STEVEN A. KING, MD, MS

	For many years, the major focus on the adverse events associated with the use of the non-steroidal anti-inflammatory drugs (NSAIDs) was on the gastrointestinal problems they could cause or exacerbate. More recently there has been a growing focus on cardiovascular (CV) problems, most notably myocardial infarction (MI) and stroke, that may be related to their use. Of special concern is the relative CV safety of the various NSAIDs and especially of the selective COX-2 inhibitors as opposed to the older non-selective NSAIDs.

	The Prospective Randomized Evaluation Of Celecoxib Integrated Safety Vs Ibuprofen Or Naproxen (PRECISION) cardiovascular safety study was ordered by the FDA more than a decade ago in response to these concerns. After 2 selective COX-2 inhibitors--rofecoxib and valdecoxib--were taken off the market for associations with increased CV morbidity, celecoxib manufacturer Pfizer was allowed to continue marketing the drug but was ordered to conduct the PRECISION trial. The results were first reported at the late-breaking clinical trials session at the American Heart Association annual meeting in November  and published simulatenously in the 

online.

	What do you know about the results?

1. The recently released results of the PRECISION study on CV safety of celecoxib, naproxen, and ibuprofen found that:

 Celecoxib was inferior to naproxen and ibuprofen with regard to CV safety

.  All three of the medications were similar with regard to CV safety

Ibuprofen was less likely than the other two medications to be associated with CV safety

Answer: B. All three of the medications were similar with regard to CV safety

	The PRECISION study was initiated to determine if celecoxib carried same increased risks of MI and stroke that were associated with rofecoxib. The major findings were that celecoxib appeared to carry the same risk for CV problems as ibuprofen and naproxen and that, contrary to the findings of some previous studies, naproxen carried no lower risk for these problems.

2.  Criticisms of the PRECISION study include:

  The significant drop-out rate during the study

 The fact that the doses of ibuprofen and naproxen could be increased during the study but the dose of celecoxib was limited

 Most of the patients enrolled in the study had a low risk for cardiovascular disease

	Almost 69% of the patients enrolled in the study stopped taking the trial medication and over 27% were lost to follow-up.

3. Use of which of the following NSAIDs appear to be associated with an increased risk for heart failure:

	Ibuprofen, naproxen, diclofenac, and ketorolac were all associated with an increased risk for heart failure.

4. When taken at greater than the recommended dose, which of the following NSAIDs carry the greatest risk for heart failure:

Answer: E. A (ibuprofen) and C (diclofenac) 

	When taken at greater than recommended doses, ibuprofen and diclofenac appear to markedly increase the risk for heart failure with diclofenac carrying the highest risk.

5.  True or False: All NSAIDs carry an FDA required warning regarding the increased risk for MI and stroke.

	Aspirin is the only NSAID not required to carry this warning.

6. True or False: The use of topical NSAIDs appears to be associated with an increased risk for systemic problems including cardiac issues.

	The use of topical NSAIDs does not appear to carry any significant risk for the systemic problems associated with oral or parenteral NSAIDs.

7. According to recent research, if the use of NSAIDs is taken into account, chronic pain itself appears to:

 Have no effect on the risk of cardiac disease

Answer: A. Increase the risk of cardiac disease. 

	Apart from the risk associated with the use of NSAIDs, chronic pain itself appears to increase the risk of cardiac disease.

8.  In patients with chronic pain, which of the following factors appears to be most likely to increase the risk of cardiac disease?

	Severity of chronic pain and the impact the pain has on the patient's life appear to be associated with an increased risk for cardiac disease.

9. The PRECISION trial found that with regard to interactions between celecoxib, naproxen, ibuprofen, and low-dose aspirin:

There was no significant interaction between aspirin and any of the three other medications

There was only significant interaction between aspirin and celecoxib

There was only significant interaction between aspirin and naproxen

There was only significant interaction between aspirin and ibuprofen

Answer: A. There was no significant interaction between aspirin and any of the three other medications.

	However, patients in the study were not randomly assigned to receive or not receive aspirin and the use of aspirin was based only on patient self-report.

10. Although the primary goal of the PRECISION study was to determine the relative CV safety of celecoxib, naproxen, and ibuprofen, it also reported that:

 Celecoxib carried a significantly lower risk for gastrointestinal events than the other two medications

 All three of the medications carried the same level of risk for renal events

Celecoxib carried a significantly lower risk for renal events than ibuprofen but not naproxen

	Celecoxib carried a significantly lower risk for GI events than the naproxen and ibuprofen and a significantly lower risk for renal events than ibuprofen but not naproxen.

	1. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis.  N Engl J Med.2016;DOI:10.1056/NEJMoa1611593.

	2. FitzGerald GA. ImPRECISION: Limitations to interpretation of a large randomized clinical trial. Circulation. published online Nov. 13, 2016. http://circ.ahajournals.org/content/early/2016/11/11/CIRCULATIONAHA. 116.026324.citation

	3. Arfe A, Scotti L, Varas-Lorenzo C, et al. Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study. BMJ.2016;354:i4857.

	4. Derry S, Wiffen P, Moore A. Topical Nonsteroidal anti-inflammatory drugs for acute musculoskeletal pain. JAMA. 2016;325:813-814.

	5. Fayaz A, Watt, HC, Langford RM, et al. The association between chronic pain and cardiac disease: a cross-sectional population study. Clin J Pain. 2016;32:1062-1068.

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