), 109 bone fractures occurred. Unadjusted bone fracture incidences were 13.99/1,000 pt-yrs vs. 5.86/1,000 pt-yrs in PPI and non-PPI users, respectively. The adjusted hazard ratio for new bone fractures was 3.87 (95 % CI 2.46-6.08) (p < 0.001) in PPI users. CONCLUSIONS: In patients with chronic HCV, use of PPI for >1 year increased the risk of new bone fractures by more than threefold.