Introduction Rheumatoid arthritis (RA) is a risk factor for cardiovascular disease. The clinical consequences of coincident RA and coronary artery disease (CAD) are unknown.
Objective We aimed to estimate the impact of RA on the risk of adverse cardiovascular events in patients with and without CAD.
Methods A population-based cohort of patients registered in the Western Denmark Heart Registry, who underwent coronary angiography (CAG) between 2003 and 2016, was stratified according to the presence of RA and CAD. Endpoints were myocardial infarction (MI), major adverse cardiovascular events (MACE; MI, ischaemic stroke and cardiac death) and all-cause mortality.
Results A total of 125 331 patients were included (RA: n=1732). Median follow-up was 5.2 years. Using patients with neither RA nor CAD as reference (cumulative MI incidence 2.7%), the 10-year risk of MI was increased for patients with RA alone (3.8%; adjusted incidence rate ratio (IRRadj) 1.63, 95% CI 1.04 to 2.54), for patients with CAD alone (9.9%; IRRadj 3.35, 95% CI 3.10 to 3.62), and highest for patients with both RA and CAD (12.2%; IRRadj 4.53, 95% CI 3.66 to 5.59). Similar associations were observed for MACE an all-cause mortality.
Conclusions In patients undergoing CAG, RA is significantly associated with the 10-year risk of MI, MACE and all-cause mortality regardless of the presence of CAD. However, patients with RA and CAD carry the largest risk, while the additive risk of RA in patients without CAD is minor. Among patients with RA, risk stratification by presence or absence of documented CAD may allow for screening and personalised treatment strategies
- cardiovascular disease
- rheumatoid arthritis
- outcomes research
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What is already known about this subject?
Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular disease.
It would be of significant importance to allow for more personalised risk stratification in patients with RA.
What does this study add?
RA is significantly associated with the 10-year risk of myocardial infarction, major cardiovascular events and all-cause mortality regardless of the presence of coronary artery disease (CAD).
Patients with RA and CAD carry the largest risk, while the additive risk of RA in patients without CAD is minor.
How might this impact on clinical practice or future developments?
Among patients with RA, risk stratification by presence or absence of CAD may allow for personalised treatment strategies.
Rheumatoid arthritis (RA) is a chronic autoimmune disease, which is associated with increased risk of cardiovascular disease.1–7 Patients with RA have a larger coronary plaque burden than patients without RA,8 conceivably due to coinciding inflammatory processes in RA and atherosclerotic coronary disease.9–12
In patients with established obstructive coronary artery disease (CAD), observational studies have suggested an increased risk of in-hospital and long-term cardiovascular events after coronary intervention in patients with RA compared with patients without RA.13–17 However, it has not been examined whether it is possible to improve risk stratification of patients with RA dependent on the absence or presence of CAD. In this study, we hypothesised that RA patients without CAD would have a similar risk of myocardial infarction (MI) and major adverse cardiovascular events (MACE) when compared with patients with neither RA nor CAD, but that RA and CAD are additive risk factors.
Research design and methods
The Western Denmark Heart Registry contains information about all cardiac procedures performed in Western Denmark since 1999 and covers a population of 3.5 million people.18 It includes a detailed description of the presence and extent of CAD. Each hospital that performs cardiac procedures in western Denmark contributes to the registry.
All Danish citizens are assigned a unique civil personal registration (CPR) number enabling patient tracking and linkage between all Danish registries at the individual level. The Danish Civil Registration System (CRS) has data on CPR number, name, sex, date of birth, residence, address in Denmark, vital status and data of death since 1968. Vital status (dead, alive, emigrated) along with a status data was retrieved from CRS.19
The unique CPR is used by every regional and national registry in Denmark, including the Danish National Patient Register (DNPR), which contains data on all inpatient hospitalisations in Denmark since 1977, and on all outpatient and emergency room visits to hospital specialist clinics since 199520; the Danish Register of Causes of Death21 and the Danish National Database of Reimbursed Prescriptions.22
Patients registered with a coronary angiography (CAG) procedure in the Western Denmark Heart Registry from 1 January 2003 to 31 December 2016 were included in this study (figure 1). The first CAG was used as the index procedure when a patient had multiple CAG procedures during the study period. All patients were >18 years of age. Patients with MI, percutaneous coronary intervention, or coronary artery bypass grafting prior to CAG were excluded (n=25 292). Patients with missing CAD status were also excluded (n=471). Furthermore, patients who died or emigrated <30 days after inclusion were excluded (n=3088). Using the DNPR, we identified all patients with a diagnosis of RA using the International Classification of Diseases (ICD)-10 codes (DM05.0-DM05.9 and DM06.0-DM06.9). CAD was defined as obstructive CAD and non-obstructive CAD according to the Western Denmark Heart Registry. Patients were then classified according to presence or absence of RA and CAD.
Information on hypertension, ischaemic stroke, transient ischaemic attack, peripheral artery disease and atrial fibrillation was ascertained through the DNPR based on ICD-10 codes. Heart failure was based on ICD-10 codes and cross-linked with information from the Western Denmark Heart Registry, while diabetes was identified through the DNPR, Western Denmark Heart Registry and prescription data from the DNPR.
Records of treatment with statin (Anatomical Therapeutic Chemical (ATC) codes C10AA), aspirin (ATC codes B01AC06, N02BA01), oral anti-coagulants (B01AA03, B01AA04, B01AF02, B01AE07, B01AF01), ACE inhibitors/angiotensin II receptor blockers (ATC codes C09A–C09D) and beta-blockers (ATC codes C07) were obtained through the DNPR.23 Treatment was defined as filling ≥1 prescription(s) between 6 months before and 1 month after the index CAG.
MI: MI diagnoses were ascertained through the DNPR by using the ICD-10 code for MI (DI-21) and classified as either a primary (A) or secondary (B) diagnosis during an acute hospital admission. Because of interhospital transfers of patients with acute coronary syndrome, the use of registries to diagnose MI is less valid for the first 30 days after CAG. Beyond 30 days, the sensitivity and specificity of the MI diagnosis was 94% and 98%, respectively.24 Consequently, follow-up was initiated 30 days after CAG.
Ischaemic stroke: ischaemic stroke events were ascertained through the DNPR by using the ICD-10 codes for cerebral infarction (DI-63 or DI-64) as a primary or secondary discharge diagnosis.25
All-cause death: the CRS provided data on the patient vital status (dead, alive or emigrated).
Cardiac death: cardiac death was defined as death resulting from ischaemic heart disease (ICD-10 codes I-20–25); sudden cardiac death (I-46); death resulting from ventricular tachycardia (I-47.2); death due to ventricular fibrillation or flutter (I-49); death resulting from heart failure (I-50); or sudden death, unspecified (R-96, R-98, R-99), as recorded on death certificates from the Danish Register of Causes of Death.
MACE: MACE was defined as either MI, ischaemic stroke or cardiac death, whichever came first.
Follow-up started 30 days after CAG for MI, ischaemic stroke, cardiac death and all-cause death. Follow-up continued until endpoint event, death, emigration or end of follow-up (31 December 2018). Follow-up was additionally capped at the 75th percentile of overall follow-up (10 years). Events after 10 years were censored. The number of each endpoint was counted and event rates per 100 person-years were estimated. The 10-year cumulative incidence proportions (CIP) and CIP curves were estimated and adjusted for the competing risk of all-cause death. With non-RA patients without CAD as the reference, incidence rate ratios (IRRs) were estimated using a modified Poisson regression approach with robust variance-covariance estimator and natural log of person-years as the offset.26 IRRs were adjusted for potential confounding variables (age, sex, hypertension, diabetes, peripheral artery disease, active smoking, oral anticoagulant treatment, antiplatelet treatment and statin treatment). In the case of ischaemic stroke, we additionally adjusted for previous ischaemic stroke/transient ischaemic attack and atrial fibrillation. Smoking status was missing in 10% of patients, which was handled through multiple imputation using chained equations generating 10 imputed datasets assuming data missing at random.27 We also performed subgroup analysis limited to patients with CAD using patients without RA as reference. Stata/MP V.15.1 (StataCorp LLC, College Station, Texas, USA) was used for statistical analyses. We performed a sensitivity analysis using the capture–recapture method to verify the RA diagnosis as used by Pedersen et al.28 Finally, in order to accommodate time-varying confounders, we have added a landmark analysis assuming start of follow-up 3 months after the CAG (online supplementary table 2), which incorporates interventions related to the identification of CAD.
Patient and public involvement
No patient or public involvement was applied.
Out of 125 331 patients followed after CAG, 1732 (1.4%) had RA at the time of examination. In the total patient population, 1061 (0.85%) patients had combined RA and CAD, 671 (0.54%) had RA alone, 75 082 (59.9%) had CAD alone. Finally 48 517 (38.7%) had neither RA nor CAD (table 1). Median follow-up was 5.2 years.
Patient characteristics are presented in table 1. Patients with RA were more frequently female and were characterised by higher proportions of heart failure, hypertension, prior ischaemic stroke and atrial fibrillation than patients without RA.
During the follow-up period, 6907 patients had a MI, 3841 had ischaemic stroke, 26 692 patients died and 4937 suffered a cardiac death. The event rates stratified by RA and CAD are shown in table 2.
Patients with neither RA nor CAD had the lowest 10-year numerical rates of MI (2.7%), ischaemic stroke (2.9%), all-cause death (21.6%), cardiac death (2.3%) and MACE (7.3%). An incremental risk was observed in patients with RA alone, followed by patients with CAD alone, and was highest in patients with combined RA and CAD (table 2). The only exceptions were ischaemic stroke and all-cause mortality where RA alone and CAD alone had a similar intermediary risk. Using patients with neither RA nor CAD as reference, patients with RA alone remained at increased 10-year relative risk of MI after adjustment (IRRadj 1.63 (95% CI 1.04 to 2.54)), ischaemic stroke (IRRadj 1.68 (95% CI 1.14 to 2.48), cardiac death (IRRadj 1.25 (95% CI 0.77 to 2.02)), all-cause death (IRRadj 1.42 (95% CI 1.22 to 1.63)) and MACE (IRRadj 1.6 (95% CI 1.23 to 2.07)). CAD was associated with large incremental relative risks for both patients with CAD alone and for patients with combined RA and CAD. Using patients with CAD alone as reference, combined RA and CAD was associated with increased risk of MI (IRRadj 1.34 (95% CI 1.10 to 1.65)), all-cause death (IRRadj 1.47 (95% CI 1.33 to 1.63)), cardiac death (IRRadj 1.50 (95% CI 1.21 to 1.86)) and MACE (IRRadj 1.35 (95% CI 1.16 to 1.56)). The 10-year CIP curves of MACE, cardiac death, all-cause death and MI are shown in figure 2.
In patients with established CAD,we observed increased prevalence of non-obstructive CAD in patients with RA compared with patients without RA. The presence of obstructive CAD was equally distributed among 1-vessel, 2-vessel and 3-vessel disease between patients with and without RA (table 1).
Sensitivity analysis regarding RA diagnosis and confounder time-varying analysis
We performed a sensitivity analysis to see if use of repeated listing of the RA diagnosis in DNPR would change the point estimates in our dataset; however, this change of registry-based RA definition had no major impact, thus confirming the robustness of our data (online supplementary table 1). Furthermore, the largest possible confounding must be expected to occur in relation to the hospitalisation and the following period. In order to accommodate this, we have added a landmark analysis assuming start of follow-up 3 months after the CAG (online supplementary table 2), which incorporates interventions related to the identification of CAD. This did not lead to relevant changes in the risk estimates.
In the present study, we examined how RA affected the risk of cardiovascular events in patients without and with CAD. The novel findings from this study are that: (1) among patients without CAD, RA was associated with a statistically significant, but numerically marginally, increased risk of cardiovascular events with the exception of stroke; and (2) among patients with CAD, RA was associated with an increased risk of MI, MACE, cardiac death and all-cause mortality. These findings indicate that RA may have a potential impact for precipitating cardiovascular events beyond CAD and, even more importantly, that RA seems to exacerbate the clinical risk of cardiovascular events in the presence of CAD.
In the absence of CAD, RA was associated with an increased relative risk of cardiovascular events ranging from 25% for cardiac death to 63% for MI. This finding was in opposition to our hypothesis. However, with the cumulative 10-year incidence being just above 2%, these differences are numerically small. Our findings suggests that the biological significance remains subtle and thus raises reservations about the justification for routine cardiovascular prophylaxis in all high to very high cardiovascular risk RA patients. This finding is not unique for RA. A similar lack of increased risk of MI and cardiac death has been demonstrated for diabetes mellitus, another well-known cardiovascular risk factor, when classifying CAD by CAG or coronary CT angiography.29 30 It is important to notice that the low risk among patients without CAD was observed in a relatively old population with a high prevalence of conventional risk factors including hypertension, heart failure, atrial fibrillation and diabetes. Our observation suggests that risk calculators based on conventional risk factors may inappropriately classify a large proportion of these patients with RA as high-risk patients. Accordingly, it has been shown that algorithms including RA-specific risk factors did not improve cardiovascular risk predictions for patients with RA compared with general population cardiovascular risk calculators.31 Our result indicates that adding appropriate evaluation for the absence of CAD could add information to established risk calculators for future risk stratification in patients with RA.
An important finding of our study is that presence of CAD distinguished between low-risk and high-risk patients and that presence of RA added significant risk beyond CAD. In comparison to patients with RA alone, the combination of RA and CAD was associated with an increased 10-year risk of cardiovascular events ranging from relative 55% (stroke) to 453% (MI). In comparison to patients with CAD alone, the presence of RA was associated with increased relative risks ranging from 34% to 50%. With a cumulative 10-year risk of almost 25% for MACE, we show that patients with the combination of RA and CAD are at high risk of cardiovascular events. This information may be used to guide personalised prophylactic strategies but this concept warrants validation in prospective randomised trials.
We used CAG for the diagnosis of CAD, which is too invasive to be used for CAD evaluation and not sufficiently accurate to detect non-obstructive CAD. However, coronary CT angiography is a widely available non-invasive method that can be used to diagnose CAD non-invasively.30 32 A review of more than 85,000 patients concluded that absence of coronary calcium by coronary CT angiography is associated with a very low risk of future cardiovascular events.33 Risk stratification based on non-invasive imaging will have the advantage of allowing individualised risk stratification based on knowledge of CAD rather than suspicion of CAD based on traditional scoring systems.31 34–36
Extent of CAD
We found more non-obstructive CAD but no increased incidence of 1-vessel, 2-vessel and 3-vessel disease in patients with RA than in patients without RA. These findings are concordant with results from an autopsy study comparing patients with RA versus patients without RA37 as well as data of patients with RA versus patients without RA undergoing percutaneous coronary intervention.14 However, other researchers demonstrated an increased plaque burden and a higher frequency of multivessel disease in patients with RA than among non-RA controls.8 The different findings may be attributed to differences in study methodology, definitions of vessel disease, and differences between study populations as the duration of RA varied.
Despite equal extent of CAD between groups, the higher frequency of cardiovascular events in RA with CAD might represent a different plaque composition and a higher susceptibility of such plaques to rupture.37
Strengths and limitations
All subjects in our cohort had a clinical reason for referral to CAG. Our cohort may therefore not be representative for asymptomatic patients with RA. The current data are limited to 10-year follow-up, and we can only conclude that the clinical outcomes associated to the baseline angiographic findings were evident for this 10-year period. CAG does not depict lesion morphology and vulnerability, and some patients may have had vulnerable plaques that could not be identified by CAG. On a cohort level, however, the angiographic categorisation predicts outcomes.38 The data collection period was during the era of biological treatment options and the treat to target paradigm, which may have favourably influenced cardiac outcomes in patients with and without CAD given that biologic disease-modifying antirheumatic drugs may constrain plaque progression directly or indirectly.39 40
Finally, use of registry data is associated with the chance of false-positive and false-negative RA diagnoses, which both will tend to mask the true effect of the parameter, in this case RA, under investigation.41 The positive predictive value of the RA diagnosis based on DNPR has been assessed in three studies with values ranging from 60% in older studies, with limited number of patients to 79% in the largest and most recent dataset.28 41 42 It has been shown that >1 RA diagnosis in the DNPR has an improved positive predictive value, which comes at the cost of reduced sensitivity, but it is not known if this changes the relative risk estimates.28 We performed a sensitivity analysis to clarify whether use of repeated listing of the RA diagnosis in DNPR would change the point estimates in our dataset, but this change of registry-based RA definition had no major impact, thus confirming the robustness of our data.
In patients undergoing CAG, RA is significantly associated with the 10-year risk of MI, MACE and all-cause mortality regardless of the presence of CAD. However, patients with RA and CAD carry the largest risk, while the additive risk of RA in patients without CAD is minor. Among patients with RA, risk stratification by presence or absence of documented CAD may allow for screening and personalised treatment strategies.
Handling editor Josef S Smolen
Contributors All authors, BBL, KKWO, DM, CG, PGT, TE, HEB and MM, have substantially contributed to all aspects of this study. BBL, KKO, HEB and MM were involved in the conception and design of the study and performed acquisition of data. BBL, KKWO, HEB and MM were involved in the analysis and interpretation of clinical results. BBL, KKWO, HEB and MM performed drafting of the manuscript. BBL, KKWO, DM, CG, PGT, TE, HEB and MM were involved in the critical revision of the manuscript for important intellectual content. All authors approved the final manuscript before submission.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.
Patient consent for publication Not required.
Ethics approval The study was approved by the Danish Data Protection Agency (record no. 1-16-02-193-18).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data may be obtained from a third party and are not publicly available. Registry data used with the approval from the Danish authorities.