ANAHEIM, CA — Although the use of the nonsteroidal anti-inflammatory drug (NSAID) celecoxib appears to be safer than the NSAIDs naproxen or ibuprofen in treating patients with arthritis who are at increased cardiovascular risk, adding aspirin into the mix may decrease some of that safety advantage, new research suggests[1].
In a prespecified, secondary analysis of the PRECISION trial, almost 24,000 participants were assessed, all of whom had NSAID-dependent osteoarthritis or rheumatoid arthritis. Among those not also taking aspirin, the patients who received naproxen or ibuprofen had significantly greater risk for the primary composite end point of major adverse CV events (MACE), non-CV death, gastrointestinal (GI) events, and renal events than those receiving celecoxib.
The ibuprofen group also had significantly greater risk for MACE alone, for GI events, and for renal events vs the study-drug group; while the naproxen group had significantly greater risk for just GI and renal events.
However, among those who were taking aspirin, the risk for the composite end point and for renal events was significantly greater only for the ibuprofen group; the risk for GI events was still greater for both groups vs those receiving celecoxib; and there were no longer any significant between-group differences in risk for MACE alone.
Dr Grant W Reed
“The main study was reassuring and showed that celecoxib is safe to use in these patients. This new analysis showed that overall cardiovascular safety differed whether or not aspirin was used in addition to the NSAID,” Dr Grant W Reed (Cleveland Clinic, OH) told theheart.org | Medscape Cardiology.
“I think the main message is: if you don’t need to start a patient on aspirin, don’t do it,” said Reed.
He presented the findings at the American Heart Association (AHA) 2017 Scientific Sessions.
Drug Interaction Concerns
With reports of more than 43 million regular adult aspirin users in the US in 2010 and more than 28 million regular users of other NSAIDs, there have been concerns about possible drug interactions. Reed noted that NSAIDs are nonselective for cyclooxygenase (COX)-1 and COX-2 and “compete with aspirin for binding with COX-1, blocking aspirin’s ability to inhibit platelets.”
“Studies report conflicting results on whether adding aspirin to NSAIDs with various degrees of COX selectivity modifies risks, [and] the optimal management of patients with NSAID-dependent arthritis who need aspirin is unclear,” he told meeting attendees.
While aspirin is a selective COX-1 inhibitor, celecoxib is a selective COX-2 inhibitor. In addition, naproxen and ibuprofen are nonselective inhibitors of COX-2 and COX-1.
PRECISION was a multicenter, randomized controlled trial. For the current analysis, 23,953 participants were examined. All were randomly assigned to receive celecoxib 100 to 200 mg twice a day, naproxen 375 to 500 mg twice a day, or ibuprofen 600 to 800 mg three times a day.
In addition, 46% of the patient population were on aspirin (57.2% women; mean age 65.1 years) vs 54% who were not (70.1% women; mean age 61.6 years).
In the subgroup not on aspirin, the patients taking the study drug had significantly less risk for the composite end point, GI events, and renal events than those taking naproxen or ibuprofen.
Safety Outcomes Among Treatment Groups Without Aspirin
| Outcome | Hazard ratio (95% CI) | P |
|---|---|---|
| Composite end point | ||
| Naproxen vs celecoxib | 1.52 (1.22–1.90) | <0.001 |
| Ibuprofen vs celecoxib | 1.81 (1.46–2.26) | <0.001 |
| GI events | ||
| Naproxen vs celecoxib | 2.60 (1.59–4.27) | <0.001 |
| Ibuprofen vs celecoxib | 3.20 (1.97–5.22) | <0.001 |
| Renal events | ||
| Naproxen vs celecoxib | 2.09 (1.10–3.96) | <0.05 |
| Ibuprofen vs celecoxib | 1.93 (1.00–3.73) | <0.05 |
The risk was also significantly less, albeit tempered, for these three outcomes in the study-drug vs ibuprofen groups among those who were taking aspirin; and there was significantly less risk for GI events vs the naproxen group.
Table 2. Safety Outcomes Among Treatment Groups With Aspirin
| Outcome | Hazard ratio (95% CI) | P |
|---|---|---|
| Composite end point | ||
| Naproxen vs celecoxib | 1.18 (0.98–1.41) | NS* |
| Ibuprofen vs celecoxib | 1.27 (1.06–1.51) | <0.01 |
| GI events | ||
| Naproxen vs celecoxib | 1.91 (1.24–2.94) | <0.05 |
| Ibuprofen vs celecoxib | 1.71 (1.10–2.67) | <0.05 |
| Renal events | ||
| Naproxen vs celecoxib | 1.30 (0.76–2.23) | NS* |
| Ibuprofen vs celecoxib | 2.01 (1.23–3.30) | <0.05 |
*NS=not significant
The only treatment-group difference for increased MACE risk was in those taking ibuprofen without aspirin (P<0.05).
“Our findings do not support the premise that selective COX-2 inhibitors as a class increase cardiovascular risk compared with nonselective COX-1 and COX-2 inhibitors,” summarized Reed.
He noted that this was an on-treatment analysis, so there are some differences from the primary findings of PRECISION—which assessed different end points and looked at the intention-to-treat population.
The primary PRECISION results showed that celecoxib was noninferior for CV safety, while the new results show that it’s superior to naproxen and ibuprofen for overall safety.
“The current analysis . . . is clinically more relevant with regard to safety end points and showed the most favorable cardiovascular safety profile in those with the selective COX-2 inhibitor alone. But adding COX-1 inhibition with aspirin attenuated the safety advantage and rendered the relative cardiovascular safety profiles of the NSAIDs as approximately equivalent,” he said.
“Our findings underscore the importance of appropriate patient counseling on safety profiles when initiating therapy. NSAID administration should be tailored to each patient.”
“Informative First Step”
After the presentation, session moderator Dr Mercedes Carnethon (Northwestern University, Chicago, IL) noted that this is an especially interesting topic because it’s been in the news over the past few years.
Dr Mercedes Carnethon
“We heard so much in the media about possible ill effects of celecoxib, so to actually see where the problem is, and to see the effect from aspirin, was a notable finding—particularly in such a large study,” she said to theheart.org | Medscape Cardiology.
“The speaker’s conclusions that the consideration really is about the dual use of drugs that becomes problematic and that the drug used on its own is not necessarily associated with higher risk of events were really important.”
She added that she appreciated Reed being cautious and saying that this is hypothesis generating, while the investigators continue to do more subgroup analyses.
“But overall, I found this to be a very informative first step,” concluded Carnethon.
The study was funded by Pfizer. Reed, the other study authors, and Carnethon did not report any relevant financial relationships.
Follow Deborah Brauser on Twitter: @MedscapeDeb. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.
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