Coronary artery disease in rheumatoid arthritis: Implications for prevention and management

Coronary artery disease in rheumatoid arthritis: Implications for prevention and management

Authors
Katherine P Liao, MD, MPH
Paul Cohen, MD, PhD

Section Editors
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Heidi M Connolly, MD

Deputy Editor
Paul L Romain, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2016. &#124 This topic last updated: Jan 05, 2016.

INTRODUCTION — The prevalence of atherosclerotic coronary artery disease (CAD) is increased in patients with chronic inflammatory rheumatic diseases, particularly rheumatoid arthritis (RA) and systemic lupus erythematosus [1]. Some differences exist in the presentation of CAD in this setting, and the increased risk of CAD has implications for drug therapy, although the clinical manifestations and diagnostic approach to CAD are generally similar in patients with or without RA. (See "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications", section on 'Clinical manifestations' and "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications", section on 'Diagnosis and screening'.)
The preventive and therapeutic implications specifically related to CAD in patients with RA will be reviewed here. The epidemiology, pathogenesis, risk factors, clinical manifestations, and diagnosis of CAD in patients with RA, and other cardiac manifestations of RA including pericarditis, myocarditis, atrioventricular block, valvular regurgitation, embolic events, and rheumatoid nodules, are presented separately. (See "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications" and "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis", section on 'Cardiac disease' and "Rheumatoid nodules", section on 'Cardiac nodules'.)
PREVENTION — The key elements in the prevention of coronary artery disease (CAD) in patients with rheumatoid arthritis (RA) are aggressive management of traditional risk factors and optimization of antiinflammatory and immunomodulatory therapy to achieve effective disease control. (See 'General prevention measures' below and 'DMARDs for control of inflammation due to RA' below.)
This approach is consistent with recommendations of the European League Against Rheumatism (EULAR) [2]. The prevention (whether primary or secondary) and treatment of CAD are generally similar in patients with and without RA, but are influenced by factors particular to RA and similar disorders. Efforts have been made to try to quantify the increase in risk in patients with RA, which results from multiple interacting factors (See 'Risk estimation' below and "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications", section on 'Pathogenesis' and "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications", section on 'Risk factors'.)
Some issues of particular concern in RA that may affect cardiovascular disease (CVD) risk include:
●Effects of systemic inflammation on CAD
●Issues related to concomitant use of low-dose aspirin with nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs), such as nonselective NSAIDs or cyclooxygenase (COX)-2 selective inhibitors
●Benefits and adverse effects of glucocorticoids and other RA therapies, including nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs)
Screening for cardiovascular disease is discussed separately. (See "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications", section on 'Screening for CAD in RA'.)
Risk estimation — We use validated cardiovascular risk estimators, such as the Framingham risk model, the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) atherosclerotic CVD risk calculator, or the Reynolds’ Risk Score (RRS) to estimate CVD risk in RA, although it is important to note that these risk calculators underestimate risk in RA [3,4]. Qrisk2 [5], a general-population CV risk calculator applied in the United Kingdom, was found to overestimate CV risk in a cohort of RA patients [6]. There are insufficient data to guide tailoring of treatment targets based on rheumatologic disease status, other than the evidence that patients with rheumatologic and inflammatory disorders, including RA, are at greater risk than the general population.
A method for risk adjustment in patients with RA has been proposed by the EULAR expert panel, which suggested multiplying commonly used risk calculators, such as the Systematic COronary Risk Evaluation (SCORE) method (often used in Europe) or the Framingham risk model (often used in the United States), by a factor of 1.5 in patients with RA who satisfy at least two of three criteria [2]. These criteria include:
●RA for longer than 10 years
●Positive testing for anti-cyclic citrullinated peptide antibodies or rheumatoid factor
●The presence of extraarticular manifestations of RA
However, the EULAR recommendation for use of the multiplier was based upon expert opinion, without validation in multiple cohorts, and we do not use it in clinical practice as a basis for making treatment decisions. The use of multivariate risk models for the estimation of cardiovascular risk in individual patients is discussed in detail separately. (See "Estimation of cardiovascular risk in an individual patient without known cardiovascular disease", section on 'Multivariate risk models' and "Estimation of cardiovascular risk in an individual patient without known cardiovascular disease", section on 'Framingham risk score (1998)' and "Estimation of cardiovascular risk in an individual patient without known cardiovascular disease", section on 'SCORE CVD death risk score (2003)'.)
Another method developed for CV risk estimation specifically for RA patients is the expanded CV risk prediction score for RA (ERS-RA). The score includes four RA-related variables that contributed, together with traditional risk factors, to more accurate risk estimation compared with use of traditional risk factors alone [7]. These included disease activity (Clinical Disease Activity Index >10 versus ≤10), disability (modified Health Assessment Questionnaire disability index >0.5 versus ≤0.5), daily prednisone use (any versus none), and disease duration (≥10 versus <10 years). Although developed and internally validated using data from a large North American registry, the model requires external validation; however, the data confirm and reinforce the importance of taking into account RA-specific clinical factors in addition to traditional risk when estimating CV risk.
General prevention measures — We recommend a primary prevention strategy in patients with RA that is comparable to that widely recommended in the general population to reduce the risk of cardiovascular events and cardiovascular deaths, consistent with expert guidelines [2]. This includes identifying modifiable risk factors for coronary heart disease and employing interventions that include:
●Smoking cessation
●Lipid lowering
●Healthy diet
●Moderate exercise
●Weight control
●Blood pressure control
These general preventive strategies are discussed in detail separately. (See "Overview of primary prevention of coronary heart disease and stroke".)
Special considerations in patients with RA influence several of these interventions. (See 'Blood pressure control' below and 'Exercise' below and 'Lipid lowering with statins' below and 'Low-dose aspirin' below.)
Blood pressure control — Blood pressure in patients with RA may be increased to a modest degree by several of the medications used to treat the arthritic disorder, including NSAIDs (both nonselective and COX-2-selective), glucocorticoids, and leflunomide [8,9]. Thus, for those in whom these agents are necessary, monitoring blood pressure before and after starting such medications, with initiation or adjustment of antihypertensive therapy to maintain optimal blood pressure control, is suggested as a means of reducing the risk of CVD. Early initiation of DMARDs in most patients may avoid the need for regular use of NSAIDs and reduce the need for glucocorticoids. (See "Overview of hypertension in adults" and "Nonselective NSAIDs: Adverse cardiovascular effects", section on 'Patients with hypertension' and "COX-2 selective inhibitors: Adverse cardiovascular effects" and "Major side effects of systemic glucocorticoids", section on 'Kidney and systemic hemodynamics' and "Leflunomide in the treatment of rheumatoid arthritis", section on 'Hypertension'.)
Exercise — It may be difficult or impossible for patients with RA and either active synovitis or structural damage to joints of the lower extremities to perform the desired level of aerobic exercise. Exercise programs should be prescribed by a physical therapist and tailored for each patient’s disease severity, body build, and previous activity level. High-intensity weightbearing exercises may not be appropriate for patients with preexisting structural damage of lower extremity joints. Less intense or non-weightbearing exercises are alternatives for such patients. (See "Nonpharmacologic therapies and preventive measures for patients with rheumatoid arthritis", section on 'Exercise' and "Exercise and fitness in the prevention of cardiovascular disease".)
Lipid lowering with statins — Primary and secondary prevention of CVD with statin therapy is warranted in patients with RA using similar guidelines to those used in patients without RA; the available data are insufficient, in our view, to warrant the use of statins in patients whose sole evidence of increased cardiovascular risk is the presence of RA. There is widespread agreement that clinicians should have a high degree of alertness to monitor patients with RA for CVD and to manage risk factors aggressively. The use of statins for lipid management in the primary and secondary prevention of CVD is discussed separately. (See "Treatment of lipids (including hypercholesterolemia) in primary prevention" and "Treatment of lipids (including hypercholesterolemia) in secondary prevention".)
Given the low rate of serious side effects from statins, their capacity to reduce lipids and cardiovascular risk, and evidence of antiinflammatory effects [10], it may be reasonable to have a lower threshold for initiating these drugs in patients with active RA than in those without the disease. However, despite these potential benefits, their use should not be considered a substitute either for cardiovascular risk factor modification through lifestyle changes and other interventions or for use of indicated DMARDs [11].
Although relatively limited data are available concerning the efficacy and safety of statins in patients with RA, one population-based cohort study of patients with RA receiving DMARD therapy found that all-cause mortality was reduced 21 percent in patients receiving statins compared with similar patients not on these agents (hazard ratio 0.79, 95% CI 0.68-0.91; absolute mortality risk of 32.6 versus 42.6/1000 patient-years) [12]. These benefits were similar to those seen in randomized trials in the general population. Another study demonstrating benefits for cardiovascular disease in patients with RA, as well as other inflammatory joint diseases, found that intensive statin therapy (with rosuvastatin) induced atherosclerotic regression in carotid plaque and significantly reduced low-density lipoprotein (LDL) cholesterol levels [13]. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)
Despite its recognition as an emerging risk factor for CAD, RA is not considered a class I indication for lipid lowering as a primary prevention strategy for CVD in the United States. Some experts have proposed that the diagnosis of RA may constitute a risk equivalent similar to type 2 diabetes mellitus and that patients with RA should routinely be placed on lipid-lowering therapy [11,14]. This issue remains controversial, as statins are not free of side effects, and their effect in slowing progression of atherosclerosis in RA has not been adequately tested. Despite the lack of recognition of RA as a formal risk factor for CAD, lipid lowering with a statin can be an effective primary prevention strategy for CVD in selected patients in the general population, including healthy individuals with normal lipid levels and an elevated serum C-reactive protein (CRP). (See "Overview of primary prevention of coronary heart disease and stroke" and "Clinical trials of cholesterol lowering for primary prevention of coronary heart disease", section on 'JUPITER trial'.)
There is limited evidence of an antiinflammatory effect of statins in RA. A randomized trial involving 116 patients examined the lipid-lowering and antiinflammatory efficacy of atorvastatin in patients with active RA and a mean serum LDL cholesterol levels of approximately 125 mg/dL (3.2 mmol/L) [10]. Treatment with atorvastatin (40 mg/day) was well-tolerated and was associated with significantly greater reductions in LDL cholesterol levels compared with placebo (54 versus 3 mg/dL [1.4 versus 0.1mmol/L]) and in markers of inflammation such as serum CRP, the erythrocyte sedimentation rate (ESR), and indices of disease activity such as the disease activity score in 28 joints (DAS28). However, the trial was not designed to assess cardiovascular outcomes, and further research is required to determine whether statins may have a role in treating joint inflammation in patients with RA or whether statin therapy should be used solely to improve cardiovascular outcomes in patients with RA who do not have traditional cardiovascular risk factors. Additional trials testing the effects of statins on cardiovascular endpoints in patients with RA are needed. These trials will need to address the relationship between disease activity, lipid levels, inflammation, and cardiovascular risk in RA [15].
Low-dose aspirin — Use of aspirin in patients with RA for cardiovascular prevention does not differ from patients in the general population without RA, but may affect the use of NSAIDs employed for treating the arthritis. Low-dose aspirin is recommended for secondary prevention of cardiovascular events in patients with an established diagnosis of coronary heart disease and may also have a role in primary prevention. Aspirin use in primary and secondary prevention in the general patient population is discussed in detail elsewhere. (See "Benefits and risks of aspirin in secondary and primary prevention of cardiovascular disease".)
Among those with RA, the use of low-dose aspirin in primary or secondary prevention of CAD may be complicated by the following:
●Nonselective nonaspirin NSAIDs may interfere with the beneficial effects of low-dose aspirin when used for prevention of CVD. This interaction is discussed in more detail elsewhere. (See "Nonselective NSAIDs: Adverse cardiovascular effects", section on 'Patients taking aspirin for prevention'.)
●The COX-2-selective NSAIDs do not appear to interfere with the antiplatelet effect of aspirin. In addition, the risk of coronary events appears to be less with celecoxib than with rofecoxib. Nevertheless, until the issue of cardiovascular safety is clarified, it is prudent to also avoid the use of COX-2-selective drugs in patients without a diagnosis of CAD but with multiple risk factors. (See "Nonselective NSAIDs: Adverse cardiovascular effects", section on 'Patients taking aspirin for prevention'.)
●When low-dose aspirin and COX-2-selective agents are used together, the incidence of gastrointestinal events is similar to that of patients treated with a nonselective NSAID.
Whether or not low-dose aspirin mitigates the cardiovascular risk in patients who use COX-2-selective agents is uncertain. Limited data from clinical trials of at least two COX-2 inhibitors, rofecoxib (subsequently withdrawn from the market), and lumiracoxib, suggest that concomitant low-dose aspirin may reduce the risk of cardiovascular events. (See "COX-2 selective inhibitors: Adverse cardiovascular effects", section on 'Ischemic cardiovascular disease'.)
Implications for RA therapeutic drug selection — The increased risk of CVD in patients with RA, and the presence of CAD in some patients, leads to important considerations in the selection and use of therapeutic agents for the treatment of RA. (See 'Nonsteroidal antiinflammatory drugs' below and 'Limiting glucocorticoid exposure' below and 'DMARDs for control of inflammation due to RA' below.)
Nonsteroidal antiinflammatory drugs — The use of many, but not all, NSAIDs has been associated with an increased risk of CVD in the general population, particularly among patients with established CAD. Whether these drugs similarly increase risk in RA, where their antiinflammatory effects might reduce risk (see 'NSAID effects on CVD risk' below), is uncertain. The risks associated with these medications may have important implications for the selection of agents used to treat patients with RA. (See 'Our approach to NSAID use' below.)
In patients with RA without known CAD, we use the same general approach to NSAID prescribing as in patients without RA, prescribing the lowest amount necessary for the shortest amount of time to achieve the desired clinical outcome. (See "Nonselective NSAIDs: Adverse cardiovascular effects" and "COX-2 selective inhibitors: Adverse cardiovascular effects".)
Our approach to NSAID use — Specific issues that influence the treatment decision include the presence or absence of CVD, the degree of risk for gastroduodenal damage, and/or the need for long-term oral anticoagulation. The optimal approach is uncertain in the patient with RA who is at high risk for gastroduodenal damage (ie, who has one or more risk factors for developing NSAID-associated gastroduodenal ulcer and complications).
Among patients with both RA and CAD, our approach is as follows:
●In patients with an average risk for gastroduodenal ulcers, we prefer a nonselective NSAID (preferably naproxen) and avoid the use of COX-2-selective NSAIDs. As discussed in detail elsewhere, all of the selective COX-2 inhibitors appear to have some potential cardiovascular risk. As a result, these agents should be avoided in the patient with RA who is not at high risk for gastroduodenal damage. (See "COX-2 selective inhibitors: Adverse cardiovascular effects".)
●In patients at increased risk for gastroduodenal complications of NSAID therapy we use a nonselective NSAID (preferably naproxen) and a proton pump inhibitor. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)
●In patients with CAD receiving anticoagulation with warfarin or other vitamin-K antagonists, for whom the use of nonselective NSAIDs is associated with an increased risk of serious bleeding, we suggest the use of celecoxib, which does not interfere with platelet function, in the lowest effective dose. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Other risk factors for bleeding'.)

An alternative approach for such patients is the use of a glucocorticoid at the lowest effective dose instead of a COX-2-selective NSAID. A similar approach is suggested for those receiving dual antiplatelet therapy with aspirin and a P2Y12 inhibitor such as clopidogrel or prasugrel [16].
NSAID effects on CVD risk — The effect of nonselective NSAIDs on cardiovascular outcomes in patients with RA has not been extensively studied, but limited data suggest that the CVD risk of NSAIDs may be less in patients with RA than in the general population. In the general population, nonselective NSAIDs have no significant benefit on cardiovascular risk, and the available data suggest an adverse effect with diclofenac and probably with several other agents. COX-2-selective NSAIDs have been associated with increased risk of CVD. (See "Nonselective NSAIDs: Adverse cardiovascular effects" and "COX-2 selective inhibitors: Adverse cardiovascular effects".)
As examples, studies that have suggested that the cardiovascular risk of NSAIDs is significantly less in patients with RA compared with the general population include the following:
●A protective effect of NSAIDs was suggested in an observational study of 923 patients with inflammatory polyarthritis from a primary care-based inception cohort, of whom two-thirds were eventually diagnosed with RA [17]. All-cause and CVD mortality were significantly reduced in association with baseline NSAID use (adjusted odds ratio [OR] 0.62 and 0.54). Only 4.4 percent of patients were receiving DMARDs. The most often-used NSAIDs were diclofenac, naproxen, and ibuprofen (27, 17, and 17 percent). Because of the nature of the study, the possibility that unmeasured confounders may have influenced a decision to prescribe NSAIDs could not be excluded. However, the findings suggested that the increased cardiovascular risk seen in patients with RA is not due to any major degree to the use of NSAIDs, and are consistent with the observation that control of inflammation, as documented with DMARDs, can reduce cardiovascular risk. (See 'DMARDs for control of inflammation due to RA' below.)
●A longitudinal cohort study (median follow-up of 4.9 years) using a Danish national registry [18], demonstrated that major CVD (a composite of myocardial infarction, stroke, and cardiovascular mortality) was significantly lower among patients with RA compared with controls (hazard ratio [HR] 1.22, 95% CI 1.09-1.37, versus 1.51, 95% CI 1.36-1.66). When individual NSAIDs were analyzed, increased risk was seen only with rofecoxib and diclofenac, but not with other medications.
Limiting glucocorticoid exposure — When chronic therapy with glucocorticoids is required, we suggest trying to taper the dose as quickly as possible to the lowest effective dose, usually 5 to 10 mg/day of prednisone or its equivalent, based upon disease activity. The use of supraphysiologic doses of glucocorticoids may be associated with increased rates of myocardial infarction, stroke, heart failure, and all-cause mortality. These effects may be mediated, at least in part, by elevated lipoprotein levels. Such adverse effects of chronic glucocorticoid therapy, including dyslipidemia, are typically seen at doses of 7.5 mg/day or higher and may be increased at lower doses as well. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis".)
The risk of CVD with use of systemic glucocorticoids is reviewed in detail separately. (See "Major side effects of systemic glucocorticoids", section on 'Cardiovascular disease' and "Major side effects of systemic glucocorticoids", section on 'Lipids'.)
DMARDs for control of inflammation due to RA — Effective control of disease activity in patients with RA appears to reduce CVD risk. Although the hypothesis has not been adequately tested in a prospective trial, observational data suggest that strict control of inflammation in RA by use of therapy that effectively decreases synovial inflammation may favorably affect some CVD risk factors and reduce the development and progression of CVD [19]. These data are strongest for treatment with methotrexate (MTX) or tumor necrosis factor (TNF) inhibitors [2]. In addition, limited observational data suggest that biologic DMARDs and MTX are associated with comparable risk of hospitalization for cardiovascular events in older patients with RA [20]. The potential benefit of treatment of joint inflammation with nonbiologic and biologic DMARDs, particularly MTX and the TNF inhibitors, is an additional factor that favors aggressive attempts to control synovitis.
One of the mechanisms that may contribute to reduction of risk is an improvement in lipid profiles that may be associated with treatment with most DMARD therapies [21]. However, the relationship between chronic inflammation and lipid metabolism is complex and remains incompletely understood. In patients with RA and suboptimally controlled disease activity, total and low-density cholesterol levels can be lower than in non-RA individuals [15,22]. Also, biologics targeting proinflammatory cytokines, such as TNF-alpha, interleukin (IL)-6, and the small molecule tofacitinib, which can suppress RA inflammation, appear to increase lipid levels [23-25]. Moreover, some agents, such as tocilizumab, may substantially increase total cholesterol, triglycerides, high-density lipoproteins (HDL), and low-density lipoproteins (LDL), while reducing some vascular risk surrogates [26]. In a prospective evaluation of 20 patients with active RA treated with tocilizumab, proatherogenic shifts in the lipid profile were unrelated to changes in disease activity [27]. The long-term impact on cardiovascular morbidity and mortality is unknown.
Examples of improved cardiovascular outcomes in association with DMARD therapy with the following medications include:
●Methotrexate
•A 2010 systematic review suggested that the use of MTX in the treatment of RA is associated with a reduced risk of CVD events [28]. As an example of the studies included in the review, favorable effects of MTX treatment on cardiovascular risk factors were observed in a study that followed 40 patients with early RA (disease duration less than one year) treated with MTX and prednisone for one year [29]. Lipid levels and ultrasonographically determined carotid artery intima-media thickness as a surrogate for atherosclerosis were measured. After a year of treatment, there were significant increases in mean HDL and decreases in mean LDL blood levels, as well as decreases in carotid artery intima-media thickness, compared with baseline values. These findings may be explained in part by in vitro data, which suggest that MTX may reverse cholesterol transport and may limit foam cell transformation in monocytes and macrophages [30].
•A cohort study of 1240 patients with RA at one clinical center in North America addressed the question of a possible survival benefit among those treated with MTX [31]. After adjustment for possible confounding factors, the risk of death due to CVD was shown to be significantly lower among MTX-treated patients compared with those who did not receive MTX (hazard ratio 0.3, 95% CI 0.2-0.7). This study is discussed in greater detail elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis".)
●TNF-alpha inhibitors
•Potentially beneficial effects of TNF-alpha inhibitors on atherosclerotic CVD were noted in a retrospective study of 983 Swedish patients with RA who received a TNF inhibitor when compared with RA patients not treated with one of these drugs [32]. After controlling for age, sex, and disability, the incidence rates of new cardiovascular events for TNF inhibitor-treated and untreated patients were 1.4 and 3.5 per 100 patient-years, respectively (adjusted risk ratio of 0.46 [95% CI 0.25-0.85]). However, TNF inhibitors may be harmful to some patients with preexisting heart failure and should be used with caution in patients with heart failure or decreased left ventricular function; worsening and new-onset heart failure have been reported with these agents.
•The cardiovascular benefit of the TNF inhibitors may be limited to patients with RA whose synovitis responds to these agents. This was illustrated in a study that used registry data on 10,840 patients with RA [33]. Rates of myocardial infarction were assessed in 8670 patients treated with TNF inhibitors and 2170 patients treated with traditional nonbiologic DMARDs. Overall, both groups had similar incidence rates of myocardial infarction. However, those patients whose disease activity was reduced by TNF inhibitor therapy within the first six months of treatment had a markedly decreased risk of myocardial infarction compared with those who continued to have active disease. Myocardial infarction rates per 1000 patient-years were 3.5 and 9.4, respectively (rate ratio 0.36 [95% CI 0.19-0.69]). (See "Overview of biologic agents in the rheumatic diseases", section on 'TNF inhibition'.)
TREATMENT OF ANGINA AND ACUTE CORONARY SYNDROMES — The medical management of patients with rheumatoid arthritis (RA) and with angina and/or acute coronary syndromes is the same as in patients without RA. (See "Stable ischemic heart disease: Overview of care", section on 'Antianginal therapy' and "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department" and "Overview of the acute management of unstable angina and non-ST elevation myocardial infarction" and "Overview of the acute management of ST elevation myocardial infarction" and "Overview of the non-acute management of unstable angina and non-ST elevation myocardial infarction".)
However, patients with RA who present with acute coronary syndromes may have poorer outcomes than other patients. As an example, in a retrospective study of 40 patients with RA and 40 age- and sex-matched controls, all with acute coronary syndromes, subsequent cardiovascular deaths were significantly more likely in those with RA (40 versus 15 percent), as was the all-cause mortality (47 versus 25 percent) [34].
Issues related to the use of nonsteroidal antiinflammatory drugs (NSAIDs) in patients with cardiovascular disease (CVD) and the interference of some NSAIDs (eg, ibuprofen) with the beneficial antiplatelet effects of aspirin are described separately. (See 'Nonsteroidal antiinflammatory drugs' above and 'Low-dose aspirin' above.)
When cardiac surgery is needed, there are issues unique to patients with RA that must be addressed, including risk of cervical spine instability and preoperative and perioperative antirheumatic drug management. These issues are discussed separately. (See "Preoperative evaluation and perioperative management of patients with rheumatic diseases".)
PROGNOSIS — Cardiovascular disease (CVD) is a major contributor to the increased risk of premature death in patients with rheumatoid arthritis (RA). This is discussed separately. (See "Disease outcome and functional capacity in rheumatoid arthritis", section on 'Mortality'.)
Acute coronary syndromes may be more severe in patients with RA than in the general population (see "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications", section on 'Clinical manifestations'). In addition, patients with RA with acute coronary syndromes have increased short-term mortality compared with controls from the general population who experience events of similar type and severity, even following adjustment for previous comorbidities, demographics, and educational level (seven-day hazard ratio [HR] 1.44, 95% CI 1.14-1.82; 30-day HR 1.36, 95% CI 1.13-1.64) [35].
The magnitude of the acute phase responses to inflammation, as indicated particularly by the erythrocyte sedimentation rate (ESR) and by the C-reactive protein (CRP) concentration, may be predictors of the risk of death due to CVD, supporting the view that aggressive disease-modifying antirheumatic drug (DMARD) therapy is indicated in patients with active joint inflammation. As examples of this association:
●One study evaluated the relationship between traditional and nontraditional cardiovascular risk factors and cardiovascular death in a cohort of 603 patients with RA followed for a mean period of 15 years [36]. When corrected for other risk factors for CVD death, patients with at least three measurements of sedimentation rates ≥60 mm/hour were twice more likely to die of CVD than other RA patients (HR 2.03, 95% CI 1.45-2.83).
●A study of 506 patients with newly diagnosed inflammatory polyarthritis (one-half with RA) found that elevated CRP levels at the time of diagnosis of RA were an independent risk factor for cardiovascular death [37]. After adjustment for other risk factors, a CRP level of ≥5 mg/L was associated with an increased risk of death due to CVD (HR 3.3, 95% CI 1.4-7.6).
●In addition, CRP levels >10 mg/mL predict all-cause mortality after standardization for traditional risk factors in patients with RA, psoriasis, or ankylosing spondylitis [38].
Although an elevated CRP level is recognized as a risk factor for coronary artery disease (CAD) in the general population, lower threshold levels are generally used than those present in patients with an inflammatory disease. Information is lacking regarding the effect of comorbid inflammatory illnesses, such as RA, on the discriminatory power of CRP in CVD risk stratification. (See "Screening for cardiovascular risk with C-reactive protein".)
SUMMARY AND RECOMMENDATIONS
●The key elements in the prevention of coronary artery disease (CAD) in patients with rheumatoid arthritis (RA) are aggressive management of traditional risk factors and optimization of antiinflammatory and immunomodulatory therapy to achieve effective disease control. We use validated cardiovascular risk estimators, such as the Framingham risk model, the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) atherosclerotic cardiovascular disease (CVD) risk calculator, or the Reynolds’ Risk Score, to estimate CVD risk in RA, although these risk calculators underestimate risk in RA. (See 'Prevention' above and 'Risk estimation' above.)
●We recommend a primary prevention strategy in patients with RA that is comparable to that widely recommended in the general population to reduce the risk of cardiovascular events and cardiovascular deaths. This includes identifying modifiable risk factors for coronary heart disease and employing interventions that include smoking cessation, lipid lowering, healthy diet, moderate exercise, and weight control. (See 'General prevention measures' above.)
●Statin therapy reduces cardiovascular risk even in individuals with normal or elevated lipid levels and may have a beneficial effect on markers of inflammation in RA (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]). However, we do not use statins in patients whose sole evidence of increased cardiovascular risk is the presence of RA. (See 'General prevention measures' above and 'Lipid lowering with statins' above.)
●Nonsteroidal antiinflammatory drugs (NSAIDs) should be used with particular caution in patients with RA, with attention to presence or absence of CVD, the degree of risk for gastroduodenal damage, and the need for long-term oral anticoagulation or antiplatelet therapy (see 'Nonsteroidal antiinflammatory drugs' above):
•In patients with RA and known CAD who have an average risk of gastroduodenal damage, we suggest use of a NSAID (eg, naproxen) rather than a cyclooxygenase (COX)-2-selective inhibitor (Grade 2B).
•In patients with RA and known CAD who are at increased risk of serious gastroduodenal toxicity (eg, ulcer, bleeding, perforation) and who need an antiinflammatory agent, we suggest use of a nonselective NSAID (eg, naproxen) and a proton pump inhibitor (eg, omeprazole, lansoprazole, esomeprazole, etc) rather than a COX-2-selective inhibitor (Grade 1B).
•For patients with RA and CAD who are receiving anticoagulation with a vitamin-K antagonist (eg, warfarin) or dual antiplatelet therapy for whom use of a nonselective NSAID is associated with an increased risk of bleeding, we suggest use of the lowest effective dose of celecoxib (Grade 2C). An alternative to a selective COX-2 inhibitor in this setting is use of the lowest effective dose of a glucocorticoid.
●Nonselective nonaspirin NSAIDs may interfere with the antiplatelet effects of aspirin. When low-dose aspirin and COX-2-selective agents are used together, the incidence of gastrointestinal events is similar to that of patients treated with a nonselective NSAID. (See 'Low-dose aspirin' above.)
●The risk of atherosclerosis associated with glucocorticoid use should be minimized by using the minimum effective dose of a glucocorticoid for the shortest possible time. (See 'Limiting glucocorticoid exposure' above.)
●Strict control of inflammation due to RA with both nonbiologic disease-modifying antirheumatic drugs (DMARDs) (eg, methotrexate) and/or biologic DMARDs (eg, anti-tumor necrosis factor [TNF] therapy) may reduce the increased cardiovascular risk seen in patients with RA. Some medications used in RA can adversely impact the lipoprotein profile, while simultaneously reducing vascular risk surrogates, including inflammatory markers. The net effect on cardiovascular morbidity/mortality of such changes is unknown. (See 'DMARDs for control of inflammation due to RA' above.)