Cardiovascular Safety of Celecoxib

Tyler Marie Kiles, PharmD, Mercer University College of Pharmacy

The selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib was withdrawn from the market in 2004 due to evidence of adverse cardiovascular outcomes in a placebo-controlled trial.1 In 2005, the U.S. Food and Drug Administration (FDA) concluded that an increased risk of serious adverse cardiovascular events appears to be a class effect of non-steroidal anti-inflammatory drugs (NSAIDs).  Further research was mandated by the FDA in response to observed cardiovascular effects of another marketed COX-2 inhibitor,  Celebrex™ (celecoxib).2

Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION)
Design Randomized, multicenter, double-blind, noninferiority trial; N= 24,081
Objective To compare the cardiovascular safety of celecoxib to naproxen and ibuprofen
Study Groups Celecoxib (n= 8,072); ibuprofen (n= 7,969); naproxen (n= 8,040)
Methods Patients received celecoxib (100mg twice daily), ibuprofen (600mg three times a day), or naproxen (375mg twice a day). Dose increases were permitted to manage symptoms of rheumatoid arthritis: celecoxib to 200 mg twice a day, ibuprofen to 800 mg three times a day, or naproxen to 500 mg twice a day. For patients with osteoarthritis, increases in the doses of ibuprofen and naproxen were allowed; however, regulatory dosing restrictions precluded dose escalation for celecoxib in these patients.

Esomeprazole (20 to 40 mg) was provided to all patients for gastric protection. Investigators were encouraged to provide cardiovascular preventive management in accordance with local standards and guidelines. Patients who were taking low-dose aspirin (≤325 mg daily) were permitted to continue this therapy.

Antiplatelet Trialists’ Collaboration (APTC) criteria included death from cardiovascular causes, including; hemorrhagic death, nonfatal myocardial infarction, or nonfatal stroke.

Duration October 23, 2006 to June 30, 2014

Mean treatment duration of 20.3  ± 16.0 months

Mean follow up period of 34.1 ± 13.4 months

Primary Outcome Measure The first occurrence of an adverse event that met ATCP criteria
Secondary Outcomes Composite of serious gastrointestinal events, renal events, hospitalization for congestive heart failure, hospitalization for hypertension, and death from any cause
Baseline Characteristics Celecoxib Ibuprofen Naproxen
Mean age ± SD yrs 63 ± 9.5 63.4 ± 9.4 63.2 ± 9.4
Female sex, n (%) 5175 (64.1) 5096 (63.9) 5174 (64.4)
Race, n (%)
White 6058 (75.0) 5926 (74.4) 5991 (74.5)
Black 1090 (13.5) 1134 (14.2) 1108 (13.2)
Asian 164 (2.0) 172 (2.2) 173 (2.2)
Unspecified or Other 760 (9.4) 737 (9.2) 768 (9.6)
Current aspirin use, n (%) 3701 (45.8) 3652 (45.8) 3712 (46.2)
Results Intention to Treat Analysis
  Celecoxib Naproxen Ibuprofen Celecoxib vs Naproxen Celecoxib vs Ibuprofen
n (%) HR (95% CI) p value HR (95% CI) p value
Primary APTC end point 188 (2.3) 201 (2.5) 218 (2.7) 0.93 (0.76-1.13) 0.45 0.85 (0.70-1.04) 0.12
Secondary Endpoints
Major Adverse Cardiovascular Events 337 (4.2) 346 (4.3) 384 (4.8) 0.97 (0.83-1.12) 0.64 0.87 (0.75-1.01) 0.06
Composite of serious GI events 86 (1.1) 119 (1.5) 130 (1.6) 0.71 (0.54-0.93) 0.01 0.65 (0.50-0.85) 0.002
Renal Events 57 (0.7) 71 (0.9) 92 (1.1) 0.79 (0.56-1.12) 0.19 0.61 (0.44-0.85) 0.004
Hospitaliz-ation for CHF 45 (0.6) 48 (0.6) 46 (0.6) 0.92 (0.62-1.39) 0.70 0.98 (0.65-1.47) 0.91
Hospitaliz-ation for HTN 24 (0.3) 34 (0.4) 40 (0.5) 0.69 (0.41-1.17) 0.17 0.60 (0.36-0.99) 0.04
Death from any cause 132 (1.6) 163 (2.0) 142 (1.8) 0.9 (0.63-1.00) 0.052 0.92 (0.73-1.17) 0.49
Adverse Events Common Adverse Events (celecoxib, naproxen, ibuprofen): abdominal pain (3.0%, 2.9%, 3.1%), constipation (3.4%, 4.3%, 5.2%), diarrhea (8.0%, 6.8%, 7.2%), dyspepsia (4.9%, 5.3%, 5.5%), GERD (5.0%, 5.1%, 4.9%), nausea (5.4%, 6.1%, 6.4%)
Serious Adverse Events (celecoxib, naproxen, ibuprofen): clinically significant gastrointestinal events (0.7%, 0.7%, 0.9%), iron-deficiency anemia of gastrointestinal origin (0.4%, 0.9%, 0.8%), death from cardiovascular causes (0.8%, 1,1%, 1.0%), revascularization (2.2%, 2.0%, 2.5%)
Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions With regard to cardiovascular safety, celecoxib at moderate doses was found to be noninferior to ibuprofen or naproxen.

Rates of adherence and retention, while comparable to other pain studies, were lower than in most trials that assess cardiovascular outcomes.  As expected with the selective nature of COX-2 inhibition, fewer gastrointestinal adverse events occurred in the celecoxib group even with administration of esomeprazole to all patients.  There may also be a potential safety advantage for celecoxib versus other NSAIDs due to regulatory restrictions on the dose of celecoxib to 200mg daily.

 

References

1.U.S. Food and Drug Administration: FDA public health advisory: safety of Vioxx. U.S. Department of Health and Human Services. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm106274.htm. Accessed January 31, 2017.

2.U.S. Food and Drug Administration: Information for Healthcare Professionals: Celecoxib (marketed as Celebrex). U.S. Department of Health and Human Services. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124655.htm. Accessed January 31, 2017.

3. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. N Engl J Med. 2016;375(26):2519-29.

 

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s