PRECISION-ABPM Reveals Differential Blood Pressure Effects with Chronic Use of 3 NSAIDs

Among patients taking daily NSAID therapy for arthritis, the nonselective NSAID ibuprofen was associated with a significant rise in systolic blood pressure (BP) and a higher incidence of new-onset hypertension compared with the selective COX-2 inhibitor celecoxib, according to a substudy of the milestone PRECISION trial published late last year.

The substudy, known as PRECISION-ABPM, was presented as a late-breaking trial this week at the European Society of Cardiology Congress 2017 and simultaneously published by the European Heart Journal. It was conducted to evaluate the BP effects of celecoxib versus ibuprofen and another nonselective NSAID, naproxen, which was found to have BP effects intermediate to those of the other two agents.

“These findings concur with the primary outcome results of the overall PRECISION trial and could impact clinical outcomes for patients who use NSAIDs chronically,” says PRECISION-ABPM co-author Steven Nissen, MD, who chaired the PRECISION study and is Chairman of Cardiovascular Medicine at Cleveland Clinic. The Cleveland Clinic Coordinating Center for Clinical Research (C5Research) served as study coordinator, and the writing team included several Cleveland Clinic cardiology and rheumatology specialists.

Big public health implications

Noting that more than 40 percent of the 30 million Americans with osteoarthritis also have hypertension, Dr. Nissen says both nonselective NSAIDs and selective inhibitors of COX-2 have been shown to raise BP or interfere with BP control. “Given that even small differences in BP can affect cardiovascular morbidity and mortality,” he explains, “there was a particular need to investigate the differential effects on BP among NSAIDs.”

That’s why PRECISION-ABPM was a prespecified substudy of the 24,000-patient PRECISION trial, which found cardiovascular events to occur at the highest rate among those randomized to ibuprofen, at the lowest rate among those randomized to celecoxib and at an intermediate rate among those randomized to naproxen. PRECISION was published in the New England Journal of Medicine and summarized in this Consult QD post.

60-site substudy of PRECISION

Like the overall study, PRECISION-ABPM was designed as a cardiovascular safety trial to assess noninferiority of celecoxib vis-à-vis the two nonselective NSAIDs. Patients in this substudy were adults from 60 centers across the U.S. who had osteoarthritis (92 percent) or rheumatoid arthritis (8 percent) with established cardiovascular disease or elevated cardiovascular risk.

Patients were randomized in a double-blind manner to one of the following arms:

• Celecoxib (100-200 mg twice daily; mean, 208 ± 34 mg/d) (n = 146)
• Ibuprofen (600-800 mg thrice daily; mean, 2,031 ± 237 mg/d) (n = 151)
• Naproxen (375-500 mg twice daily; mean, 852 ± 98 mg/d) (n = 147)

A clear BP safety edge for celecoxib

Results on the primary end point of change from baseline in mean 24-hour ambulatory systolic BP after four months were as follows:

• Celecoxib, –0.3 mmHg (95% CI, –2.25 to 1.74)
• Ibuprofen, 3.7 mmHg (95% CI, 1.72 to 5.58)
• Naproxen, 1.6 mmHg (95% CI, –0.4 to 3.57)

These changes amounted to a difference of –3.9 mmHg between celecoxib and ibuprofen (P = .009), a difference of –1.8 mmHg between celecoxib and naproxen (P = .12) and a difference of –2.1 mmHg between naproxen and ibuprofen (P = .08).

Notably, the percentage of patients who developed new-onset hypertension during the course of the four-month study was highest in the ibuprofen group (23.2 percent) followed by the naproxen group (19.0 percent) and then the celecoxib group (10.3 percent). The difference in cases of new-onset hypertension between the celecoxib group and the other groups was statistically significant (P = .004 vs. ibuprofen and P = .03 vs. naproxen).

Primary PRECISION results underscored

“PRECISION-ABPM shows that the nonselective NSAID ibuprofen is associated with a significant rise in systolic BP and a higher rate of hypertension development compared with the selective COX-2 inhibitor celecoxib,” observes Dr. Nissen. “These findings support and extend the primary results of the PRECISION trial demonstrating noninferior cardiovascular safety for moderate-dose celecoxib relative to the two nonselective NSAIDs. They also suggest that elevated cardiovascular risk with NSAIDs may depend on medication-specific BP increases in addition to proposed mechanisms involving effects on platelets and the vascular endothelium.”

In light of the widespread use of NSAIDs, he notes, “even a small rise in systolic BP among hypertensive patients with osteoarthritis could substantially elevate cardiovascular events at the population level.”

Cannot extrapolate beyond chronic use

But he’s quick to add that these findings are limited to patients taking NSAIDs daily on a chronic basis. “Any extrapolation to the occasional use of these drugs for pain flares demands extreme caution,” Dr. Nissen says.

He notes that the PRECISION-ABPM findings may have the most clinical significance for the elderly, who have high rates of both arthritis and hypertension — and who may be most likely to be on chronic NSAID therapy.

“Just as clinicians weigh the risks to gastrointestinal safety when considering NSAIDs, they need to account for the potential dangers of worsening BP control and its clinical effects when considering these agents, especially ibuprofen,” Dr. Nissen says.