Mitigating Risk of Cardiovascular Disease in Rheumatoid Arthritis

Slideshow

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  Slideshow Take-Home Messages

  •Inflammation related to RA increased patients’ risk of CV morbidity and mortality. •Classic CV risk factors also contribute to CV risk in RA patients. •Often, patients with RA are not screened for CV risk or CV risk is underestimated. •Rheumatologists must ensure their patients’ CV risk is managed appropriately. •Patients should be screened routinely for CV risk and counseled to make lifestyle changes that reduce risk. •Controlling inflammation is essential for reducing CV risk. •CV risk should be considered when prescribing anti-rheumatic treatment. •Synthetic and biologic DMARDs are associated with better CV outcomes than NSAIDs or corticosteroids. •Modifiable CV risk factors such as hypertension or hypercholesterolemia should be managed in line with national guidelines. •Educating patients and PCPs about the increased risk of CVD in RA could improve screening and management. •Educating patients could also improve their ability to recognize CV symptoms and receive lifesaving care.

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  Guidelines for CV Risk Assessment in RA

  Despite a clear link between RA and CVD, many RA practice guidelines—including the 2015 ACR guidelines—do not address screening for CV risk.^10,11 The European League Against Rheumatism (EULAR) offers the only dedicated guideline for CV risk management in RA.¹² EULAR recommends performing a CV risk assessment at least once every 5 years or after treatment changes. Variables are the same as those used for the general population and featured in common tools for estimating 10-year CVE risk, such as Framingham or Systematic Coronary Risk Evaluation (SCORE). They include gender, age, smoking status, blood pressure, lipid levels, and diabetes. Few CV risk models specific to RA are available.¹² If the risk calculator does not factor in RA, EULAR suggests multiplying risk by 1.5. Another approach is to increase the patient’s age by 15 years. Carotid ultrasonography to identify plaques and cIMT values and biomarker tests could help identify high-risk RA patients not captured by risk models.⁷

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  Management of CV Risk in Patients With RA

  Despite RA patients’ increased CV risk, they are less likely to receive proper CV care.^3,4 This may be partly because patients with RA see many physicians, including PCPs, who may lack knowledge of CV risk in RA.³ The “lipid paradox” and lack of knowledge about RA-related CV risk may lead PCPs to underestimate patients’ risk.^4,13,14 Data show some RA patients with significantly elevated inflammatory markers paradoxically have lower cholesterol levels.¹³ EULAR cautions rheumatologists against assuming the PCP is monitoring CV health and to instead take responsibility for ensuring patients’ CV risk is managed appropriately.¹² Reducing patients’ CV risk begins with optimal control of inflammation.¹² One study found patients with high disease activity and high C-reactive protein levels in the 2 years after RA diagnosis had twice as many CVEs.¹⁵ Patients with modifiable risk factors should be advised to make lifestyle changes.¹² Pharmacological treatment should be used per national CVD guidelines.

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  Epidemiology of Heart Disease in RA

  Rheumatoid arthritis (RA) is an independent risk factor for CVD. Patients with RA are twice as likely as the general population to develop CAD or congestive heart failure (CHF).⁴ To calculate excess risks of morbidity and mortality due to CVD, Juan Aviña-Zubieta, MD, and colleagues conducted 2 meta-analyses.^5,6 The first included 24 observational studies and found patients with RA were 50% more likely to die of CVD than the general population, 59% more likely to die of ischemic heart disease, and 52% more likely to die of a cerebrovascular accident (CVA).⁵ The second meta-analysis included 14 observational studies and found a 48% increased risk of incident CVD (fatal and nonfatal myocardial infarction [MI], CVA, or CHF), a 68% increased risk of incident MI, and a 41% increased risk of incident CVA.⁶ The risk of CVD appears to correlate with RA severity. The magnitude of excess CV risk in RA is on par with the excess risk associated with type 2 diabetes.¹⁰

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  Mechanisms of CVD Development in RA

  Growing evidence implicates chronic inflammation in the development of atherosclerosis and premature heart disease in patients with systemic autoimmune conditions such as RA.^1-7 Post-mortem and imaging studies suggest that although patients with RA have plaque levels similar to the general population, persistent arterial inflammation leaves the plaque unstable and vulnerable to rupture.¹ Inflammation also causes endothelial dysfunction, which promotes atherosclerosis formation and damage to the vascular wall. This damage contributes to carotid intima-media thickening (cIMT). Studies have observed endothelial dysfunction in patients with newly diagnosed or longstanding RA.⁷ Genetic factors also contribute to CV risk in RA.⁷ The HLA-DRB1*04 shared epitope alleles are thought to enhance the risk of CVD mortality and morbidity, possibly through promotion of endothelial dysfunction and development of carotid plaques. Genetic variants in the TNF family have also been linked to CVD in RA.⁷ Photo credit: Living Art Enterprises, LLC / Science Source

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  Role of Classic CVD Risk factors in CVD Development in RA

  Classic risk factors for CVD, such as hypertension, type 2 diabetes, smoking, hypercholesterolemia, and obesity increase the risk of cardiovascular mortality or morbidity patients with RA.⁸ Some evidence suggests RA inflammation and genetic factors act synergistically with classic risk factors to enhance development of atherosclerosis.^1,7 Other data point to classic CV risk factors as having a greater effect on CV risk than inflammation.⁹ A prospective study that followed 201 RA patients for 6 years found baseline hypertension, dyslipidemia, and insulin resistance were better long-term predictors of worse microvascular endothelial function than systemic disease-related inflammation.

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  Effects of RA Pharmacotherapy on CVD Risk

  Several studies have reported significant reductions in CVD risk in patients with RA treated with conventional synthetic DMARDs or TNF inhibitors.¹² Long-term use is associated with further declines in CVD risk, supporting the hypothesis that controlling inflammation reduces CV risk in patients with RA. A recent meta-analysis of clinical trials compared CV outcomes of CVE, MI, stroke, major adverse cardiac events, and congestive heart failure between different classes of anti-rheumatic drugs. Data showed TNF inhibitors significantly reduced the risk of CVE, MI, stroke, and major cardiac events but had a neutral effect on CHF.³ Methotrexate reduced the risk of CVE and MI and had no significant effect on stroke, major adverse cardiac events, or CHF. Nonsteroidal anti-inflammatory drugs significantly increased the risk of CVE and stroke and had a neutral effect on MI, CHF, and major adverse cardiac events. Corticosteroids significantly increased the risk of all CV outcomes assessed.³ Image Credit: Scott Camazine / Science Source

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  Are There Differences in Cardiovascular Risk Between Various NSAIDs?

  PRECISION is the largest randomized controlled trial to compare CV safety between NSAIDs commonly used to treat arthritis.¹⁶ The 10-year trial enrolled 24,081 patients with osteoarthritis or RA who had a history of CVEs or elevated CV risk and assigned them to daily celecoxib, ibuprofen, or naproxen. The primary outcome was a composite of CV death, nonfatal MI, and nonfatal stroke. Overall, there was no significant difference in the CV outcome between NSAIDs. However, ibuprofen was associated with a significantly greater risk of nonfatal MI than naproxen and a significantly greater risk of hospitalization for hypertension than celecoxib. Also, hypertension occurred more often with ibuprofen than with celecoxib or naproxen. The celecoxib dose was limited to 200 mg, and authors noted studies have associated 400 to 800 mg doses with a higher risk of CVE. Overall, the findings show the 3 NSAIDs are relatively safe in patients with osteoarthritis or RA who have CV risk factors.¹⁶

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  Benefits of Patient Education on Mitigating CVD Risk in RA

  Patients are often unaware of their increased CV risk related to RA. One study found 95% of patients with RA stratified as having a high risk of CVD underestimated their risk.¹⁷ Data show patients with RA are less likely to report angina symptoms, which increases their chances of an unrecognized MI or sudden cardiac death and decreases their likelihood of getting a needed coronary artery bypass graft.¹⁸ Some studies have shown interventions to educate RA patients about their risk of CVD have the potential to increase screening for CV risk by PCPs and treatment.^19,20 Results from other studies have been less positive. One trial found although educational interventions improved patients’ understanding of their CV risk and prompted intentions to make lifestyle changes, patients did not carry through with their stated intentions.²¹ Nevertheless, patients should be made aware of all important aspects of their disease.

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  Treatment of Established CVD Risk Factors in RA

  Treatment selection is important for patients with RA who have established risk factors for CVD. Limited data from studies that have examined the relationship between RA treatment and CVD suggest non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids increase the risk of some cardiovascular events (CVEs), whereas disease-modifying antirheumatic drugs (DMARDs) such as tumor necrosis factor (TNF) inhibitors and methotrexate decrease the risk of CVEs. ³ The reduction in CVEs associated with DMARD use may result from decreased systemic inflammation. More data from randomized controlled studies are needed to determine the degree of cardiovascular benefit patients with RA receive from different DMARDs and how it should factor into treatment decisions. ³