Management of Cardiovascular Disease Risk in Rheumatoid Arthritis

Managing RA-related CVD Risk Factors

Disease Activity

In addition to traditional risk factors, several studies have identified associations between the level of RA disease activity and risk of CVD. In a cohort of US Veterans with RA, CVD-related mortality increased in a dose-dependent manner with higher disease activity categories. In stark contrast, the CVD mortality rates of those in remission paralleled the rates from the general population (standardized mortality ratio [SMR], 0.68; 95% CI, 0.37-1.27).⁶⁹ In a separate cohort of 1157 RA patients without prior CVD, achieving low disease activity was associated with a lower risk of incident CVD events (HR, 0.65; 95% CI, 0.43-0.99).⁷⁰ Additionally, high disease activity has been associated with surrogate markers of CVD and other CVD risk factors including NT-proBNP and systolic blood pressure.^71,72 While no randomized controlled trial data is available to inform this recommendation, observational data suggest RA should be aggressively treated (ideally to achieve and maintain remission or low disease activity) to minimize CVD risk. While keeping this treatment goal in mind, the differential effects of specific RA therapies on CVD must also be considered.

Glucocorticoids and NSAIDs

With the expanding repertoire of DMARDs available and more aggressive treatment approaches, the role of glucocorticoids and NSAIDs in RA treatment is decreasing over time. While their efficacy for improving pain and stiffness is well established, concern regarding their contribution to CVD risk in RA patients is warranted.

Glucocorticoids are known to have detrimental effects on traditional CVD risk factors such as hypertension, insulin resistance, and dyslipidemia in the general population, as well as in RA patients.^73,74 In a meta-analysis of predominantly observational studies of RA patients, glucocorticoid use was associated with an increased risk of CVD events (RR, 1.47; 95% CI, 1.34-1.60), including MI, congestive heart failure (CHF), and cerebrovascular accident (CVA).⁷⁵ Evidence is conflicting in regards to a clear dose threshold that leads to increased CVD risk with glucocorticoids, though higher doses are associated with greater risk.^76-81 As RA patients requiring glucocorticoids typically have higher disease activity, confounding by indication remains a complicating factor in assessing the relative contributions of glucocorticoid use and RA disease activity to elevated CVD risk in many analyses.

The increased CVD risk with NSAID use is not specific to RA and has been well established in the general population.^82-84 In the previously mentioned meta-analysis, an increased overall risk of CVD events was observed with NSAID use in RA (RR, 1.18; 95% CI, 1.01-1.38). It should be noted that cyclo-oxygenase 2 (COX-2) inhibitors, in particular rofecoxib (now removed from the market), appeared to drive the majority of this risk (RR, 1.36; 95% CI, 1.10-1.67 in COX-2 inhibitors and RR 1.08, 95% CI, 0.94-1.24 in nonselective NSAIDs), suggesting a potential differential risk among NSAIDs.⁷⁵ While naproxen has been thought to carry the lowest risk of CVD based on initial studies, this has not been universally observed, including in a recent randomized controlled trial of more than 24,000 RA and osteoarthritis patients.^82,85,86

Providers should use the lowest possible dose and duration of glucocorticoids and NSAIDs to achieve symptom relief, with continual efforts to taper or discontinue. Candidates for glucocorticoid and NSAID therapy should be selected carefully, and use of these therapies should be avoided in those with prior CVD or at high risk for CVD based on traditional CVD risk factors. Most importantly, providers should focus on utilizing DMARDs for the management of RA, which more effectively treat RA as well as reduce CVD risk.