Individual NSAIDs and Upper Gastrointestinal Complications A Systematic Review and Meta-Analysis of Observational Studies (the SOS Project (original) (raw)
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Individual NSAIDs and Upper Gastrointestinal Complications
Drug Safety, 2012
Background: The risk of upper gastrointestinal (GI) complications associated with the use of NSAIDs is a serious public health concern. The risk varies between individual NSAIDs; however, there is little information on the risk associated with some NSAIDs and on the impact of risk factors. These data are necessary to evaluate the benefit-risk of individual NSAIDs for clinical and health policy decision making. Within the European Community's Seventh Framework Programme, the Safety Of non-Steroidal anti-inflammatory drugs (NSAIDs) [SOS] project aims to develop decision models for regulatory and clinical use of individual NSAIDs according to their GI and cardiovascular safety. Objective: The aim of this study was to conduct a systematic review and metaanalysis of observational studies to provide summary relative risks (RR) of upper GI complications (UGIC) associated with the use of individual NSAIDs, including selective cyclooxygenase-2 inhibitors. Methods: We used the MEDLINE database to identify cohort and case-control studies published between 1 January 1980 and 31 May 2011, providing adjusted effect estimates for UGIC comparing individual NSAIDs with non-use of NSAIDs. We estimated pooled RR and 95% CIs of UGIC for individual NSAIDs overall and by dose using fixed-and random-effects methods. Subgroup analyses were conducted to evaluate methodological and clinical heterogeneity between studies. Results: A total of 2984 articles were identified and 59 were selected for data abstraction. After review of the abstracted information, 28 studies met the SYSTEMATIC REVIEW
Gastroenterology, 2007
Background & Aims: Traditional nonaspirin, nonsteroidal anti-inflammatory drugs (tNSAIDs) have been associated with a 3- to 5-fold increased risk in upper gastrointestinal complications (UGIC). Whether use of selective inhibitors of cyclooxygenase-2 (COXIBs) will translate into a clinically relevant reduced toxicity has not been widely investigated in the general population. Methods: We conducted a nested case control study using The Health Improvement Network Database identifying 1561 cases of UGIC between January 2000 and 2005. A random sample of 10,000 controls was frequency matched to the cases by age, sex, and calendar year. Results: The adjusted relative risk (RR) of UGIC associated with current use was 3.7 (95% CI: 3.1–4.3) for tNSAIDs and 2.6 (95% CI: 1.9–3.6) for COXIBs. Daily dose was a predictor of increased risk for both tNSAIDs and COXIBs. Users of tNSAIDs with a prolonged plasma half-life or slow release formulations had an augmented risk of UGIC. Overall, the estimate of RR associated with COXIBs was 0.8 (95% CI: 0.6–1.1) compared with current use of tNSAIDs, and, among nonusers of aspirin, the corresponding estimate of RR associated with COXIBs was 0.6 (95% CI: 0.4–0.9). Conclusions: COXIBs present a better upper gastrointestinal safety than tNSAIDs, although the risk of UGIC for an individual drug is determined by its daily dose and plasma drug exposure in addition to its selectivity for cyclooxygenase-2. Also, concomitant use of aspirin is a strong effect modifier of COXIBs that negates the superior gastrointestinal safety over tNSAIDs in the absence of aspirin use.
Osteoporosis International, 2003
To provide an updated document assessing the global, NSAID-specific, and time dependent risk of gastrointestinal (GI) complications through meta-analyses of high quality studies. Methods: An exhaustive systematic search was performed. Inclusion criteria were: RCT or controlled study, duration of 5 days at least, inactive control, assessment of minor or major NSAID adverse effects, publication range January 1985 to January 2003. The publications retrieved were assessed during a specifically dedicated WHO meeting including leading experts in all related fields. Statistics were performed conservatively. Meta-regression was performed by regressing NSAID adjusted estimates against study duration categories. Results: Among RCT data, indolic derivates provided a significantly higher risk of GI complications related to NSAID use than for non-users: RR = 2.25 (1.00; 5.08
Clinical Pharmacology and Therapeutics, 2011
as part of the safety of non-steroidal anti-inflammatory Drugs (sos) project, we reviewed the incidence of cardiovascular (CV) and gastrointestinal (gi) events associated with the use of this category of drugs. We collected data from published meta-analyses (mas) of clinical trials of nonsteroidal anti-inflammatory drugs (nsaiDs). The medline, Cochrane, isi, and sCopus databases were systematically searched for mas of nsaiD clinical trials that could potentially contain data on adverse incidents such as myocardial infarction (mi), cerebrovascular events (CeVs), stroke, thromboembolic events (Thes), heart failure (hF), gastrointestinal bleeding (giB), and perforation, ulcer, and bleeding (puB). From 1,733 identified references, 29 mas were selected for the review. This allowed 109 estimations of incidence rates of CV adverse events and 26 estimations of incidence rates for gi adverse events. no data were found on hemorrhagic stroke or lgiB. Coxibs were studied in more mas than traditional nsaiDs were (21 mas for coxibs vs. 7 for traditional nsaiDs; one meta-analysis studied both). many nsaiDs were not considered in any of the mas. our systematic review of mas included information on the incidence of CV and gi events and identified important knowledge gaps regarding, in particular, the CV safety of traditional nsaiDs.
Drug, Healthcare and Patient Safety, 2009
Background: 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. Methods: 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. Results: 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. Conclusion: 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.
Cardiovascular and gastrointestinal safety of NSAIDs
Pharmaceutisch weekblad, 2014
Background Coxibs cardiovascular (CV) safety continues being a current issue after rofecoxib worldwide withdrawal in 2004. Objective To evaluate the cardiovascular and gastrointestinal (GI) risk of coxibs through case/non-case study. Setting The Spanish Pharmacovigilance System for Human Use Drugs (FEDRA) and the Uppsala Monitoring Centre (VigiBase) databases. Method We identified adverse drug reactions (ADRs) cases reported under the MedDRA system organ classes of "cardiac disorders", "vascular disorders", "nervous system disorder" and "gastrointestinal disorders". Disproportionality was considered when the following criteria were met simultaneously: proportional reporting ratio (PRR) ≥ 2, 95% confidence interval lower limit of reporting odds ratio (ROR) > 1, Chi square test (χ 2) ≥ 4; and number of ADR reports (n rep.) > 3. Main outcome measure Potential disproportionality between cardiovascular and GI ADRs as reported to FEDRA and VigiBase and the use of coxibs. Results We found association between coxibs and CV-ADRs in FEDRA [PRR 2.11 (95% CI 1.97-2.27); ROR 2.53 (95% CI 2.29-2.89); χ 2 367.81; n rep., 561] and VigiBase [PRR 2.67 (95% CI 2.64-2.71); ROR 3.26 (95% CI 3.20-3.31); χ 2 23,950.93; n rep., 21,047]; and between coxibs and GI-ADRs in VigiBase [PRR 2.91 (95% CI 2.84-2.97); ROR 3.08 (95% CI 3.01-3.16); χ 2 8762.82; n rep. 6954]. No association was found between coxibs and GI-ADRs in FEDRA. Conclusion The association found support a potential coxibs class effect in terms of cardiovascular safety. Classical NSAIDs GI risk may be higher than that for coxibs. Keywords Cardiovascular disease • Cyclooxygenase 2 inhibitors • Epidemiologic study • Gastrointestinal disease • Non steroidal anti inflammatory agents Impacts on practice • The results support a potential coxibs class effect in terms of cardiovascular safety • Coxibs CV risk may be higher than that for Classical NSAIDs • Classical NSAIDs GI risk may be higher than that for coxibs, although both pharmacological groups seem to have some risk of gastrointestinal events Electronic supplementary material The online version of this article (
Drug Safety, 2008
often prescribed to patients who have not responded satisfactorily to established related drugs or as first-line therapy to patients with a high baseline risk for adverse outcomes (i.e. channelling). However, these patients are less likely to benefit from the prescribed drug and/or are more prone to adverse drug reactions. Therefore, it is difficult to unravel whether observed risks or increases in risk of new drugs are real, i.e. related to the pharmacology, or whether these are related to selective prescribing to patients who are more susceptible to adverse events because of some underlying risk factor(s). The channelling paradox may exist for cyclo-oxygenase (COX)-2 selective inhibitors ('coxibs') instead of traditional nonselective NSAIDs in relation to both gastrointestinal (GI) and cardiovascular (CV) safety. Objective: To evaluate the risk profiles for GI and CV adverse effects in nonselective NSAID and coxib new-user populations over time, in terms of a quantitative measure since the introduction of coxibs. Methods: This was a population-based cohort study using the Dutch pharmaceutical claims database (Foundation for Pharmaceutical Statistics). Eligible patients (≥18 years) were those where the date of their first prescription (index date) of an NSAID (first-line [e.g. ibuprofen] or second-line [e.g. piroxicam] nonselective NSAID, COX-2 preferential NSAID or coxib) was between January 1999 and December 2003. For each patient, GI and CV risk profiles at index date were defined by a cumulative score derived from dispensing data (patient age, sex and history of medication use within 6 months of index date). Risk scores were categorized as low (score = 0), medium (1) or high (2+). Patients were recorded as switchers based on other NSAID use prior to the index date. Other information collected included the Chronic Disease Score (CDS). Crude odds ratios (ORs) were calculated for risk factors for each NSAID group versus first-line nonselec-
Rheumatology, 2005
Objectives. To examine prescribing of non-steroidal anti-inflammatory drugs (NSAIDs) in general practice and to compare the results with a 1993 study. To assess numbers at risk of gastrointestinal adverse events using the National Institute for Clinical Excellence (NICE) guidance on the use of cyclo-oxygenase (Cox) II selective drugs. Methods. Patients currently prescribed a NSAID for 2 months or more were identified from practice records. Demographic information, indications, previous gastrointestinal disease, serious co-morbidity and concomitant prescriptions were recorded. Data were compared with the 1993 survey and the NICE guidance. Results. Seven thousand nine hundred and fifty-eight patients were registered with the practice in 2003. Two hundred and four patients were receiving repeat prescriptions for conventional NSAIDs and 63 for Cox II selective drugs. As in 1993 diclofenac (38%) and ibuprofen (24%) were the commonest individual agents and the main indication was regional pain. Seventy-three per cent of patients prescribed Cox II selective drugs and 64% of patients prescribed conventional NSAIDs had at least one NICE risk factor for gastrointestinal adverse events. Frequency of co-prescription of aspirin or antacids was similar for conventional NSAIDs and Cox II selective drugs, but prescription of antacids was higher with NICE risk factors. Conclusion. The indications for NSAIDs have not changed since 1993. Cox II selective drug prescribing was within the NICE guidance but a substantial proportion of patients taking other NSAIDs had risk factors for gastrointestinal adverse events. Discussion with the GPs highlighted the difficulties of balancing perceived risk of gastrointestinal adverse events with cardioprotection and further guidance is urgently needed.