Nonselective Nonsteroidal Anti-inflammatory Drugs Users Research Articles

Effects of Therapies on Cardiovascular Events in Ankylosing Spondylitis: A Systematic Review and Meta-Analysis.

IntroductionNon-steroidal anti-inflammatory drugs (NSAIDs) and tumor necrosis factor inhibitors (TNFi) are the most common therapies used in AS, however, the associated long-term cardiovascular risk is unclear. We performed a systematic review and meta-analysis on the association of therapies used for ankylosing spondylitis (AS) such as NSAIDs and TNFi on cardiovascular events (CVE) in AS.MethodsA comprehensive search was performed from database inception to May 29, 2020 to include controlled studies of AS treated with NSAIDs, oral small molecules, or biologics reporting CVE. Study-specific risk ratios (RR) were pooled using a random effects model.ResultsNine non-randomized studies from 1570 studies screened fulfilled inclusion criteria. Among NSAID users as a whole versus no NSAIDs, no increased risk of CVE (composite outcome) was observed; however, the risk of cerebrovascular accident was significantly lower (RR 0.58, 95% CI 0.37–0.93, I2 = 66%). Cox-2 inhibitor use was associated with reduced risk of all CVE (RR 0.48, 95% CI 0.33–0.70, I2 = 0%). Non-selective NSAIDs were not associated with any increased/decreased risk of any CVE. Meta-analysis of three studies of MI did not show a significant association with TNFi (RR 0.88, 95% CI 0.57–1.35, I2 = 76%).ConclusionsIn this meta-analysis of non-randomized studies, NSAID users as a whole and users of non-selective NSAIDs did not seem to have a higher risk of any CVE. Limited data suggest a lower risk of composite CVE outcome with Cox-2 inhibitors, unlike the increased risk reported in the general population. No significant association between TNFi and MI was observed. The certainty in evidence was very low due to all studies being observational. More studies are needed to study the association between TNFi use and CVE in general to evaluate a possible protective role in AS.Electronic Supplementary MaterialThe online version of this article (10.1007/s40744-020-00248-x) contains supplementary material, which is available to authorized users.

Maintenance use of non-steroidal anti-inflammatory drugs and risk of gastrointestinal cancer in a nationwide population-based cohort study in Sweden

ObjectivesAspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are potential candidates for chemoprevention of gastrointestinal cancer. We aimed to assess the association between contemporary NSAID use (≥180 days) and gastrointestinal cancer.DesignNationwide...

Evaluation of community pharmacists' roles in screening and communication of risks about non-steroidal anti-inflammatory drugs in Thailand.

AimThis study aimed to explore community pharmacists' roles on screening for risk factors, providing safety information-related non-steroidal anti-inflammatory drugs (NSAIDs) to patients. BACKGROUND: NSAIDs are widely dispensed without a prescription from pharmacies in Thailand, while they are frequently reported as causing adverse events. METHODS: Self-administered questionnaires were distributed to all accredited pharmacies in Thailand, inviting the main pharmacist in each pharmacy to participate in this study.FindingsOut of 406 questionnaires distributed, 159 were returned (39.2%). Almost all pharmacists claimed to engage in NSAID dispensing practice, but not all of them provided relevant good practice, such as, screening for risk factors (56.3-95.5%), communication on adverse drug reactions (ADRs) (36.9-63.2%) and ADR management (58.9-79.7%), history of gastrointestinal (GI) problems was frequently mentioned for screening, but many pharmacists did not screen for history of NSAID use (24.7-35.5%), older age (45.2-48.9%), concomitant drug (63.7%), and problems of cardiovascular (24.1%), renal (34.9-43.3%), and liver systems (60.3-61.0%). Male pharmacists were significantly less likely to inform users of non-selective NSAIDs about ADRs [odds ratio (OR) 0.44], while provision of information about selective NSAID ADRs was higher among pharmacy owners (OR 2.28), pharmacies with more pharmacists (OR 3.18), and lower in pharmacies with assistants (OR 0.41). Screening for risk factors, and risk communication about NSAIDs were not generally conducted in Thai accredited community pharmacists, nor were NSAID complications fully communicated. Promoting of community pharmacists' roles in NSAID dispensing should give priority to improving, especially in high-risk patients for taking NSAIDs.

Comparative cardiovascular safety of nonsteroidal anti‐inflammatory drugs in patients with hypertension: a population‐based cohort study

Previous studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with higher cardiovascular risks. However, few have been active comparison studies that directly assessed the potential differential cardiovascular risk between NSAID classes or across individual NSAIDs. We compared the risk of major cardiovascular events between cyclooxygenase 2 (COX-2)-selective and nonselective NSAIDs in patients with hypertension. We conducted a cohort study of patients with hypertension who initiated COX-2-selective or nonselective NSAIDs in a population-based Taiwanese database. The outcomes included hospitalization for the following major cardiovascular events: ischaemic stroke, acute myocardial infarction, congestive heart failure, transient ischaemic attack, unstable angina or coronary revascularization. We followed patients for up to 4weeks, based on the as-treated principle. We used inverse probability weighting to control for baseline and time-varying covariates, and estimated the on-treatment hazard ratios (HRs) and 95% conservative confidence interval (CIs). We identified 2749 eligible COX-2-selective NSAID users and 52 880 eligible nonselective NSAID users. The HR of major cardiovascular events comparing COX-2-selective with nonselective NSAIDs after adjusting for baseline and time-varying covariates was 1.07 (95% CI 0.65, 1.74). We did not observe a differential risk when comparing celecoxib to diclofenac (HR 1.17; 95% CI 0.61, 2.25), ibuprofen (HR 1.36; 95% CI 0.58, 3.18) or naproxen (HR 0.75; 95% CI 0.23, 2.44). There was an increased risk with COX-2-selective NSAIDs, however, when comparing COX-2-selective NSAIDs with mefenamic acid (HR 2.11; 95% CI 1.09, 4.09). Our results provide important information about the comparative cardiovascular safety of NSAIDs in patients with hypertension.

Postoperative nonsteroidal antiinflammatory drugs and the prevention of heterotopic ossification after cervical arthroplasty: analysis using CT and a minimum 2-year follow-up.

OBJECT Heterotopic ossification (HO) after cervical arthroplasty is not uncommon and may cause immobility of the disc. To prevent HO formation, study protocols of clinical trials for cervical arthroplasty undertaken by the US FDA included perioperative use of nonsteroidal antiinflammatory drugs (NSAIDs). However, there are few data supporting the use of NSAIDs to prevent HO after cervical arthroplasty. Therefore, this study aimed to evaluate the efficacy of NSAIDs in HO formation and clinical outcomes. METHODS Consecutive patients who underwent 1- or 2-level cervical arthroplasty with a minimum follow-up of 24 months were retrospectively reviewed. All patients were grouped into 1 of 2 groups, an NSAID group (those patients who had used NSAIDs postoperatively) and a non-NSAID group (those patients who had not used NSAIDs postoperatively). The formation of HO was detected and classified using CT in every patient. The incidence of HO formation, disc mobility, and clinical outcomes, including visual analog scale (VAS) scores of neck and arm pain, neck disability index (NDI) scores, and complications were compared between the two groups. Furthermore, a subgroup analysis of the patients in the NSAID group, comparing the selective cyclooxygenase (COX)-2 to nonselective COX-2 NSAID users, was also conducted for each of the above-mentioned parameters. RESULTS A total of 75 patients (mean age [± SD] 46.71 ± 9.94 years) with 107 operated levels were analyzed. The mean follow-up duration was 38.71 ± 9.55 months. There were no significant differences in age, sex, and levels of arthroplasty between the NSAID and non-NSAID groups. There was a nonsignificantly lower rate of HO formation in the NSAID group than the non-NSAID group (47.2% vs. 68.2%, respectively; p = 0.129). During follow-up, most of the arthroplasty levels remained mobile, with similar rates of immobile discs in the NSAID and non-NSAID groups (13.2% and 22.7%, respectively; p = 0.318). Furthermore, there was a nonsignificantly lower rate of HO formation in the selective COX-2 group than the nonselective COX-2 group (30.8% vs 52.5%, respectively; p = 0.213). The clinical outcomes, including VAS neck, VAS arm, and NDI scores at 24 months postoperatively, were all similar in the NSAID and non-NSAID groups, as well as the selective and nonselective COX-2 groups (all p > 0.05). CONCLUSIONS In this study there was a trend toward less HO formation and fewer immobile discs in patients who used postoperative NSAIDs after cervical arthroplasty than those who did not, but this trend did not reach statistical significance. Patients who used selective COX-2 NSAIDs had nonsignificantly less HO than those who used nonselective COX-2 NSAIDs. The clinical outcomes were not affected by the use of NSAIDs or the kinds of NSAIDs used (selective vs nonselective COX-2). However, the study was limited by the number of patients included, and the efficacy of NSAIDs in the prevention of HO after cervical arthroplasty may need further investigation to confirm these results.

How safe is Celecoxib for Asian-Indian patients with rheumatic diseases?

Cyclo-oxygenase (COX)-2 inhibitors have been the target of severe criticism, more so following the withdrawal of Rofecoxib. Post-marketing surveillance of Celecoxib in Asian Indians, who are predisposed to premature athero-thrombotic events, has not been studied. To study the adverse effects of Celecoxib and compare them with those of other non-steroidal anti-inflammatory drugs (NSAIDs) in an Asian Indian cohort. This is a retrospective chart review with convenience sampling of patients on NSAIDs (at least five tablets a week, for at least 3months prior to the study), attending the Rheumatology clinic of a tertiary care institution in south India between June 2004 and November 2004. Those with pre-existing heart disease, hypertension, thrombo-embolic disease, peptic ulcer and patients on corticosteroids were excluded. All the recorded adverse events were noted and compared between the Celecoxib and non-selective NSAID users. Univariate analysis using Chi-square test was performed. Of the 1387 patients included, 915 were on Celecoxib. In the NSAID group, 204 had used multiple NSAIDs in sequence. Of the Celecoxib users, 164 had switched over to an NSAID during the study period. New onset of hypertension was significantly higher in the Celecoxib users as compared to non-selective NSAID users (3.06% vs. 1.27%, P=0.04). However, those who had switched over to NSAIDs did not show this trend. NSAID users, on the other hand, had significant gastrointestinal (GI) toxicity (2.54% vs. 0.327%, P=0.001). A significant number of Celecoxib users who switched over to NSAIDs also developed GI toxicity (6.1% vs. 1.21%, P=0.018) over a shorter time span, as compared to the continuous NSAID users. Multiple NSAID users had higher adverse events (6.37% vs. 2.23%, P=0.023) as compared to single NSAID users. Celecoxib significantly increased the incidence of new onset hypertension in this cohort of Indian patients with rheumatic diseases. No thromboembolic events were documented.

Esomeprazole relieves upper gastrointestinal symptoms in high-risk and average-risk NSAID users in daily clinical practice

To investigate whether esomeprazole can provide relief for nonsteroidal anti-inflammatory drug (NSAID)-associated upper gastrointestinal symptoms in patients at different gastrointestinal risk. A multicentre, prospective, open-label study was conducted, wherein NSAID users visiting their general practitioner for upper gastrointestinal symptoms were asked to participate. Patients were treated with 20 mg esomeprazole and treatment effect was evaluated within 8 weeks. Response was defined as a maximum of 1 day per week with gastrointestinal symptoms during the last week of treatment. Partial response was defined as more than 50% improvement in the number of days per week with symptoms compared with baseline. Patients not meeting the above-mentioned criteria were classified as nonresponders. Patients who completely responded were compared with partial responders and nonresponders and were analysed according to their baseline gastrointestinal risk. A total of 1042 patients (mean age: 57 years; standard deviation: 15; 43% male) were analysed. Complete response, partial response and nonresponse were achieved in 57, 24 and 19% of the patients, respectively. Similar response was seen in average-risk and high-risk patients (58 and 56%; P=0.46) and in nonselective NSAID and selective cyclooxygenase-2 users (57 and 53%; P=0.32). Esomeprazole (20 mg) improved NSAID-associated upper gastrointestinal symptoms. Baseline gastrointestinal risk did not influence esomeprazole effectiveness.

Non-steroidal anti-inflammatory drug use and risk of atrial fibrillation or flutter: population based case-control study

Objectives To examine the risk of atrial fibrillation or flutter associated with use of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) or selective cyclo-oxygenase (COX) 2 inhibitors. Design Population based case-control study...

Genetic Polymorphisms and the Cardiovascular Risk of Non-Steroidal Anti-Inflammatory Drugs

The cardiovascular safety of cyclooxygenase-2-selective (coxibs) and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) is of concern, although most users remain free of adverse outcomes. A gene-drug interaction could modulate this cardiovascular risk through prostaglandin synthesis or inflammatory pathways. From an existing acute coronary syndrome cohort (Recurrence and Inflammation in the Acute Coronary Syndromes Study) (n = 1,210), a case-only study was performed by identifying 115 patients exposed to NSAIDs (rofecoxib [n = 43], celecoxib [n = 49], or nonselective NSAIDs [n = 23]) and 345 unexposed patients matched for age, gender, and hospital center. These patients were genotyped for 115 candidate single-nucleotide polymorphisms (SNPs). Statistically significant associations between NSAID exposure and 9 SNPs in 6 genes were observed. Analyzing patients exposed only to coxibs and their matched unexposed cases, significant associations remained for 5 SNPs at 4 loci (prostaglandin-endoperoxide synthase-1 [PTGS1], chromosome 9p21.3, C-reactive protein [CRP], and klotho [KL]). Two independent SNPs from the PTGS1 gene gave similar results under a recessive model, with odds ratios for the association with NSAID exposure of 6.94 (95% confidence interval 1.35 to 35.65, p = 0.016) and 7.11 (95% confidence interval 1.38 to 36.74, p = 0.033). A significant association was also observed for a SNP in the CRP gene (rs1205) (additive odds ratio 1.64, 95% confidence interval 1.18 to 2.27, p = 0.003). In conclusion, these findings suggest that genetic variability may contribute to the susceptibility for acute coronary syndromes observed in some NSAID users. In particular, genetic polymorphisms in the PTGS1 and CRP genes appear to be candidates for a possible gene-drug interaction influencing the acute coronary risk associated with NSAID use, but these findings will require confirmation in larger cohorts.

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.

High-dimensional Propensity Score Adjustment in Studies of Treatment Effects Using Health Care Claims Data

Adjusting for large numbers of covariates ascertained from patients' health care claims data may improve control of confounding, as these variables may collectively be proxies for unobserved factors. Here, we develop and test an algorithm that empirically identifies candidate covariates, prioritizes covariates, and integrates them into a propensity-score-based confounder adjustment model. We developed a multistep algorithm to implement high-dimensional proxy adjustment in claims data. Steps include (1) identifying data dimensions, eg, diagnoses, procedures, and medications; (2) empirically identifying candidate covariates; (3) assessing recurrence of codes; (4) prioritizing covariates; (5) selecting covariates for adjustment; (6) estimating the exposure propensity score; and (7) estimating an outcome model. This algorithm was tested in Medicare claims data, including a study on the effect of Cox-2 inhibitors on reduced gastric toxicity compared with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). In a population of 49,653 new users of Cox-2 inhibitors or nonselective NSAIDs, a crude relative risk (RR) for upper GI toxicity (RR = 1.09 [95% confidence interval = 0.91-1.30]) was initially observed. Adjusting for 15 predefined covariates resulted in a possible gastroprotective effect (0.94 [0.78-1.12]). A gastroprotective effect became stronger when adjusting for an additional 500 algorithm-derived covariates (0.88 [0.73-1.06]). Results of a study on the effect of statin on reduced mortality were similar. Using the algorithm adjustment confirmed a null finding between influenza vaccination and hip fracture (1.02 [0.85-1.21]). In typical pharmacoepidemiologic studies, the proposed high-dimensional propensity score resulted in improved effect estimates compared with adjustment limited to predefined covariates, when benchmarked against results expected from randomized trials.

Nonselective and Cyclooxygenase-2-Selective NSAIDs and Acute Kidney Injury

Objective The association between nonsteroidal anti-inflammatory drugs (NSAIDs) and acute kidney injury is well established, but it is less clear whether this risk is focused with specific agents. We undertook a large pharmacoepidemiologic analysis of the risk of acute kidney injury among older adults using nonselective NSAIDs or cyclooxygenase (COX)-2 inhibitors. Methods Medicare beneficiaries from 2 large states with drug benefit were eligible for study. Patients were included if they filled a prescription for a nonselective NSAID or COX-2 inhibitor after more than 6 months without any such prescriptions and without a previous diagnosis of acute kidney injury. Incident acute kidney injury was ascertained from hospitalization claims within 45 days of initiating nonselective NSAID or COX-2 inhibitor therapy. Adjusted proportional hazards models estimated the relative risk of acute kidney injury associated with each agent compared with celecoxib. Results We included 183,446 patients whose mean age was 78 years; 80% were women. Acute kidney injury was identified in 870 (0.47%) of nonselective NSAID or COX-2 inhibitor users. The agents with significantly elevated risk compared with celecoxib were indomethacin (rate ratio [RR] = 2.23; 95% confidence interval [CI], 1.70-2.93), ibuprofen (RR = 1.73; 95% CI, 1.36-2.19), and rofecoxib (RR = 1.52; 95% CI, 1.26-1.83). These findings were robust in several subgroups. Conclusion Acute kidney injury requiring hospitalization is a relatively rare adverse event among older adults after initiation of nonselective NSAIDs or COX-2 inhibitor treatment, observed in approximately 1 in 200 new users within 45 days. There seems to be a marked gradient of risk for acute kidney injury across agents, specifically for indomethacin, ibuprofen, and rofecoxib.

Hospitalization for peptic ulcer and bleeding in users of selective COX‐2 inhibitors and nonselective NSAIDs with special reference to celecoxib

To assess the relative incidence of peptic ulcer bleeding and perforation (PUBP) in users of selective cyclooxygenase-2 (COX-2) inhibitors and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). This was a retrospective case-control study based on insurance claims, with chart review to confirm cases. The base population consisted of 2.2 million adult users of celecoxib, diclofenac, ibuprofen, naproxen, rofecoxib, or valdecoxib who were covered by commercial health insurance in the United States from 1999-2003. For 790 persons hospitalized for PUBP and 7887 controls, most recent NSAID/COX-2 use and a variety of medical and pharmacy risk factors were ascertained from the insurance files and analyzed by conditional logistic regression. The main outcome measure was the odds ratio (OR) associated with use of each drug by comparison to naproxen, and in successive intervals after last dispensing. Hospitalization for PUBP was highest from the date of NSAID/COX-2 dispensing through the end of an exposure period that corresponded to the days supply; the rate dropped steadily thereafter. The covariate-adjusted ORs by comparison to naproxen were: ibuprofen 0.86 (95% confidence interval (CI) 0.68, 1.09), rofecoxib 0.79 (0.62, 1.02), diclofenac 0.66 (0.47, 0.94), valdecoxib 0.50 (0.26, 0.97), and celecoxib 0.45 (0.35, 0.58). The nonselective NSAIDs had an OR for PUBP of 1.51 (1.26, 1.98) compared to the selective COX-2 inhibitors. Nonselective NSAIDs convey half again as much risk of hospitalization for PUBP as do COX-2 inhibitors. Celecoxib users had about half the hospitalization rate of users of naproxen.

Subgroup analyses to determine cardiovascular risk associated with nonsteroidal antiinflammatory drugs and coxibs in specific patient groups

To explore the extent to which clinical characteristics influence the association between cyclooxygenase 2 inhibitors (coxibs) and/or nonselective nonsteroidal antiinflammatory drugs (NSAIDs) and increased cardiovascular disease (CVD) risk in specific patient subgroups. There is substantial concern regarding the potential cardiovascular adverse effects of selective coxibs and nonselective NSAIDs, but many patients with arthritis experience important clinical benefits from these agents. The study population consisted of Medicare beneficiaries also eligible for a drug benefits program for older adults during the years 1999-2004. We calculated the relative risk (RR) for CVD events (myocardial infarction [MI], stroke, congestive heart failure, and cardiovascular death) among users of coxibs or nonselective NSAIDs in the prior 6 months compared with nonusers. We assessed biologic interaction between these medication exposures and important patient characteristics. In the primary cohort, we identified 76,082 new users of coxibs, 53,014 new users of nonselective NSAIDs, and 46,558 nonusers. Compared with nonusers, the adjusted RR of CVD events for new users of each agent increased for rofecoxib (RR 1.22, 95% confidence interval [95% CI] 1.14, 1.30) and decreased for naproxen (RR 0.79, 95% CI 0.67, 0.93). Several patient characteristics were found to increase the risk of CVD events among users of some agents in both the primary and secondary cohorts, including age >/=80 years, hypertension, prior MI, prior CVD, rheumatoid arthritis, chronic renal disease, and chronic obstructive pulmonary disease. Rofecoxib and ibuprofen appeared to confer an increased risk in multiple patient subgroups. Many nonselective NSAIDs and coxibs are not associated with an increased risk of CVD events. However, several patient characteristics identify important subgroups that may be at an increased risk when using specific agents.

New Diagnosis of Hypertension among Celecoxib and Nonselective NSAID Users: A Population-Based Cohort Study

The use of nonsteroidal antiinflammatory drugs (NSAIDs) has been associated with increased blood pressure and hypertension. However, less is known about how the risk of hypertension is associated with cyclooxygenase 2 selective inhibitors (coxibs), especially celecoxib, the only coxib remaining on the market. To compare the risk of incident hypertension associated with the use of celecoxib and nonselective (NS) NSAIDs. A cohort study was conducted using secondary data from the GE Centricity Electronic Medical Record database, which contains millions of patient records seen by thousands of physicians across the US. The index date was defined as the date of the first NSNSAID or celecoxib prescription between January 1, 1999, and June 30, 2004. Patients were included if they were aged 18 years or older and were enrolled for at least 365 days prior to the index date. Excluded were patients who had any prior diagnosis of hypertension or pregnancy-related hypertension during the pre- or postindex date period. Also excluded were patients who had any prior prescription for antihypertensive drugs, coxibs, or NSNSAIDs. After applying inclusion/exclusion criteria, each celecoxib user was matched to 2 NSNSAID users by sex, age (+/-5 y), propensity score (within 0.2 SD), and number of unique drugs (+/-20%). Descriptive and survival analyses were conducted. The final sample consisted of 51,444 patients, of whom 17,148 were on celecoxib and 34,296 were on NSNSAIDs. Relative to NSNSAID users, patients on celecoxib had a similar rate of postexposure hypertension incidence (HR 1.013; 95% CI 0.862 to 1.190). Results from a population-based cohort analysis of electronic medical records did not show any difference in the hazard rates of incident hypertension between celecoxib and NSNSAID users.

Outcome of Upper GI Bleeding in NSAID Users

Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with increased incidence of peptic-ulcer bleeding, whereas selective

NSAID Use and Progression of Chronic Kidney Disease

Purpose The effects of nonselective and selective cyclooxygenase-2 specific (COX-2) nonsteroidal anti-inflammatory drug (NSAID) use on the progression of chronic kidney disease (CKD) is uncertain. Due to the high prevalence of both CKD and NSAID use in older adults, we sought to determine the association between NSAID use and the progression of CKD in an elderly community-based cohort. Methods All subjects ≥66 years of age who had at least one serum creatinine measurement in 2 time periods (July-December, 2001 and July-December, 2003) were included. Multiple logistic regression analyses, including covariates for age, sex, baseline estimated glomerular filtration rate (eGFR), diabetes, and comorbidity were used to explore the associations of NSAID use on the primary (decrease in eGFR of ≥15 mL/min/1.73 2) and secondary (mean change in eGFR) outcomes. Results A total of 10,184 subjects (mean age 76 years; 57% female) were followed for a median of 2.75 years. High-dose NSAID users (upper decile of cumulative NSAID exposure) experienced a 26% increased risk for the primary outcome (odds ratio [OR] 1.26, 95% confidence interval [CI], 1.04-1.53). A linear association between cumulative NSAID dose and change in mean GFR also was seen. No risk differential was identified between selective and nonselective NSAID users. Conclusions High cumulative NSAID exposure is associated with an increased risk for rapid CKD progression in the setting of a community-based elderly population. For older adult patients with CKD, these results suggest that nonselective NSAIDs and selective COX-2 inhibitors should be used cautiously and chronic exposure to any NSAID should be avoided.

Channeling and prevalence of cardiovascular contraindications in users of cyclooxygenase 2 selective nonsteroidal antiinflammatory drugs

To assess use and channeling of cyclooxygenase 2 selective inhibitors (coxibs) over time and to estimate the percentage of coxib users with cardiovascular contraindications. The study population comprised all coxib and nonselective nonsteroidal antiinflammatory drug (NSAID) users in the Integrated Primary Care Information project between January 2000 and December 2004. The prevalence of risk factors for NSAID-related upper gastrointestinal ulcer complications, cardiovascular disease, and cerebrovascular disease at the start of treatment was compared between users of coxibs and users of nonselective NSAIDs. The study population included 72,841 nonselective NSAID users and 10,739 coxib users. The prevalence of risk factors for NSAID-related gastrointestinal complications was higher in coxib users than nonselective NSAID users (odds ratio [OR] 1.18, 95% confidence interval [95% CI] 1.10-1.26). Similarly, the prevalence of prior cardiovascular disease was higher in coxib users than in nonselective NSAID users (OR 1.35, 95% CI 1.28-1.43). Channeling of coxibs to patients with NSAID-related gastrointestinal risk factors declined after 2001 but increased again in 2004, whereas the channeling of coxibs to patients with cardiovascular disease remained constant. Less than 15% of all coxib users had history of ischemic coronary or cerebrovascular disease. Among coxib users with increased risk for NSAID-related gastrointestinal disorders, 27% had history of ischemic coronary or cerebrovascular disease. This study demonstrates that coxibs were preferentially prescribed to patients with risk factors for NSAID-related gastrointestinal disorders and/or cardiovascular diseases. Only one-quarter of coxib users with increased risk for NSAID-related gastrointestinal complications had cardiovascular conditions compatible with recent European safety contraindications for coxibs.

Instrumental Variable Analysis of Secondary Pharmacoepidemiologic Data

Instrumental Variable Analysis of Secondary Pharmacoepidemiologic Data

Response to: Appropriate choice of proton pump inhibitor therapy in the prevention and management of NSAID-related gastrointestinal damage

To the Editor: Singh and Triadafilopoulos provide an informative review of the use of proton pump inhibitors (PPIs) with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) (1). We endorse the authors' call for more rigorous clinical evaluation of the overall efficacy/safety of this approach and raise a question they did not address about patients' compliance with this regimen in clinical practice. We share the authors' opinion that further study is needed in large numbers of long-term NSAID users to evaluate risk reductions for ulcer-related complications rather than surrogate endoscopic ulcers. Ideally, large trials would be conducted with PPI/NSAID cotherapy vs. other gastroprotective therapies, such as a cyclo-oxygenase-2-selective (COX-2) inhibitor or misoprostol/NSAID cotherapy. Risk reductions for ulcer-related complications have already been evaluated in large clinical trials with these latter approaches (2–4) but not with PPI/NSAID cotherapy. A pitfall of relying solely on endoscopic markers is illustrated by the authors' reference to a clinical trial that purported to demonstrate the superiority of pantoprazole over misoprostol in the prevention of endoscopically detected NSAID-induced gastrointestinal injury (5). Closer inspection of that trial reveals that the endoscopic endpoints included reflux esophagitis, which, to our knowledge, is not an NSAID-induced effect. At the best, the inclusion of irrelevant endpoints confounds interpretation of study results; at the worst, it may be misleading. The need for more thorough evaluation of PPI/NSAID cotherapy is also highlighted by the findings from several studies, which showed that PPI/NSAID cotherapy may not be as fully efficacious in protecting the upper and lower gastrointestinal system from NSAID-associated damage as these other approaches (6–10). We know of no evidence nor reason to expect that PPIs protect the small bowel from NSAID damage, whereas some supportive evidence is available for a COX-2 inhibitor and for misoprostol (6,10). Clearly, additional clinical evaluation is needed to shed much needed light on the comparative efficacy of PPI/NSAID cotherapy in the prevention of NSAID-induced gastrointestinal complications. Large trials are also needed to provide information about the long-term safety of PPI/NSAID cotherapy, which has not been evaluated as rigorously as have the safety profiles of the other gastroprotective approaches. The unanticipated cardiovascular events with rofecoxib in the VIGOR trial serve as enduring reminders of the value of evidence-based medicine. Accordingly, we urge caution before drawing conclusions about the long-term safety of PPI/NSAID cotherapy in the absence of clinical evidence. We note that an increased risk of unexpected adverse effect (community-acquired pneumonia) of acid-suppressive therapy has been reported and may be greater than is generally appreciated (11). We would also point out that mounting evidence strongly suggests that conventional NSAIDs share with the COX-2 inhibitors a potential for increased cardiovascular risks. This evidence eliminates the prior assumption that NSAIDs might be safer. The question we raise about PPI/NSAID cotherapy is this: will patients reliably comply with multiple-drug regimens or will their lack of compliance continue to expose them to unacceptable gastrointestinal risks? Compliance with multiple, separate medications is notoriously poor outside of the clinical trial setting, especially when attempting to prevent a largely asymptomatic condition, such as gastrointestinal ulceration (12,13). Single-agent therapy with a COX-2 inhibitor or the commercial combination of misoprostol/diclofenac, for example, eliminates uncertainties about compliance with both NSAID and gastroprotective therapies. For these reasons, physicians need to consider the full spectrum of therapies, including COX-2 inhibitors and misoprostol/diclofenac, when selecting therapy for their patients.