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.
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.
epidemiology; chemoprevention; GERD; VA; Medicare
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.
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
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.
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.
Non-steroidal anti-inflammatory drugs (NSAIDs), which are used for the treatment of several inflammatory disorders including rheumatoid arthritis, are well known to cause gastroduodenal mucosal lesions as an adverse effect. Recently, the serious problem of NSAID-induced small intestinal damage has become a topic of great interest to gastroenterologists, since capsule endoscopy and double-balloon enteroscopy are available for the detection of small intestinal lesions. Such lesions have been of great concern in clinical settings, and their treatment and prevention must be devised as soon as possible. Proton pump inhibitors (PPI), such as lansoprazole and omeprazole, show a potent anti-secretory effect. PPIs also have a gastroprotective effect, independent of their anti-secretory actions, which is probably mediated by inhibition of neutrophil functions as well as antioxidant actions. Administration of lansoprazole reduced the severity of the intestinal lesions in a dose-dependent manner, but omeprazole had no effect. The amount of heme oxygenase-1 (HO-1) protein in the intestinal mucosa was significantly increased by lansoprazole, but not by omeprazole. These results suggest that lansoprazole, but not omeprazole, ameliorates indomethacin-induced small intestinal ulceration through upregulation of HO-1/carbon monoxide. Therefore, lansoprazole may be useful for preventing the adverse effects of NSAIDs not only in the stomach but also in the small intestine.
NSAID; small intestinal injury; lansoprazole; PPI
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.
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.
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.
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.
To review proper use of gastroprotective strategies in family medicine for
patients requiring chronic nonsteroidal anti-inflammatory drug (NSAID)
QUALITY OF EVIDENCE
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
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.
Non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) are regarded as two types of drugs that respectively increase and decrease the risk of peptic ulcer bleeding. However, their relation to occurrence, recurrence and death of bleeding in the population level is not clear.
To clarify recent calendar-time correlations between sales of NSAIDs and PPIs and the occurrence of peptic ulcer bleeding, re-bleeding and death.
The time trend of peptic ulcer bleeding did not correlate with PPI sales but did correlate with NSAIDs in mem (Rmale=0.6571, Pmale=0.05). Sales of PPIs (inverse) and NSAIDs correlated with re-bleeding in women (Rmale=−0.8754, Pmale=0.002 and Rfemale=0.7161, Pfemale=0.03, respectively), but not in men. An inverse correlation between PPI sales and 30-day death after bleeding was found (Rmale=−0.9392, Pmale=0.0002 and Rfemale=−0.8561, Pfemale=0.003), and NSAID sales were found to correlate with increased death after bleeding ((Rmale=0.7278, Pmale=0.03, Rfemale=0.7858, Pfemale=0.01).
The sales of NSAIDs and PPIs correlate with recurrence of peptic ulcer bleeding in women and death after peptic ulcer bleeding in both genders in the population level.
Peptic Ulcer Bleeding; Non-Steroidal Anti-Inflammatory Drugs; Propton Pump Inhibitors
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.
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.
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
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.
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.
antibiotic; Clostridium difficile; outbreak; proton pump inhibitor; risk factor; antibiotique; éclosion de Clostridium difficile; inhibiteur de la pompe à protons; facteur de risque
The use of oral non-steroidal anti-inflammatory drugs (NSAIDs) in 31 patients with collagenous colitis and in 31 matched control patients with irritable bowel syndrome or colonic diverticular disease who had also undergone colonoscopy and biopsy was investigated. The long term use (greater than 6 months) of NSAIDs was significantly commoner in the study group (19/31) than in the control group (4/31) (p less than 0.02), even assuming the most adverse drug history in six patients in whom this could not be established. In all patients with collagenous colitis taking NSAIDs, diarrhoea followed the use of these drugs, and by a mean (SD) of 5.5 (4.4) years (range 0.5 to 15 years). In three patients with collagenous colitis, diarrhoea improved after withdrawing NSAIDs; rechallenge in one was followed by a recurrence of diarrhoea, which improved after withdrawing the drug again. It is suggested that NSAIDs may play an aetiological role in the diarrhoea and thickened collagen band in some patients with collagenous colitis.
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.
Non-steroidal anti-inflammatory drugs; gastroduodenal ulcers; proton pump inhibitors; ranitidine
Functional neuroendocrine tumors are often low-grade malignant neoplasms that can be cured by surgery if detected early, and such detection may in turn be accelerated by the recognition of neuropeptide hypersecretion syndromes. Uniquely, however, relief of peptic symptoms induced by hypergastrinemia is now available from acid-suppressive drugs such as proton-pump inhibitors (PPIs). Here we describe a clinical case in which time to diagnosis from the onset of peptic symptoms was delayed more than 10 years, in part reflecting symptom masking by continuous prescription of the PPI omeprazole. We propose diagnostic criteria for this under-recognized new clinical syndrome, and recommend that physicians routinely measure serum gastrin levels in persistent cases of PPI-dependent dyspepsia unassociated with H. pylori.
Neuroendocrine carcinoma; Pancreatic tumor; Zollinger–Ellison syndrome; Gastrin; Omeprazole
BACKGROUND & AIMS
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.
calcium; bone; medication; gastroesophageal reflux
This study aimed to assess if proton pump inhibitors (PPIs) may reduce the effectiveness of clopidogrel, than H2 antagonist (anti-H2) in order to determine rehospitalization for acute coronary syndrome (re-ACS), target vessel revascularization (TVR) and cardiac death. This case-control study included 176 patients with ACS undergoing angioplasty (PCI) with drug-eluting stent implantation. The population was divided into two groups: PPI group (n = 121) consisting of patients receiving at discharge dual antiplatelet therapy (DAT) plus PPI and anti-H2 group (n = 55), consisting of patients receiving at discharge DAT + H2 receptor antagonist (H2RA). In a followup of 36 months the prevalence of ACS event (P = 0.014), TVR (P = 0.031) was higher in the PPI group than in the anti-H2 group; instead there was no statistically significant difference between groups for death. The variables independently associated with ACS were the diabetes, omeprazole, and esomeprazole; instead the variables independently associated with TVR were only omeprazole. Our data shows that the use of omeprazole and esomeprazole, with clopidogrel, is associated with increased risk of adverse outcomes after PCI with drug-eluting stent implantation.
This pharmacoepidemiologic study was conducted to determine whether risk factors for upper gastrointestinal bleeding influenced the prescription of cyclo-oxygenase (COX)-2 inhibitors and traditional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) at the time when COX-2 inhibitors were first included in the formulary of reimbursed medications. A population-based case–control study was conducted in which the prevalence of risk factors and the medical histories of patients prescribed COX-2 inhibitors and traditional nonselective NSAIDs were compared. The study population consisted of a random sample of members of the Quebec drug plan (age 18 years or older) who received at least one dispensation of celecoxib (n = 42,422; cases), rofecoxib (n = 25,674; cases), or traditional nonselective NSAIDs (n = 12,418; controls) during the year 2000. All study data were obtained from the Quebec health care databases. Adjusting for income level, Chronic Disease Score, prior use of low-dose acetylsalicylic acid, acetaminophen, antidepressants, benzodiazepines, prescriber specialty, and time period, the following factors were significantly associated with the prescription of COX-2 inhibitors: age 75 years or older (odds ratio [OR] 4.22, 95% confidence interval [CI] 3.95–4.51), age 55–74 years (OR 3.23, 95% CI 3.06–3.40), female sex (OR 1.52, 95% CI 1.45–1.58), prior diagnosis of gastropathy (OR 1.21, 95% CI 1.08–1.36) and prior dispensation of gastroprotective agents (OR 1.57, 95% CI 1.47–1.67). Patients who received a traditional nonselective NSAID recently were more likely to switch to a coxib, especially first-time users (OR 2.17, 95% CI 1.93–2.43). Associations were significantly greater for celecoxib than rofecoxib for age, chronic NSAID use, and last NSAID use between 1 and 3 months before the index date. At the time of introduction of COX-2 inhibitors into the formulary, prescription channeling could confound risk comparisons across products.
administrative health care databases; COX-2 inhibitors; nonsteroidal anti-inflammatory drugs; pharmacoepidemiology; prescription channeling
Traditional NSAIDs (tNSAIDs) and COX-2 inhibitors (COX-2s) are important agents for the treatment of a variety or arthritic conditions. The purpose of this study was to systematically review the effectiveness of misoprostol, H2-receptor antagonists (H2RAs), and proton pump inhibitors (PPIs) for the prevention of tNSAID related upper gastrointestinal (GI) toxicity, and to review the upper gastrointestinal (GI) safety of COX-2s.
An extensive literature search was performed to identify randomized controlled trials (RCTs) of prophylactic agents used for the prevention of upper GI toxicity, and RCTs that assessed the GI safety of the newer COX-2s. Meta-analysis was performed in accordance with accepted techniques.
39 gastroprotection and 69 COX-2 RCTs met inclusion criteria. Misoprostol, PPIs, and double doses of H2RAs are effective at reducing the risk of both endoscopic gastric and duodenal tNSAID-induced ulcers. Standard doses of H2RAs are not effective at reducing the risk of tNSAID-induced gastric ulcers, but reduce the risk of duodenal ulcers. Misoprostol is associated with greater adverse effects than the other agents, particularly at higher doses. COX-2s are associated with fewer endoscopic ulcers and clinically important ulcer complications, and have fewer treatment withdrawals due to GI symptoms than tNSAIDS. Acetylsalicylic acid appears to diminish the benefit of COX-2s over tNSAIDs. In high risk GI patients, tNSAID with a PPI or a COX-2 alone appear to offer similar GI safety, but a strategy of a COX-2 with a PPI appears to offer the greatest GI safety.
Several strategies are available to reduce the risk of upper GI toxicity with tNSAIDs. The choice between these strategies needs to consider patients’ underlying GI and cardiovascular risk.
NSAID; gastrointestinal toxicity; COX-2 inhibitors
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.
BACKGROUND: Clostridium difficile-associated diarrhea (CDAD) has been increasingly diagnosed in hospitalized patients. The number of prescriptions for proton pump inhibitors (PPIs) has also increased significantly over time. Few studies have reported an association between CDAD and PPI use; however, the results are inconclusive. OBJECTIVE: To determine the relationship between CDAD and PPI use in African-American and Hispanic patients. METHODS: We retrospectively reviewed medical records of 640 cases with CDAD over nine years, diagnosed by the presence of C. difficile toxin in the stools. Age-/ sex-matched 650 patients with diarrhea but absent C. difficile toxin in stools were used as controls. RESULTS: Of the 640 cases, 576 (90%) received antibiotics and 32 (5%) received chemotherapy during the preceding three months. Of the 650 controls, 540 (83%) received antibiotics and 39 (6%) received chemotherapy during the preceding three months. CDAD was associated with the use of antibiotics or chemotherapy (OR = 2.3, 95% CI: 1.5-3.7). Of the 608 cases receiving antibiotics or chemotherapy, 274 (45%) also received PPI within the preceding three months. Of the 579 controls who received antibiotics or chemotherapy, 169 (29%) also received PPI within preceding three months. CDAD was associated with the use of PPI (OR = 2.0, 95% CI: 1.6-2.6). CONCLUSION: Our findings indicate that PPI may be an emerging and potentially modifiable risk factor for CDAD and point out the importance of vigilance in prescribing PPI, particularly to patients who are hospitalized, taking multiple antibiotics and suffering from multiple comorbidities.