According to newly published results of the Celecoxib Rofecoxib Efficacy and Safety in Comorbidities Evaluation Trial (CRESCENT), rofecoxib (VioxxR) significantly increases 24-hour systolic blood pressure after 6 weeks of therapy, while celecoxib (CelebrexR) and naproxen do not.1
The new study, along with two others addressing the risks and benefits of COX-2 use in select populations, appear in the January 24 issue of the Archives of Internal Medicine.
The CRESCENT study, which evaluated the effects of celecoxib, rofecoxib, and naproxen on 24-hour blood pressure (BP) in patients with type 2 diabetes, hypertension, and knee osteoarthritis (OA), showed that while reductions in OA symptoms were similar across all groups, patients taking rofecoxib had a mean increase of 4 mm Hg in 24-hour systolic BP. Patients taking rofecoxib also had increases in pulse pressure.
The mean change in 24-hour ambulatory systolic BP from baseline to week 6 between rofecoxib and celecoxib was 3.78 mm Hg; a change of 3.86 mm Hg occurred between rofecoxib and naproxen. There were no significant differences between celecoxib and naproxen. Moreover, the percentage of study participants who developed hypertension was higher for people taking rofecoxib than celecoxib.
"We found that the reduction in symptoms related to [OA] stiffness and pain that these patients complained about was reduced by about 30% in all groups," study author William B. White, MD, of the University of Connecticut School of Medicine in Farmington, Connecticut, tells CIAOMed. "Rofecoxib caused a quite remarkable sustained blood pressure increase in this older population through the entire daytime period."
Dr. White points out that this increase is clinically relevant and occurred in the absence of edema and any evidence of renal insufficiency, which suggests an interference with hypertensive drugs as a possible mechanism.
In this randomized, double blind trial of 404 patients from 65 centers in 7 countries, patients received 200 mg of celecoxib, 25 mg of rofecoxib or 500 mg of naproxen once daily for 12 weeks. Study participants were randomized only if they had knee OA requiring daily treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), type 2 diabetes, and hypertension.
White tells CIAOMed that he does not believe the cardiovascular risks are a class effect.
"They all reduce prostacyclin, they all reduce prostaglandin-E, but as far as clinical ability to increase cardiovascular events or death, that may not be a class effect."
In a related study published in the same journal,2 Fadia T. Shaya, PhD, MPH, of the University of Maryland in Baltimore reported that COX-2 blockers did not increase the risk for cardiovascular events over non-naproxen NSAIDs in a high-risk population.
This observational study of 6250 patients analyzed patients in the Maryland Medicaid program who received at least a 60-day supply of COX-2 inhibitors or other prescription NSAIDs between June 2000 and June 2002. Naproxen users were excluded from the investigation.
"In our study of Medicaid patients initiated on NSAIDs or COX-2 inhibitors, there was no increased risk of cardiovascular events among those taking COX-2s compared to those taking NSAIDs," Dr. Shaya tells CIAOMed.
Among the participants, 1005 used a COX-2 inhibitor and 5245 used another type of NSAID. Overall, 70% of patients were female, 50% were African American, and 30% were older than age 50. Moreover, 12% of patients had at least one thrombotic event within the follow-up period.
"These findings underscore the need to look at real world, postmarketing effectiveness data," she adds. "They complement the previous findings in presenting data about a subpopulation that traditionally has been under-represented in most previous studies: female, African American, younger, and lower socioeconomic status."
Until more is known, "physicians should continue to monitor patients taking either NSAIDs or COX-2 inhibitors, but not replace the prescribing of these drugs, if necessary, with others whose benefit may not outweigh their risk," Dr. Shaya suggests. "The indications for these drugs, including arthritis, are very prevalent and burdensome to patients and health systems."
While patients taking the drugs are at risk of cardiovascular events, she points out, it's important to qualify the risk, look at pre-existing risk in different patients, and look at alternative risks from other drugs, including gastrointestinal (GI) bleeds and ulcers from NSAIDs. "Our findings suggest that the risk may vary across different populations and that it is important to look at the relative risk of taking these COX-2 inhibitors, versus taking NSAIDs, versus taking nothing."
For now, Dr. Shaya says, "I would recommend that physicians who are prescribing these drugs keep a very close watch on their patients."
In the third related study—the first to look at the comparative safety of COX-2s in patients receiving warfarin—researchers reported that patients taking warfarin concomitantly with COX-2 inhibitors have an increased risk of hospitalization for upper GI hemorrhage. 3 While it is well-known that warfarin and traditional NSAIDs increase the risk of GI bleed, these findings suggest that a COX-2 blocker taken with an agent that increases risk of bleeding may not be any safer than NSAIDs alone.
Researchers, led by Marisa Battistella, PharmD, of the University Health Network of Toronto General Hospital in Toronto, Ontario, identified 98,821 elderly patients receiving warfarin. Of these, 361 (0.3%) were admitted to the hospital with an upper GI hemorrhage. After adjustment, researchers found that such patients were more likely to be taking COX-2 inhibitors compared with control patients taking warfarin but not NSAIDs or COX-2 blockers.
Writing in the same issue of the journal, editorialists are calling for broad stroke measures to restore public trust. In an editorial accompanying the new studies,4 Daniel H. Solomon, MD, MPH, of Brigham and Women's Hospital in Boston, Massachusetts, and Jerry Avorn, MD, of Harvard University School of Medicine, also in Boston, suggest possible solutions to the drug safety and policy issues raised by the abrupt withdrawal of rofecoxib from the market on September 30, 2004.
Regaining the public's trust should start with careful analysis of the current situation at the US Food and Drug Administration (FDA), a task the Institute of Medicine is currently undertaking. "I think we will find that the FDA has too little funding and too little authority to do the job that the public believes they should be doing," Dr. Solomon tells CIAOMed.
Drs. Solomon and Avorn see the need for better postmarketing surveillance. "The agency will need to be more effective in requiring specially designed premarketing clinical safety trials when phase II or small phase III trials suggest reason for specific concerns," they write. "Mandated postmarketing observational studies should be rigorous and timely for drugs to remain on the market," their editorial continues. Moreover, provisional approvals after phase III testing should only become final after such assessments.
The onus is also on clinicians to make judgment calls on the remaining coxibs without having access to "perfect information." However, plenty of good options exist, including medication, exercise, and a variety of effective surgical interventions, Dr. Solomon points out to CIAOMed.
When asked by CIAOMed what he predicts will happen to this class of drugs after the FDA meeting in February, Dr. Solomon replied that "this depends on what data are presented." The FDA's meeting will take place February 16-18, 2005, and will assess the overall benefit-to-risk considerations of COX-2s. In addition, a group called the International COX-2 Study Group is scheduled to meet in Arlington, VA, at the end of January to deliberate whether there is a class effect.
References:
- Sowers JR, White WB, Pitt B, et al. The effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis and type 2 diabetes mellitus. Arch Intern Med. 2005;165:161-168.
- Shaya FT, Blume SW, Blanchette CM, et al. Selective cycoloxygenase-2 inhibition and cardiovascular effects: an observational study of a Medicaid population. Arch Intern Med. 2005;165:181-186.
- Battistella M, Mamdami MM, Juurlink DN, et al. Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Arch Intern Med. 2005;165:189-192.
- Solomon DH, Avorn J. Coxibs, science and the public trust. Arch Intern Med. 2005;165:158-160.