Cleveland Clinic-Led Trial of Pain-Relieving Drugs Demonstrates Cardiovascular Safety of Celecoxib

New Orleans: Cleveland Clinic researchers have found that prescription doses of widely used pain-relieving drugs demonstrated no greater heart risk for celecoxib (Celebrex) than naproxen (Naprosyn) or ibuprofen (Motrin).

The decade-long PRECISION trial – Prospective Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen – enrolled more than 24,000 osteoarthritis (OA) or rheumatoid arthritis (RA) patients who required daily prescription use of NSAIDs for pain relief. All participants had pre-existing heart disease or increased risk for developing heart disease and 64 percent were female, with an average age of 64.

Following the withdrawal of rofecoxib (Vioxx) from the market in 2004, the FDA mandated a clinical trial to determine if celecoxib shared a similar increased risk of heart-related complications. This study, known as a non-inferiority trial, demonstrated celecoxib is not more risky than the two older drugs. The primary outcomes of heart attack, stroke or death occurred in 2.3 percent of patients taking celecoxib, 2.5 percent of patients taking naproxen, and 2.7 percent of patients taking ibuprofen.

Steven Nissen, M.D., chairman of the Robert and Susan Tomsich Department of Cardiovascular Medicine at Cleveland Clinic, directed the study, which was presented today at the American Heart Association Scientific Sessions in New Orleans and simultaneously published in the New England Journal of Medicine.

PRECISION also assessed a broader measure cardiovascular safety, the primary outcome – heart attack, stroke or death – plus hospitalization for unstable angina or coronary revascularization (stenting or bypass) and showed a 15 percent higher risk for ibuprofen than celecoxib, but this difference was borderline in statistical significance.

Although the primary intent of the trial was determination of the cardiovascular safety of celecoxib, a wide variety of other outcomes were assessed. Gastrointestinal (GI) problems including ulcers or chronic bleeding are known complications of NSAIDs. Celecoxib and rofecoxib were introduced in 1999 as a new type of NSAID designed to reduce the risk of GI complications. In the PRECISION trial, the rate of ulcers or GI bleeding was 54 percent higher for ibuprofen, and 41 percent higher for naproxen than celecoxib.

NSAIDs are also known to cause kidney complications and the trial showed a statistically significant 64 percent higher risk of worsening kidney function for ibuprofen compared with celecoxib. Numerically more kidney complications occurred with naproxen, but the difference was not statistically significant. Death from any cause was approximately 25 percent higher with naproxen than celecoxib, but this difference was borderline in statistical significance.

“The trial’s primary message is that celecoxib is not riskier for the heart than other NSAIDs,” said Dr. Nissen, who cautioned against over-interpretation of these findings. “The PRECISION trial studied full prescription doses of these drugs, not the lower doses available in over-the-counter preparations. The safety findings may or may not apply to the typical intermittent use of lower doses of these drugs by many patients.”

NSAIDs (non-steroidal anti-inflammatory drugs) were first introduced in the 1960s and are now among the world’s most widely-prescribed treatments with 100 million prescriptions written in the United States alone in 2013.

Osteoarthritis (OA) is the most common form of arthritis affecting more than 16 million Americans. Rheumatoid arthritis is a type of chronic arthritis that is an autoimmune disease affecting joints on both sides of the body. RA is 2.5 times more common in women than men and affects more than 1.3 million people in the United States. Patients with RA are at an increased risk for heart disease. In the trial, 90 percent of patients had OA and 10 percent had RA.

The trial gathered data from 926 medical centers globally. Limitations of the trial included a low retention rate (68.8 percent of participants stopped study drug) and the lack of a placebo comparison.

The study was funded by Pfizer. Dr. Nissen has served as a consultant for many pharmaceutical companies and has overseen clinical trials for Amgen, AstraZeneca, Cerenis, Eli Lilly, Novartis, Novo Nordisk, The Medicines Company, Orexigen, Takeda and Pfizer. However, he does not accept honoraria, consulting fees or other compensation from commercial entities. Four of the study’s co-authors are employed at Pfizer. Pfizer participated in study design, development of protocol and assisted with data collection and maintained the trial database. After completion of the trial, a complete copy of the database was transferred to the Cleveland Clinic Coordinating Center for Clinical Research, where statistical analyses were performed by an independent statistician.

Editor’s Note: B-roll and videotaped comments from Dr. Nissen and Elaine Husni, M.D., director of Cleveland Clinic’s Arthritis & Musculoskeletal Treatment Center, can be found at ftp://139.137.221.100 (LOGIN: dailyvosots; PASSWORD: dailyvosotsftp)

• Dr. Elaine Husni comments on PRECISION
• Dr. Steve Nissen comments on PRECISION
• Celecoxib b-roll
• Ibuprofen b-roll
• Naproxen b-roll

For more information about the PRECISION trial, please see the following “Frequently Asked Questions:”

BACKGROUND:

What was this trial testing?

The primary objective of the PRECISION trial (Prospective Randomized Evaluation Of Celecoxib Integrated Safety Vs Ibuprofen Or Naproxen) was to assess the relative cardiovascular risk of the nonsteroidal anti-inflammatory drug (NSAID) celecoxib versus prescription doses of two other widely used NSAIDs, naproxen and ibuprofen, in osteoarthritis and rheumatoid arthritis patients. The trial also compared all-cause mortality, gastrointestinal and renal safety of celecoxib with naproxen and ibuprofen.

Why was this trial necessary?

Celecoxib is in the same class of drugs of rofecoxib (Vioxx™), which was withdrawn from the market in 2004 because of an increased risk of heart attack and stroke. This raised questions about the cardiovascular safety of selective COX-2 inhibitors, of which celecoxib is the only one left on the market in the United States.

How was the trial designed?

The PRECISION trial looked at approximately 24,000 osteoarthritis and rheumatoid arthritis patients who had established cardiovascular disease or were at an increased risk for cardiovascular disease and who required an NSAID for symptom relief for more than 6 months. These patients were randomized to either 100 mg of celecoxib twice a day, 600 mg of ibuprofen three times a day or 375 mg naproxen twice a day. Patients were followed for a minimum of 18 months, but the mean follow-up was 34 months.

What types of patients were studied?

The study looked at osteoarthritis and rheumatoid arthritis patients who had established cardiovascular disease or were at an increased risk for cardiovascular disease and who required an NSAID for symptom relief for more than 6 months. Approximately 90% of patients were osteoarthritis patients, and about 10% were rheumatoid arthritis. Participants averaged 64 years in age. 64 percent of patients were female, and 75 percent were white.

What is an NSAID?

Introduced in the 1960s, NSAIDs (nonsteroidal anti-inflammatory drugs) are medications that effectively reduce inflammation and relieve pain. The drugs work by blocking the production of certain body chemicals that cause inflammation. NSAIDS are available in low doses over the counter or in prescription doses, which is what was studied in PRECISION. They are among the most widely prescribed class of drugs in the world, with 100 million prescriptions in the US in 2013.

What is the difference in how these three drugs work?

NSAIDs work by inhibiting cyclooxygenase enzymes (COX) from working. COX enzymes control the production of compounds called prostaglandins, which mediate things like inflammation and pain. There are two types of COX enzymes (COX 1 and 2). NSAIDs are non-selective, which means they block both types. Celecoxib is a COX-2 inhibitor.

The differences between ibuprofen and naproxen lie in the time to onset and duration of action. Also, these drugs vary in their potency and how they are eliminated from the body

Going into PRECISION, why did many experts assume celecoxib would be the most risky of the medications?

After the withdrawal of rofecoxib due to increased risks of heart attack and stroke, many made assumptions about the cardiovascular safety of all drugs in this class. Some investigators and some expert commentary used observational data, small trials and theoretical concerns to “confirm” what they expected. The PRECISION trial demonstrates the hazards inherent in prejudgment about the risks and benefits of therapies based upon indirect methods.

TRIAL

What were the main findings?

This study, known as a non-inferiority trial, provided statistically strong evidence that celecoxib is not more risky than naproxen or ibuprofen in terms of cardiovascular safety. The primary outcomes of heart attack, stroke or death occurred in 2.3% of patients taking celecoxib, 2.5% of patients taking naproxen, and 2.7% of patients taking ibuprofen.

Other studied outcomes included a broader measure of cardiovascular safety that included the primary outcome plus hospitalization for unstable angina or coronary revascularization (stenting or bypass) and showed a 15% higher risk for ibuprofen than celecoxib, but this difference was marginal in statistical significance.

Besides non-inferiority, what else was studied in the trial?

Although the primary intent of the trial was determination of the cardiovascular safety of celecoxib, a wide variety of other outcomes were assessed. Gastrointestinal problems including ulcers or chronic bleeding are known complications of NSAIDs. In the PRECISION trial, the rate of ulcers or GI bleeding was 54% higher for ibuprofen and 47% higher for naproxen than celecoxib.

NSAIDs are also known to cause kidney complications and the PRECISION trial showed a statistically significant 64% higher risk of worsening kidney function for ibuprofen compared with celecoxib. Numerically, more kidney complications occurred with naproxen, but the difference was not statistically significant.

Death from any cause was approximately 25% higher with naproxen than celecoxib, but this difference was borderline in statistical significance.

Why do investigators think that ibuprofen and naproxen were found to be riskier drugs?

We cannot say for certain why this was the case; however, it may stem from the increased risk of gastrointestinal bleeding, which could in turn, lead to additional complications including heart attack and stroke.

What conditions are the drugs studied in this trial typically prescribed for?

NSAIDs are prescribed for conditions such as arthritis, muscle aches, back pain, dental pain, gout, bursitis and menstrual cramps.

What is the difference between the dosages in the study and what consumers can buy over the counter?

The PRECISION trial studied patients who took prescription doses of these drugs long term. The over-the-counter dosage for ibuprofen is 200 mg compared to the at least 600 mg patients in the study took, three times per day. For naproxen, the over-the-counter dosage is 220 mg compared with the at least 375mg doses study patients took, twice per day.

What were the limitations of the trial?

Adherence and retention in the trial were lower than most cardiovascular outcome trials, although they were similar to other pain studies. This is likely because patients with chronic painful conditions frequently experience unrelieved symptoms and switch therapies. Another limitation was that at 100 mg twice a day, the dosage of celecoxib was moderate. Third, this trial reflects only the relative safety of the three drugs studied, and not the more than 20 other currently marketed NSAIDs.

How did investigators account for patients who switched or went off treatment during the trial?

Investigators looked at the results of the PRECISION trial in two ways – through the standard method of “intention-to-treat” (ITT) analysis and “on treatment” analysis. ITT looks at all participants regardless of how long they stayed on the treatment. It is preferred in efficacy studies because it preserves the integrity of randomization and represents a conservative assessment of benefits. However, ITT analysis can dilute safety signals by including events occurring after patients stop the therapy. On treatment analysis offers complementary insights in safety studies because it includes events occurring only within one month of patients actually taking study drugs.

IMPLICATIONS

Should any of these drugs be taken off the market?

These findings will require careful review by global health authorities to determine what, if any, changes in labeling or regulatory status of these drugs are warranted.

What does this mean for patients who are on any of these drugs? Should doctors recommend patients that are on ibuprofen or naproxen be taken off these medications?

If patients are concerned, they should have a conversation with their physicians to discuss their individual risks.

What do the findings mean for consumers who take these drugs over the counter occasionally?

This study was only done in patients taking prescription level doses of NSAIDs daily for a long period of time. The study also looked at a population that already had cardiovascular disease or was at a higher risk for it. Therefore, the findings cannot be applied to those individuals who take occasional over-the-counter doses.