Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies

Background

Concerns have been raised about the risk of fractures with acid-suppressive medications, such as proton pump inhibitors and histamine₂-receptor antagonists.

Methods

This meta-analysis evaluated the association between proton pump inhibitor or histamine₂-receptor antagonist use and fractures. We performed a systematic search of published literature (1970 to October 10, 2010) in MEDLINE, EMBASE, and other sources. Ten publications reporting 11 studies were considered eligible for analysis.

Results

All studies were observational case-control or cohort studies and primarily evaluated older adults. The summary effect estimate for risk of hip fracture increased modestly among individuals taking proton pump inhibitors (relative risk [RR] 1.30, 95% confidence interval [CI], 1.19-1.43). There also was an increase in spine (RR 1.56, 95% CI, 1.31-1.85) and any-site fractures (RR 1.16, 95% CI, 1.04-1.30) among proton pump inhibitor users. These findings were similar in both men and women and after stratification by duration of use. In contrast, histamine₂-receptor antagonist use was not significantly associated with increased risk of hip fracture (RR 1.12, 95% CI, 0.97-1.30).

Conclusion

In this meta-analysis of observational studies, proton pump inhibitors modestly increased the risk of hip, spine, and any-site fractures, whereas histamine₂-receptor antagonists were not associated with fracture risk. The possibility of residual confounding cannot be excluded. Further skeletal evaluation should be considered for patients who are taking proton pump inhibitors and also at risk for osteoporotic fracture.     

Risk of peptic ulcer hospitalizations in users of NSAIDs with gastroprotective cotherapy versus coxibs

BACKGROUND & AIMS: The primary strategies to reduce the risk of serious gastropathy caused by traditional nonsteroidal anti-inflammatory drugs (NSAIDs) are use of a coxib or concurrent use of a proton pump inhibitor or double-dose histamine-2 receptor antagonist. However, the relative clinical effectiveness of these therapeutic alternatives is understudied. METHODS: We studied peptic ulcer hospitalizations in a cohort of Tennessee Medicaid enrollees between 1996 and 2004. To decrease potential "channeling" bias, the study included only new episodes of prescribed NSAID or coxib use and controlled for multiple baseline risk factors for upper gastrointestinal disease. There were 234,010 and 48,710 new episodes of NSAID and coxib use, respectively, with 363,037 person-years of follow-up and 1223 peptic ulcer hospitalizations. RESULTS: Current users of NSAIDs with no gastroprotective cotherapy had an adjusted incidence of peptic ulcer hospitalizations of 5.65 per 1000 person-years, 2.76 (95% confidence interval, 2.35-3.23) times greater than that for persons not currently using either NSAIDs or coxibs. This risk was reduced by 39% (16%-56%, 95% CI) for current users of NSAIDs with gastroprotective cotherapy and 40% (23%-54%) for current users of coxibs without such cotherapy. Concurrent users of NSAIDs and proton pump inhibitors had a 54% (27%-72%) risk reduction, very similar to the 50% (27%-66%) reduction for concurrent users of proton pump inhibitors and coxibs. CONCLUSIONS: These findings suggest that coprescribing a proton pump inhibitor with an NSAID is as effective as use of a coxib for reducing the risk of NSAID-induced gastropathy.     

Gastroesophageal reflux disease in pregnancy

Opinion statement Gastroesophageal reflux disease (GERD) in pregnancy presents a special challenge for the clinician, predominantly because of the potential side effects of pharmacologic interventions on the fetus. Lifestyle and dietary modifications, change in sleeping posture, and antacid medications are emphasized, as these options pose little risk to the fetus. When these interventions are not successful, sucralfate, a mucosal protectant with little to no systemic absorption, should be considered next. Therapy with H₂ receptor antagonists or proton pump inhibitors can be considered in patients with refractory symptoms; though not approved for this use, they are likely safe, particularly in third trimester. Prokinetic agents should be used with extreme caution or avoided altogether in the pregnant patient.     

The prevention of gastropathy and upper abdominal symptoms caused by nonsteroidal anti-inflammatory drugs

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is increasing, primarily due to arthritis in the aging population. This article reviews current data on the risk of gastrointestinal complications related to NSAIDs and strategies to manage risk in patients taking these agents. Risks of NSAID use include gastrointestinal ulceration, hemorrhage, or perforation; renal dysfunction; death; and dyspepsia. Alternate therapies include use of non-NSAID analgesics; low-dose NSAIDs; and concurrent administration of cytoprotective agents with NSAIDs, acid inhibitors, proton pump inhibitors, and COX-2 agents.     

Head-to-head comparison of H2-receptor antagonists and proton pump inhibitors in the treatment of erosive esophagitis： A meta-analysis

AIM: To systematically evaluate the efficacy of H2-receptor antagonists (H2RAs) and proton pump inhibitors in healing erosive esophagitis (EE). METHODS: A meta-analysis was performed. A literature search was conducted in PubMed, Medline, Embase, and Cochrane databases to include randomized controlled head-to-head comparative trials evaluating the efficacy of H2RAs or proton pump inhibitors in healing EE. Relative risk (RR) and 95% confidence interval (CI) were calculated under a random-effects model. RESULTS: RRs of cumulative healing rates for each comparison at 8 wk were: high dose vs standard dose H2RAs, 1.17 (95%CI, 1.02-1.33); standard dose proton pump inhibitors vs standard dose H2RAs, 1.59 (95%CI, 1.44-1.75); standard dose other proton pump inhibitors vs standard dose omeprazole, 1.06 (95%CI, 0.98-1.06). Proton pump inhibitors produced consistently greater healing rates than H2RAs of all doses across all grades of esophagitis, including patients refractory to H2RAs. Healing rates achieved with standard dose omeprazole were similar to those with other proton pump inhibitors in all grades of esophagitis. CONCLUSION: H2RAs are less effective for treating patients with erosive esophagitis, especially in those with severe forms of esophagitis. Standard dose proton pump inhibitors are significantly more effective than H2RAs in healing esophagitis of all grades. Proton pump inhibitors given at the recommended dose are equally effective for healing esophagitis.     

The Simple Predictors of Pseudomembranous Colitis in Patients with Hospital-Acquired Diarrhea: A Prospective Observational Study

Background/Aims

As the incidence rate of and mortality from pseudomembranous colitis (PMC) are increasing worldwide, it is important to study the simple predictive risk factors for PMC among patients with hospital-acquired diarrhea (HAD). This study focused on identifying the clinical risk factors that can easily predict PMC.

Methods

The presumed HAD patients were prospectively recruited at the Hallym University Kangdong Sacred Heart Hospital.

Results

Age of 70 and older (adjusted odds ratio [OR], 1.76; 95% confidence interval [CI], 1.12 to 0.75), use of proton pump inhibitors (adjusted OR, 4.07; 95% CI, 2.512 to 6.57), use of cephalosporins (adjusted OR, 2.99; 95% CI, 1.82 to 4.94), and underlying cancer (adjusted OR, 1.72; 95% CI, 1.04 to 2.82) were independent risk factors for PMC in the multivariate logistic regression analysis. The prevalence of PMC was very low in the patients with HAD who exhibited no risk factors.

Conclusions

The risk factors for PMC in patients with HAD included cephalosporin use, proton pump inhibitor use, old age, and cancer. Considering the strongly negative predictive values of these risk factors, endoscopic evaluation can be delayed in patients with HAD without risk of developing PMC.     

Inibidores da bomba de protões e o risco de eventos adversos graves – uma bomba cardiovascular?

Proton pump inhibitors are currently one of the most prescribed pharmacological classes in developed countries, given their effectiveness and safety profile, which has until now been considered favorable.However, in recent years, several papers have been published that associate prolonged use of these drugs with a wide range of adverse effects, posing doubts about their safety. Among the adverse effects described is an increased risk of cardiovascular events. This relationship was first described in subjects after acute coronary syndrome due to the interference of proton pump inhibitors in the cytochrome P450 2C19 and the conversion of clopidogrel to its active metabolite. More recent studies have also reported this relationship with the use of antiplatelet agents that do not depend on cytochrome P450 2C19 activation. The proposed mechanism is inhibition of dimethylarginine dimethylaminohydrolase, a physiological inhibitor of asymmetric dimethylarginine, which increases plasma concentrations of the latter enzyme, leading to lower levels of nitric oxide.By reviewing in this article the relationship between the use of proton pump inhibitors and increased risk of cardiovascular and cerebrovascular events, the authors aim to alert the medical community to the potentially harmful effects of these drugs, and recommend the setting of a moratorium on their prolonged use.     

The early effect of proton pump inhibitor therapy on the accuracy of the C-urea breath test

BACKGROUND: The intake of proton pump inhibitors may interfere with the reliability of the urea breath test. AIM: Prospective study to assess the accuracy of the urea breath test during the first days of therapy with proton pump inhibitors. PATIENTS: Thirty patients who needed to start proton pump inhibitors therapy and 53 volunteers. METHODS: A 13C-urea breath test was performed respectively before starting proton pump inhibitors therapy and every morning before its intake up until 10 days. The test was considered positive for values of 13CO2 > or = 3.0% delta over baseline. The coefficient of reproducibility for 95% interval of confidence of the urea breath test was calculated in both groups. RESULTS: Of the 30 patients receiving proton pump inhibitors, 47% were positive for Helicobacter pylori. Among these, 43% developed false negative breath tests in the first 10 days. False positive results occurred in 37.5% of H. pylori-negative subjects in the first 10 days. The coefficient of reproducibility of the urea breath test was significantly higher in the group treated with proton pump inhibitors (11.0 versus 1.8 for the control group, p < 0.0001). CONCLUSION: The intake of proton pump inhibitors impairs the accuracy of the 13C-urea breath test. False negative and false positive 13C-urea breath tests are common, occur as soon as after 1 day and increase with prolonged duration of treatment. The coefficient of reproducibility of the test in patients receiving proton pump inhibitors is not acceptable for clinical purpose and the test should not be performed once the medication has been started.     

Effect of proton pump inhibitors and antacid therapy on 13C urea breath tests and stool test for Helicobacter pylori infection

OBJECTIVE: There is uncertainty about the best method of testing patients for Helicobacter pylori (H. pylori) infection while they are taking proton pump inhibitors. The aim of this study was to determine: (i) if the decreased sensitivity of the urea breath test during proton pump inhibitor is corrected by different techniques for breath testing and (ii) if the sensitivity of stool test is decreased with the administration of proton pump inhibitors. METHODS: Prospective randomized single-blind study was performed in a tertiary care university hospital. Out of 72 H. pylori infected patients endoscoped for upper abdominal symptoms 48 were randomized to proton pump inhibitors (omeprazole 20 mg each day or esomeprazole 40 mg each day) and 24 to antacid (aluminum hydroxide 800 mg each day) for 14 days. Several breath tests (standard 75 mg (13)C-UBT with citric acid, with orange juice, a tablet breath test with 100 and 50 mg of (13)C), and a stool test were carried out. Baseline samples were collected before and after treatment. RESULTS: The baseline sensitivity for all breath tests was 100% in both groups; for stool test it was 97.8% (95% CI: 88.7-96.6) and 90% (95% CI: 69.9-97.2) in the proton pump inhibitor and antacid group, respectively. After treatment, the sensitivity of tests was significantly low (UBTs range: 77.1%-85.4%; stool test: 83%; 95% CI: 63.9-91.1), while it was unchanged in the antacid group. CONCLUSIONS: False negative breath and stool tests are equally common in patients taking proton pump inhibitors. Antacids do not impair the sensitivity of the breath tests or the stool test.     

New therapies for the pregnant patient with diabetes

Gestational diabetes complicates 3-5% of pregnancies. Of diabetes seen during pregnancy, 10% is pregestational and the remaining 90% represents gestational diabetes. (1,2) Pregnancy in women with pregestational diabetes is especially high risk. Spontaneous abortion, preterm labor, congenital malformations, preeclampsia, macrosomia, birth injury, and cesarean section are all increased in these pregnancies. Deterioration of maternal health during pregnancy, especially in the setting of diabetes-induced end-organ disease, is a real concern. Vigilant surveillance and management of associated disorders such as retinopathy, nephropathy, and chronic hypertension are required. During the preinsulin era, maternal and perinatal mortality in pregnancies complicated by pregestational diabetes was approximately 50%. (1,2) Although modern obstetrical management and the appropriate use of insulin have dramatically improved maternal-fetal outcomes, pregnant patient with diabetes remains at increased risk for complications. There is no doubt that optimizing maternal glucose control is a key element in avoiding established perinatal risks. The most effective means to accomplish this control are topics of active research. Further, hormonal changes during pregnancy can make glycemic control difficult even for the most compliant and educated patient. This paper discusses several new approaches, either currently in practice or under consideration, to pregnancies complicated by diabetes, including oral hypoglycemic agents, lispro, the insulin pump, and transplantation.     

Helicobacter pylori infection and the prevention of peptic ulcer with proton pump inhibitors in elderly subjects taking low-dose aspirin

INTRODUCTION: The role of Helicobacter pylori infection on the risk of low-dose aspirin-related gastroduodenal damage and on the efficacy of the prevention therapy in elderly chronic users of low-dose aspirin is still controversial. AIM: To evaluate in symptomatic elderly chronic users of low-dose aspirin: (1) the association between H. pylori infection and the prevalence of upper gastrointestinal lesions; and (2) the effect of H. pylori infection on the efficacy of proton pump inhibitors in the prevention of aspirin-related gastroduodenal lesions. PATIENTS AND METHODS: Two hundred and forty-five symptomatic elderly who were taking aspirin 75-300 mg daily, at least during the last 3 months, were evaluated by endoscopy. A structured interview was carried out to evaluate gastrointestinal symptoms and the use of proton pump inhibitors. H. pylori infection was diagnosed according to histology and the rapid urease test on gastric biopsies. RESULTS: One hundred and twelve patients were H. pylori-positive and 133 patients were H. pylori-negative. A significantly higher prevalence of peptic ulcers was observed in H. pylori-positive than in H. pylori-negative subjects (36.6% versus 15.8%, P = 0.0002). The use of proton pump inhibitors was associated with a significant decreased risk of peptic ulcer both in H. pylori-positive (absolute risk reduction, ARR = -36.2, 95% confidence interval: -51.2 to -21.3, P < 0.001) and H. pylori-negative patients (ARR = -12.6, 95% confidence interval: -23.9 to -1.2, P = 0.03). However, the number of patients who needed to be treated in order to gain a reduction of one peptic ulcer (number needed to treat, NnT) was lower in H. pylori-positive than in H. pylori-negative patients (NnT = 3 versus 8). CONCLUSIONS: In symptomatic elderly chronic users of low-dose aspirin, H. pylori infection may influence the prevalence of peptic ulcers and the cost-effectiveness of the proton pump inhibitor prevention therapy.     

Proton pump inhibitors in children: a review

Proton pump inhibitors are often used to treat disorders associated with gastric hypersecretion in children, despite the lack of pediatric formulations. They are highly effective in the treatment of ulcers, gastro-esophageal reflux disorders and hypersecretory diseases. They provide a high level of gastric acid inhibition with few adverse effects. The aim of this article is to review the available studies concerning the use of proton pump inhibitors in pediatric populations and to point out: indications for use in children, optimal dosage, risk of adverse effects and consequences of the mechanism of action, and drug interactions. We performed a Medline and Embase search of publications printed from January 1980 to December 2002 concerning the use of proton pump inhibitors in children. We consider the available randomised controlled trials and several other uncontrolled studies conducted in the pediatric population, including all available information concerning the pediatric use of proton pump inhibitors. In children as well as in adults, there are clinical conditions (i.e., severe esophagitis or eradication of Helicobacter pylori) in which proton pump inhibitors offer clear advantages over histamine-2 receptor antagonists. The relatively common use of acid inhibitors (proton pump inhibitors and histamine-2 receptor antagonists) in uncomplicated gastro-esophageal reflux disorders or in the prevention of non-steroidal anti-inflammatory drugs/steroid gastropathy is often unsubstantiated and should be limited to very specific situations. Multicentre randomised controlled studies are needed to better define the efficacy profile, the optimal dosage with respect to the different indications and the safety profile for chronic therapy of proton pump inhibitors in children.     

Association of Antisecretory Drugs with Upper Gastrointestinal Bleeding in Patients Using Oral Anticoagulants: A Systematic Review and Meta-Analysis

BackgroundThe role of antisecretory drugs for the prevention of upper gastrointestinal bleeding in patients using anticoagulants is unclear. We investigated this question in a systematic review and meta-analysis.MethodsWe searched Embase, PubMed, Web of Science, Scopus, the Cochrane Library, and clinicaltrials.gov thru April 2021 for controlled randomized trials and observational studies evaluating the association of proton pump inhibitors (PPIs) or H2-receptor antagonists with overt upper gastrointestinal bleeding in patients using anticoagulants. Independent duplicate review, data extraction, and risk of bias assessment were performed. Observational studies were included only if they provided results controlled for at least 2 variables. Meta-analyses were performed using random effects models.ResultsSix observational studies and 1 randomized trial were included. All but 1 study had low risk of bias. None of the studies excluded patients with concomitant aspirin or nonsteroidal anti-inflammatory drug use. For PPIs, the pooled relative risk of upper gastrointestinal bleeding was 0.67 (95% confidence interval 0.61, 0.74) with low statistical heterogeneity (I² = 15%). Individual studies showed greater treatment effect in patients with higher risk for upper gastrointestinal bleeding (eg, nonsteroidal anti-inflammatory drug or aspirin use, elevated bleeding risk score). A single observational study evaluating the association of H2-receptor antagonists with upper gastrointestinal bleeding found a relative risk of 0.69 (95% confidence interval 0.24-2.02).ConclusionsEvidence drawn mostly from observational studies with low risk of bias demonstrate that PPIs reduce upper gastrointestinal bleeding in patients prescribed oral anticoagulants. The benefit appears to be most clearcut and substantial in patients with elevated risk of upper gastrointestinal bleeding.     

Proton pump inhibitor use increases hepatic encephalopathy risk: A systematic review and meta-analysis

BACKGROUND Several studies have been conducted to explore the association between the use of proton pump inhibitors (PPIs) and hepatic encephalopathy (HE) risk in patients with liver cirrhosis. However, their results are controversial. AIM To perform a systematic review and meta-analysis to evaluate the HE risk among PPI users. METHODS A systematic search on PubMed, Web of Science, EMBase, and ScienceDirect databases was conducted up to December 31, 2018 for eligible studies involving PPI use and HE risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the fixed or random effects model. Publication bias was evaluated using Begg’s test, Egger’s test, and trim-and-fill method. RESULTS Seven studies with 4574 patients were included in the present meta-analysis. The meta-analysis results indicated a significant association between the PPI use and HE risk (OR = 1.50;95%CI: 1.25-1.75) with low heterogeneity (I2 = 14.2%, P = 0.321). Although publication bias existed when Egger’s tests were used (P = 0.005), the trim-and-fill method verified the stability of the pooled result. Sensitivity analyses suggested that the results of this meta-analysis were robust. CONCLUSION The current evidence indicates that PPI use increases HE risk in patients with liver cirrhosis. Further studies with a large data set and well-designed models are needed to validate our findings.     

Clostridium difficile--associated disease in a setting of endemicity: identification of novel risk factors.

BACKGROUND: Previous studies of risk factors for Clostridium difficile-associated disease (CDAD) have been limited by small sample sizes and case-control study designs. Many of these studies were performed during outbreaks of CDAD. Colonization pressure and use of fluoroquinolones, vancomycin, and gastric acid suppressors have not been fully evaluated as risk factors for CDAD. The purpose of this study was to determine risk factors for endemic CDAD, including CDAD pressure, a modified version of colonization pressure. METHODS: We performed a retrospective cohort study of 36,086 patients admitted to Barnes-Jewish Hospital (St. Louis, MO) during the period from 1 January 2003 through 31 December 2003. Administrative, laboratory, and pharmacy data were collected from electronic hospital databases. Colonization pressure was measured through a surrogate variable (i.e., CDAD pressure). Multivariable pooled logistic regression models were used to evaluate independent risk factors for CDAD. RESULTS: The analysis included 382 CDAD case patient admissions and 35,704 non-case patient admissions. Significant independent risk factors for CDAD included increasing age, admission(s) in the previous 60 days, hypoalbuminemia, leukemia and/or lymphoma, mechanical ventilation, and receipt of antimotility drugs, histamine-2 blockers, proton pump inhibitors, intravenous vancomycin, fluoroquinolones, and first-, third-, or fourth-generation cephalosporins. Increasing CDAD pressure was a strong risk factor for CDAD (for a CDAD pressure >1.4, the odds ratio was 4.0; 95% confidence interval, 2.9-5.6). Receipt of metronidazole was protective against CDAD (odds ratio, 0.5; 95% confidence interval, 0.3-0.6). CONCLUSIONS: This study identified the previously underrecognized CDAD risk factors of CDAD pressure and vancomycin. More studies are needed to evaluate the relationship between CDAD, these risk factors, and use of gastric acid suppressors and fluoroquinolones.