Cardiovascular Risk of Celecoxib in 6 Randomized Placebo-Controlled Trials

Perspective on Bertagnolli et al., p. 310 Raymond N. DuBoisConclusive findings of cardiovascular (CV) toxicity associated with nonsteroidal anti-inflammatory drugs (NSAID) in two major colorectal-adenoma prevention trials (1, 2) shocked the world of biomedical research in 2005. Sometimes called coxibs, the NSAIDs used in these trials specifically inhibit cyclooxygenase-2 (COX-2) and were widely prescribed for relief of pain and inflammation related to arthritis. In response to reports of this CV toxicity, one major COX-2-specific NSAID (rofecoxib) was removed from the market; the use of other COX-2 inhibitors for standard pain relief was reduced; and investigations of the role of COX-2 in cancer and other disease prevention were scaled back. Despite their adverse CV effects, these drugs still have major beneficial effects that potentially could be very important for public health. Fortunately, clinical evaluations of COX-2-specific inhibitors and other NSAIDs have continued and are shedding new light on the effects of this important class of drugs. Two major areas of investigation involve the prevention of colorectal adenomas and cancer and CV toxicity (3), which include investigations into the poorly understood biological mechanisms of this toxic effect.Originally reported in 2005 and 2006 in two articles in The New England Journal of Medicine, the Adenoma Prevention with Celecoxib (APC) trial randomized 2,035 high-risk patients (following colorectal adenoma resection) to receive celecoxib at either 200 mg twice daily (low dose) or 400 mg twice daily (high dose) or placebo for 3 years (2, 4). With a 3-year adenoma risk of >60% in the placebo arm, the APC trial population was a very high-risk group. Significant overall reductions in adenoma risk (versus placebo) were 33% for low-dose celecoxib and 45% for high-dose celecoxib; celecoxib also reduced adenoma size, number, and burden (versus placebo). Greater reductions occurred in advanced adenoma risk, and patients at the highest colorectal cancer risk had the greatest benefit. The adenoma risk reduction at 1 year was highly significant and similar in magnitude to that at 3 years. APC adenoma results are similar to those of another large randomized trial of celecoxib for colorectal adenoma prevention (5). The two-part history of adverse CV events in the APC will be discussed later in this article. In this issue of Cancer Prevention Research, Bertagnolli and colleagues (6) report the planned follow-up analysis of adenomas and CV events in the APC trial at 5 years.The original design for this APC follow-up study included the option for patients to stay on celecoxib for the full 5 years. The drug was discontinued, however, when adverse CV effects were discovered in December 2004, and 933 of the original 2,035 study patients agreed to participate in the long-term follow-up after discontinuing treatment. Therefore, treatment of the long-term APC patients comprised a median of ∼3 years of intervention, a median of ∼2 years of follow-up surveillance off intervention,...

supporting

confidence: 82%

New, Long-term Insights from the Adenoma Prevention with Celecoxib Trial on a Promising but Troubled Class of Drugs

DuBois¹

2009

“…The case of celecoxib is particularly intriguing because this has been one of the most promising chemopreventive agents, with proven efficacy, and yet is associated with serious adverse cardiovascular events (32)(33)(34), raising serious medical and social obstacles to its use in chemoprevention. Safety issues involving celecoxib in chemoprevention have been discussed in detail elsewhere (35).…”

Section: The Case Of Oral Premalignancymentioning

confidence: 99%

Assessing Efficacy in Early-Phase Cancer Prevention Trials: The Case of Oral Premalignancy

Szabó

2008

In the current drug development paradigm, regulatory approval requires agent efficacy and safety that is demonstrated in rigorous randomized controlled clinical trials. Given the length of time and intense resource commitment that are required for phase III cancer prevention clinical trials, it is imperative that only agents that are highly likely to meet these standards be selected for late-phase clinical development. The major challenge for the field of cancer prevention (and cancer treatment) is to identify the best agents to move forward into definitive phase III testing. Preliminary indications of activity against carcinogenesis are obtained from in vitro and animal in vivo experiments (including mechanistic analyses), epidemiologic case-control and cohort studies, and early-phase clinical trials or secondary end points from clinical trials done for other indications (1). Early-phase clinical trials have the potential to be most informative because they actually test the specific agent at the requisite dose in human beings and assess a surrogate end point that should predict the phase III end point of cancer development. Identification of suitable end points for early-phase clinical trials, however, has been problematic.

“…The adjusted HR was 0.69 [95% confidence interval (CI), 0.37-1.29)], and the absolute 12-month recurrence-free rates were 88% (95% CI, 81%-96%) in the celecoxib group and 78% (95% CI, 69%-89%) in the placebo group (log-rank test: P ¼ 0.17). The study did not detect a difference in the number of adverse cardiovascular (CV) events between the celecoxib and placebo arms, although based on the known CV event rate of celecoxib at the trial's dose and duration, a measurable effect would not have been expected (5).…”

mentioning

confidence: 95%

Boxing Bladder Cancer with COX-2–specific Inhibition

Kelly¹,

Hall²

2011

Preventing recurrence of non-muscle-invasive bladder cancer (NMIBC) is important for improving patient well-being and reducing the health economic burden of this disease. To date, no oral agent has shown sufficient benefit to be adopted in clinical practice, where current strategies rely on topical (intravesical) administration of chemotherapy and immunotherapy. In this issue of the journal (beginning on page 1580), Sabichi and colleagues report the first phase II randomized controlled trial of the COX-2 inhibitor celecoxib in bladder cancer. The trial set out to measure an overly ambitious effect size but nevertheless showed encouraging signs of celecoxib activity. It lends support to COX-2 inhibition in NMIBC, which is being tested in several subsequent trials, and to the need for conclusive evidence. Cancer Prev Res; 4(10); 1534-5. Ó2011 AACR.The body of evidence pointing to the COX-2 pathway playing an important role in the development of bladder neoplasia is compelling and supported by several epidemiologic studies (1). Paralleling early development in colorectal cancer prevention, where the COX-2-specific inhibitor celecoxib [a nonsteroidal anti-inflammatory drug (NSAID)] is clinically effective, preclinical studies confirm that celecoxib can prevent neoplastic transformation of urothelium and reduce urothelial tumor burden in vivo as a single agent or in combination with the immunomodulator Bacillus Calmette-Guerin (BCG; refs. 2, 3), which is standard adjuvant treatment for preventing recurrence of non-muscle-invasive bladder cancer (NMIBC). It is therefore not surprising that celecoxib is being tested in clinical trials in patients with NMIBC.Sabichi and colleagues report the results of such a trial in this issue of the journal (4), but do the trial's results paint a clear picture of the role of COX-2 inhibition in the setting of bladder cancer prevention? They conducted a phase IIb randomized placebo-controlled trial of celecoxib (200 mg twice a day) for a minimum of 12 months to prevent recurrence in 146 patients following transurethral resection of established NMIBC and adjuvant BCG. Time to recurrence was the primary endpoint, and the statistical design powered the trial to detect a 53% relative reduction in the risk of recurrence at 12 months. The trial was initiated in an era when an effect of celecoxib may have seemed assured, but designing a trial to detect a halving of the recurrence rate in a heavily pretreated population was overly optimistic. It is not surprising that the primary endpoint did not reach statistical significance-the results are based on just 48 events and it is important to keep in mind that the estimated treatment effect was overly ambitious. Nevertheless, the results do support the possibility of a clinically beneficial effect of celecoxib. The adjusted HR was 0.69 [95% confidence interval (CI), 0.37-1.29)], and the absolute 12-month recurrence-free rates were 88% (95% CI, 81%-96%) in the celecoxib group and 78% (95% CI, 69%-89%) in the placebo group (log-rank test: P...