In the JournalsPerspective

CV effects of NSAIDs similar when combined with aspirin

Steven E. Nissen, MD
Steven E. Nissen

In a new post hoc analysis from the PRECISION trial, celecoxib had a better CV safety profile vs. ibuprofen and naproxen among patients not taking aspirin, but significant differences in CV events were not seen in patients taking aspirin.

As Cardiology Today previously reported, in the main results of PRECISION, among 24,081 patients with osteoarthritis or rheumatoid arthritis and CVD or elevated CV risk, the selective COX-2 inhibitor celecoxib (Celebrex, Pfizer) was noninferior to the nonselective NSAIDs ibuprofen and naproxen with regard to CV safety, and celecoxib was associated with lower rates of gastrointestinal (GI) events compared with ibuprofen and naproxen, and lower rates of renal adverse events compared with ibuprofen.

In the present analysis, Steven E. Nissen, MD, MACC, chairman of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at the Cleveland Clinic’s Sydell and Arnold Miller Family Heart and Vascular Institute and Cardiology Today Editorial Board Member, and colleagues investigated the safety of the three NSAIDs when combined with low-dose aspirin in 23,953 patients from the PRECISION cohort who had data on aspirin use; the analysis was based on on-treatment data.

“Over the years, there have been many research papers suggesting that certain NSAIDs such as ibuprofen and naproxen interfere with the antiplatelet effect of aspirin because they operate on the same receptor of the platelet,” Nissen told Cardiology Today. “That is not the case for celecoxib. With this study, we had an ideal platform to test that theory.”

Aspirin and NSAIDs

In the cohort, 46% were taking aspirin at baseline. Compared with nonusers, aspirin users were older (65 years vs. 62 years; P < .001), less likely to be women (57% vs. 70%; P < .001), more likely to use statins at baseline (66% vs. 43%; P < .001) and more likely to have a history of the following conditions at baseline: CAD, diabetes, hypertension and dyslipidemia (P < .001 for all).

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Elliott Antman, MD
Elliott M. Antman

Among patients not taking aspirin, compared with those assigned celecoxib, those assigned naproxen (HR = 1.52; 95% CI, 1.22-1.9) and those assigned ibuprofen (HR = 1.81; 95% CI, 1.46-2.26) had greater risk for the primary composite outcome of major adverse cardiovascular events, non-CV mortality, clinically significant GI events, iron-deficiency anemia of GI origin or serious renal events, Nissen and colleagues found.

In addition, for patients not taking aspirin, compared with celecoxib, ibuprofen was associated with more CV events (P < .05), and ibuprofen and naproxen were associated with more GI (P < .001) and renal (P < .05) events.

Among patients taking aspirin, compared with those assigned celecoxib, those assigned ibuprofen had greater risk for the primary composite outcome (HR = 1.27; 95% CI, 1.06-1.51), but those assigned naproxen did not (HR = 1.18; 95% CI, 0.98-1.41), Nissen and colleagues wrote.

For those on aspirin, there was no difference between the three NSAIDs in major adverse CV events, but compared with celecoxib, ibuprofen was associated with more GI and renal events and naproxen was associated with more GI events (P < .05 for all), according to the researchers.

“These results were a huge surprise because we found the exact opposite of what the pharmacology would have predicted,” Nissen said in an interview. “What you see in a petri dish or in an animal doesn’t always play out that way in the clinical world. There was not interference of the aspirin function by ibuprofen or naproxen, and the advantage of celecoxib seen in the main PRECISION results was still there, but narrowed.”

Interpretation difficult

In a related editorial, Elliott M. Antman, MD, senior physician at Brigham and Women’s Hospital, associate dean for clinical and translational research at Harvard Medical School and past president of the American Heart Association, wrote that the analysis was not designed to detect an interaction between NSAIDs and aspirin, the statistical methodology for the present analysis was developed post hoc, there are limited data on actual use of aspirin during the trial and there are limitations of the main PRECISION trial, all of which “make it difficult to provide any definitive recommendations to direct clinical practice.”

“It seems best to minimize the use of NSAIDs in general and especially in patients with CVD,” he wrote. “If they must be used, the drug with the safest profile in the lowest dose for the shortest period of time remains the best advice for practice.”

Pfizer has filed a supplemental new drug application to the FDA to incorporate the main results of PRECISION and the present analysis into the labeling for celecoxib. The FDA’s Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee are meeting on April 24 and 25 to discuss the application and make recommendations.

“These are some of the most-used drugs in the world, so the regulators are going to have some important decisions to make about appropriate use,” Nissen, who will present findings from the main PRECISION study and the present analysis at the meeting, said in an interview. – by Erik Swain

For more information:

Steven E. Nissen, MD, MACC, can be reached at Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Ave., Desk J2-3, Cleveland, OH 44195; email: nissens@ccf.org.

Disclosures: PRECISION was funded by Pfizer. Nissen reports he received an institutional research grant from Pfizer during the study. He does not accept personal fees or honoraria from drug and device companies. Please see the study for all other authors’ relevant financial disclosures. Antman reports no relevant financial disclosures.

Steven E. Nissen, MD
Steven E. Nissen

In a new post hoc analysis from the PRECISION trial, celecoxib had a better CV safety profile vs. ibuprofen and naproxen among patients not taking aspirin, but significant differences in CV events were not seen in patients taking aspirin.

As Cardiology Today previously reported, in the main results of PRECISION, among 24,081 patients with osteoarthritis or rheumatoid arthritis and CVD or elevated CV risk, the selective COX-2 inhibitor celecoxib (Celebrex, Pfizer) was noninferior to the nonselective NSAIDs ibuprofen and naproxen with regard to CV safety, and celecoxib was associated with lower rates of gastrointestinal (GI) events compared with ibuprofen and naproxen, and lower rates of renal adverse events compared with ibuprofen.

In the present analysis, Steven E. Nissen, MD, MACC, chairman of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at the Cleveland Clinic’s Sydell and Arnold Miller Family Heart and Vascular Institute and Cardiology Today Editorial Board Member, and colleagues investigated the safety of the three NSAIDs when combined with low-dose aspirin in 23,953 patients from the PRECISION cohort who had data on aspirin use; the analysis was based on on-treatment data.

“Over the years, there have been many research papers suggesting that certain NSAIDs such as ibuprofen and naproxen interfere with the antiplatelet effect of aspirin because they operate on the same receptor of the platelet,” Nissen told Cardiology Today. “That is not the case for celecoxib. With this study, we had an ideal platform to test that theory.”

Aspirin and NSAIDs

In the cohort, 46% were taking aspirin at baseline. Compared with nonusers, aspirin users were older (65 years vs. 62 years; P < .001), less likely to be women (57% vs. 70%; P < .001), more likely to use statins at baseline (66% vs. 43%; P < .001) and more likely to have a history of the following conditions at baseline: CAD, diabetes, hypertension and dyslipidemia (P < .001 for all).

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Elliott Antman, MD
Elliott M. Antman

Among patients not taking aspirin, compared with those assigned celecoxib, those assigned naproxen (HR = 1.52; 95% CI, 1.22-1.9) and those assigned ibuprofen (HR = 1.81; 95% CI, 1.46-2.26) had greater risk for the primary composite outcome of major adverse cardiovascular events, non-CV mortality, clinically significant GI events, iron-deficiency anemia of GI origin or serious renal events, Nissen and colleagues found.

In addition, for patients not taking aspirin, compared with celecoxib, ibuprofen was associated with more CV events (P < .05), and ibuprofen and naproxen were associated with more GI (P < .001) and renal (P < .05) events.

Among patients taking aspirin, compared with those assigned celecoxib, those assigned ibuprofen had greater risk for the primary composite outcome (HR = 1.27; 95% CI, 1.06-1.51), but those assigned naproxen did not (HR = 1.18; 95% CI, 0.98-1.41), Nissen and colleagues wrote.

For those on aspirin, there was no difference between the three NSAIDs in major adverse CV events, but compared with celecoxib, ibuprofen was associated with more GI and renal events and naproxen was associated with more GI events (P < .05 for all), according to the researchers.

“These results were a huge surprise because we found the exact opposite of what the pharmacology would have predicted,” Nissen said in an interview. “What you see in a petri dish or in an animal doesn’t always play out that way in the clinical world. There was not interference of the aspirin function by ibuprofen or naproxen, and the advantage of celecoxib seen in the main PRECISION results was still there, but narrowed.”

Interpretation difficult

In a related editorial, Elliott M. Antman, MD, senior physician at Brigham and Women’s Hospital, associate dean for clinical and translational research at Harvard Medical School and past president of the American Heart Association, wrote that the analysis was not designed to detect an interaction between NSAIDs and aspirin, the statistical methodology for the present analysis was developed post hoc, there are limited data on actual use of aspirin during the trial and there are limitations of the main PRECISION trial, all of which “make it difficult to provide any definitive recommendations to direct clinical practice.”

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“It seems best to minimize the use of NSAIDs in general and especially in patients with CVD,” he wrote. “If they must be used, the drug with the safest profile in the lowest dose for the shortest period of time remains the best advice for practice.”

Pfizer has filed a supplemental new drug application to the FDA to incorporate the main results of PRECISION and the present analysis into the labeling for celecoxib. The FDA’s Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee are meeting on April 24 and 25 to discuss the application and make recommendations.

“These are some of the most-used drugs in the world, so the regulators are going to have some important decisions to make about appropriate use,” Nissen, who will present findings from the main PRECISION study and the present analysis at the meeting, said in an interview. – by Erik Swain

For more information:

Steven E. Nissen, MD, MACC, can be reached at Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Ave., Desk J2-3, Cleveland, OH 44195; email: nissens@ccf.org.

Disclosures: PRECISION was funded by Pfizer. Nissen reports he received an institutional research grant from Pfizer during the study. He does not accept personal fees or honoraria from drug and device companies. Please see the study for all other authors’ relevant financial disclosures. Antman reports no relevant financial disclosures.

    Perspective
    Jeffrey S. Berger

    Jeffrey S. Berger

    The use of NSAIDs is commonplace in society, and it is important to understand the potential harmful effects of NSAIDs when thinking about which one patients should be taking for pain relief. There has been a lot of controversy in this area. The PRECISION trial attempted to answer some very important questions and moved the field along.

    What this paper adds is that patients who are taking many of these NSAIDs are often older and have other concomitant disease states, some of which require the use of aspirin. There are a lot of data showing co-administration of aspirin with NSAIDs may adversely affect the use of aspirin. Unfortunately, there are not enough data here to answer whether the effects of aspirin are attenuated by the use of NSAIDs in this population.

    The authors did a nice job with what they could, but the dramatic baseline differences between patients taking and not taking aspirin, and the fact that the event rates are so much higher in patients on aspirin in the unadjusted analysis, makes me question the ability to use propensity modeling in this case.

    The authors did a good job comparing the different NSAIDs. Those data, consistent in patients with and without aspirin, are noteworthy. But based on these findings, I am still very hesitant as a practitioner to use NSAIDs in patients on aspirin.

    There are a lot of data suggesting caution about giving NSAIDs to patients at risk for CVD. These data are important if the patient has to take an NSAID, to help determine which NSAID is best to take. But we still do not favor the use of NSAIDs in patients on aspirin.

    There are a lot of pharmacodynamic data suggesting NSAIDs interfere with the mechanism of aspirin. Until someone shows clinical data that NSAIDs do not adversely affect the clinical outcomes of patients on aspirin, I would not be able to change my opinion that we should be cautious about giving NSAIDs to these patients.

    • Jeffrey S. Berger, MD
    • Associate Professor of Medicine and Surgery Co-Director, Center for the Prevention of Cardiovascular Disease NYU Langone Health

    Disclosures: Berger reports no relevant financial disclosures.