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.     

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.     

Risk of peptic ulcer hospitalizations in users of NSAIDs with gastroprotective cotherapy versus coxibs

BACKGROUND & AIMS: The primary strategies to reduce the risk of serious gastropathy caused by traditional nonsteroidal anti-inflammatory drugs (NSAIDs) are use of a coxib or concurrent use of a proton pump inhibitor or double-dose histamine-2 receptor antagonist. However, the relative clinical effectiveness of these therapeutic alternatives is understudied. METHODS: We studied peptic ulcer hospitalizations in a cohort of Tennessee Medicaid enrollees between 1996 and 2004. To decrease potential "channeling" bias, the study included only new episodes of prescribed NSAID or coxib use and controlled for multiple baseline risk factors for upper gastrointestinal disease. There were 234,010 and 48,710 new episodes of NSAID and coxib use, respectively, with 363,037 person-years of follow-up and 1223 peptic ulcer hospitalizations. RESULTS: Current users of NSAIDs with no gastroprotective cotherapy had an adjusted incidence of peptic ulcer hospitalizations of 5.65 per 1000 person-years, 2.76 (95% confidence interval, 2.35-3.23) times greater than that for persons not currently using either NSAIDs or coxibs. This risk was reduced by 39% (16%-56%, 95% CI) for current users of NSAIDs with gastroprotective cotherapy and 40% (23%-54%) for current users of coxibs without such cotherapy. Concurrent users of NSAIDs and proton pump inhibitors had a 54% (27%-72%) risk reduction, very similar to the 50% (27%-66%) reduction for concurrent users of proton pump inhibitors and coxibs. CONCLUSIONS: These findings suggest that coprescribing a proton pump inhibitor with an NSAID is as effective as use of a coxib for reducing the risk of NSAID-induced gastropathy.     

Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure

BACKGROUND: Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed and are associated with blood pressure (BP) elevation. The development of selective cyclooxygenase-2 inhibitors (coxibs) raises the issue of the magnitude of BP response compared with nonselective NSAIDs. We therefore performed a meta-analysis comparing the effects of coxibs with placebo, nonselective NSAIDs, and each other on BP elevation and hypertension. METHODS: Nineteen randomized controlled trials involving coxibs were published before May 2004, with a total of 45 451 participants in which BP data were available. The Cohen method statistically combined weighted mean difference (WMD). The Der Simonian and Laird method pooled results concerning the relative risk (RR) of developing hypertension and the RR of clinically important BP elevations. RESULTS: Among the trials analyzed, coxibs caused a WMD point estimate increase in systolic and diastolic BP compared with placebo (3.85/1.06 mm Hg) and nonselective NSAIDs (2.83/1.34 mm Hg). Cyclooxygenase-2 inhibitors were associated with a nonsignificantly higher RR of causing hypertension compared with placebo (RR, 1.61; 95% confidence interval [CI], 0.91-2.84; P = .10) and nonselective NSAIDs (RR, 1.25; 95% CI, 0.87-1.78; P = .23). Rofecoxib induced a WMD point estimate increase in systolic BP (2.83 mm Hg) and a nonsignificantly higher risk of developing clinically important systolic BP elevation (RR, 1.50; 95% CI, 1.00-2.26; P = .05) compared with celecoxib. CONCLUSIONS: Cyclooxygenase-2 inhibitors were associated with a point-estimate BP elevation compared with placebo and nonselective NSAIDs. There was a nonsignificantly higher incidence of developing hypertension compared with nonselective NSAIDs, as was observed with rofecoxib compared with celecoxib. These BP elevations may be clinically significant in relation to increased cardiovascular risk.     

Need for common internal controls when assessing the relative efficacy of pharmacologic agents using a meta-analytic approach: case study of cyclooxygenase 2-selective inhibitors for the treatment of osteoarthritis

OBJECTIVE: To evaluate the role of common internal controls in a meta-analysis of the relative efficacy of cyclooxygenase 2-selective inhibitors (coxibs) in the treatment of osteoarthritis (OA). METHODS: A systematic search of Medline and US Food and Drug Administration electronic databases was performed to identify randomized, placebo-controlled clinical trials of coxibs (etoricoxib, celecoxib, rofecoxib, valdecoxib) in patients with hip and/or knee OA. The effect size for coxibs and common active internal controls (nonsteroidal antiinflammatory drugs [NSAIDs], naproxen) were determined by the mean changes from baseline in Western Ontario and McMaster Universities Osteoarthritis Index pain subscores as compared with placebo. RESULTS: The effect size for all coxib groups combined (0.44) indicated greater efficacy as compared with placebo, but significant heterogeneity (P < 0.0001) was observed. Rofecoxib at dosages of 12.5 mg/day and 25 mg/day and etoricoxib at a dosage of 60 mg/day had similar effect sizes (0.68 and 0.73, respectively), but these effect sizes were comparatively greater than those for both celecoxib at dosages of 200 mg/day and 100 mg twice daily or valdecoxib at a dosage of 10 mg/day (0.26 and 0.16, respectively). The effect sizes for NSAIDs or naproxen versus placebo, as determined using data from rofecoxib/etoricoxib trials, were consistently higher than the effect sizes derived from trials of celecoxib/valdecoxib. Significant heterogeneity was present in the overall effect size for NSAIDs (P = 0.007) and naproxen (P = 0.04) groups based on data available from all coxib trials. CONCLUSION: Coxibs and common active internal controls showed larger effect sizes versus placebo in the rofecoxib/etoricoxib trials than in the celecoxib/valdecoxib trials. These findings suggest systematic differences among published coxib trials and emphasize the need for direct-comparison trials. In the absence of such trials, common internal controls should be assessed when performing indirect meta-analytic comparisons.     

Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly

BACKGROUND: Recent debate has emerged regarding the cardiovascular safety of selective cyclooxygenase 2 inhibitors and the possible cardioprotective effect of naproxen sodium. We compared the rates of acute myocardial infarction (AMI) among elderly patients dispensed selective cyclooxygenase 2 inhibitors, naproxen, and nonselective nonnaproxen nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: We conducted a population-based retrospective cohort study using administrative health care data from Ontario, Canada, from April 1, 1998, to March 31, 2001. We identified NSAID-naive cohorts of subjects aged 66 years and older in whom treatment was initiated with celecoxib (n = 15 271), rofecoxib (n = 12 156), naproxen (n = 5669), and nonnaproxen nonselective NSAIDs (n = 33 868), along with a randomly selected control cohort not exposed to NSAIDs (n = 100 000). Multivariate Cox proportional hazards models were used to compare AMI rates between study drug groups while controlling for potential confounders. RESULTS: Relative to control subjects, the multivariate model showed no significant differences in AMI risk for new users of celecoxib (adjusted rate ratio [aRR], 0.9; 95% confidence interval [CI], 0.7-1.2), rofecoxib (aRR, 1.0; 95% CI, 0.8-1.4), naproxen (aRR, 1.0; 95% CI, 0.6-1.7), or nonnaproxen nonselective NSAIDs (aRR, 1.2; 95% CI, 0.9-1.4). CONCLUSIONS: The findings of this observational study suggest no increase in the short-term risk of AMI among users of selective cyclooxygenase 2 inhibitors as commonly used in clinical practice. Furthermore, the findings do not support a short-term reduced risk of AMI with naproxen.     

Risk of congestive heart failure with nonsteroidal antiinflammatory drugs and selective Cyclooxygenase 2 inhibitors: a class effect?

OBJECTIVE: Nonsteroidal antiinflammatory drugs (NSAIDs) as a class have been shown to increase the risk of congestive heart failure (CHF) compared with celecoxib. The magnitude of the risk for individual NSAIDs is not known. METHODS: Using administrative databases, we performed a nested case-control study in a population-based cohort of patients ages >or=66 years admitted for CHF between January 1998 and March 2003. Cases were patients readmitted for CHF after cohort entry (index date). Four controls were matched to each case on date of cohort entry and time between cohort entry and index date. Exposure was the current use of an NSAID or a coxib in the 7 days prior to CHF readmission. Using conditional logistic regression, we calculated the odds of readmission for CHF in patients exposed to naproxen, diclofenac, ibuprofen, indomethacin, or rofecoxib compared with celecoxib, after adjusting for possible confounding variables. RESULTS: We identified 8,512 cases and 34,048 controls. The baseline characteristics between the groups were similar in general. The odds of being readmitted for CHF were higher in patients currently exposed to indomethacin (odds ratio [OR] 2.04, 95% confidence interval [95% CI] 1.16-3.58) or rofecoxib (OR 1.58, 95% CI 1.19-2.11) compared with celecoxib. There was no difference between naproxen, diclofenac, and ibuprofen compared with celecoxib, although the numbers of exposed cases and controls were small. CONCLUSION: In elderly patients with known CHF, indomethacin and rofecoxib are associated with a greater risk of recurrent CHF compared with celecoxib. Alternatives should be considered for patients with CHF who require antiinflammatory drugs.     

Cardiovascular Effects of Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) include aspirin, other traditional NSAIDs, and coxibs. Evidence obtained during the past 10 years has focused attention on the cardiovascular hazard associated with coxibs and some traditional NSAIDs. The large randomized trials of prolonged coxib treatment added importantly to information provided by epidemiological studies that had previously associated regular use of NSAIDs with increased blood pressure and enhanced risk of congestive heart failure, and identified an increased risk of myocardial infarction as a class effect of cyclooxygenase-2 inhibitors. The aim of this article is to review the cardiovascular effects of aspirin, other traditional NSAIDs, and coxibs, to discuss the mechanisms underlying these effects, and to provide a clinical perspective on the cardiovascular hazard associated with their use.     

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.

     

Simultaneous assessment of short-term gastrointestinal benefits and cardiovascular risks of selective cyclooxygenase 2 inhibitors and nonselective nonsteroidal antiinflammatory drugs: an instrumental variable analysis

OBJECTIVE: To simultaneously assess the short-term reduction in risk of gastrointestinal (GI) complications and increase in risk of acute myocardial infarction (MI) by celecoxib compared with rofecoxib and several nonselective nonsteroidal antiinflammatory drugs (NSAIDs) using instrumental variable analysis. METHODS: A population of 49,711 Medicare beneficiaries ages 65 years and older who initiated nonselective NSAID or selective cyclooxygenase 2 inhibitor therapy between January 1, 1999, and December 31, 2002, was identified. The increase in risk of GI complications and MI within 180 days after initiation of NSAID (rofecoxib, diclofenac, ibuprofen, and naproxen compared with celecoxib) therapy was assessed using instrumental variable analysis. RESULTS: Compared with nonselective NSAIDs, celecoxib reduced the risk of GI complications by 1.4 per 100 users but increased the risk of MI by 0.3 per 100 users. Rofecoxib decreased GI complications by 1.1 per 100 users and increased the risk of MI by 0.3 per 100 users. Using celecoxib as the reference exposure showed an increase in the MI risk for rofecoxib (risk difference [RD] 1.40, 95% confidence interval [95% CI] -0.20, 3.01) and diclofenac (RD 6.07, 95% CI -0.02, 12.15). The RD for naproxen as well as its upper 95% CI was the lowest of all NSAIDs (RD -0.30, 95% CI -2.74, 2.14) and there was no significant difference in GI complication rates among all NSAIDs. CONCLUSION: In this instrumental variable analysis, diclofenac and rofecoxib had the least favorable benefit-risk balance among NSAIDs in older adults.     

Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations

BACKGROUND: The risks and benefits of coxibs, non-steroidal anti-inflammatory drugs (NSAIDs), and aspirin treatment are under intense debate. OBJECTIVE: To determine the risk of peptic ulcer upper gastrointestinal bleeding (UGIB) associated with the use of coxibs, traditional NSAIDs, aspirin or combinations of these drugs in clinical practice. METHODS: A hospital-based, case-control study in the general community of patients from the National Health System in Spain. The study included 2777 consecutive patients with endoscopy-proved major UGIB because of the peptic lesions and 5532 controls matched by age, hospital and month of admission. Adjusted relative risk (adj RR) of UGIB determined by conditional logistic regression analysis is provided. RESULTS: Use of non-aspirin-NSAIDs increased the risk of UGIB (adj RR 5.3; 95% confidence interval (CI) 4.5 to 6.2). Among non-aspirin-NSAIDs, aceclofenac (adj RR 3.1; 95% CI 2.3 to 4.2) had the lowest RR, whereas ketorolac (adj RR 14.4; 95% CI 5.2 to 39.9) had the highest. Rofecoxib treatment increased the risk of UGIB (adj RR 2.1; 95% CI 1.1 to 4.0), whereas celecoxib, paracetamol or concomitant use of a proton pump inhibitor with an NSAID presented no increased risk. Non-aspirin antiplatelet treatment (clopidogrel/ticlopidine) had a similar risk of UGIB (adj RR 2.8; 95% CI 1.9 to 4.2) to cardioprotective aspirin at a dose of 100 mg/day (adj RR 2.7; 95% CI 2.0 to 3.6) or anticoagulants (adj RR 2.8; 95% CI 2.1 to 3.7). An apparent interaction was found between low-dose aspirin and use of non-aspirin-NSAIDs, coxibs or thienopyridines, which increased further the risk of UGIB in a similar way. CONCLUSIONS: Coxib use presents a lower RR of UGIB than non-selective NSAIDs. However, when combined with low-dose aspirin, the differences between non-selective NSAIDs and coxibs tend to disappear. Treatment with either non-aspirin antiplatelet or cardioprotective aspirin has a similar risk of UGIB.     

Problems of cardiovascular toxicity of coxibs and non-selective NSA

Non-steroidal antirheumatics (NSA) belong to the most often prescribed drugs. Certain observation studies indicate that they are used by 20 to 30% of population of developed countries. The most common NSA's adverse effects are gastrointestinal complications. Coxibs have been developed as an alternative to conventional non-selective NSA; with similar efficacy, they should reduce the risk of development of gastrointestinal complications. In the few last years, possible toxicity of coxibs and other non-steroidal antirheumatics has been widely discussed. The VIGOR study, which was performed 6 years ago, showed five times higher incidence of nonfatal myocardial infarction in patients with rofecoxib therapy as compared with naproxen. Afterwards, there was much debate about rofecoxib, and coxibs in general, whose cardiotoxicity was supported and confuted at the same time. Possible cardioprotective effect of naproxen was discussed too. Later on, results of the APPROVE study (Adenoma Polyp Prevention on Vioxx) made Merck & Co., Inc. withdraw rofecoxib from all markets voluntarily. In the end of 2004, three controversial studies on celecoxib were published. Although the first study (Adenoma Prevention with Celecoxib study, APC) showed higher cardiovascular risk of celecoxib, the second study (Prevention of Adenomatosus Polyps, PreSAP) did not verify these results. Surprisingly, the third study (Alzheimer Disease and Prevention Trial, ADAPT) proved 50% increase of the risk of cardiovascular (CV) toxicity of naproxen. In the last year, researchers have tried to decide whether CV toxicity is a class effect of coxib group or a class effect of all NSA. Many observation studies proved higher CV risk both of coxibs (particularly rofecoxib) and non-selective NSA including naproxen. These new findings moved the American FDA (Food and Drug Administration) to publish guidance concerning higher CV risk of all coxibs and NSA. For the time being, the EMEA (European Agency for Evaluation of Medicinal Products) does not change its attitude to NSA; coxibs are contraindicated in patients with ischemic heart disease, cerebrovascular disease and peripheral artery disease; they should be used with caution in high-risk patients. Final assessment of the problems of CV toxicity of NSA and coxibs will be a case of a long-term randomized study focused on the incidence of cardiovascular adverse effects.     

Prevention and treatment of NSAID-induced gastroduodenal injury

Opinion statement NSAIDs increase the risk of gastrointestinal (GI) complications. Those at risk should be considered for alternatives to NSAID therapy, modifications of risk factors, and prevention strategies with co-therapy with gastroprotective agents (proton-pump inhibitors [PPIs] or misoprostol) or COX-2 selective inhibitors (coxibs). Since coxibs, and probably other nonselective NSAIDs, may increase the risk of cardiovascular events, prevention strategies must take into account both GI and cardiovascular risk factors. All NSAIDs and coxibs should be prescribed at the lowest possible dose and for the shortest period of time. In patients with GI risk factors but no cardiovascular risk, coxibs or NSAIDs plus PPI or misoprostol are valid options. Patients with a history of ulcer bleeding should receive coxib plus PPI therapy and should be tested and treated for Helicobacter pylori infection. Most patients with increased cardiovascular risk will be treated with antiplatelet agents. It is not known whether co-therapy with low-dose aspirin will reduce the incidence of cardiovascular events, but it will further increase GI risk. It is currently unclear whether the risk of developing upper GI events with coxib plus aspirin is lower than it is with NSAIDs plus aspirin. However, all these patients should benefit from PPI co-therapy. Helicobacter pylori eradication should be considered as an additional therapeutic option when we want to further reduce the GI risk in specific patients. When the lower GI tract is of concern, coxib rather than NSAID therapy should be considered as the first option. Coxib therapy has better GI tolerance than NSAIDs, but patients with peptic ulcers or dyspepsia during NSAID/coxib treatment need PPI co-therapy.