By Michael H. Crawford, MD

Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco

Dr. Crawford reports no financial relationships relevant to this field of study.

SYNOPSIS: An ambulatory blood pressure monitoring substudy of the PRECISION trial showed that ibuprofen use significantly increased mean 24-hour systolic blood pressure compared to celecoxib. Further, naproxen produced intermediate results despite equivalent pain relief in patients with arthritis.

SOURCES: Ruschitzka F, Borer JS, Krum H, et al. Differential blood pressure effects of ibuprofen, naproxen, and celecoxib in patients with arthritis: The PRECISION-ABPM (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement) trial. Eur Heart J 2017;38:3282-3292.

Weintraub WS. Safety of non-steroidal anti-inflammatory drugs. Eur Heart J 2017;38:3293-3295.

Selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are used often and on a regular basis in osteoarthritis patients, many of whom present with concomitant hypertension. However, the relative effect of various agents on blood pressure (BP) is unclear. Thus, the ambulatory blood pressure measurements (ABPM) substudy of the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen or Naproxen (PRECISION) study of patients with osteoarthritis with or at increased risk of cardiovascular (CV) disease is of interest. Patients were randomized to three NSAIDs at a low dose that could be increased as needed (celecoxib 100-200 mg twice per day vs. ibuprofen 600-800 mg three times per day vs. naproxen 375-500 twice per day). ABPMs were performed every 20 minutes during awake times and every 30 minutes during sleep times. The primary endpoint was the change from baseline in mean systolic BP (SBP) at four months. Also, the relationship between the change in BP and subsequent major CV events were analyzed. Successful completion of the study was accomplished in 374 of the 545 subjects enrolled at 60 centers in the United States. The change in mean SBP was significant for ibuprofen (3.7 mmHg; P < 0.001) but not for celecoxib (-0.3 mmHg) or naproxen (1.6 mmHg). Clinic SBP showed similar results (5.2 mmHg with ibuprofen, 1.0 mmHg with celecoxib, and 3.2 mmHg with naproxen). During the 2.5-year follow-up, few patients experienced major CV events (nine with ibuprofen, seven with celecoxib, and six with naproxen). The authors concluded that the nonselective NSAID ibuprofen compared to the selective NSAID celecoxib showed a significant increase in mean SBP on ABPM.

COMMENTARY

Celecoxib is the only selective COX-2 inhibitor left on the market in most of the world. Thus, it was reassuring to see in the full PRECISION trial that hard CV endpoints were not significantly different with celecoxib compared to ibuprofen or naproxen (2.3% vs. 2.7% vs. 2.5%, respectively). Also, there were no differences in arthritis quality-of-life measures, but there were less observed gastrointestinal and renal adverse effects with celecoxib. It is well known that NSAIDs can increase BP. Small increases in SBP can increase the likelihood of adverse CV events significantly. Indeed, the observed adverse CV effects of NSAIDs may be more due to BP changes than their effect on endothelial function. Hence, this substudy of PRECISION patients undergoing ABPM is pertinent. PRECISION-ABPM demonstrated several important points. Mean SBP/24 hours was increased only by the nonselective NSAIDs. Also, hospitalizations for hypertension were 69% higher for patients on ibuprofen than those on celecoxib. Among subjects with normal BP at baseline, new hypertension was diagnosed in 10% on celecoxib, 23% on ibuprofen, and 19% on naproxen. The odds ratio for new hypertension on celecoxib was 0.39 (P = 0.004). These results were consistent across all subgroups, including factors such as race, diabetes, chronic kidney disease, and aspirin use. This more favorable effect on BP was accomplished at equivalent efficacy with arthritis relief. The major limitation of this study was that the FDA limited the dose of celecoxib that could be used to a maximum of 400 mg/day. Most patients were on 200 mg/day. Previous studies that used higher doses showed increased CV adverse events with celecoxib vs. placebo. Also, there was no placebo group in PRECISION, although it would have been difficult to conduct such a study in patients with symptomatic arthritis. However, the study was blinded and randomized. It is reassuring that low-dose celecoxib is reasonably safe. However, it is not completely safe, as a COX-2 inhibitor reduces prostacyclin and increases thrombosis risks. Finally, the results of PRECISION cannot be extrapolated to intermittent use of these drugs for arthritis flares.