Vioxx Gastrointestinal Outcomes Research Study Research Articles

Rofecoxib and Clinically Significant Upper and Lower Gastrointestinal Events Revisited Based on Documents From Recent Litigation

IntroductionOn the basis of published data, it is widely believed and cited that rofecoxib use is associated with approximately a 50% reduction in significant gastrointestinal (GI) complications such as bleeding. MethodsData made available as part of litigation, including the Vioxx Gastrointestinal Outcomes Research trial and an Alzheimer’s study, allow a reassessment of the reported benefits of rofecoxib in terms of a significant reduction in complicated GI events and in lower GI bleeding. ResultsDuring the review process of the Vioxx Gastrointestinal Outcomes Research study, it was suggested that rofecoxib might have little benefit, with regard to GI toxicity, for patients with rheumatoid arthritis not treated with corticosteroids. Reanalysis of the original Merck data set showed 9 complicated confirmed events in the rofecoxib group compared with 10 in the naproxen group among corticosteroid nonusers and 7 versus 27 among corticosteroid users so that the difference between rofecoxib and naproxen in the occurrence of confirmed complicated perforations, ulcers or bleeds seemed to be entirely because of the effects within corticosteroid users. The claim that serious lower GI events were 54% lower with the use of the selective cyclooxygenase-2 inhibitor rofecoxib was stated to be based on an assessment blinded to treatment allocation. In fact, the choice did not represent the original blinded analysis that showed a nonsignificant difference, but rather was based on an assessment after treatment allocation was disclosed. ConclusionExamination and reanalysis of unpublished data regarding rofecoxib has failed to confirm a safety advantage of rofecoxib over traditional nonsteroidal anti-inflammatory drugs in terms of complicated upper or lower GI events.

Parecoxib – getting to the heart of the matter

Parecoxib – getting to the heart of the matter

Expression of Concern: Bombardier et al., “Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis,” N Engl J Med 2000;343:1520-8.

Drs. Gregory Curfman, Stephen Morrissey, and Jeffrey Drazen report on recently obtained information regarding inaccuracies in data in the report of the Vioxx Gastrointestinal Outcomes Research study that raises concern about certain conclusions in the article.

FDA’s drug safety initiative: Resolutions or more questions?

The storm of controversy surrounding the safety of antidepressants and nonsteroidal antiinflammatory drugs (NSAIDs) is part of a normal cycle that hits FDA every few years, Steven K. Galson, acting director of the Center for Drug Evaluation and Research (CDER), told agency employees, industry stakeholders, and news reporters during a May 20 webcast. Galson and other top FDA officials defended the agency’s actions in dealing with postmarketing reports of cardiovascular events associated with the use of cyclooxygenase-2 (COX-2)-selective NSAIDs, specifically Merck’s rofecoxib, or Vioxx, and Pfizer’s valdecoxib, sold as Bextra—both no longer on the market—and an increased risk of suicidal thoughts and behavior in pediatric patients using antidepressants. A cloud of controversy has loomed over FDA throughout the past year after lawmakers and other critics condemned the agency for being too slow to warn the public about risks linked to NSAIDs and antidepressants. John K. Jenkins, director of FDA’s Office of New Drugs, maintained that regulators in 2002 “thought we were going through the process of making sure that the public was aware” of the risks of using rofecoxib after FDA asked Merck to add information to the drug’s labeling reflecting the findings of the Vioxx Gastrointestinal Outcomes Research study, which found an increased risk of serious cardiovascular events.

Risk of cardiovascular events and rofecoxib: Cumulative meta-analysis

Summary Background The cyclo-oxygenase 2 inhibitor rofecoxib was recently withdrawn because of cardiovascular adverse effects. An increased risk of myocardial infarction had been observed in 2000 in the Vioxx Gastrointestinal Outcomes Research study (VIGOR), but was attributed to cardioprotection of naproxen rather than a cardiotoxic effect of rofecoxib. We used standard and cumulative random-effects meta-analyses of randomised controlled trials and observational studies to establish whether robust evidence on the adverse effects of rofecoxib was available before September, 2004. Methods We searched bibliographic databases and relevant files of the US Food and Drug Administration. We included all randomised controlled trials in patients with chronic musculoskeletal disorders that compared rofecoxib with other non-steroidal anti-inflammatory drugs (NSAIDs) or placebo, and cohort and case-control studies of cardiovascular risk and naproxen. Myocardial infarction was the primary endpoint. Findings We identified 18 randomised controlled trials and 11 observational studies. By the end of 2000 (52 myocardial infarctions, 20742 patients) the relative risk from randomised controlled trials was 2·30 (95% CI 1·22–4·33, p=0·010), and 1 year later (64 events, 21432 patients) it was 2·24 (1·24–4·02, p=0·007). There was little evidence that the relative risk differed depending on the control group (placebo, non-naproxen NSAID, or naproxen; p=0·41) or trial duration (p=0·82). In observational studies, the cardioprotective effect of naproxen was small (combined estimate 0·86 [95% CI 0·75–0·99]) and could not have explained the findings of the VIGOR trial. Interpretation Our findings indicate that rofecoxib should have been withdrawn several years earlier. The reasons why manufacturer and drug licensing authorities did not continuously monitor and summarise the accumulating evidence need to be clarified.

Risk of cardiovascular events and rofecoxib: cumulative meta-analysis

The cyclo-oxygenase 2 inhibitor rofecoxib was recently withdrawn because of cardiovascular adverse effects. An increased risk of myocardial infarction had been observed in 2000 in the Vioxx Gastrointestinal Outcomes Research study (VIGOR), but was attributed to cardioprotection of naproxen rather than a cardiotoxic effect of rofecoxib. We used standard and cumulative random-effects meta-analyses of randomised controlled trials and observational studies to establish whether robust evidence on the adverse effects of rofecoxib was available before September, 2004. We searched bibliographic databases and relevant files of the US Food and Drug Administration. We included all randomised controlled trials in patients with chronic musculoskeletal disorders that compared rofecoxib with other non-steroidal anti-inflammatory drugs (NSAIDs) or placebo, and cohort and case-control studies of cardiovascular risk and naproxen. Myocardial infarction was the primary endpoint. We identified 18 randomised controlled trials and 11 observational studies. By the end of 2000 (52 myocardial infarctions, 20742 patients) the relative risk from randomised controlled trials was 2.30 (95% CI 1.22-4.33, p=0.010), and 1 year later (64 events, 21432 patients) it was 2.24 (1.24-4.02, p=0.007). There was little evidence that the relative risk differed depending on the control group (placebo, non-naproxen NSAID, or naproxen; p=0.41) or trial duration (p=0.82). In observational studies, the cardioprotective effect of naproxen was small (combined estimate 0.86 [95% CI 0.75-0.99]) and could not have explained the findings of the VIGOR trial. Our findings indicate that rofecoxib should have been withdrawn several years earlier. The reasons why manufacturer and drug licensing authorities did not continuously monitor and summarise the accumulating evidence need to be clarified.

Balancing gastroprotection and cardioprotection with selective cyclo-oxygenase-2 inhibitors: clinical implications.

NSAIDs have been the mainstay of treatment in the management of pain and inflammation associated with chronic inflammatory disorders. They are effective. However, complications arising from chronic NSAID use are common and are primarily due to gastrointestinal (GI) toxicity in the form of gastritis, peptic erosions and ulceration and GI bleeds. GI toxicity has been attributed to the blockade of the cyclo-oxygenase (COX)-1-mediated generation of the cytoprotective prostanoids, such as prostaglandin (PG) E2 and PGI2 (prostacyclin). More recently, selective COX-2 inhibitors ('coxibs') were designed to inhibit the production of COX-2-dependent inflammatory prostanoids and to leave intact the cytoprotective COX-1 products. The coxibs, while exhibiting similar efficacy to traditional NSAIDs in controlled clinical trials of their efficacy in chronic inflammatory conditions, such as osteoarthritis and rheumatoid arthritis, have been associated with a reduced incidence of surrogate or actual indices of GI toxicity. However, concerns regarding cardiovascular safety in high-risk patients have evolved. These concerns were driven initially by the concept that inhibition of COX-2-derived endothelial PGI2 without concomitant inhibition of platelet thromboxane A2 would result in increased cardiovascular risk. This was borne out in the Vioxx Gastrointestinal Outcomes Research study of rofecoxib, but not demonstrated in the Celecoxib Long Term Arthritis Safety Study trial. Further elucidation of the relative roles of COX-1- and COX-2-generated prostanoids has enabled a greater understanding of the biology of these pathways. However, it is still not completely clear how this understanding may be appropriately translated into clinical medicine.

Review: studies on the cardiovascular effects of selective COX-2 inhibitors show mixed results

(2001) JAMA 286, 954. Mukherjee D, Nissen SE, Topol EJ. . Risk of cardiovascular events associated with selective COX-2 inhibitors. . Aug 22/29; . : . –9 . [OpenUrl][1][CrossRef][2][PubMed][3][Web of...

Risk of cardiovascular events associated with selective COX-2 inhibitors

Atherosclerosis is a process with inflammatory features and selective cyclooxygenase 2 (COX-2) inhibitors may potentially have antiatherogenic effects by virtue of inhibiting inflammation. However, by decreasing vasodilatory and antiaggregatory prostacyclin production, COX-2 antagonists may lead to increased prothrombotic activity. To define the cardiovascular effects of COX-2 inhibitors when used for arthritis and musculoskeletal pain in patients without coronary artery disease, we performed a MEDLINE search to identify all English-language articles on use of COX-2 inhibitors published between 1998 and February 2001. We also reviewed relevant submissions to the US Food and Drug Administration by pharmaceutical companies.Our search yielded 2 major randomized trials, the Vioxx Gastrointestinal Outcomes Research Study (VIGOR; 8076 patients) and the Celecoxib Long-term Arthritis Safety Study (CLASS; 8059 patients), as well as 2 smaller trials with approximately 1000 patients each. The results from VIGOR showed that the relative risk of developing a confirmed adjudicated thrombotic cardiovascular event (myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, and transient ischemic attacks) with rofecoxib treatment compared with naproxen was 2.38 (95% confidence interval, 1.39-4.00; P = .002). There was no significant difference in cardiovascular event (myocardial infarction, stroke, and death) rates between celecoxib and nonsteroidal anti-inflammatory agents in CLASS. The annualized myocardial infarction rates for COX-2 inhibitors in both VIGOR and CLASS were significantly higher than that in the placebo group of a recent meta-analysis of 23 407 patients in primary prevention trials (0.52%): 0.74% with rofecoxib (P = .04 compared with the placebo group of the meta-analysis) and 0.80% with celecoxib (P = .02 compared with the placebo group of the meta-analysis).The available data raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors. Further prospective trial evaluation may characterize and determine the magnitude of the risk.

Risk of cardiovascular events associated with selective COX-2 inhibitors.

Atherosclerosis is a process with inflammatory features and selective cyclooxygenase 2 (COX-2) inhibitors may potentially have antiatherogenic effects by virtue of inhibiting inflammation. However, by decreasing vasodilatory and antiaggregatory prostacyclin production, COX-2 antagonists may lead to increased prothrombotic activity. To define the cardiovascular effects of COX-2 inhibitors when used for arthritis and musculoskeletal pain in patients without coronary artery disease, we performed a MEDLINE search to identify all English-language articles on use of COX-2 inhibitors published between 1998 and February 2001. We also reviewed relevant submissions to the US Food and Drug Administration by pharmaceutical companies. Our search yielded 2 major randomized trials, the Vioxx Gastrointestinal Outcomes Research Study (VIGOR; 8076 patients) and the Celecoxib Long-term Arthritis Safety Study (CLASS; 8059 patients), as well as 2 smaller trials with approximately 1000 patients each. The results from VIGOR showed that the relative risk of developing a confirmed adjudicated thrombotic cardiovascular event (myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, and transient ischemic attacks) with rofecoxib treatment compared with naproxen was 2.38 (95% confidence interval, 1.39-4.00; P =.002). There was no significant difference in cardiovascular event (myocardial infarction, stroke, and death) rates between celecoxib and nonsteroidal anti-inflammatory agents in CLASS. The annualized myocardial infarction rates for COX-2 inhibitors in both VIGOR and CLASS were significantly higher than that in the placebo group of a recent meta-analysis of 23 407 patients in primary prevention trials (0.52%): 0.74% with rofecoxib (P =.04 compared with the placebo group of the meta-analysis) and 0.80% with celecoxib (P =.02 compared with the placebo group of the meta-analysis). The available data raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors. Further prospective trial evaluation may characterize and determine the magnitude of the risk.