Continuous use of NSAIDs could increase the risk of incident hypertension among patients with ankylosing spondylitis (AS), according to findings from a recent prospective study.
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Against expectations, data also suggested that tumor necrosis factor inhibitor (TNFi) therapy could increase blood pressure, although this finding was not significant across all methods of analysis, reported lead author Jean W. Liew, MD, of the University of Washington, Seattle, and colleagues.
The investigators noted that patients with AS already have a greater risk of cardiovascular disease than that of the general population, making any added risks that much more concerning.
“[T]he evidence for increased cardiovascular disease burden and cardiovascular risk in patients with inflammatory rheumatic diseases is well recognized,” the investigators wrote in Arthritis Care & Research. “Multiple population-based studies have demonstrated increased cardiovascular events and cardiovascular-related mortality in AS. There is a high prevalence of cardiovascular risk factors among individuals with AS, particularly hypertension.”
Exacerbation of this risk by NSAIDs has been previously studied with mixed results, according to the investigators. Meta-analyses have suggested that NSAIDs increase blood pressure in normotensive and hypertensive individuals, but some data point to a cardioprotective effect among those with AS, possibly as a consequence of dampened inflammation, and/or improved physical activity, which could lead to a secondary CV benefit. Still, the relationship between NSAIDs and CV risk was unclear, prompting the current study.
The investigators enrolled 1,282 patients with AS at five centers in the United States and Australia. Using a combination of clinical evaluations and self-reporting, enrollees were monitored at regular intervals. Disease activity was tracked with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), while the Bath Ankylosing Spondylitis Functional Index (BASFI) was used for functional impairments. Patients were also checked for a variety of comorbidities such as hypertension, coronary artery disease, mental health conditions, and renal disorders. Medication data included type, dosage, frequency, duration, and number of missed doses.
Including only baseline normotensive patients with at least 1 year of follow-up, 628 participants were eligible for analysis, of whom 200 used NSAIDs continuously. After a median of 7 years follow-up, 129 out of 628 patients developed hypertension. This translated to a hazard ratio (HR) for incident hypertension of 1.12 (95% confidence interval, 1.04-1.20), compared with nonusers or those who took NSAIDs intermittently. This relationship did not differ across subgroups defined by age, disease activity, body mass index, or TNFi use. Multiple sensitivity analyses added support to the association between continuous NSAID use and hypertension.
“The association of NSAIDs and incident hypertension remains particularly concerning, as the early development of hypertension may portend a higher risk of premature CV events due to cumulative exposure,” the investigators wrote.
In contrast with NSAIDs, TNFi therapy was not associated with hypertension across all models; however, against expectations, two models of analysis pointed to an 8% increased risk.
“Although TNFi use did not reach statistical significance in the main model, the direction of association was opposite that hypothesized based on prior data, specifically that TNFi use reduces CV risk by suppressing chronic inflammation,” the investigators wrote.
Considering the present findings, and previous studies, which have reported conflicting associations between TNFi use and hypertension, the investigators suggested that more research is needed, and offered specific methods to approach the topic.
“The association of TNFi use and incident hypertension requires further clarification in future studies,” they wrote, “which may be done by applying a marginal structural modeling (MSM) framework and inverse probability of treatment weighting (IPTW) statistical analyses to account for the relationships between TNFi use, disease activity, and NSAID use.”
In their concluding remarks, the investigators further emphasized the current knowledge gap in this area.
“There is an unmet need to clarify how treatment choices, particularly the use of NSAIDs and TNFi, impact CV risk factors and CV events in AS,” they wrote. “Further studies are needed to focus on precision medicine and predicting risk and benefit for patients in whom continuous NSAIDs are being considered. These further studies can inform the revision of guidelines to address the management of CV risk factors and CV disease in AS and axial spondyloarthritis more broadly.”
The investigators reported funding from the National Institutes of Health, the Assessment of Spondyloarthritis International Society, the Spondylitis Association of America, and the Russel Engleman Rheumatology Research Center at the University of California, San Francisco. Some authors reported ties with Eli Lilly, Novartis, and other pharmaceutical companies..
SOURCE: Liew et al. Arthritis Care Res. 2019 Sep 17. doi: 10.1002/acr.24070.