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1.  The use of proton pump inhibitors in treating and preventing NSAID-induced mucosal damage 
Arthritis Research & Therapy  2013;15(Suppl 3):S5.
NSAIDs are prescribed widely but have rare serious gastrointestinal side effects. More recently, adverse cardiovascular effects of these drugs have also been recognized, leading to the withdrawal of some agents and continuing uncertainty about the best approach for patients requiring NSAID therapy. Proton pump inhibitors (PPIs) provide potent and long-lasting inhibition of gastric acid secretion and have proven efficacy in healing NSAID-associated ulcers, including those with continued exposure to NSAIDs. PPIs have also shown efficacy in reducing the risk of ulcerations due to NSAID use compared with NSAIDs alone in randomized controlled trials (RCTs) where endoscopic ulcers are used as the primary endpoint, albeit a surrogate marker for clinical ulcers and complications. Large RCT outcome trials comparing patients exposed to NSAIDs with and without PPI co-therapy have not been performed, but adequately powered RCTs in high-risk patients demonstrate that PPI + nonselective NSAID provides similar rates of symptomatic ulcer recurrence rates as the use of a cyclooxygenase (COX)-2 selective inhibitor. A RCT in high-risk patients with previous ulcer complications supports the additive bene3 t of two risk-reducing strategies, as ulcer complication recurrence was eliminated in high-risk patients who were given a COX-2 selective agent with a PPI. Helicobacter pylori, an independent risk factor for ulcers, should be sought out and eradicated in patients at increased gastrointestinal risk, typically those with an ulcer history. Following H. pylori eradication, however, patients remain at risk and co-therapy with a PPI is recommended. NSAID medication selection should consider both the individual patients' gastrointestinal and cardiovascular risks.
PMCID: PMC3891010  PMID: 24267413
2.  Medications (NSAID, Statins, PPI) and the Risk of Esophageal Adenocarcinoma in Patients with Barrett’s Esophagus 
Gastroenterology  2010;138(7):2260-2266.
Background & Aims
Limited evidence suggests that proton pump inhibitors (PPI), non-steroidal anti inflammatory drugs (NSAID)/aspirin and statins may be associated with low risk of esophageal neoplasia. However, the possible effect these medications may have on the risk of esophageal adenocarcinoma (EAC) in patients with existing Barrett’s esophagus (BE) is unclear.
We conducted a nested case-control study in a cohort of patients with BE identified in the national Department of Veterans Affairs (VA) computerized databases. Cases with incident EAC were matched by incidence density sampling to controls with BE who remained without EAC at the date of the EAC diagnosis for the corresponding case. We identified prescriptions for PPI, NSAID/aspirin, and statins that were filled between BE diagnosis and EAC diagnosis. Incidence density ratios were calculated using conditional logistic regression models that adjusted for race, outpatient encounters, a disease comorbidity index, and socio-economic status.
In a cohort of 11,823 patients with first time BE diagnosis, we examined 116 EAC cases and 696 matched controls. Most cases and controls had at least one filled PPI prescription (95% vs. 94%, p=0.5). In this setting of almost universal PPI use, filled NSAID/aspirin prescriptions were associated with a reduced risk of EAC (adjusted incidence density ratio: 0.64; 95% CI, 0.42–0.97). Filled statin prescriptions were also associated with a reduction in EAC risk (0.55; 95% CI, 0.36–0.86), with a significant trend toward greater risk reduction with longer duration of statin use. However, the strong inverse associations with even short periods of use raise concerns of uncontrolled confounding.
This observational study indicates that in patients with Barrett’s esophagus using PPI, NSAID/aspirin or statin therapy might reduce the risk of developing esophageal adenocarcinoma.
PMCID: PMC2883678  PMID: 20188100
epidemiology; chemoprevention; GERD; VA; Medicare
3.  Incremental cost effectiveness of proton pump inhibitors for the prevention of non-steroidal anti-inflammatory drug ulcers: a pharmacoeconomic analysis linked to a case-control study 
Arthritis Research & Therapy  2008;10(6):R144.
We estimated the cost effectiveness of concomitant proton pump inhibitors (PPIs) in relation to the occurrence of non-steroidal anti-inflammatory drug (NSAID) ulcer complications.
This study was linked to a nested case-control study. Patients with NSAID ulcer complications were compared with matched controls. Only direct medical costs were reported. For the calculation of the incremental cost effectiveness ratio we extrapolated the data to 1,000 patients using concomitant PPIs and 1,000 patients not using PPIs for 1 year. Sensitivity analysis was performed by 'worst case' and 'best case' scenarios in which the 95% confidence interval (CI) of the odds ratio (OR) and the 95% CI of the cost estimate of a NSAID ulcer complication were varied. Costs of PPIs was varied separately.
In all, 104 incident cases and 284 matched controls were identified from a cohort of 51,903 NSAID users with 10,402 NSAID exposition years. Use of PPIs was associated with an adjusted OR of 0.33 (95% CI 0.17 to 0.67; p = 0.002) for NSAID ulcer complications. In the extrapolation the estimated number of NSAID ulcer complications was 13.8 for non-PPI users and 3.6 for PPI users. The incremental total costs were € 50,094 higher for concomitant PPIs use. The incremental cost effectiveness ratio was € 4,907 per NSAID ulcer complication prevented when using the least costly PPIs.
Concomitant use of PPIs for the prevention of NSAID ulcer complications costs € 4,907 per NSAID ulcer complication prevented when using the least costly PPIs. The price of PPIs highly influenced the robustness of the results.
PMCID: PMC2656249  PMID: 19077318
4.  The rate of prescribing gastrointestinal prophylaxis with either a proton pump inhibitor or an H2-receptor antagonist in Nova Scotia seniors starting nonsteroidal anti-inflammatory drug therapy 
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used agents that can cause serious gastrointestinal (GI) side effects. For patients at increased risk of NSAID-related GI complications, prophylaxis with either a nonselective NSAID plus gastroprotective agent (GPA) or, alternatively, therapy with a cyclooxygenase-2 selective inhibitor with or without a GPA such as a proton pump inhibitor (PPI), is recommended.
To describe the rate, timing and duration of GI prophylaxis in Nova Scotia seniors receiving nonselective NSAIDs.
The Nova Scotia Seniors’ Pharmacare Program beneficiaries for the years 1998 to 2002 were studied. A cohort of incident NSAID and GPA users was selected from all nonselective NSAID users (no prescribed NSAID dispensed 12 months before the index month and no GPA dispensed two months before the index prescription). Monthly coprescribing rates were calculated by dividing the number of patients in the cohort using GPAs by the number of NSAID users. GI prophylactic coprescribing was defined as the coprescribing rate present at the first month (index month) of prescribing an NSAID.
The cohort consisted of 12,906 patients. Seventy-five per cent of the nonselective NSAID prescriptions dispensed were for up to two months duration, with only 2.3% longer than one year. GI prophylaxis was given to only 3.8% of patients starting NSAIDs who were not on a GPA in the two months before starting NSAIDs. Of this 3.8%, 92.7% of the patients received H2-receptor antagonists (H2RAs), and 7% received PPIs. The rate of H2RA coprescribing increased with the number of consecutive months on an NSAID from 3.5% in the first month to 24.1% at 48 months. For PPIs, the coprescribing rate increased from 0.3% to 1.9% of all NSAID users in the cohort. The rate of gastroprophylaxis coprescribing for patients receiving NSAIDs did not rise with increasing age.
In Nova Scotian seniors using nonselective NSAIDs, the rate of GI prophylaxis was low. Most patients received H2RAs as GPAs despite evidence that they offer insufficient protection.
PMCID: PMC2947001  PMID: 20711527
Cohort study; Cyclooxygenase-2 selective inhibitor; Drug utilization; Gastrointestinal prophylaxis; Histamine-2 receptor antagonist; Misoprostol; Nonsteroidal anti-inflammatory drugs; NSAIDs; Proton pump inhibitor; Prescribing; Seniors
5.  Medication Usage and the Risk of Neoplasia in Patients with Barrett's Esophagus 
Background & Aims
Experimental evidence indicates that proton pump inhibitors (PPI), non-steroidal anti inflammatory drugs (NSAID)/aspirin and statins can protect patients with Barrett's esophagus (BE) from developing neoplasias. However, only limited data are available on chemoprevention in patients with BE.
A retrospective observational study was performed using data from patients with documented BE. Prescription information was collected from pharmacy records. Cox regression analyses were performed to examine the association between prescriptions for PPI, NSAID/aspirin or statins and the risk of developing esophageal dysplasia or adenocarcinoma during follow-up (from 1982 to 2005).
We examined data from 344 patients diagnosed with BE (mean age 61 years, 90.4% Caucasian, 94.2% male). After BE diagnosis, 67.2% of the patients were prescribed PPI for a mean duration of 5.1 years; 49.1% were prescribed NSAID for a mean duration of 3.6 years and 25.3% were prescribed statins for a mean duration of 2.8 years. During 2,620 patient-years following BE diagnosis, high-grade dysplasia or esophageal adenocarcinoma developed in 33 patients. PPI treatment after BE diagnosis was associated with a reduced risk of high-grade dysplasia or cancer; this association persisted after adjustment for gender, age, and the length of BE at time of the diagnosis. NSAID and/or aspirin therapy were associated with a non-significant trend toward lower incidence of high-grade dysplasia or esophageal cancer.
PPI therapy reduces the risk of neoplasms in patients with BE. NSAID/aspirin appear to reduce cancer risk whereas statin use is not significantly associated with the risk of neoplasia in patients with BE.
PMCID: PMC2789910  PMID: 19523538
6.  Factors associated with the initiation of proton pump inhibitors in corticosteroid users 
Proton pump inhibitors (PPIs) and corticosteroids are commonly prescribed drugs; however, each has been associated with fracture and community acquired pneumonia. How physicians select patients for co-therapy may have implications for potential additive or synergistic toxicities.
We conducted a retrospective cohort study of 13,749 incident corticosteroid users with no prior PPI exposure using the HealthCore Integrated Research DatabaseSM. We used logistic regression to evaluate the association between PPI initiation in the first 30 days of steroid therapy and corticosteroid dose, clinical risk factors including co-morbid diseases, and medication use including prescription nonsteroidal anti-inflammatory drugs (NSAIDs).
1,050 (7.6%) patients filled a new PPI prescription within 30 days of starting corticosteroids. PPI use was associated with the number of baseline co-morbid conditions (OR 1.21 for each additional condition, CI 1.13–1.28), recent hospitalization (OR 4.71, CI 4.02–5.52), prednisone dose above 40mg/day (OR 1.87, CI1.45–2.41), history of gastroesophageal reflux or gastric ulcer disease (OR 1.54, CI 1.24– 1.91), renal insufficiency (OR 2.06, CI 1.73–2.46), and liver disease (OR 1.82, CI 1.45–2.28). Concomitant use of prescription NSAIDs was also associated with PPI use (OR 1.89, CI 1.32–2.70); however, the total use of PPIs in this group was low (6.3%, CI 4.4–8.2%).
Overall, PPI therapy among corticosteroid users was uncommon, even among those with risk factors for gastrointestinal toxicity. PPI use was significantly more common among patients who had recently been hospitalized, had a greater burden of co-morbid illness, or were receiving high daily doses of corticosteroids.
PMCID: PMC3970554  PMID: 22278844
proton pump inhibitors; corticosteroids; gastroprotection; adverse events
7.  In vitro and in vivo protection against indomethacin-induced small intestinal injury by proton pump inhibitors, acid pump antagonists or indomethacin-phosphatidylcholine 
Digestion  2012;86(2):171-177.
Proton pump inhibitors (PPI) are widely used to prevent NSAID-induced peptic ulcers. NSAIDs produce small intestinal injury and some PPIs have been reported to have a protect against NSAID-induced small bowel injury in rats. To compare PPIs, revaprazan, and phosphatidylcholine-associated indomethacin (Indo-PC) for protection against indomethacin (Indo) induced small bowel injury. Methods: Rat intestinal epithelial cells (IEC-6) were pretreated with omeprazole, lansoprazole or revaprazan prior to exposure to Indo or Indo-PC. Cell viability was assessed by methyl thiazolyl tetrazolium assay. Omeprazole, lansoprazole or revaprazan were administered orally to rats prior to vehicle or Indo. Indo-PC was administered alone. After 24h small intestinal erosions were counted; intestinal bleeding was assessed as hemoglobin concentration of small intestinal fluid. Results: Omeprazole, lansoprazole and revaprazan did not protect against Indo-induced IEC-6 cell injury. Indo-PC was less damaging in vitro than Indo alone. In vivo neither omeprazole nor lansoprazole protected against Indo-induced small bowel injury, however, revaprazan pretreatment and Indo-PC resulted in significantly fewer erosions (>50% reduction) or bleeding (>80% reduction).
PPIs showed no small bowel protective effect in vitro or in vivo. Revaprazan showed a small bowel protective effect in vivo whereas Indo-PC was protective both in vitro and in vivo.
PMCID: PMC3477857  PMID: 22907267
8.  Proton-pump inhibitors are associated with a reduced risk for bleeding and perforated gastroduodenal ulcers attributable to non-steroidal anti-inflammatory drugs: a nested case-control study 
Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is hampered by gastrointestinal ulcer complications, such as ulcer bleeding and perforation. The efficacy of proton-pump inhibitors in the primary prevention of ulcer complications arising from the use of NSAIDs remains unproven. Selective cyclooxygenase-2 (COX-2) inhibitors reduce the risk for ulcer complications, but not completely in high-risk patients. This study determines which patients are especially at risk for NSAID ulcer complications and investigates the effectiveness of different preventive strategies in daily clinical practice. With the use of a nested case-control design, a large cohort of NSAID users was followed for 26 months. Cases were patients with NSAID ulcer complications necessitating hospitalisation; matched controls were selected from the remaining cohort of NSAID users who did not have NSAID ulcer complications. During the observational period, 104 incident cases were identified from a cohort of 51,903 NSAID users with 10,402 patient years of NSAID exposure (incidence 1% per year of NSAID use, age at diagnosis 70.4 ± 16.7 years (mean ± SD), 55.8% women), and 284 matched controls. Cases were characterised by serious, especially cardiovascular, co-morbidity. In-hospital mortality associated with NSAID ulcer complications was 10.6% (incidence 21.2 per 100,000 NSAID users). Concomitant proton-pump inhibitors (but not selective COX-2 inhibitors) were associated with a reduced risk for NSAID ulcer complications (the adjusted odds ratio 0.33; 95% confidence interval 0.17 to 0.67; p = 0.002). Especially at risk for NSAID ulcer complications are elderly patients with cardiovascular co-morbidity. Proton-pump inhibitors are associated with a reduced risk for NSAID ulcer complications.
PMCID: PMC2206342  PMID: 17521422
9.  Proton pump inhibitors: perspectives of patients and their GPs. 
BACKGROUND: There is growing concern with the rapid increase in prescribing proton pump inhibitor drugs (PPIs) for a variety of gastrointestinal disorders, and the escalating costs associated with this trend. Explanations have included that general practitioners (GPs) prescribe PPIs inappropriately and that patients demand PPIs and use them as a way of avoiding having to make lifestyle changes. AIM: To compare the perspectives of GPs and their patients on the need for PPIs, to examine the pressure to prescribe, and to examine the effect of PPIs on lifestyle. DESIGN OF STUDY: Qualitative comparative study based on semi-structured interviews. SETTING: Twenty-six GPs in seven practices in the West Midlands and 82 of their patients on repeat prescriptions for PPIs. METHOD: Interviews were conducted covering a wide range of topics, including: experience, cause, course, and outcome of stomach problems; effectiveness of PPIs; and role of lifestyle in controlling symptoms. The transcripts were studied repeatedly to look for the occurrence and distribution of material relating to these issues, as well as other responder-driven issues. Codebooks were devised to enable a simple categorisation and systematic comparison of cases. RESULTS: GPs and patients agreed about the severity and unpleasantness of stomach symptoms for which PPIs were prescribed. While GPs and patients regarded PPIs as a very effective treatment, GPs rated their efficacy more highly than patients. Half of the GP interviews reproduced the stereotype of the demanding patient and of patients using PPIs to support unhealthy lifestyles. There was little evidence from patient interviews to support either stereotype. Doctors underestimated patient concerns about side-effects, safety, and long-term use of PPIs, and the willingness of patients to achieve the minimum effective dose by experimenting with their treatment. GPs felt that the pressure to prescribe PPIs was outweighed by the pressure not to prescribe, and most GPs had responded to the call to cut the prescribing of PPIs. Different strategies were employed to cut prescribing, including the wholesale switching of patients on a treatment dose of one brand of PPI to a maintenance dose of a cheaper brand of PPI, known as 'double switching'. CONCLUSION: The stereotypes of 'profligate prescriber', 'demanding patient', and 'adverse lifestyle', as explanations for the increase in the prescribing of PPIs, were not upheld. The stereotype of patients demanding PPIs may arise from GPs' internal pressure to prescribe being externalised onto patients. The extent to which health behaviour contributes to gastric disorders needs to be established empirically. Labelling PPI patients as having a poor lifestyle may be used as a means of reducing legitimate need for PPIs. Current policy relating to switching of dose and brand of PPI should be reviewed.
PMCID: PMC1314097  PMID: 11593830
10.  Is ranitidine therapy sufficient for healing peptic ulcers associated with non-steroidal anti-inflammatory drug use? 
Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) increases the risk of serious gastroduodenal events. To minimise these risks, patients often require concomitant acid-suppressive therapy. We conducted a literature review of clinical trials examining use of ranitidine 150 mg twice daily to heal gastroduodenal ulcers (GU) in NSAID recipients. Seven studies were identified. After 8 weeks’ treatment with ranitidine, GU healing rates ranged from 50% to 74% and rates of duodenal ulcer (DU) healing ranged from 81% to 84%. Ranitidine was more effective when NSAIDs were discontinued (healing rates reaching 95% and 100%, respectively). The ulcer healing rate with sucralfate was similar to that of ranitidine. However, proton pump inhibitor (PPI) therapy was associated with significantly greater rates of both GU and DU healing than ranitidine; 8-week GU rates were 92% and 88% with esomeprazole 40 mg and 20 mg, respectively (vs. 74% with ranitidine, p < 0.01). For omeprazole, 8-week healing rates were 87% with omeprazole 40 mg and 84% with omeprazole 20 mg (vs. 64% for ranitidine, p < 0.001), and for lansoprazole the corresponding values were 73–74% and 66–69% for the 30 mg and 15 mg doses, respectively (vs. 50–53% for ranitidine, p < 0.05). In the PPI study reporting DU healing the values were 92% for omeprazole 20 mg (vs. 81% for ranitidine, p < 0.05) and 88% for omeprazole 40 mg (p = 0.17 vs. ranitidine). NSAID-associated GU are more likely to heal when patients receive concomitant treatment with a PPI rather than ranitidine.
PMCID: PMC1636688  PMID: 17073837
Non-steroidal anti-inflammatory drugs; gastroduodenal ulcers; proton pump inhibitors; ranitidine
11.  The appropriate use of non-steroidal anti-inflammatory drugs in rheumatic disease: opinions of a multidisciplinary European expert panel 
Annals of the Rheumatic Diseases  2010;70(5):818-822.
Given the safety issues of non-steroidal anti-inflammatory drugs (NSAID) and the robustness of guidelines, making treatment choices in daily clinical practice is increasingly difficult. This study aimed systematically to analyse the opinions of a multidisciplinary European expert panel on the appropriateness of different NSAID, with or without the use of a proton pump inhibitor (PPI), in individual patients with chronic rheumatic disease.
Using the Research and Development/University of California at Los Angeles appropriateness method, the appropriateness of five (non-)selective NSAID with or without a PPI was assessed for 144 hypothetical patient profiles, ie, unique combinations of cardiovascular and gastrointestinal risk factors. Appropriateness statements were calculated for all indications.
All options without PPI were considered appropriate in patients with no gastrointestinal/cardiovascular risk factors. Cyclooxygenase-2 selective inhibitors (C2SI) alone and non-selective NSAID plus PPI were preferred for patients with elevated gastrointestinal risk and low cardiovascular risk. Naproxen plus PPI was favoured in patients with high cardiovascular risk. For the combination of high gastrointestinal/high cardiovascular risk the use of any NSAID was discouraged; if needed, naproxen plus PPI or a C2SI plus PPI could be considered.
The panel results may support treatment considerations at the level of individual patients, according to their gastrointestinal/cardiovascular risk profile.
PMCID: PMC3070276  PMID: 20833736
12.  Decreasing incidence of peptic ulcer complications after the introduction of the proton pump inhibitors, a study of the Swedish population from 1974–2002 
BMC Gastroenterology  2009;9:25.
Despite a decreasing incidence of peptic ulcer disease, most previous studies report a stabile incidence of ulcer complications. We wanted to investigate the incidence of peptic ulcer complications in Sweden before and after the introduction of the proton pump inhibitors (PPI) in 1988 and compare these data to the sales of non-steroid anti-inflammatory drugs (NSAID) and acetylsalicylic acid (ASA).
All cases of gastric and duodenal ulcer complications diagnosed in Sweden from 1974 to 2002 were identified using the National hospital discharge register. Information on sales of ASA/NSAID was obtained from the National prescription survey.
When comparing the time-periods before and after 1988 we found a significantly lower incidence of peptic ulcer complications during the later period for both sexes (p < 0.001). Incidence rates varied from 1.5 to 7.8/100000 inhabitants/year regarding perforated peptic ulcers and from 5.2 to 40.2 regarding peptic ulcer bleeding. The number of sold daily dosages of prescribed NSAID/ASA tripled from 1975 to 2002. The number of prescribed sales to women was higher than to males. Sales of low-dose ASA also increased. The total volume of NSAID and ASA, i.e. over the counter sale and sold on prescription, increased by 28% during the same period.
When comparing the periods before and after the introduction of the proton pump inhibitors we found a significant decrease in the incidence of peptic ulcer complications in the Swedish population after 1988 when PPI were introduced on the market. The cause of this decrease is most likely multifactorial, including smoking habits, NSAID consumption, prevalence of Helicobacter pylori and the introduction of PPI. Sales of prescribed NSAID/ASA increased, especially in middle-aged and elderly women. This fact seems to have had little effect on the incidence of peptic ulcer complications.
PMCID: PMC2679757  PMID: 19379513
13.  Gastroprotective strategies among NSAID users 
Canadian Family Physician  2006;52(9):1100-1105.
To review proper use of gastroprotective strategies in family medicine for patients requiring chronic nonsteroidal anti-inflammatory drug (NSAID) therapy.
Evidence of the efficacy and safety of strategies currently in use (prostaglandin analogues, cyclooxygenase-2 inhibitors, proton pump inhibitors) is derived from randomized controlled trials (level I evidence). The simultaneous use of multiple medications for very high-risk NSAID users is supported only by expert opinion (level III evidence).
Gastroprotective strategies should be reserved for NSAID users at substantially increased risk of gastrointestinal complications; low-risk patients can safely use NSAIDs alone. Cyclooxygenase-2 inhibitors, prostaglandin analogues, and proton pump inhibitors reduce the risk of NSAID-related gastointestinal complications by 40% to 90%. Cyclooxygenase-2 inhibitors should be avoided by patients who have or are at risk for cardiovascular disease.
Chronic NSAID use has been implicated in the development of severe and potentially life-threatening gastointestinal complications, though certain strategies are known to decrease the risk of these NSAID-related gastointestinal complications. Prescribing physicians must know which of their patients should be prescribed medications and which strategies are appropriate for particular patients.
PMCID: PMC1783737  PMID: 17279220
14.  Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis 
Gut  2013;63(4):552-558.
Previous observational studies suggest that the use of proton pump inhibitors (PPIs) may increase the risk of hospitalisation for community-acquired pneumonia (HCAP). However, the potential presence of confounding and protopathic biases limits the conclusions that can be drawn from these studies. Our objective was, therefore, to examine the risk of HCAP with PPIs prescribed prophylactically in new users of non-steroidal anti-inflammatory drugs (NSAIDs).
We formed eight restricted cohorts of new users of NSAIDs, aged ≥40 years, using a common protocol in eight databases (Alberta, Saskatchewan, Manitoba, Ontario, Quebec, Nova Scotia, US MarketScan and the UK's General Practice Research Database (GPRD)). This specific patient population was studied to minimise bias due to unmeasured confounders. High-dimensional propensity scores were used to estimate site-specific adjusted ORs (aORs) for HCAP at 6 months in PPI patients compared with unexposed patients. Fixed-effects meta-analytic models were used to estimate overall effects across databases.
Of the 4 238 504 new users of NSAIDs, 2.3% also started a PPI. The cumulative 6-month incidence of HCAP was 0.17% among patients prescribed PPIs and 0.12% in unexposed patients. After adjustment, PPIs were not associated with an increased risk of HCAP (aOR=1.05; 95% CI 0.89 to 1.25). Histamine-2 receptor antagonists yielded similar results (aOR=0.95, 95% CI  0.75 to 1.21).
Our study does not support the proposition of a pharmacological effect of gastric acid suppressors on the risk of HCAP.
PMCID: PMC3963530  PMID: 23856153
Proton Pump Inhibition; Gastroesophageal Reflux Disease; Epidemiology; Meta-Analysis
15.  Association Between Use of Proton Pump Inhibitors and a Clostridium difficile–Associated Disease Outbreak: Case–Control Study 
The use of proton pump inhibitors (PPIs) has been implicated as a potential contributor to the development of Clostridium difficile–associated disease (CDAD) because of the ability of these drugs to substantially reduce the bactericidal effect of gastric acid. This study focused on the impact of PPIs, among other known risk factors, during an outbreak of CDAD in a hospital setting.
The primary objective was to determine whether there was an association between current use of a PPI and the CDAD outbreak. Secondary objectives were to evaluate any correlations between the CDAD outbreak and past use of PPIs, use of antibiotics, diabetes mellitus, enteral feeding, cancer, gastrointestinal surgery, inflammatory bowel disease, and previous care or residence in an institutional setting.
A retrospective case–control study was conducted. One hundred and fifty cases of hospital-acquired Clostridium difficile were identified. Patients were individually matched to controls for age, sex, date of admission to hospital, and hospital unit. The groups were compared with respect to each exposure.
Eight case patients could not be matched with suitable controls. Therefore, data from 142 cases and 142 controls were analyzed. There was no association between current use of a PPI and the CDAD outbreak (odds ratio [OR] 1.0, 95% confidence interval [CI] 0.99–1.01). Similarly, there was no correlation between the CDAD outbreak and diabetes, enteral feeding, cancer, gastrointestinal surgery, inflammatory bowel disease, or previous care or residence in an institution. However, the development of CDAD was positively associated with use of antibiotics within the 30 days preceding the infection (OR 12.0, 95% CI 4.0–35.7) and with past use of a PPI (OR 2.4, 95% CI 1.4–4.3).
The development of CDAD during a hospital outbreak was associated with use of antibiotics and with past, not current, use of PPIs.
PMCID: PMC2832569  PMID: 22478951
antibiotic; Clostridium difficile; outbreak; proton pump inhibitor; risk factor; antibiotique; éclosion de Clostridium difficile; inhibiteur de la pompe à protons; facteur de risque
16.  Therapy and prevention of gastric ulcer. 
After establishing the benign nature of a gastric ulcer, the treatment is primarily medical. This medical therapy is aimed to alleviate symptoms, to heal the ulcer and to prevent relapses. Based on the history of non-steroidal anti-inflammatory drugs (NSAIDs) and the Helicobacter pylori-status, gastric ulcer patients can be divided into four categories (1) H. pylori positive plus NSAID-use, (2) H. pylori positive without NSAID use, (3) NSAID use with negative H. pylori-status, (4) Negative H. pylori-status and no NSAID use. Patients taking NSAIDs should stop this therapy if possible. Patients with gastric H. pylori infection should be treated by a regimen of a proton pump inhibitor with at least two appropriate antibiotics. This treatment will result in early alleviation of symptoms, rapid healing of the ulcer and prophylaxis of ulcer relapse. In patients with gastric ulcer who cannot stop NSAIDs, maintenance therapy with prostaglandins or potent antisecretory drugs should be considered. The few patients with gastric ulcer who do not take NSAIDs and do not have gastric H. pylori infection should be treated by antisecretory drugs, and they should be carefully followed endoscopically to exclude malignant (carcinoma, lymphoma) or non-peptic (Crohn's disease) disease. All patients with gastric ulcer should be re-endoscoped to verify complete ulcer healing. Surgery may be considered in gastric ulcer patients with complications, in those with severe dysplasia of the gastric mucosa, and in those who are not able or willing to take the medication.
PMCID: PMC2589011  PMID: 9165695
17.  Perspectives on gastroesophageal reflux disease in primary care: the REFLEX study of patient-physician agreement 
BMC Gastroenterology  2011;11:25.
Physicians may be unaware of the severity and extent of gastroesophageal reflux disease (GERD) in their patients. The aim of this study was to evaluate patient-physician agreement concerning proton pump inhibitor (PPI) treatment.
1818 French primary-care physicians and 5174 adult patients with GERD who were taking PPIs answered questions regarding symptoms and treatment satisfaction. Patient-physician agreement was scored using the Kappa (κ) method.
There was moderate patient-physician agreement for PPI treatment satisfaction (κ = 0.60), PPI prescription adherence (κ = 0.57) and use of over-the-counter gastrointestinal medications (κ = 0.44-0.51). Patient satisfaction with PPI therapy and PPI treatment adherence rates were both ~90%. There was poor patient-physician agreement concerning PPI therapy expectations (κ = 0.22-0.33). Residual reflux symptoms occurred in 61% of patients. Physicians underestimated residual symptom severity compared with their patients (κ = 0.43-0.47), though there was good agreement regarding the presence (κ = 0.62-0.78) and frequency (κ = 0.61-0.66) of these symptoms and their effect on patients' daily life (κ = 0.64).
Patient-physician agreement regarding PPI therapy for GERD was moderate or good for the presence of residual symptoms and moderate for treatment satisfaction, but poor for treatment expectations. PPI treatment resulted in high satisfaction rates, but residual symptoms were fairly common and their severity was underestimated by physicians.
PMCID: PMC3074557  PMID: 21435198
18.  Poor awareness of preventing aspirin-induced gastrointestinal injury with combined protective medications 
AIM: To investigate prescribing pattern in low-dose aspirin users and physician awareness of preventing aspirin-induced gastrointestinal (GI) injury with combined protective medications.
METHODS: A retrospective drug utilization study was conducted in the 2nd Affiliated Hospital, School of Medicine, Zhejiang University. The hospital has 2300 beds and 2.5 million outpatient visits annually. Data mining was performed on all aspirin prescriptions for outpatients and emergency patients admitted in 2011. Concomitant use of proton-pump inhibitors (PPIs), histamine 2-receptor antagonists (H2RA) and mucoprotective drugs (MPs) were analyzed. A defined daily dose (DDD) methodology was applied to each MP. A further investigation was performed in aspirin users on combination use of GI injurious medicines [non-steoid anti-inflammatory drugs (NSAIDs), corticosteroids and clopidogrel and warfarin] or intestinal protective drugs (misoprostol, rebamipide, teprenone and gefarnate). Data of major bleeding episodes were derived from medical records and adverse drug reaction monitoring records. The annual incidence of major GI bleeding due to low-dose aspirin was estimated for outpatients.
RESULTS: Prescriptions for aspirin users receiving PPIs, H2RA and MPs (n = 1039) accounted for only 3.46% of total aspirin prescriptions (n = 30 015). The ratios of coadministration of aspirin/PPI, aspirin/H2RA, aspirin/MP and aspirin/PPI/MP to the total aspirin prescriptions were 2.82%, 0.12%, 0.40% and 0.12%, respectively. No statistically significant difference was observed in age between patients not receiving any GI protective medications and patients receiving PPIs, H2RA or MPs. The combined medication of aspirin and PPI was used more frequently than that of aspirin and MPs (2.82% vs 0.40%, P < 0.05) and aspirin/H2RA (2.82% vs 0.12%, P < 0.05). The values of DDDs of MPs in descending order were as follows: gefarnate, hydrotalcite > teprenone > sucralfate oral suspension > L-glutamine and sodium gualenate granules > rebamipide > sucralfate chewable tablets. The ratio of MP plus aspirin prescriptions to the total MP prescriptions was as follows: rebamipide (0.47%), teprenone (0.91%), L-glutamine and sodium gualenate granules (0.92%), gefarnate (0.31%), hydrotalcite (1.00%) and sucralfate oral suspension (0.13%). Percentages of prescriptions containing aspirin and intestinal protective drugs among the total aspirin prescriptions were: rebamipide (0.010%), PPI/rebamipide (0.027%), teprenone (0.11%), PPI/teprenone (0.037%), gefarnate (0.017%), and PPI/gefarnate (0.013%). No prescriptions were found containing coadministration of aspirin and other NSAIDs. Among the 3196 prescriptions containing aspirin/clopidogrel, 3088 (96.6%) prescriptions did not contain any GI protective medicines. Of the 389 prescriptions containing aspirin/corticosteroids, 236 (60.7%) contained no GI protective medicines. None of the prescriptions using aspirin/warfarin (n = 22) contained GI protective medicines. Thirty-five patients were admitted to this hospital in 2011 because of acute hemorrhage of upper digestive tract induced by low-dose aspirin. The annual incidence rates of major GI bleeding were estimated at 0.25% for outpatients taking aspirin and 0.5% for outpatients taking aspirin/warfarin, respectively.
CONCLUSION: The prescribing pattern of low-dose aspirin revealed a poor awareness of preventing GI injury with combined protective medications. Actions should be taken to address this issue.
PMCID: PMC3386331  PMID: 22791953
Low-dose aspirin; Gastrointestinal injury; Small bowel injury; Drug utilization; Prescribing patterns; Combined medications; Proton-pump inhibitors; Histamine 2-receptor antagonists; Mucoprotective drugs; Defined daily dose
19.  Prevention of upper gastrointestinal haemorrhage: current controversies and clinical guidance 
Acute upper gastrointestinal (GI) bleeding is a common medical emergency and associated with significant morbidly and mortality. The risk of bleeding from peptic ulceration and oesophagogastric varices can be reduced by appropriate primary and secondary preventative strategies. Helicobacter pylori eradication and risk stratification with appropriate gastroprotection strategies when used with antiplatelet drugs and nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in preventing peptic ulcer bleeding, whilst endoscopic screening and either nonselective beta blockade or endoscopic variceal ligation are effective at reducing the risk of variceal haemorrhage. For secondary prevention of variceal haemorrhage, the combination of beta blockade and endoscopic variceal ligation is more effective. Recent data on the possible interactions of aspirin and NSAIDs, clopidogrel and proton pump inhibitors (PPIs), and the increased risk of cardiovascular adverse events associated with all nonaspirin cyclo-oxygenase (COX) inhibitors have increased the complexity of choices for preventing peptic ulcer bleeding. Such choices should consider both the GI and cardiovascular risk profiles. In patients with a moderately increased risk of GI bleeding, a NSAID plus a PPI or a COX-2 selective agent alone appear equivalent but for those at highest risk of bleeding (especially those with previous ulcer or haemorrhage) the COX-2 inhibitor plus PPI combination is superior. However naproxen seems the safest NSAID for those at increased cardiovascular risk. Clopidogrel is associated with a significant risk of GI haemorrhage and the most recent data concerning the potential clinical interaction of clopidogrel and PPIs are reassuring. In clopidogrel-treated patients at highest risk of GI bleeding, some form of GI prevention is indicated.
PMCID: PMC3752180  PMID: 23997925
cyclooxygenase; gastrointestinal haemorrhage; Helicobacter pylori; nonsteroidal anti-inflammatory agents; oesophageal and gastric varices; peptic ulcer
20.  Proton Pump Inhibitors and Histamine-2 Receptor Antagonists are Associated with Hip Fractures among At-Risk Patients 
Gastroenterology  2010;139(1):93-101.
Drugs that inhibit gastric acid might increase the risk of hip fracture. However, little long-term exposure data exist and no large studies have been conducted in the United States.
We conducted a case-control study using data from an integrated health services organization. We evaluated 33,752 patients with incident diagnoses of hip/femur fractures (cases), 130,471 matched members without fractures (controls), prescription data for use of proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) (up to 10 years cumulative duration), and confounders.
Patients with hip fractures were more likely than controls to have previously received ≥2 years supply of PPIs (odds ratio [OR]=1.30, 95% confidence interval [CI]=1.21–1.39) or H2RAs (OR=1.18, 95% CI=1.08–1.29). The risk was reduced after medication discontinuation (OR=1.30, 95% CI 1.21–1.41 for current PPI users vs. OR=1.09, 95% CI 0.64–1.85 for patients who received their last prescription was 3–5 years ago). Higher dosages (but not increasing cumulative durations) were associated with increased risk (e.g. ≥1.5 pills/day OR=1.41, 95% CI 1.21–1.64; <0.74 pills/day OR=1.12, 95% CI 0.94–1.33). Excess fracture risk for PPI use was only present among persons with at least one other fracture risk factor.
Use of drugs that inhibit gastric acid is associated with an increased risk of hip fracture; however, this association was only found among persons with at least one other risk factor for hip fracture. Acid inhibition might therefore be associated with fracture risk in persons already at risk for osteoporosis, although other confounding cannot be excluded.
PMCID: PMC2902649  PMID: 20353792
calcium; bone; medication; gastroesophageal reflux
21.  Bacterial Overgrowth and Irritable Bowel Syndrome: Unifying Hypothesis or a Spurious Consequence of Proton Pump Inhibitors? 
Some studies indicate that small intestinal bacterial overgrowth (SIBO), as measured by hydrogen breath tests (HBT), is more prevalent in patients with irritable bowel syndrome (IBS) vs. matched controls without IBS. Although the data are conflicting, this observation has led to the hypothesis that SIBO may be a primary cause of IBS. Yet, it remains unclear whether SIBO is truly fundamental to the pathophysiology of IBS, or is instead a mere epiphenomenon or bystander of something else altogether. We hypothesize that SIBO might be a byproduct of the disproportionate use of proton pump inhibitors (PPIs) in IBS, as follows: (1) IBS patients are more likely than controls to receive PPI therapy; (2) PPI therapy may promote varying forms of SIBO by eliminating gastric acid; and (3) existing studies linking SIBO to IBS have not adjusted for or excluded the use of PPI therapy. When linked together, these premises form the basis for a simple and testable hypothesis: the relationship between SIBO and IBS may be confounded by PPIs. Our article explores these premises, lays out the argument supporting this “PPI hypothesis,” discusses potential implications, and outlines next steps to further investigate this possibility.
PMCID: PMC2949084  PMID: 19086951
22.  Current state of therapy for pain and inflammation 
Arthritis Research & Therapy  2005;7(Suppl 4):S1-S6.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including both traditional nonselective NSAIDs and the selective cyclo-oxygenase (COX)-2 inhibitors, are among the most widely used medications in the USA. Traditional NSAIDs, although effective at relieving pain and inflammation, are associated with a significant increase in the risk for gastrointestinal adverse events. Throughout the 1990s these events were estimated to result in approximately 100,000 hospitalizations and 16,500 deaths each year nationally. Recent studies have indicated that the risk for serious NSAID gastropathy has declined substantially during the past decade as a result of a number of factors, including lower doses of NSAIDs, the use of gastroprotective agents such as proton pump inhibitors and misoprostol, and the introduction of the selective COX-2 inhibitors. One therapeutic approach that may reduce the risk for gastrointestinal side effects associated with traditional NSAIDs while retaining their efficacy is the inclusion of co-therapy with a proton pump inhibitor; these agents inhibit acid secretion and have been demonstrated to promote ulcer healing in patients with NSAID-related gastric ulcers. Alternatively, COX-2 selective agents have been used to treat patients at high risk for such events. Both nonselective and selective COX-2 inhibitors have now been shown to be associated with an increased risk for cardiovascular events. These studies, together with the outcomes of the recent US Food and Drug Administration decision to require 'black box' warnings regarding potential cardiovascular risks associated with NSAIDs, suggest that the use of COX-2 inhibitors as the sole strategy for gastroprotection in patients with arthritis and other pain syndromes must be reconsidered, particularly among those at risk for cardiovascular events.
PMCID: PMC2833975  PMID: 16168076
23.  Comparative effects of non-steroidal anti-inflammatory drugs (NSAIDs) on blood pressure in patients with hypertension 
Nonsteroidal anti-inflammatory drugs (NSAIDs) may disrupt control of blood pressure in hypertensive patients and increase their risk of morbidity, mortality, and the costs of care. The objective of this study was to examine the association between incident use of NSAIDs and blood pressure in patients with hypertension.
We conducted a retrospective cohort study of adult hypertensive patients to determine the effects of their first prescription for NSAID on systolic blood pressure and antihypertensive drug intensification. Data were collected from an electronic medical record serving an academic general medicine practice in Indianapolis, Indiana, USA. Using propensity scores to minimize bias, we matched a cohort of 1,340 users of NSAIDs with 1,340 users of acetaminophen. Propensity score models included covariates likely to affect blood pressure or the use of NSAIDs. The study outcomes were the mean systolic blood pressure measurement after starting NSAIDs and changes in antihypertensive therapy.
Compared to patients using acetaminophen, NSAID users had a 2 mmHg increase in systolic blood pressure (95% CI, 0.7 to 3.3). Ibuprofen was associated with a 3 mmHg increase in systolic blood pressure compared to naproxen (95% CI, 0.5 to 4.6), and a 5 mmHg increase compared to celecoxib (95% CI, 0.4 to 10). The systolic blood pressure increase was 3 mmHg in a subgroup of patients concomitantly prescribed angiotensin converting enzyme inhibitors or calcium channel blockers and 6 mmHg among those prescribed a beta-adrenergic blocker. Blood pressure changes in patients prescribed diuretics or multiple antihypertensives were not statistically significant.
Compared to acetaminophen, incident use of NSAIDs, particularly ibuprofen, is associated with a small increase in systolic blood pressure in hypertensive patients. Effects in patients prescribed diuretics or multiple antihypertensives are negligible.
PMCID: PMC3502533  PMID: 23092442
NSAIDs; Hypertension; Blood pressure; Propensity score
24.  The Diamine Oxidase Gene Is Associated with Hypersensitivity Response to Non-Steroidal Anti-Inflammatory Drugs 
PLoS ONE  2012;7(11):e47571.
Non-steroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in hypersensitivity drug reactions. Histamine is released in the allergic response to NSAIDs and is responsible for some of the clinical symptoms. The aim of this study is to analyze clinical association of functional polymorphisms in the genes coding for enzymes involved in histamine homeostasis with hypersensitivity response to NSAIDs. We studied a cohort of 442 unrelated Caucasian patients with hypersensitivity to NSAIDs. Patients who experienced three or more episodes with two or more different NSAIDs were included. If this requirement was not met diagnosis was established by challenge. A total of 414 healthy unrelated controls ethnically matched with patients and from the same geographic area were recruited. Analyses of the SNPs rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742 and rs1049793 in the HDC, HNMT and DAO genes were carried out by means of TaqMan assays. The detrimental DAO 16 Met allele (rs10156191), which causes decreased metabolic capacity, is overrepresented among patients with crossed-hypersensitivity to NSAIDs with an OR  = 1.7 (95% CI  = 1.3–2.1; Pc  = 0.0003) with a gene-dose effect (P = 0.0001). The association was replicated in two populations from different geographic areas (Pc  = 0.008 and Pc  = 0.004, respectively).
Conclusions and implications
The DAO polymorphism rs10156191 which causes impaired metabolism of circulating histamine is associated with the clinical response in crossed-hypersensitivity to NSAIDs and could be used as a biomarker of response.
PMCID: PMC3495953  PMID: 23152756
25.  Microscopic colitis and Medication Use 
The incidence of microscopic colitis (MC) is increasing, but its etiology remains unknown. Case reports and limited controlled data suggest that commonly prescribed drugs may be triggers. The aim of this study was to evaluate the prevalence of selected medication use [Proton pump inhibitors (PPIs), HMG-CoA reductase inhibitors (statins), and Selective serotonin reuptake inhibitors (SSRIs)] in patients with MC compared to ‘random controls’ and ‘diarrhea controls.’
All patients were selected from primary care practices of a university health system during 2002 to 2007. Patients with biopsy proven lymphocytic or collagenous colitis were identified as cases. Diarrhea controls consisted of a 10:1 random sample of patients with chronic diarrhea and normal colon biopsies. Ten random controls were matched to each case on sex and index date (date of biopsy proven diagnosis). Drugs prescribed within the year prior to the index date were collected from the electronic medical record system.
26 cases (median age 68.9 yrs), 259 random, and 259 diarrhea controls were identified. The adjusted ORs for PPI, SSRI, and statin prescription within 12 months of diagnosis of MC between cases and diarrhea controls were 0.28 (0.07-1.07), 0.87 (0.28-2.64), 1.12 (0.34-3.71) respectively. Use of PPI and statins was less common in MC patients than in random controls (p<0.05 for both comparisons).
While prior data suggest that PPIs, statins, and SSRIs may be etiologically related to MC, our study found no increased association with these drugs.
PMCID: PMC2903747  PMID: 20640056

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