Meeting NewsPerspective

PRECISION: CV risk with celecoxib not greater than with ibuprofen, naproxen

NEW ORLEANS — When used at moderate doses, the selective COX-2 inhibitor celecoxib was noninferior to the nonselective nonsteroidal anti-inflammatory drugs ibuprofen and naproxen with regard to CV safety, according to results of the PRECISION study.

The drugs were studied in patients with osteoarthritis or rheumatoid arthritis and CVD or increased CV risk.

Moreover, treatment with celecoxib was associated with lower rates of gastrointestinal events compared with ibuprofen and naproxen, and lower rates of renal adverse events compared with ibuprofen.

NSAIDs are among the most commonly used treatments worldwide. Concerns about the CV safety of selective COX-2 inhibitors arose in 2004 after rofecoxib (Vioxx, Merck) was withdrawn from the market. Thereafter, the FDA required a postmarketing CV safety trial to compare celecoxib, another selective COX-2 inhibitor in the same class, with traditional and popular nonselective NSAIDs.

The results were presented by Steven E. Nissen, MD, MACC, chair of cardiovascular medicine at Cleveland Clinic and Cardiology Today Editorial Board member, at the American Heart Association Scientific Sessions and simultaneously published in The New England Journal of Medicine.

Steven E. Nissen, MD
Steven E. Nissen

“After the withdrawal of rofecoxib, everyone thought they knew the answer: that COX-2 inhibitors had an unfavorable CV profile. We didn’t find that [in PRECISION],” Nissen said during a press conference. “This type of study, once again, teaches us that if we jump to conclusions … based on mechanistic considerations, that we often make very bad decisions. … We recognized that this trial … is not perfect, but [it] does not show an excess of CV events with celecoxib.”

Anticipated results

A total of 24,081 patients at 924 sites in 13 countries were randomly assigned on a 1:1:1 basis to receive celecoxib (mean daily dose, 209 mg), ibuprofen (2,045 mg) or naproxen (852 mg) with matching placebo. Esomeprazole 20 mg to 40 mg was also prescribed to all patients for gastric protection. Patients could additionally take up to 100 mg of aspirin per day, according to guideline recommendations.

Patients enrolled had osteoarthritis (90%) or rheumatoid arthritis (10%) and established CVD or increased CV risk who required NSAIDs for 6 months or more for symptom relief. At baseline, the mean age was 63 years, 64% were women, 75% were white and 35% had diabetes.

Mean treatment duration was 20 months. Patients were followed for a mean of 34 months. During the study period, 68% of patients stopped taking the study drug and 27.4% stopped follow-up.

The primary endpoint of the trial was a composite of CV death, nonfatal MI or nonfatal stroke based on the Antiplatelet Trialists Collaboration (APTC) criteria.

The results reported at AHA 2016 were as follows:

  • Intention-to-treat cohort: A primary outcome event occurred in 2.3% of patients assigned celecoxib, 2.5% assigned naproxen and 2.7% assigned ibuprofen (HR for celecoxib vs. naproxen = 0.93; 95% CI, 0.76-1.13, P for noninferiority < .001; HR for celecoxib vs. ibuprofen = 0.85; 95% CI, 0.7-1.04; P for noninferiority < .001; HR for ibuprofen vs. naproxen = 1.08; 95% CI, 0.9-1.31; P for noninferiority = .02).
  • On-treatment cohort: A primary outcome event occurred in 1.7% of the celecoxib group, 1.8% of the naproxen group and 1.9% of the ibuprofen group (HR for celecoxib vs. naproxen = 0.9; 95% CI, 0.71-1.15, P for noninferiority < .001; HR for celecoxib vs. ibuprofen = 0.81; 95% CI, 0.65-1.02, P for noninferiority < .001; HR for ibuprofen vs. naproxen = 1.12; 95% CI, 0.89-1.4; P for noninferiority = .025).

The researchers also adjudicated gastrointestinal and renal outcomes and found that the event rate for gastrointestinal events was lower with celecoxib vs. naproxen (HR = 0.71; 95% CI, 0.54-0.93; P = .01) and celecoxib vs. ibuprofen (HR = 0.65; 95% CI, 0.5-0.85; P = .002). Compared with ibuprofen, celecoxib was associated with a significantly lower event rate for serious renal events (HR = 0.61; 95% CI, 0.44-0.85); however, the difference in renal events was not significantly different between celecoxib and naproxen (HR = 0.79; 95% CI, 0.56-1.12).

In other results, the rate of hospitalization for hypertension was significantly lower with celecoxib vs. ibuprofen, but not significantly different with celecoxib vs. naproxen.

“These findings challenge the widely held view that naproxen provides superior CV safety,” Nissen said here. “Results were consistent regardless of baseline administration of aspirin.”

Interpreting the findings

During the press conference, Nissen noted several limitations of the trial, including lower adherence and retention than in other CV outcome trials and use of a moderate dose of celecoxib (100 mg twice daily). He noted that previous trials that provided signals suggesting harm studied supratherapeutic doses of celecoxib of up to 800 mg daily.

He cautioned that “the results reflect the relative safety of these three drugs and not the more than 20 other currently marketed NSAIDs” and that “no direct inferences are possible regarding the effects of NSAIDs compared with placebo.”

The researchers concluded that the findings of this study will require further review to determine whether changes in labeling or regulatory status are warranted.

Elliott Antman, MD
Elliot Antman

During a discussion of the trial results, Elliot Antman, MD, senior physician at Brigham and Women’s Hospital and associate dean for clinical and translational research at Harvard Medical School, noted that while the trial addressed an important question, “this is not a comparison of drugs; [rather], this is a comparison of drug regimens.”

Antman, past president of the AHA, continued, “This was a trial that was supposed to compare outcomes in high CV risk patients, but I actually still have that question, because we don’t have enough of those high CV risk patients represented here.

“What do we do today? I would recommend that we … avoid NSAIDs in patients with known heart disease. If one must treat a patient with an NSAID, attempt to identify [those at] lowest risk, use the lowest-risk drug in the lowest dose needed for the shortest period of time.”

References:

Nissen SE, et al. LBCT.01 – Big Trials for Big Questions. Presented at: American Heart Association Scientific Sessions; Nov. 12-16, 2016; New Orleans.

Nissen SE, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1611593.

Disclosure: The PRECISION study was sponsored by Pfizer. Nissen reports consulting for various pharmaceutical companies and involvement with clinical trials for AbbVie, Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion, Novartis, Novo Nordisk, Medtronic, Pfizer and The Medicines Company.

NEW ORLEANS — When used at moderate doses, the selective COX-2 inhibitor celecoxib was noninferior to the nonselective nonsteroidal anti-inflammatory drugs ibuprofen and naproxen with regard to CV safety, according to results of the PRECISION study.

The drugs were studied in patients with osteoarthritis or rheumatoid arthritis and CVD or increased CV risk.

Moreover, treatment with celecoxib was associated with lower rates of gastrointestinal events compared with ibuprofen and naproxen, and lower rates of renal adverse events compared with ibuprofen.

NSAIDs are among the most commonly used treatments worldwide. Concerns about the CV safety of selective COX-2 inhibitors arose in 2004 after rofecoxib (Vioxx, Merck) was withdrawn from the market. Thereafter, the FDA required a postmarketing CV safety trial to compare celecoxib, another selective COX-2 inhibitor in the same class, with traditional and popular nonselective NSAIDs.

The results were presented by Steven E. Nissen, MD, MACC, chair of cardiovascular medicine at Cleveland Clinic and Cardiology Today Editorial Board member, at the American Heart Association Scientific Sessions and simultaneously published in The New England Journal of Medicine.

Steven E. Nissen, MD
Steven E. Nissen

“After the withdrawal of rofecoxib, everyone thought they knew the answer: that COX-2 inhibitors had an unfavorable CV profile. We didn’t find that [in PRECISION],” Nissen said during a press conference. “This type of study, once again, teaches us that if we jump to conclusions … based on mechanistic considerations, that we often make very bad decisions. … We recognized that this trial … is not perfect, but [it] does not show an excess of CV events with celecoxib.”

Anticipated results

A total of 24,081 patients at 924 sites in 13 countries were randomly assigned on a 1:1:1 basis to receive celecoxib (mean daily dose, 209 mg), ibuprofen (2,045 mg) or naproxen (852 mg) with matching placebo. Esomeprazole 20 mg to 40 mg was also prescribed to all patients for gastric protection. Patients could additionally take up to 100 mg of aspirin per day, according to guideline recommendations.

Patients enrolled had osteoarthritis (90%) or rheumatoid arthritis (10%) and established CVD or increased CV risk who required NSAIDs for 6 months or more for symptom relief. At baseline, the mean age was 63 years, 64% were women, 75% were white and 35% had diabetes.

Mean treatment duration was 20 months. Patients were followed for a mean of 34 months. During the study period, 68% of patients stopped taking the study drug and 27.4% stopped follow-up.

The primary endpoint of the trial was a composite of CV death, nonfatal MI or nonfatal stroke based on the Antiplatelet Trialists Collaboration (APTC) criteria.

The results reported at AHA 2016 were as follows:

  • Intention-to-treat cohort: A primary outcome event occurred in 2.3% of patients assigned celecoxib, 2.5% assigned naproxen and 2.7% assigned ibuprofen (HR for celecoxib vs. naproxen = 0.93; 95% CI, 0.76-1.13, P for noninferiority < .001; HR for celecoxib vs. ibuprofen = 0.85; 95% CI, 0.7-1.04; P for noninferiority < .001; HR for ibuprofen vs. naproxen = 1.08; 95% CI, 0.9-1.31; P for noninferiority = .02).
  • On-treatment cohort: A primary outcome event occurred in 1.7% of the celecoxib group, 1.8% of the naproxen group and 1.9% of the ibuprofen group (HR for celecoxib vs. naproxen = 0.9; 95% CI, 0.71-1.15, P for noninferiority < .001; HR for celecoxib vs. ibuprofen = 0.81; 95% CI, 0.65-1.02, P for noninferiority < .001; HR for ibuprofen vs. naproxen = 1.12; 95% CI, 0.89-1.4; P for noninferiority = .025).

The researchers also adjudicated gastrointestinal and renal outcomes and found that the event rate for gastrointestinal events was lower with celecoxib vs. naproxen (HR = 0.71; 95% CI, 0.54-0.93; P = .01) and celecoxib vs. ibuprofen (HR = 0.65; 95% CI, 0.5-0.85; P = .002). Compared with ibuprofen, celecoxib was associated with a significantly lower event rate for serious renal events (HR = 0.61; 95% CI, 0.44-0.85); however, the difference in renal events was not significantly different between celecoxib and naproxen (HR = 0.79; 95% CI, 0.56-1.12).

In other results, the rate of hospitalization for hypertension was significantly lower with celecoxib vs. ibuprofen, but not significantly different with celecoxib vs. naproxen.

“These findings challenge the widely held view that naproxen provides superior CV safety,” Nissen said here. “Results were consistent regardless of baseline administration of aspirin.”

Interpreting the findings

During the press conference, Nissen noted several limitations of the trial, including lower adherence and retention than in other CV outcome trials and use of a moderate dose of celecoxib (100 mg twice daily). He noted that previous trials that provided signals suggesting harm studied supratherapeutic doses of celecoxib of up to 800 mg daily.

He cautioned that “the results reflect the relative safety of these three drugs and not the more than 20 other currently marketed NSAIDs” and that “no direct inferences are possible regarding the effects of NSAIDs compared with placebo.”

The researchers concluded that the findings of this study will require further review to determine whether changes in labeling or regulatory status are warranted.

Elliott Antman, MD
Elliot Antman

During a discussion of the trial results, Elliot Antman, MD, senior physician at Brigham and Women’s Hospital and associate dean for clinical and translational research at Harvard Medical School, noted that while the trial addressed an important question, “this is not a comparison of drugs; [rather], this is a comparison of drug regimens.”

Antman, past president of the AHA, continued, “This was a trial that was supposed to compare outcomes in high CV risk patients, but I actually still have that question, because we don’t have enough of those high CV risk patients represented here.

“What do we do today? I would recommend that we … avoid NSAIDs in patients with known heart disease. If one must treat a patient with an NSAID, attempt to identify [those at] lowest risk, use the lowest-risk drug in the lowest dose needed for the shortest period of time.”

References:

Nissen SE, et al. LBCT.01 – Big Trials for Big Questions. Presented at: American Heart Association Scientific Sessions; Nov. 12-16, 2016; New Orleans.

Nissen SE, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1611593.

Disclosure: The PRECISION study was sponsored by Pfizer. Nissen reports consulting for various pharmaceutical companies and involvement with clinical trials for AbbVie, Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion, Novartis, Novo Nordisk, Medtronic, Pfizer and The Medicines Company.

    Perspective
    Richard A. Chazal

    Richard A. Chazal

    One of the studies that has generated a great deal of interest, clinically, for all of us is the PRECISION [trial]. This is an important [trial] that looks very carefully at some of the NSAIDs and their effects on CV event rates. As most of us recall, in 2004 the FDA removed a selective Cox-2 inhibitor from the marketplace, commonly known as Vioxx (rofecoxib). This agent was associated with an increased risk for adverse CV events. Subsequently, the FDA has labeled all NSAIDs as being associated with higher risk in patients with regard to CV event rates. The distinction between the different types of agents is very important, especially for those patients who feel as though they must take some sort of an anti-inflammatory agent because of refractory musculoskeletal symptoms.

    In this very large and carefully constructed trial, three different agents were compared. The selective COX-2 inhibitor celecoxib was compared with ibuprofen and naproxen, looking for CV event rates and also side effects. The end result was that there was no inferiority of the selective COX-2 inhibitor with regard to hard CV event rates, in comparison with the other commonly utilized NSAIDs. There was a slightly lower risk for GI bleeding with celecoxib than there was with either ibuprofen or naproxen, and there was a slightly lower renal impairment risk with the Cox-2 inhibitor compared with ibuprofen.

    We still need to remind all of our patients that these agents are associated with increased CV risk and cannot be used without caution. Nonetheless, this information helps inform decision making and helps set the plate for further investigation to clarify how to properly use agents like this in patients with CVD or at risk for CVD who may require the use of an anti-inflammatory agent for other conditions.

    • Richard A. Chazal, MD
    • Medical Director, Heart and Vascular Institute Lee Memorial Health System, Fort Myers, Florida President, American College of Cardiology

    Disclosures: Chazal reports no relevant financial disclosures.

    Perspective
    Carl J. Pepine

    Carl J. Pepine

    I was an investigator for this this trial at our site. This was an important trial, but one of the most difficult to recruit and even more difficult to retain patients. As a result, the trial took much longer than planned (more than 10 years), had recruited a population with a very low CV event rate (approximately 1% per year), and more than one of every four patients enrolled dropped out. At our site, these difficulties were largely related to patient concern about their pain control. As a user of these drugs for arthritis, I found that the doses of ibuprofen and naproxen were relatively high (2,045 mg per day and 852 mg per day, respectively), while the dose of celecoxib was only 209 mg per day. Furthermore, these were the mean doses reported and are difficult to interpret since these distributions are usually skewed, often bimodal and also are difficult to translate to the pill size we actually take. So overall, I had concern attempting to interpret the results. Also, I invite our readers to read a perspective by Garret A. FitzGerald, MD, FRS, about limitations to interpretation of such a large randomized clinical trial (Circulation. 2016;doi:10.1161/CIRCULATIONAHA.116.026324).

    • Carl J. Pepine, MD, MACC
    • Cardiology Today Chief Medical Editor University of Florida, Gainesville

    Disclosures: Pepine reports being a PRECISION site principal investigator, receiving grants from Bayer and Pfizer, and consulting for Bayer.

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