Use Of Histamine-2 Receptor Antagonists Research Articles

Risk of peptic ulcer bleeding associated with Helicobacter pylori infection, nonsteroidal anti‐inflammatory drugs, low‐dose aspirin, and antihypertensive drugs: A case‐control study

The associations between antithrombotic or antihypertensive drugs and peptic ulcer bleeding (PUB) remain unknown, particularly in Asia, where Helicobacter pylori infection is prevalent. This study aims to evaluate the risks of PUB from antithrombotic drugs, angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, α-blockers, and β-blockers. This prospective hospital-based case-control study included 230 patients with endoscopically verified PUB and 920 age and sex-matched controls (1:4) without bleeding on screening endoscopy. Adjusted odds ratios (AOR) for the risk of PUB were determined by conditional logistic regression analysis. In multivariate analysis, alcohol consumption (AOR, 2.2; P < 0.001), history of peptic ulcer (AOR, 4.8; P < 0.001), H. pylori infection (AOR, 2.1; P < 0.001), comorbidity index (AOR, 1.1; P = 0.089), nonsteroidal anti-inflammatory drugs (NSAIDs) (AOR, 2.0; P = 0.025), and low-dose aspirin (AOR, 2.8; P = 0.003) increased the risk of PUB, whereas H. pylori eradication (AOR, 0.03; P < 0.001), proton pump inhibitors (PPIs) (AOR, 0.1; P < 0.001), and histamine 2-receptor antagonists (H2RA) (AOR, 0.1; P < 0.001) reduced it. No significant interactions were observed between H. pylori infection and NSAIDs use for PUB (P = 0.913). ARBs (P = 0.564), ACE inhibitors (P = 0.213), calcium channel blockers (P = 0.215), α-blockers (P = 0.810), and β-blockers (P = 0.864) were not associated with PUB. We found that alcohol consumption, history of peptic ulcer, H. pylori infection, NSAIDs use, and low-dose aspirin use were independent risk factors for PUB, whereas H. pylori-eradication, PPIs use, and H2RA use reduced its risk. Interactions between H. pylori and NSAIDs use in PUB were not observed. No antihypertensive drug was associated with PUB.

Mortality associated with proton pump inhibitors in cirrhotic patients with spontaneous bacterial peritonitis

The aims of this study were to investigate whether acid suppressive therapy increases the risk of spontaneous bacterial peritonitis (SBP) and to define factors associated with mortality in cirrhotic patients with SBP. Cirrhotic patients who had undergone paracentesis after hospitalization were included. Those patients were divided into two groups according to the presence or absence of SBP. Factors associated with the development of SBP were analyzed. Mortality rates during hospitalization or within 30 days after SBP and the factors associated with mortality were also analyzed. A total of 1140 patients (median age, 62; men, 75%; model for end-stage liver disease [MELD] score, 17) were included. Five hundred thirty-three patients were identified as having SBP. In the logistic regression, the use of histamine-2 receptor antagonists, the use of proton pump inhibitors (PPIs), a high admission MELD score, and old age were associated with the development of SBP. The use of PPIs within 30 days (adjusted odds ratio [aOR] 1.960; 95% confidence interval [CI] 1.190-3.227; P = 0.008), a higher admission MELD score (aOR 1.054; 95% CI 1.032-1.076; P < 0.001), and hepatocellular carcinoma (aOR 1.852; 95% CI 1.256-2.730; P = 0.002) were associated with mortality after SBP. Acid suppressive therapy is associated with the development of SBP in cirrhotic patients with ascites. The use of PPIs is associated with mortality after SBP independent of the severity of the underlying liver disease in our retrospective cohort study.

Proton Pump Inhibitor and Histamine 2 Receptor Antagonist Use and Vitamin B12Deficiency

Proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RAs) suppress the production of gastric acid and thus may lead to malabsorption of vitamin B12. However, few data exist regarding the associations between long-term exposure to these medications and vitamin B12 deficiency in large population-based studies. To study the association between use of PPIs and H2RAs and vitamin B12 deficiency in a community-based setting in the United States. We evaluated the association between vitamin B12 deficiency and prior use of acid-suppressing medication using a case-control study within the Kaiser Permanente Northern California population. We compared 25,956 patients having incident diagnoses of vitamin B12 deficiency between January 1997 and June 2011 with 184,199 patients without B12 deficiency. Exposures and outcomes were ascertained via electronic pharmacy, laboratory, and diagnostic databases. Risk of vitamin B12 deficiency was estimated using odds ratios (ORs) from conditional logistic regression. Among patients with incident diagnoses of vitamin B12 deficiency, 3120 (12.0%) were dispensed a 2 or more years' supply of PPIs, 1087 (4.2%) were dispensed a 2 or more years' supply of H2RAs (without any PPI use), and 21,749 (83.8%) had not received prescriptions for either PPIs or H2RAs. Among patients without vitamin B12 deficiency, 13,210 (7.2%) were dispensed a 2 or more years' supply of PPIs, 5897 (3.2%) were dispensed a 2 or more years' supply of H2RAs (without any PPI use), and 165,092 (89.6%) had not received prescriptions for either PPIs or H2RAs. Both a 2 or more years' supply of PPIs (OR, 1.65 [95% CI, 1.58-1.73]) and a 2 or more years' supply of H2RAs (OR, 1.25 [95% CI, 1.17-1.34]) were associated with an increased risk for vitamin B12 deficiency. Doses more than 1.5 PPI pills/d were more strongly associated with vitamin B12 deficiency (OR, 1.95 [95% CI, 1.77-2.15]) than were doses less than 0.75 pills/d (OR, 1.63 [95% CI, 1.48-1.78]; P = .007 for interaction). Previous and current gastric acid inhibitor use was significantly associated with the presence of vitamin B12 deficiency. These findings should be considered when balancing the risks and benefits of using these medications.

Proton-pump inhibitor use is associated with low serum magnesium concentrations

Although case reports link proton-pump inhibitor (PPI) use and hypomagnesemia, no large-scale studies have been conducted. Here we examined the serum magnesium concentration and the likelihood of hypomagnesemia (<1.6 mg/dl) with a history of PPI or histamine-2 receptor antagonist used to reduce gastric acid, or use of neither among 11,490 consecutive adult admissions to an intensive care unit of a tertiary medical center. Of these, 2632 patients reported PPI use prior to admission, while 657 patients were using a histamine-2 receptor antagonist. PPI use was associated with 0.012 mg/dl lower adjusted serum magnesium concentration compared to users of no acid-suppressive medications, but this effect was restricted to those patients taking diuretics. Among the 3286 patients concurrently on diuretics, PPI use was associated with a significant increase of hypomagnesemia (odds ratio 1.54) and 0.028 mg/dl lower serum magnesium concentration. Among those not using diuretics, PPI use was not associated with serum magnesium levels. Histamine-2 receptor antagonist use was not significantly associated with magnesium concentration without or with diuretic use. The use of PPI was not associated with serum phosphate concentration regardless of diuretic use. Thus, we verify case reports of the association between PPI use and hypomagnesemia in those concurrently taking diuretics. Hence, serum magnesium concentrations should be followed in susceptible individuals on chronic PPI therapy.

Stress Ulcer Prophylaxis in the ICU

Bleeding from stress-related mucosal disease (SRMD) in critically ill patients remains an important clinical management issue. Although only a small proportion (2% to 6%) of patients admitted to an ICU setting will bleed (1), a significant proportion exhibit the clinical risk factors, mainly mechanical ventilation for more than 48 hrs and the presence of a coagulpathy (2), that predict a higher risk of bleeding; furthermore, upper gastrointestinal mucosal lesions can be found in 75% to 100% of ICU patients (3). Although uncommon, stress-ulcer bleeding (SUB) is a severe complication as it is estimated that up to 50% patients will die, mostly from decompensation of an underlying condition or multiorgan failure (4). The use of SUB prophylaxis remains a matter of concern, its efficacy has been questioned with, in addition, some concerns about the risk of adverse events such as nosocomial pneumonia and clostridium difficile infection (5). Several medications have been assessed, including sucralfate, histamine-2 receptor antagonists (H2RAs), and protonpump inhibitors (PPIs). As H2RAs were shown to be superior to sucralfate (6), use of prophylactic pharmacotherapy comes down to opting for H2RAs or PPIs—a choice that has remained controversial as the underlying pathophysiology of SRMD differs from that of bleeding peptic ulcers, relating less on acid secretion and more on decreased mucosal blood flow, local ischemia, hypoperfusion, and reperfusion injury (3). In this issue of Critical Care Medicine, Dr. Alhazzani et al (7), report a systematic review and meta-analysis on the use of H2RAs or PPIs for stress ulcer prophylaxis in critically ill patients. The authors conclude that PPIs compared with H2RAs are more effective at reducing clinically important upper gastrointestinal bleeding (relative risk [RR] 0.36; 95% CI 0.19, 0.68) and overt upper gastrointestinal bleeding (RR 0.35; 95% CI 0.21, 0.59), without significantly increasing the risk of nosocomial pneumonia (RR 1.06; 95% CI 0.73, 1.52; p = 0.76). PPIs, however, appear to reduce neither ICU mortality nor length of stay, confirming and expanding findings of our meta-analysis published earlier this year (8). The major strength of this study

Acid suppressive drugs and gastric cancer: A meta-analysis of observational studies

To evaluate the association between acid suppressive drug use and the development of gastric cancer. A systematic search of relevant studies that were published through June 2012 was conducted using the MEDLINE (PubMed), EMBASE, and Cochrane Library databases. The search included observational studies on the use of histamine 2-receptor antagonists (H₂RAs) or proton pump inhibitors and the associated risk of gastric cancer, which was measured using the adjusted odds ratio (OR) or the relative risk and 95%CI. An independent extraction was performed by two of the authors, and a consensus was reached. Of 4595 screened articles, 11 observational studies (n = 94558) with 5980 gastric cancer patients were included in the final analyses. When all the studies were pooled, acid suppressive drug use was associated with an increased risk of gastric cancer risk (adjusted OR = 1.42; 95%CI: 1.29-1.56, I² = 48.9%, P = 0.034). The overall risk of gastric cancer increased among H₂RA users (adjusted OR = 1.40; 95%CI: 1.24-1.59, I² = 59.5%, P = 0.008) and PPI users (adjusted OR = 1.39; 95%CI: 1.19-1.64, I² = 0.0%, P = 0.377). Acid suppressive drugs are associated with an increased risk of gastric cancer. Further studies are needed to test the effect of acid suppressive drugs on gastric cancer.

Proton Pump Inhibitors Reduce the Risk of Neoplastic Progression in Patients With Barrett's Esophagus

Acid exposure contributes to the development of Barrett's esophagus (BE) and its progression toward esophageal adenocarcinoma. Patients with BE are frequently treated with acid suppressants, but it is unclear whether these prevent the development of BE-related cancer. We investigated whether acid suppression reduces the risk of neoplastic progression in patients with BE. We performed a multicenter prospective cohort study of 540 patients with BE. We collected information on medication use at each surveillance visit, which was cross-checked with pharmacy records. Patients also completed a questionnaire about their use of over-the-counter medication. Incident cases of high-grade dysplasia and esophageal adenocarcinoma were identified during a median follow-up period of 5.2 years. Time-dependent Cox regression models were used to investigate the effect of acid suppression on the risk of neoplastic progression. Forty patients (7%) developed high-grade dysplasia or esophageal adenocarcinoma during the follow-up period. Use of histamine-2 receptor antagonists did not affect the incidence of neoplastic progression. However, use of proton pump inhibitors (PPIs) at inclusion in the study or during the follow-up period reduced the risk of neoplastic progression (hazard ratio, 0.41; 95% confidence interval, 0.18-0.93 and hazard ratio, 0.21; 95% confidence interval, 0.07-0.66). Prolonged use of PPIs and good adherence were associated with an additional protective effect. The prevalence of esophagitis decreased during PPI use, but length of BE was not affected. In a multicenter prospective cohort study, PPI use was associated with a reduced risk of neoplastic progression in patients with BE.

Drugs that inhibit gastric acid secretion may alter the course of inflammatory bowel disease

Recent data suggest that acid suppressive medications may alter factors central to the pathophysiology of inflammatory bowel diseases (IBD), whether through shifts in the intestinal microbiome due to acid suppression or effects on immune function. To assess the relationship between the use of proton pump inhibitors (PPIs) or histamine2-receptor antagonists (H2Ra) and incidence of 'flares' (hospitalisation/surgery and change in medication). We conducted a new user cohort study including individuals diagnosed with IBD in British Columbia using linked healthcare utilisation databases (available from July 1996 through April 2006). Propensity-score matched incidence rates during a 6-month follow-up period and rate ratios (RR) and 95% CI were calculated. Among 16151 IBD patients, 1307 Crohn's disease (CD) and 996 ulcerative colitis (UC) patients experienced a new use of PPIs, whereas 741 CD and 738 UC used H2Ra. All IBD subgroups were matched separately to an equal number of unexposed IBD patients. H2Ra use in CD doubled the risk of hospitalisation/surgery (RR=1.94; 95%CI 1.24-3.10) and numerically less so in UC patients (RR=1.11) with widely overlapping CIs (0.61-2.03). Proton pump inhibitors use was associated with medication change in UC (RR=1.39; 95%CI 1.20-1.62), but without meaningfully, increased risk of hospitalisation/surgery for UC or CD patients. Extending follow-up showed persistence, but attenuation, of all effects. Initiation of PPIs or H2Ra may be associated with short-term changes in the course of IBD. Although confounding by indication was adjusted using propensity score matching, residual confounding may persist and findings need to be interpreted cautiously.

Risk of Clostridium difficile Infection With Acid Suppressing Drugs and Antibiotics: Meta-Analysis

Several studies have raised concern regarding the possible association between proton-pump inhibitors (PPIs) and Clostridium difficile infection (CDI). We aimed to perform a systematic review of incident and recurrent CDI in PPI users, and to evaluate the relative impact of concurrent antibiotic use, or switching acid suppression to histamine-2-receptor antagonists (H2RAs). We searched MEDLINE and EMBASE from inception to December 2011 for controlled observational studies that reported on the risk of CDI with and without PPI use. We performed random effects meta-analysis and assessed statistical heterogeneity using the I(2) statistic. We included 42 observational studies (30 case-control, 12 cohort) totalling 313,000 participants overall. Pooled analysis of 39 studies showed a statistically significant association between PPI use and risk of developing CDI, odds ratio (OR) 1.74 (95% confidence interval (CI) 1.47-2.85, P<0.001, I(2)=85%) compared with non-users. A pooled analysis of three studies showed a significant associated risk of recurrent CDI associated with PPIs, OR 2.51 (95% CI 1.16-5.44, P=0.005, I(2)=78%). Subgroup analysis failed to fully clarify the source of the substantial statistical heterogeneity. Adjusted indirect comparison demonstrated that use of H2RAs as an alternative carried a lower-risk OR 0.71 (95% CI 0.53-0.97) compared with PPIs. Conversely, concomitant use of PPI and antibiotics conferred a greater-risk OR 1.96 (95% CI 1.03-3.70) above that of PPIs alone. For PPI and antibiotics, the Rothman's synergy index was 1.36 and attributable proportion of risk from interaction 0.19, indicating an increased risk from interaction beyond the effects of each drug alone. Despite the substantial statistical and clinical heterogeneity, our findings indicate a probable association between PPI use and incident and recurrent CDI. This risk is further increased by concomitant use of antibiotics and PPI, whereas H2RAs may be less harmful.

Prognosis of hospitalized patients with 2009 H1N1 influenza in Spain: influence of neuraminidase inhibitors.

BackgroundThe H1N1 influenza pandemic strain has been associated with a poor prognosis in hospitalized patients. The present report evaluates the factors influencing prognosis.MethodsA total of 813 patients hospitalized with H1N1 influenza in 36 hospitals (nationwide) in Spain were analysed. Detailed histories of variables preceding hospital admission were obtained by interview, validating data on medications and vaccine with their attending physicians. Data on treatment and complications during hospital stay were recorded. As definition of poor outcome, the endpoints of death and admission to intensive care were combined; and as a further outcome, length of stay was used.ResultsThe mean age was 38.5 years (SD 22.8 years). There were 10 deaths and 79 admissions to intensive care (combined, 88). The use of neuraminidase inhibitors was reported by 495 patients (60.9%). The variables significantly associated with a poor outcome were diabetes (OR = 2.21, 95% CI = 1.21–4.02), corticosteroid therapy (OR = 3.37, 95% CI = 1.39–8.20) and use of histamine-2 receptor antagonists (OR = 2.68, 95% CI = 1.14–6.36), while the use of neuraminidase inhibitors (OR = 0.57, 95% CI = 0.34–0.94) was protective. Neuraminidase inhibitors within the first 2 days after the influenza onset reduced hospital stay by a mean of 1.9 days (95% CI = 4.7–6.6).ConclusionsThe use of neuraminidase inhibitors decreases the length of hospital stay and admission to intensive care and/or death.

Prenatal exposure to acid‐suppressive drugs and the risk of childhood asthma: a population‐based Danish cohort study

Proton pump inhibitors (PPIs) may activate the immune system and cause asthma. To investigate the association of prenatal exposure to PPIs and histamine 2-receptor antagonists (H2RAs) with risk of asthma. In this cohort study, 197,060 singletons born between 1996 and 2008 in northern Denmark were followed until the end of 2009. Data were obtained through Danish medical registries. Asthma in offspring was defined as at least two prescriptions of both a β-agonist and an inhaled glucocorticoid and/or a hospital diagnosis of asthma during the follow-up. Cox proportional-hazard regression was used to compute incidence rate ratios, adjusting for covariates. A total of 2238 (1.1%) children were prenatally exposed to PPIs and 24,506 (12.4%) children developed asthma during follow-up (median follow-up = 6.8 years). The adjusted IRR (aIRR) of asthma associated with prenatal exposure to PPIs was 1.41 (95% confidence interval (CI): 1.27-1.56), compared with those unexposed. The association did not vary by trimester of exposure, and prenatal exposure to H2RAs was associated with similar increase in risk. The aIRR for maternal PPI and H2RA use in the year after, but not during pregnancy was 1.32 (95% CI: 1.20-1.46) and 1.13 (0.93-1.36), respectively, compared with non-use during and in the year after pregnancy. Prenatal exposure to both PPIs and H2RAs was associated with an increased risk of asthma in our study. Because the observed association is not drug specific and also observed for maternal postnatal use it may be explained by a 'class effect' or maternal underlying condition.

Proton pump inhibitors and histamine-2-receptor antagonists and pancreatic cancer risk: a nested case–control study

Background:The relationship between use of proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) and pancreatic cancer risk has yet to be examined. Data from a range of studies suggest biologically plausible mechanisms, whereby these drugs (or the conditions for which they are prescribed) may affect pancreatic cancer risk. The objective of this study was to investigate the relationship between use of PPIs/H2RAs and pancreatic cancer risk.Methods:A nested case–control study was conducted within the UK general practice research database (GPRD). Cases had a diagnosis of exocrine pancreatic cancer and controls were matched to cases on general practice site, sex and year of birth. Exposure to PPIs and to H2RAs since entry into GPRD until 2 years before the diagnosis date (corresponding date in controls) and in the 5 years before the diagnosis date were separately assessed. Conditional logistic regression analyses were used to generate odds ratios (ORs) and 95% confidence intervals (CIs) associated with PPI or H2RA use compared with nonuse.Results:Ever use of PPIs since entry into the GPRD (excluding the 2 years prior to diagnosis) was not associated with risk of pancreatic cancer; OR (95% CI) 1.02 (0.85–1.22). Neither the dose nor the duration of PPI or H2RA use was associated with pancreatic cancer risk. No consistent patterns of association were seen when cumulative exposure (dose and duration) to these drugs was examined separately or together.Conclusion:PPI/H2RA use, in a UK population, was not associated with pancreatic cancer risk.

GI-REASONS: A Novel 6-Month, Prospective, Randomized, Open-Label, Blinded End Point (PROBE) Trial

Purpose: The GI Randomized Event and Safety Open-Label NSAID Study (GI-REASONS) was a PROBE study designed to assess if celecoxib use in patients with osteoarthritis (OA) at moderate GI risk (≥55 y) is associated with a lower incidence of clinically significant upper and lower GI events compared to nonselective (ns)NSAIDs, with/without proton-pump inhibitors (PPIs), in standard U.S. clinical practice. Methods: Patients were randomized 1:1 for 6 months to receive celecoxib or any nsNSAID, stratified by H. pylori status. The primary end point was a composite of adjudicated clinically significant upper and lower GI events. Aspirin use was not permitted. Treatment doses could be adjusted per U.S. prescribing information. Patients randomized to the nsNSAID arm could switch between nsNSAIDs; however, crossover between treatment arms was not allowed. PPIs and histamine-2 receptor antagonists (H2RAs) were prescribed at the providers' discretion. Results: 4035 celecoxib and 4032 nsNSAID patients were randomized and included in the ITT analyses. Baseline demographics were similar. Overall, significantly more nsNSAID users met the primary end point at 6 months (OR, 1.82; 95% CI 1.31-2.55; p=0.0003; Table 1). The most commonly used nsNSAIDs were meloxicam (42%), naproxen (21%), diclofenac (20%) and nabumetone (14%). 2596 celecoxib (64.3%) and 2611 (64.8%) nsNSAID users completed the study. 189 patients were lost to follow-up (LTFU; 2.1% celecoxib and 2.6% nsNSAID). Attributing the primary end point to all LTFU patients (worst-case sensitivity analysis), celecoxib remained superior (OR 1.46; 95% CI 1.18-1.82; P=0.0006). AEs, SAEs and discontinuations were similar in both treatment groups. 23% of celecoxib and 24% of nsNSAID patients used a PPI (P=NS). Moderate to severe abdominal symptoms were experienced by 94 (2.3%) celecoxib and 138 (3.4%) nsNSAID patients (P=0.0035).Table: No Caption available.Conclusion: Celecoxib use had a lower risk of clinically significant upper and lower GI events than nsNSAIDs. A major strength of this study is its PROBE design. Simple inclusion and exclusion criteria allowed for a broad patient population of moderate GI risk. Switching among nsNSAIDs and allowing for dose adjustments, along with use of PPIs and H2RAs as needed, more closely reflects daily clinical practice. GI-REASONS demonstrates the improved GI safety profile of celecoxib throughout the GI tract in patients treated in a “realworld” setting. Disclosure: Dr Cryer - Consultant: Pfizer Dr Li - Employee: Pfizer, Stockholder: Pfizer Dr Simon - Consultant: Pfizer Prof Singh - Grant Support: Pfizer Dr Stillman - Study Consultant: Pfizer Dr Berger - Employee: Pfizer, Stockholder: Pfizer The study was sponsored by Pfizer Inc., New York, NY.

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 histamine 2-receptor antagonists. Methods This meta-analysis evaluated the association between proton pump inhibitor or histamine 2-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, histamine 2-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 histamine 2-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 fracture and pneumonia from acid suppressive drugs.

A recently published systematic review and meta-analysis, incorporating all relevant studies on the association of acid suppressive medications and pneumonia identified up to August 2009, revealed that for every 200 patients, treated with acid suppressive medication, one will develop pneumonia. They showed the overall risk of pneumonia was higher among people using proton pump inhibitors (PPIs) [adjusted odds ratio (OR) = 1.27, 95% CI: 1.11-1.46, I(2) = 90.5%] and Histamine-2 receptor antagonists (H2RAs) (adjusted OR = 1.22, 95% CI: 1.09-1.36, I(2) = 0.0%). In the randomized controlled trials, use of H2RAs was associated with an elevated risk of hospital-acquired pneumonia (relative risk 1.22, 95% CI: 1.01-1.48, I(2) = 30.6%). Another meta-analysis of 11 studies published between 1997 and 2011 found that PPIs, which reduce stomach acid production, were associated with increased risk of fracture. The pooled OR for fracture was 1.29 (95% CI: 1.18-1.41) with use of PPIs and 1.10 (95% CI: 0.99-1.23) with use of H2RAs, when compared with non-use of the respective medications. Long-term use of PPIs increased the risk of any fracture (adjusted OR = 1.30, 95% CI: 1.15-1.48) and of hip fracture risk (adjusted OR = 1.34, 95% CI: 1.09-1.66), whereas long-term H2RA use was not significantly associated with fracture risk. Clinicians should carefully consider when deciding to prescribe acid-suppressive drugs, especially for patients who are already at risk for pneumonia and fracture. Since it is unnecessary to achieve an achlorhydric state in order to resolve symptoms, we recommend using the only minimum effective dose of drug required to achieve the desired therapeutic goals.

Risk factors for the development of gastric mucosal lesions in rheumatoid arthritis patients receiving long-term nonsteroidal anti-inflammatory drug therapy and the efficacy of famotidine obtained from the FORCE study

The objective of this study was to investigate the prevalence of gastric mucosal injury induced by nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA). Upper gastrointestinal endoscopy was performed on 100 RA patients treated with NSAIDs. Patient factors potentially contributing to the development of NSAID-induced gastric mucosal injury were identified by logistic regression analysis; gastric mucosal injury and ulcers were used as objective variables. Gastric mucosal injury was detected in 62 of 100 patients, and eight of these patients had ulcers. Previous history of ulcers, lifestyle, NSAID dosage, and body mass index were associated with the development of gastric mucosal injury, and the use of diclofenac and steroid dose were associated with the development of ulcers. Disease-modifying antirheumatic drugs (DMARDs) did not appear to influence the risk of NSAID-induced gastric mucosal injury. RA patients treated for long periods with NSAIDs for RA symptoms should be controlled with DMARDs, without consideration of increased doses of steroids, in terms of risk for NSAID-induced gastric mucosal injury. Simultaneously, concomitant use of histamine-2 receptor antagonists (H2RA) such as famotidine should be considered.

Risk factors for the development of gastric mucosal lesions in rheumatoid arthritis patients receiving long-term nonsteroidal anti-inflammatory drug therapy and the efficacy of famotidine obtained from the FORCE study

The objective of this study was to investigate the prevalence of gastric mucosal injury induced by nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA). Upper gastrointestinal endoscopy was performed on 100 RA patients treated with NSAIDs. Patient factors potentially contributing to the development of NSAID-induced gastric mucosal injury were identified by logistic regression analysis; gastric mucosal injury and ulcers were used as objective variables. Gastric mucosal injury was detected in 62 of 100 patients, and eight of these patients had ulcers. Previous history of ulcers, lifestyle, NSAID dosage, and body mass index were associated with the development of gastric mucosal injury,and the use of diclofenac and steroid dose were associated with the development of ulcers. Disease-modifying antirheumatic drugs (DMARDs) did not appear to influence the risk of NSAID-induced gastric mucosal injury. RA patients treated for long periods with NSAIDs for RA symptoms should be controlled with DMARDs, without consideration of increased doses of steroids, in terms of risk for NSAID-induced gastric mucosal injury. Simultaneously, concomitant use of histamine-2 receptor antagonists (H2RA) such as famotidine should be considered.

The Extent and Determinants of Prescribing and Adherence With Acid-Reducing Medications: A National Claims Database Study

No community-based, large-scale studies have examined the extent of prescribing acid-reducing medications or adherence and persistence to these medication regimens. We conducted a retrospective cohort study of patients with Barrett's esophagus (BE) and gastroesophageal reflux disease (GERD) without BE, diagnosed between 2000 and 2005, who had undergone an upper endoscopy within 1 year through a managed care plan in the United States. We identified filled prescriptions for oral proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) within 365 days after the index date of BE or GERD, and several measures of adherence (medication-ownership ratio (MOR)) and persistence (length of therapy, fill-refill ratio, discontinuation rate) for PPI treatment. We identified 10,159 patients with BE and 48,965 GERD patients with no BE. The mean duration of filled PPI prescriptions accounted for only 30.2% of the available year after the index date, whereas that of either PPI or H2RA prescriptions accounted for only 31.7%. PPI prescriptions were filled by 66.6 and 60.4% of patients with and without BE, respectively. These proportions declined significantly between 2000 and 2005. For those with at least one prescription, the median duration of therapy was 241 days for PPIs and 159 for H2RAs. Both groups had low MOR and length of treatment and high discontinuation rates; however, adherence and persistence were significantly higher in BE than in non-BE patients, and significantly lower in 2005 than in 2000. The use of prescription PPIs or H2RAs, as well as adherence and persistence with these medications, is lower than expected. The absence of BE and more recent diagnosis are associated with even lower prescription rates.

Quasiexperimental Study of the Effects of Antibiotic Use, Gastric Acid-Suppressive Agents, and Infection Control Practices on the Incidence of Clostridium difficile -Associated Diarrhea in Hospitalized Patients

The objective of this study was to evaluate the effects of antimicrobial drug use, gastric acid-suppressive agent use, and infection control practices on the incidence of Clostridium difficile-associated diarrhea (CDAD) in a 426-bed general teaching hospital in Northern Ireland. The study was retrospective and ecological in design. A multivariate autoregressive integrated moving average (time-series analysis) model was built to relate CDAD incidence with antibiotic use, gastric acid-suppressive agent use, and infection control practices within the hospital over a 5-year period (February 2002 to March 2007). The findings of this study showed that temporal variation in CDAD incidence followed temporal variations in expanded-spectrum cephalosporin use (average delay = 2 months; variation of CDAD incidence = 0.01/100 bed-days), broad-spectrum cephalosporin use (average delay = 2 months; variation of CDAD incidence = 0.02/100 bed-days), fluoroquinolone use (average delay = 3 months; variation of CDAD incidence = 0.004/100 bed-days), amoxicillin-clavulanic acid use (average delay = 1 month; variation of CDAD incidence = 0.002/100 bed-days), and macrolide use (average delay = 5 months; variation of CDAD incidence = 0.002/100 bed-days). Temporal relationships were also observed between CDAD incidence and use of histamine-2 receptor antagonists (H2RAs; average delay = 1 month; variation of CDAD incidence = 0.001/100 bed-days). The model explained 78% of the variance in the monthly incidence of CDAD. The findings of this study highlight a temporal relationship between certain classes of antibiotics, H2RAs, and CDAD incidence. The results of this research can help hospitals to set priorities for restricting the use of specific antibiotic classes, based on the size-effect of each class and the delay necessary to observe an effect.

Efficacy of Oral β-Lactam versus Non-β-Lactam Treatment of Uncomplicated Cellulitis

Background Preferred therapy for purulent skin and soft tissue infections is incision and drainage, but many infections cannot be drained. Empiric therapies for these infections are ill-defined in the era of community-acquired methicillin-resistant Staphylococcus aureus. Methods A multicenter retrospective cohort study of outpatients treated for cellulitis was conducted to compare clinical failure rates of oral β-lactam and non-β-lactam treatments. Exclusion criteria included purulent infection requiring incision and drainage, complicated skin and soft tissue infection, chronic ulceration, and intravenous antibiotics. Failure rates were compared using logistic regression to adjust for both covariates associated with failure and a propensity score for β-lactam treatment. Results Of 2977 patients, 861 met inclusion criteria and were classified by treatment: β-lactam (n = 631) or non-β-lactam therapy (n = 230). Failure rates were 14.7% versus 17.0% (odds ratio [OR] 0.85, 95% confidence interval [CI], 0.56-1.31) for β-lactam and non-β-lactam therapy, respectively. Failure was associated with: age ( P = .02), acute symptom severity ( P = .03), animal bites ( P = .03), Charlson score >3 ( P = .02), and histamine-2 receptor antagonist use ( P = .09). Relative efficacy of β-lactam therapy was greater after adjustment for factors associated with failure but remained statistically insignificant (adjusted OR 0.81, 95% CI, 0.53-1.24); adjusted including propensity score covariate (OR 0.71, 95% CI, 0.45-1.13). Discontinuation due to adverse effects differed between β-lactam (0.5%) and non-β-lactam (2.2%) therapies ( P = .04). Conclusion There was no significant difference in clinical failure between β-lactam and non-β-lactam antibiotics for the treatment of uncomplicated cellulitis. Increased discontinuation due to adverse events with non-β-lactam therapy was observed.