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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

Meta‐analysis of dyspepsia and nonsteroidal antiinflammatory drugs

Objective

Nonsteroidal antiinflammatory drug (NSAID) use is a known risk factor for gastrointestinal (GI) perforations, ulcers, and bleeds, but there are limited data on its association with the very common symptom of dyspepsia. Using published and unpublished data sources, we sought to determine estimates of the risks of dyspepsia associated with NSAIDs.

Methods

We searched computerized databases (1966–1998) for primary studies of NSAIDs reporting on GI complications. We also obtained Food and Drug Administration (FDA) new drug application reviews for the 5 most common NSAIDs. We included studies reporting defined upper GI outcomes among subjects (>17 years old) who used oral NSAIDs for more than 4 days. Two reviewers evaluated 4,881 published titles, identifying 55 NSAID versus placebo randomized controlled trials (RCTs), 37 unpublished (FDA data) placebo‐controlled RCTs; 86 NSAID versus NSAID RCTs (sample size ≥50); and 103 observational studies.

Results

The majority of clinical trials were of good quality. Meta‐regression identified an increased risk of dyspepsia for users of specific NSAIDs (adjusted odds ratio [OR] of indomethacin, meclofenamate, piroxicam = 2.8), and for high dosages of other NSAIDs (OR = 3.1), but not for other NSAIDs regardless of dosage (OR = 1.1). Dyspepsia was not reported as an outcome in the case control or cohort studies.

Conclusions

Clinical trial data indicate that high dosages of any NSAID along with any dosage of indomethacin, meclofenamate, or piroxicam increase the risk of dyspepsia by about 3‐fold. Other NSAIDs at lower dosages were not associated with an increased risk of dyspepsia.

     

Minimizing complications from nonsteroidal antiinflammatory drugs: Cost‐effectiveness of competing strategies in varying risk groups

Objective

To appraise the cost‐effectiveness of competing therapeutic strategies in patient cohorts eligible for aspirin prophylaxis with varying degrees of gastrointestinal (GI) and cardiovascular risk.

Methods

Cost‐effectiveness and cost‐utility analyses were performed to evaluate 3 competing strategies for the management of chronic arthritis: 1) a generic nonselective nonsteroidal antiinflammatory drug (NSAID_NS) alone; 2) NSAID_NS plus a proton pump inhibitor (PPI); and 3) a cyclooxygenase 2‐selective inhibitor (coxib) alone. Cost estimates were from a third‐party payer perspective. The outcomes were incremental cost per ulcer complication avoided and incremental cost per quality‐adjusted life year (QALY) gained. Sensitivity analysis was performed to evaluate the impact of varying patient GI risks and aspirin use.

Results

In average‐risk patients, the NSAID_NS + PPI strategy costs an incremental $45,350 per additional ulcer complication avoided and $309,666 per QALY gained compared with the NSAID_NS strategy. The coxib strategy was less effective and more expensive than the NSAID_NS + PPI strategy. Sensitivity analysis revealed that the NSAID_NS + PPI strategy became the dominant approach in patients at high risk for an NSAID adverse event (i.e., patients taking aspirin with ≥1 risk factor for a GI complication).

Conclusion

Generic nonselective NSAIDs are most cost‐effective in patients at low risk for an adverse event. However, the addition of a PPI to a nonselective NSAID may be the preferred strategy in patients taking aspirin or otherwise at high risk for a GI or cardiovascular adverse event.

     

Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleeding

Objective

Traditional nonsteroidal antiinflammatory drugs (NSAIDs) increase the risk of upper gastrointestinal (GI) bleeding/perforation, but the magnitude of this effect for coxibs in the general population and the degree of variability between individual NSAIDs is still under debate. This study was undertaken to assess the risk of upper GI bleeding/perforation among users of individual NSAIDs and to analyze the correlation between this risk and the degree of inhibition of whole blood cyclooxygenase 1 (COX‐1) and COX‐2 in vitro.

Methods

We conducted a systematic review of observational studies on NSAIDs and upper GI bleeding/perforation published between 2000 and 2008. We calculated pooled relative risk (RR) estimates of upper GI bleeding/perforation for individual NSAIDs. Additionally, we verified whether the degree of inhibition of whole blood COX‐1 and COX‐2 in vitro by average circulating concentrations predicted the RR of upper GI bleeding/perforation.

Results

The RR of upper GI bleeding/perforation was 4.50 (95% confidence interval [95% CI] 3.82–5.31) for traditional NSAIDs and 1.88 (95% CI 0.96–3.71) for coxibs. RRs lower than that for NSAIDs overall were observed for ibuprofen (2.69 [95% CI 2.17–3.33]), rofecoxib (2.12 [95% CI 1.59–2.84]), aceclofenac (1.44 [95% CI 0.65–3.2]), and celecoxib (1.42 [95% CI 0.85–2.37]), while higher RRs were observed for ketorolac (14.54 [95% CI 5.87–36.04]) and piroxicam (9.94 [95% CI 5.99–16.50). Estimated RRs were 5.63 (95% CI 3.83–8.28) for naproxen, 5.57 (95% CI 3.94–7.87) for ketoprofen, 5.40 (95% CI 4.16–7.00) for indomethacin, 4.15 (95% CI 2.59–6.64) for meloxicam, and 3.98 (95% CI 3.36–4.72) for diclofenac. The degree of inhibition of whole blood COX‐1 did not significantly correlate with RR of upper GI bleeding/perforation associated with individual NSAIDs (r² = 0.34, P = 0.058), but a profound and coincident inhibition (>80%) of both COX isozymes was associated with higher risk. NSAIDs with a long plasma half‐life and with a slow‐release formulation were associated with a greater risk than NSAIDs with a short half‐life.

Conclusion

The results of our analysis demonstrate that risk of upper GI bleeding/perforation varies between individual NSAIDs at the doses commonly used in the general population. Drugs that have a long half‐life or slow‐release formulation and/or are associated with profound and coincident inhibition of both COX isozymes are associated with a greater risk of upper GI bleeding/perforation.

     

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

OBJECTIVE: To assess use and channeling of cyclooxygenase 2 selective inhibitors (coxibs) over time and to estimate the percentage of coxib users with cardiovascular contraindications. METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

Meta-analysis of dyspepsia and nonsteroidal antiinflammatory drugs

OBJECTIVE: Nonsteroidal antiinflammatory drug (NSAID) use is a known risk factor for gastrointestinal (GI) perforations, ulcers, and bleeds, but there are limited data on its association with the very common symptom of dyspepsia. Using published and unpublished data sources, we sought to determine estimates of the risks of dyspepsia associated with NSAIDs. METHODS: We searched computerized databases (1966-1998) for primary studies of NSAIDs reporting on GI complications. We also obtained Food and Drug Administration (FDA) new drug application reviews for the 5 most common NSAIDs. We included studies reporting defined upper GI outcomes among subjects (>17 years old) who used oral NSAIDs for more than 4 days. Two reviewers evaluated 4,881 published titles, identifying 55 NSAID versus placebo randomized controlled trials (RCTs), 37 unpublished (FDA data) placebo-controlled RCTs; 86 NSAID versus NSAID RCTs (sample size >or=50); and 103 observational studies. RESULTS: The majority of clinical trials were of good quality. Meta-regression identified an increased risk of dyspepsia for users of specific NSAIDs (adjusted odds ratio [OR] of indomethacin, meclofenamate, piroxicam = 2.8), and for high dosages of other NSAIDs (OR = 3.1), but not for other NSAIDs regardless of dosage (OR = 1.1). Dyspepsia was not reported as an outcome in the case control or cohort studies. CONCLUSIONS: Clinical trial data indicate that high dosages of any NSAID along with any dosage of indomethacin, meclofenamate, or piroxicam increase the risk of dyspepsia by about 3-fold. Other NSAIDs at lower dosages were not associated with an increased risk of dyspepsia.     

Minimizing complications from nonsteroidal antiinflammatory drugs: cost-effectiveness of competing strategies in varying risk groups

OBJECTIVE: To appraise the cost-effectiveness of competing therapeutic strategies in patient cohorts eligible for aspirin prophylaxis with varying degrees of gastrointestinal (GI) and cardiovascular risk. METHODS: Cost-effectiveness and cost-utility analyses were performed to evaluate 3 competing strategies for the management of chronic arthritis: 1) a generic nonselective nonsteroidal antiinflammatory drug (NSAID(NS)) alone; 2) NSAID(NS) plus a proton pump inhibitor (PPI); and 3) a cyclooxygenase 2-selective inhibitor (coxib) alone. Cost estimates were from a third-party payer perspective. The outcomes were incremental cost per ulcer complication avoided and incremental cost per quality-adjusted life year (QALY) gained. Sensitivity analysis was performed to evaluate the impact of varying patient GI risks and aspirin use. RESULTS: In average-risk patients, the NSAID(NS) + PPI strategy costs an incremental 45,350 US dollars per additional ulcer complication avoided and 309,666 US dollars per QALY gained compared with the NSAID(NS) strategy. The coxib strategy was less effective and more expensive than the NSAID(NS) + PPI strategy. Sensitivity analysis revealed that the NSAID(NS) + PPI strategy became the dominant approach in patients at high risk for an NSAID adverse event (i.e., patients taking aspirin with > or =1 risk factor for a GI complication). CONCLUSION: Generic nonselective NSAIDs are most cost-effective in patients at low risk for an adverse event. However, the addition of a PPI to a nonselective NSAID may be the preferred strategy in patients taking aspirin or otherwise at high risk for a GI or cardiovascular adverse event.     

Collagenous colitis in setting of nonsteroidal antiinflammatory drugs and antibiotics

Collagenous colitis is a newly recognized diarrheal disorder of unknown etiology (1). Over 80% of patients are middle-aged women with no other known predisposing factors (2). We report unusual presentations of collagenous colitis in two men in whom there was closely linked use of nonsteroidal antiinflammatory drugs and antibiotics.Supported in part by a research grant from the National Foundation for Ileitis and Colitis. Dr. Lazenby is the recipient of a fellowship from the National Foundation of Ileitis and Colitis.     

Informed consent and the prescription of nonsteroidal antiinflammatory drugs

Objective. To examine disclosure of side effects of nonsteroidal antiinflammatory drugs (NSAIDs) and to identify patient- and physician-specific factors associated with greater disclosure. Methods. Forty-six encounters between rheumatologists and new adult outpatients who were prescribed an NSAID they had not been taking prior to the visit were audiotaped. Reviewers coded the NSAID prescribed, specific side effects mentioned, demographic features of patients and physicians, and patient clinical characteristics. Neither patients nor physicians were aware that side effect disclosure was being studied. Results. A mean of 1.7 side effects was mentioned per encounter. Epigastric discomfort was mentioned in 72% of encounters, while other side effects, including hepatic, renal, hematologic, or central nervous system effects, were mentioned in ≤15% of encounters. Three factors were identified as independent predictors of less disclosure of side effects: senior clinician (versus less experienced), patient not taking another NSAID immediately prior to the visit, and patient age <40. Increased disclosure by less experienced clinicians occurred exclusively with patients who were taking another NSAID prior to the visit. Conclusion. Disclosure of side effects other than epigastric discomfort to patients who are prescribed a new NSAID is limited. Patients not taking NSAIDs previously, who presumably have the most to gain from such discussions, are told the least. These results have implications with regard to doctor—patient decision-making and malpractice litigation in the outpatient setting.     

The coxibs and traditional nonsteroidal anti-inflammatory drugs: a current perspective on cardiovascular risks

There is strong evidence from randomized clinical trials that the highly selective cox-2 inhibitors (coxibs), compared with placebo, cause an excess of serious cardiovascular events that are not mitigated by low-dose acetylsalicylic acid. Both Health Canada and the Food and Drug Administration have concluded that the excess cardiovascular events may be a 'class effect' of all the nonsteroidal anti-inflammatory drugs (NSAIDs), including traditional NSAIDs (tNSAIDs) and coxibs, and now require appropriate black box labelling of all these agents. Celecoxib and lumiracoxib are the only coxibs remaining on the market in Canada. The prostanoid pathways, the roles of cox-1 and cox-2, as well as the inhibitory effects of acetylsalicylic acid, traditional tNSAIDs and the coxibs, are briefly reviewed. Current recommendations for the ongoing use of coxibs and the tNSAIDs are summarized.