Vioxx Gastrointestinal Outcomes Research Research Articles

Pharmacologically pertinent period of effect (PPPE).

BackgroundThe period of time during which a patient is exposed to a drug does not necessarily correspond to the period during which the drug produces the adverse effect under consideration. We propose the term Pharmacologically pertinent period of effect (PPPE) to address this time window. We explored the PPPE in light of the rofecoxib saga.MethodsWe identified the observational database studies of rofecoxib at doses 25 and 50 mg daily and thromboembolic events. We also obtained the Kaplan‐Meier curves of Vioxx Gastrointestinal Outcomes Research trial (VIGOR) and Adenomatous Polyp Prevention on Vioxx (APPROVE) trials.ResultsWe found seven observational studies with nine analyses. All the studies only looked at current exposure. At the dose of 25 mg, only three of nine analyses were barely statistically significant. At the dose of 50 mg, the risk ratios were much higher. The visual inspection of the Kaplan‐Meier curves shows that in the APPROVE trial (25 mg), the placebo and rofecoxib curves start separating to become statistically significantly different only after 36 months. In contrast the VIGOR (50 mg), curves start separating very early and the divergence increases after 8 months.DiscussionThe 50 mg observational studies, looking at current exposure, correctively identified the almost immediate increase in risk evident in the VIGOR Kaplan‐Meier curves. The absence of an immediate increase in risk shown by the APPROVE trial was also correctively identified by most observational 25 mg studies. To our knowledge no observational study was done on the long‐term cardiac toxicity of the 25‐mg dose. It would thus appear that the two doses of rofecoxib have different PPPEs.

Imprecision: Limitations to Interpretation of a Large Randomized Clinical Trial.

Randomized controlled trials are viewed as providing gold standard evidence, and the declaratively named PRECISION trial (Prospective Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen)1 implies the final word on the comparative cardiovascular safety of nonsteroidal anti-inflammatory drugs (NSAIDs). The analgesic efficacy of NSAIDs derives largely from suppressing cyclooxygenase 2 (COX-2)–derived prostaglandins E2 and I2 (prostacyclin), whereas their gastrointestinal adverse effects result from the inhibition of cyclooxygenase 1 (COX-1)–derived gastroduodenal prostaglandins E2 and I2 and COX-1–derived thromboxane A2 in platelets. This prompted the development of NSAIDs engineered to inhibit COX-2 specifically, such as rofecoxib, celecoxib, and valdecoxib. Randomized comparisons, such as VIGOR (Vioxx Gastrointestinal Outcomes Research), comparing rofecoxib and naproxen, showed fewer complicated gastrointestinal events with the COX-2 inhibitors.2 The value of randomized trials was also evident when evidence, first from clinical pharmacology and then from experiments in model systems, predicted that cardiovascular events would complicate COX-2 inhibition of prostaglandin I2 in the vasculature. Evidence consistent with this hypothesis emerged from VIGOR with more serious thromboembolic events with rofecoxib. Definitive evidence of cardiovascular hazard subsequently emerged from 10 placebo-controlled trials of structurally distinct COX-2 inhibitors.2 Last, overview analysis of individual data derived from ≈750 randomized trials3 provided a risk estimate of the magnitude of this hazard from COX-2 inhibitors with a rate ratio (RR) for serious vascular events of 1.37 (95% confidence interval, 1.14–1.66). As mechanistically predicted,2 the RRs for celecoxib (average daily dose, 400 mg) and rofecoxib (average daily dose, 25 mg) were superimposable. By contrast, information on older …

COX-2 Inhibition: What We Learned—A Controversial Update on Safety Data

Cyclooxygenase type 2 (COX-2)-selective nonsteroidal anti-inflammatory drugs (NSAIDs) (c2sNSAIDs) have been scrutinized relative to the less costly nonselective NSAIDs (nsNSAIDs). The conclusions reached were not always consistent with the data, and best treatment choices for patients were not always recommended. The data that were used to criticize the c2sNSAIDs are reexamined in a controversial light, demonstrating that the presence of reverse bias was often, but not always, present. A review of both Pubmed and news media articles relating to nsNSAIDs and c2sNSAIDs was conducted. References were selected on the basis of relevance to the controversies. The initial claims for the c2sNSAIDs of reduced gastrointestinal (GI) injury and preservation of platelet function were soon dwarfed by concerns regarding increased cardiovascular (CV) risk with publication of the Vioxx Gastrointestinal Outcomes Research trial for rofecoxib. Initial prothrombotic theories had a poor basis for explaining these concerns and have since largely been replaced with more credible explanations, including blood pressure elevations known to occur with all NSAIDs. Between data suggesting increased CV risk and under political pressure and public outcry, rofecoxib was withdrawn from the market in 2004. Soon, all c2sNSAIDs were under scrutiny. The Food and Drug Administration has since grouped all NSAIDs, whether c2sNSAID or nsNSAID, into one class with similar warnings regarding skin, CV, renal, and GI side effects. The entire "COX-2 debacle" is reminiscent of past events with NSAIDs. Amid this public, media, and political hysteria, it is not clear if we will see any more NSAIDs (selective or otherwise) approved in the near future.

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.

Cardiovascular Safety of Celecoxib on Top of Dual Antiplatelet Therapy

Cardiovascular Safety of Celecoxib on Top of Dual Antiplatelet Therapy

Poison pills

Mention the nonsteroidal antiinflammatory drug (NSAID) Vioxx and you are sure to elicit an emotional response from most scientists, clinicians, regulators, and patients. Some consider the voluntary removal of Vioxx from the market in September 2004 by its manufacturer, Merck, after studies revealed that it was linked to an increase in dangerous cardiovascular events such as strokes and heart attack, a huge loss of a valuable drug. Others consider the removal of this COX inhibitor to be the final step in a drug regulatory debacle. And still others consider the removal of Vioxx evidence of a pharmaceutical industry gone mad, where profits and marketing hype rule the day. Each of these points of view may have some merit and are the topic of Tom Nesi’s book Poison pills: the untold story of the Vioxx drug scandal. While much of the Vioxx story has been laid bare in the lay press, Tom Nesi details a string of internal Merck communications that are meant to erode any remaining confidence one might have had in the pharmaceutical industry. Nesi, a former director of public affairs at Bristol-Myers Squibb, worked with attorneys representing plaintiffs in at least one of the many Vioxx court cases. In this role, he had access to internal communications from executives at Merck. Nesi attempts to piece together the scientific, marketing, and internal politics surrounding Vioxx, to suggest that the pill had little benefit, substantial toxicity, and was the product of a marketing machine rather than a rigorous scientific research and development process. As a former publicist, Nesi’s focus is on Merck’s communication efforts surrounding Vioxx. He describes their tremendous efforts on the pre-launch communications as well as much of their efforts to control the message surrounding the drug’s potential benefits and harms. The company’s focus on the marketing of the drug meant that science and safety often took a back seat. After publication of the VIGOR (Vioxx Gastrointestinal Outcomes Research) study and the revelation of a 4- to 5-fold increased risk of cardiovascular events in subjects using Vioxx compared with those using the NSAID naproxen, the FDA asked Merck whether the Data Safety Monitoring Board (DSMB) for an ongoing trial of Vioxx used to prevent Alzheimer disease had ensured that subjects were made aware of this potential risk. However, an internal Merck document quoted by Nesi states “URGENT teleconference: Topic: Need to Set Up External DSMB for Ongoing Vioxx AD [Alzheimer’s Disease] Prevention Trial”. In short, Merck had not set up a DSMB, and it appears that they never did. While Poison pills would be an enjoyable read for those interested in drug development, drug safety, and drug regulation, the book will leave most scientists flat. Nesi’s intended audience seems to be the lay public, and he focuses on revealing internal communications and personalities more than scientific issues. While the book mentions the discovery of COX isoforms, it does not adequately place this discovery in the context of drug development. Moreover, the scientific basis of selective COX2 inhibitors is not described completely accurately. This lack of attention to detail substantially dampened my confidence in Nesi’s depiction of other aspects of the Vioxx story. There were several other topics that would have been important and interesting aspects of the larger Vioxx story that were missing from this book. First, it would have been important to critically examine the FDA’s role in this scandal. What did they know and when, and how has their complicity affected the public’s confidence in the drug regulatory system? The Vioxx scandal has been a major engine of regulatory and budgetary change in Washington, DC, which is not even mentioned in the book. Second, what role did external scientists to Merck play in this scandal? There were substantial findings from many reputable groups about Vioxx’s dangers; however, the data did not effectively move regulators to action. Many lessons can be learned about how to generate valid post-marketing surveillance data and how those findings should figure into the scientific and regulatory debate. Finally, it is imperative to examine how “blockbuster” drugs have come about, allowing pharmaceutical companies to reap billions of dollars of profits. This may be the root cause of the Vioxx scandal and speaks to broader issues of a health care industrial complex that has become one of the largest aspects of the US economy. Nesi’s book raises interesting issues about Vioxx and the pharmaceutical industry. It would make a great book as a cautionary tale for a colleague considering a career in the pharmaceutical industry. However, most scientists will find it an unsatisfying coda to the Vioxx scandal.

ADVANTAGE: Merck Does Say No

LettersNovember 18, 2008ADVANTAGE: Merck Does Say NoHarold C. Sox, MD, Editor and Drummond Rennie, MDHarold C. Sox, MD, EditorFrom Annals of Internal Medicine, Philadelphia, PA 19106, and JAMA, Chicago, IL 60610.Search for more papers by this author and Drummond Rennie, MDFrom Annals of Internal Medicine, Philadelphia, PA 19106, and JAMA, Chicago, IL 60610.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-149-10-200811180-00028 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:Dr. Edelman writes that ADVANTAGE could not have been a seeding trial because the Annals editors decided to publish it, which would imply that the trial had scientific value. We knew about the VIGOR (Vioxx Gastrointestinal Outcomes Research) trial (1), which was published in 2000 and compared Vioxx with naproxen in patients with rheumatoid arthritis. VIGOR showed that Vioxx had significantly fewer gastrointestinal side effects than naproxen. We published the ADVANTAGE trial (2) because it framed the same findings in a different way: It showed that the margin between the new drug and the comparatoralso naproxenwas narrow (5.9% ...

Use of Nonsteroidal Antiinflammatory Drugs

Clinical trial data have prompted questions about the degree to which patients and their physicians should consider an increased risk of cardiovascular or cerebrovascular events when selecting medications for pain relief. Since the 2005 publication of a Science Advisory on the use of nonsteroidal antiinflammatory drugs (NSAIDs) by the American Heart Association,1 several important events have occurred that have served as the catalyst for this update for clinicians. (1) Additional data from randomized controlled trials of cyclooxygenase (COX)-2–selective agents have been reported and summarized in meta-analyses, which has reinforced the concern about cardiovascular events with COX-2 inhibitors (coxibs; Figure 1). (2) Several reports have appeared that have identified an increased risk of cardiovascular events even with the nonselective NSAIDs, which has raised concern about the use of those agents as well (Table). (3) Regulatory authorities in several regions of the world have introduced warning statements and advisories to both healthcare professionals and the lay public about the use of various NSAIDs (Figures 2 and 3⇓). Figure 1. Comparison of effects of different selective COX-2 inhibitors vs placebo on myocardial infarction. Event numbers and person-years of exposure, with corresponding mean annual event rates in parentheses, are presented for patients allocated to selective COX-2 inhibitor or placebo. Event rate ratios for pooled data with 95% CIs are indicated by a diamond; rate ratios for individual selective COX-2 inhibitors, with 99% CIs, are indicated by a square and horizontal line. Diamonds to the right of the solid line indicate hazard with a selective COX-2 inhibitor compared with placebo. As noted, there was a significant increase in the rate ratio for myocardial infarction with COX-2 inhibitors compared with placebo. Similar analyses (data not shown) include rate ratios of 1.42 (1.13 to 1.78; P =0.003) for vascular events, 1.02 (0.71 to 1.47; P …

New Policy on Disclosures at Health Services Research

The appropriate role of scientific journals is to disseminate the best science available to the public and the research community. Two principal mechanisms to fulfill this role are peer review and open disclosure of potential biases in conducting and reporting results. Peer review primarily focuses on what is presented in the submitted manuscript—reviewers cannot easily assess what has been omitted or whether the authors made choices in the design or execution of the study that may have biased their results. For example, it appears some key adverse data were omitted from the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial reported in the New England Journal of Medicine (Curfman, Morrissey, and Drazen 2005a, b). Some authors claimed to have been unaware of the problems, raising questions about what are the roles and responsibilities of all authors in ensuring “the best science available” is published in scientific journals. Increasingly, journals have adopted more explicit policies about what to disclose and who should be informed during the process of review and publication. There are also studies showing that a project's sponsorship may be related to the findings reported. Most of these have focused on trials reporting use of drugs and devices, comparing studies sponsored by the for-profit manufacturers with those sponsored by not-for-profit and government entities (Lexchin et al. 2003; Ridker and Torres 2006), or on studies relating to tobacco use (Barnes and Bero 1996). Publication of biased studies is an insidious problem because the submitted findings may not be incorrect per se and thus are unlikely to be caught by peer reviewers. Absent or incomplete disclosure, however, prevents the consumer of such published information from applying the appropriate skepticism.

Parecoxib – getting to the heart of the matter

Parecoxib – getting to the heart of the matter

Lapses at the New England Journal of Medicine

Lapses at the New England Journal of Medicine

Inconsistencies in cardiovascular data from COX-2 inhibitor trials--is it a class effect?

The recent editorials in the New England Journal of Medicine about inaccuracies in cardiovascular data in the publication of the VIGOR (Vioxx Gastrointestinal Outcomes Research) study1,2 has prompted us to report similar inaccuracies in the CLASS study (Celecoxib Long-term Arthritis Safety Study), which were identified during a systematic review of the cardiovascular effects of celecoxib.3 Like the VIGOR study, CLASS was designed primarily to compare the incidence of upper gastrointestinal adverse events resulting from a COX-2 specific inhibitor with those of conventional non-steroidal anti-inflammatory drugs (NSAIDs) in patients with arthritis. As with the VIGOR study, in CLASS there were also inconsistencies in the serious adverse cardiovascular events reported in the different published reports. The outcomes of CLASS have been reported in two peer-reviewed journals4,5 and in a number of documents posted on the Food and Drug Association website, of which the medical officer review is the most complete.6 We have reviewed the data from these three major publications.4-6 In September 2000 the initial 6-month data were published by Silverstein and colleagues in JAMA in which no cardiovascular deaths were reported (Table 1).4 Also in September 2000, the FDA medical officer review of celecoxib data supplied by GD Searle & Co, reported that in CLASS there were five and eight cardiovascular deaths in the celecoxib and NSAID groups, respectively, during the full 12-month study period or within the following 28 days (Table 1).6 In the subsequent 2002 American Journal of Cardiology publication of the cardiovascular events from CLASS, a total of 10 cardiovascular deaths were reported in each of the celecoxib and NSAID groups (Table 1).5 It is difficult to understand why all the cardiovascular deaths would have occurred after 6 months of treatment, and how there could be such major discrepancies between the two complete study reports for such a definite outcome measure as death. Table 1 Mortality data reported in the three CLASS (Celecoxib Longterm Arthritis Safety Study) publications Similarly, there were inconsistencies between the three sources of CLASS data in the reporting of myocardial infarction (Table 2). For example, in the publications of the entire CLASS data, one reported 26 myocardial infarctions in the celecoxib group and 15 in the NSAID group5, whereas the other reported 19 and 13 myocardial infarctions, respectively.6 Table 2 Myocardial infarction data reported in the three CLASS (Celecoxib Long-term Arthritis Safety Study) publications These findings add to the concerns previously expressed regarding the selective and partial reporting of the gastrointestinal side effects from the CLASS study and that the published CLASS study differs from the original protocol in primary outcomes, statistical analysis, trial duration and conclusions.7-10.7,8 Thus history appears to have repeated itself in two respects. First, in CLASS there were inconsistencies in the reporting of cardiovascular data. Of greater concern is the identification that in the two major safety studies of the most commonly used COX-2 specific inhibitors there were major inconsistencies in reporting of the cardiovascular events. Thus, there would seem to be a systemic problem in research conduct in this field. There are considerable public health, pharmaceutical, regulatory and clinical implications.

Cyclooxygenase-2 Inhibitors: A Painful Lesson

Non-steroidal anti-inflammatory drugs (NSAIDs) represent a clinically important class of agents. NSAIDs are commonly used in treatment of conditions such as headache, fever, inflammation and joint pain. Complications often arise from chronic use of NSAIDs. Gastrointestinal (GI) toxicity in the form of gastritis, peptic erosions and ulcerations and GI bleeds limit usage of NSAIDs. These toxicities are thought to be due to cyclooxygenase (COX)-1 blockade. COX-1 generates cytoprotective prostanoids such as prostaglandin (PG) E2 and prostacyclin (PGI2). COX-2 inhibitors, commonly referred to as coxibs, were developed to inhibit inflammatory prostanoids without interfering with production of COX-1 prostanoids. Concerns over cardiovascular safety, however, have evolved based on the concept of inhibition of COX-2-derived endothelial prostanoids without inhibition of platelet thromboxane A2, leading to increased cardiovascular risk. The Celecoxib Long-Term Arthritis Safety Study (CLASS) trial did not show a significant increase in cardiovascular risk for celecoxib (Celebrex), but results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) study showed an increased cardiovascular risk with long-term daily usage of rofecoxib in patients with rheumatoid arthritis. The Adenomatous Poly Prevention on Vioxx (APPROVe) trial further evaluated cardiovascular effects of rofecoxib and recently led to removal of this drug from the marketplace. Coxibs affect renal function via blockade of normal COX-2 functions. COX-2 expression increases in high renin states and in response to a high-sodium diet or water deprivation. PGI2 and PGE2 are the most important renal prostanoids. PGI2 inhibition results in hyperkalemia. PGE2 inhibition results in sodium retention, which leads to hypertension, peripheral edema and potentially exacerbation of heart failure. This review article discusses beneficial and deleterious effects associated with prostanoids produced by COX-1 and COX-2 in various organs and how blockade of these products translates into clinical medicine.

Clinical Trials in the Wake of Vioxx

Clinical trials have become the preeminent tool for investigating new diagnostic, therapeutic, and preventive treatment strategies. During these trials, periodic interim data analyses are conducted by data monitoring committees (DMCs) to ensure participant safety. If accumulated data indicate harm to participants, clear evidence of superior efficacy, or futility of collecting additional data, studies may be terminated before their planned conclusion. Editorial p 2173 These termination decisions are invariably complex and involve important subjective and ethical elements.1 Of greatest concern when studies are terminated because of clear benefit is the possibility that the superior intervention has toxicities that remain undiscovered. Early termination entails the abbreviation of clinical experience that would permit assessment of the longer-term safety profile. However, study continuation when treatments are not equally effective also means that some participants will continue to receive a less effective therapy. The tension between protecting both trial participants and future patients has been increasingly acute since rofecoxib (Vioxx [Merck]) and other cyclooxygenase-2 inhibitors were implicated in a greater risk of myocardial infarction. Thrombotic side effects of cyclooxygenase-2 inhibition were postulated as a result of the propensity for selective antagonists to decrease vascular prostacyclin production and possibly affect the balance between prothrombotic and antithrombotic eicosanoids.2 Little evidence of toxicity was evident in preapproval trials, however, and rofecoxib was approved in 1999 for relief of the signs and symptoms of osteoarthritis, the management of acute pain, and the treatment of primary dysmennorhea.3 The possibility of cardiac toxicity in human trials was recognized in the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial.4 Meta-analyses, database studies, and prospective trials further corroborated cardiac toxicity,5–8 and Merck voluntarily withdrew rofecoxib from the US market on September 30, 2004,9 amid widespread criticism of both Merck and the Food and Drug Administration.10,11 In the wake …

Dispute over Vioxx study plays out in New England journal

The New England Journal of Medicine is maintaining that a Canadian-led study of the anti-arthritis drug rofecoxib (Vioxx) that it published in November 2000 contained “misleading” conclusions regarding the drug's safety. But the authors of the Vioxx Gastrointestinal Outcomes Research (VIGOR)

Expression of Concern Reaffirmed

On December 8, 2005, we published an expression of concern1 regarding an article by Bombardier et al. on the Vioxx Gastrointestinal Outcomes Research (VIGOR) study that was published in the Journal on November 23, 2000.2 Our expression of concern was prompted by evidence that the VIGOR article did not accurately represent the safety data available to the authors when the article was being reviewed for publication. More than four months before the article was published, at least two of its authors were aware of critical data on an array of adverse cardiovascular events that were not included in the VIGOR . . .

Anti-inflammatory therapy and cardiovascular risk: new insights

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been the predominant treatment for inflammatory conditions and chronic pain for nearly 40 years. However, when taken on a regular basis, anti-inflammatory agents are associated with a high risk of adverse events involving the upper gastrointestinal tract. It is estimated that approximately 1.1% of those taking NSAIDs develop significant gastrointestinal lesions (bleeding and gastric perforation), for which hospital recovery is necessary [1]. The inhibition of cyclooxygenase (COX) by NSAIDs produces both their therapeutic and their adverse events. The distinction between the enzymatic properties of COX-1 and COX-2 has led to the inception of selective COX-2 antiinflammatory agents (coxibs). The development and commercialization of these agents have led researchers to believe that problems with safety have been resolved, and that prolonged use of these new anti-inflammatory agents would allow easier control of many chronic pathologies, especially rheumatological disorders and arthritis. However, during their clinical development, an unexpectedly high incidence of cardiovascular events was observed. Clinical trial data first demonstrating increased cardiovascular risk with the use of these drugs came from the VIoxx Gastrointestinal Outcomes Research (VIGOR) trial that compared the gastrointestinal tolerability of rofecoxib (50 mg/day) with naproxen (1000 mg/day) in patients with rheumatoid arthritis [2]. The study demonstrated that rofecoxib was associated with a four-times greater risk of myocardial infarction than naproxen. This was attributed initially to a protective effect of naproxen [2], rather than to a specific effect of rofecoxib [3–6]. The problem became more evident in the Adenomatous Polyp PRevention On Vioxx (APPROVe) study carried out in patients with a history of colon adenomas [7]; this trial was interrupted when it was found that rofecoxib was associated with a two-fold higher risk of cardiovascular events than placebo (relative risk [RR] 1.92, confidence interval [CI] 1.19–3.11). In September 2004, Merck Sharpe & Dohme announced the voluntary worldwide withdrawal of Vioxx. Following publication of the APPROVe trial, other data from randomized, controlled clinical trials, as well as epidemiological data, became available. These studies suggested that increased cardiovascular risk is not a problem specific to rofecoxib, but is common to all analogous molecules. In the Adenoma Prevention with Celecoxib (APC) study, conducted in patients with adenomatous colorectal polyps, celecoxib (200 or 400 mg twice daily) was associated with a cardiovascular risk almost three-times higher than that of placebo (RR 2.8, CI 1.3–6.3) [8]. An increased cardiovascular risk, with respect to placebo, was also seen with valdecoxib (and its precursor parecoxib) in patients undergoing a coronary bypass [9,10]. It is likely that, in similar studies, without evidence of increased cardiovascular risk, this was actually due to insufficient statistical power (inadequate number, inclusion of a lowrisk population and low number of adverse events overall) more than intrinsic properties of that particular coxib!

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.

The Cardiovascular Safety of Celecoxib

Ever since the VIoxx Gastrointestinal Outcomes Research (VIGOR) trial first suggested that rofecoxib may increase the risk of cardiovascular disease, and especially since it was withdrawn from the market based on mounting evidence of this risk, celecoxib has had to bear intense scrutiny regarding its own potential cardiovascular effects. This article reviews the current body of evidence regarding the cardiovascular effects of celecoxib, considered under two distinct, but non-mutually exclusive, headings: cardiorenal and thromboembolic. In terms of cardiorenal effects, celecoxib appears to cause a slight increase in blood pressure, and probably to the same extent as nonselective nonsteroidal anti-inflammatory drugs (NS NSAIDs) but less than rofecoxib. Limited observational data suggest that celecoxib is not associated with an increased risk of hospitalization for heart failure, but clinical studies are required. The current body of evidence regarding the thromboembolic effects of celecoxib is equivocal. If an increased risk of thromboembolic events is present at all, then it would seem to be small. This contrasts with the situation for rofecoxib, for which the evidence of an increased thromboembolic risk is much more consistent. There are emerging data that suggest that NS NSAIDs may also elevate the risk of thromboembolic events. If true, then switching patients from coxibs to NS NSAIDs for reasons of cardiovascular safety would be flawed. Certainly it would not appear at this stage that celecoxib poses any more thromboembolic risk than NS NSAIDs. A limitation of the current body of evidence regarding the cardiovascular safety of celecoxib is that most of it has only been drawn from observational studies and noncardiovascular clinical trials. A definitive answer to whether or not celecoxib increases cardiovascular risk can really only be derived from purpose-designed, adequately-powered, prospective randomized trials that include appropriate cardiovascular end points and comparators.

Selective Cyclooxygenase-2 Inhibitors Development in Cardiovascular Medicine

At the end of September 2004, Merck & Co announced the voluntary withdrawal of rofecoxib (Vioxx) worldwide because of an increased risk of cardiovascular events. Since its approval in 1999, Vioxx, a selective cyclooxygenase-2 (COX-2) inhibitor, has been Merck & Co’s leading drug for control of acute pain and chronic pain associated with osteoarthritis, rheumatoid arthritis, and menstruation. Last year, worldwide sales of rofecoxib reached US $2.5 billion, and it is estimated that the drug was prescribed ≈10 million times per month in the United States.1 Thus, given the number of patients involved and the serious nature of the side effects, the withdrawal raised serious concerns about the safety of other selective COX-2 inhibitors, collectively called coxibs, that are on the market and those currently under development. Celecoxib (Celebrex) and rofecoxib were the first 2 coxibs approved by the US Food and Drug Administration (FDA) and launched in 1999 by Pfizer and Merck & Co, respectively. Since then, a second generation of these drugs has emerged onto the market. Valdecoxib (Bextra) was approved by the FDA and launched in 2002. In that same year, the European regulatory authority approved 2 other coxibs: etoricoxib (Arcoxia) and parecoxib sodium (Dynastat), the prodrug of valdecoxib. Today, etoricoxib and a fifth coxib, lumiracoxib (Prexige), are under consideration for FDA approval. In view of the rapid development in this area, the main concern is whether the reported cardiovascular effects of rofecoxib are a class effect applicable to all coxibs that were initially designed to reduce the gastric toxicity of nonselective COX inhibitors. Although most of the data accumulated so far would suggest a class effect related to the general mode of action of all coxibs and the physiological role of COX-2, recent in vitro data would theoretically support the hypothesis that the cardiovascular side …