BARCELONA, SPAIN — For patients with arthritis and increased CV risk, prescription-strength ibuprofen has a worse effect on blood pressure than naproxen or modest-dose celecoxib, PRECISION-ABPM results suggest[1].
“Pain is a cardiovascular risk factor. If you don’t treat pain, your blood pressure goes up, your heart rate goes up, and you’re driving patients into inactivity, so it’s not an answer to not treat pain,” study author Dr Frank Ruschitzka (University Heart Center, Zurich, Switzerland) said.
“You have to treat it with the right drug, and the right drug unfortunately can’t be ibuprofen.”
The results, reported here at the European Society of Cardiology 2017 Congress and online in the European Heart Journal, are based on some 60,000 automated blood pressure readings in 444 arthritis patients (92% osteoarthritis) with established CVD or at increased CV risk who required nonsteroidal anti-inflammatory drugs (NSAIDs) for at least 6 months.
The primary outcome was change from baseline in 24-hour mean systolic blood pressure after 4 months of treatment.
It increased 3.7 mm Hg with ibuprofen and 1.6 mm Hg with naproxen and declined 0.3 mm Hg with the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib. Only the difference between ibuprofen and celecoxib was significant (P=0.009).
To put this in context, Ruschitzka said even a 3-mm-Hg difference in blood pressure multiplied by the 100,000 beats human hearts take each day equates to an extra 300 to 400 m of mercury per day or 100 km per year that the heart would have to pump against a higher pressure.
“In patients with [heart failure with preserved ejection fraction] HFpEF, an elderly lady with arthritis, that tips the balance toward decompensation, that matters. So don’t tell me it’s just 3 mm; it’s impactful long term.”
In a second analysis of patients who were normotensive at baseline, rates of new-onset hypertension over the 4-month study were 15% with celecoxib compared with 35% with ibuprofen (P=0.003) and 28% with naproxen (P=0.034).
“Prescription-strength ibuprofen is under pressure and it has a higher incidence of new-onset hypertension, particularly when compared with the more selective COX-2 inhibitor, celecoxib. And many would have—before we did this study—guessed it the other way around,” Ruschitzka said.
He noted that the findings mirror the higher rate of first hypertension hospitalization seen in the parent PRECISION study and may offer an explanation for the worse cardiovascular-event outcomes observed in ibuprofen-treated patients.
Ruschitzka cautioned, however, that the results should not be extrapolated to other currently marketed NSAIDs or to use of low-dose, over-the-counter preparations.
Clinicians need to weigh the potential hazards of worsening blood-pressure control against the arthritis-mitigating benefits associated with the use of NSAIDs, particularly ibuprofen, he concluded.
Discussant Dr Scott D Solomon (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA) said it would be wrong to conclude from the PRECISION-ABPM results that celecoxib is safer than the other agents, as this was not a true equipotent comparison.
“As we saw a decade ago when we first discussed the cardiovascular effects of celecoxib, dose does matter,” he said.
Solomon noted that because of safety concerns, federal authorities capped the dose of celecoxib at the low end of the therapeutic range but made no such restrictions on naproxen or ibuprofen, resulting in mean daily doses of 209 mg/day, 852 mg/day, and 2045 mg/day, respectively.
Direct assessment of efficacy using pain-intensity scores also suggests patients derived less benefit from celecoxib than the other agents. And the primary outcome was measured at 4 months, when there weren’t the high rates of dropout that affected the parent study.
“Compared with placebo, all NSAIDs likely raise blood pressure, especially in patients prone to hypertension, those with chronic kidney disease, and the elderly—this is exactly the type of patients who require NSAIDs for arthritis,” Solomon concluded. “Whichever NSAID is chosen, clinicians should be aware of this effect and should be treating hypertension according to guidelines.”
Study coauthor Dr Steve Nissen told theheart.org | Medscape Cardiology, “Actually the pain scores were almost identical with the three regimens, so the idea that there wasn’t enough celecoxib given is not correct.
“If you look at the clinical outcomes, ibuprofen looks worse, naproxen intermediate, and celecoxib the best. Then you look at the ambulatory blood pressure, it falls exactly the same way,” he said “So, I think you have to watch out for ibuprofen when given in full prescription doses.”
In addition, the results show that the so-called Fitzgerald hypothesis[2] floated during the rofecoxib (Vioxx, Merck) withdrawal “is completely wrong,” as is the 2007 American Heart Association (AHA) NSAID scientific statement suggesting naproxen is preferred, said Nissen.
In an AHA statement[3] released in response to PRECISION-ABPM, however, AHA past-president Dr Elliott Antman (Brigham and Women’s Hospital, Harvard University) states that the 2007 scientific statement “remains an authoritative, helpful resource for providers seeking guidance on NSAIDs.”
He argues that the same concerns of asymmetric dosing, poor protocol adherence, and low retention in the PRECISION trial apply to the substudy analysis and “become amplified because it considers only a few hundred patients.”
In addition, the higher blood pressure in patients receiving ibuprofen is “not surprising,” since the effect of NSAIDs is to cause the kidneys to retain sodium and water. The higher the dose of the NSAID received, the greater the chance of volume expansion and elevation of blood pressure.
Antman concludes: “It seems most reasonable to focus the use of NSAIDs on patients at lowest cardiovascular risk, using a drug with the lowest risk of producing cardiovascular events, in the lowest dose needed to control symptoms, and for the shortest period of time required.”
The study was funded by Pfizer. The authors did not accept any financial compensation related to NSAIDs during the study. Ruschitzka reported serving on steering committees/speaker’s bureaus for Abbott, Bayer, Biotronik, Cardiorentis, Fresenius, Merck, Novartis, Servier, and Zoll. Disclosures for the coauthors are listed in the paper. Solomon reported no relevant financial relationships.
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