Article Text

Extended report
Outcomes of percutaneous coronary intervention in patients with rheumatoid arthritis and systemic lupus erythematosus: an 11-year nationwide cohort study
1. Chao-Han Lai1,
2. Wu-Wei Lai1,
3. Meng-Jiun Chiou3,
4. Wei-Chieh Lin2,
5. Yu-Jen Yang1,
6. Chung-Yi Li3,4,
7. Liang-Miin Tsai2
1. 1Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
2. 2Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
3. 3Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
4. 4Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan
1. Correspondence to Professor Liang-Miin Tsai, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No. 138, Sheng-Li Road, Tainan 70403, Taiwan; tsailm{at}mail.ncku.edu.tw

## Abstract

Objectives Patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have an increased risk of developing coronary atherosclerosis. However, the impact of RA and SLE on the outcomes in patients undergoing percutaneous coronary intervention (PCI) remains largely underdetermined.

Methods Using the National Health Insurance Research Database of Taiwan, we identified 171 547 adult patients who underwent first-time PCI between 2000 and 2010. Among these patients, 525 had established RA, and 211 had SLE. The ORs of inhospital mortality and HRs of overall mortality and adverse cardiac outcomes after PCI (ie, ischaemic events, repeat revascularisation and major adverse cardiac events (MACE)) in relation to RA and SLE were estimated.

Results After adjustment for potential confounders, including patient characteristics and procedural variables, RA (OR=1.73, 95% CI 1.11 to 2.68) and SLE (OR=3.81, 95% CI 2.02 to 7.16) were independent predictors of inhospital mortality. In addition, RA was independently associated with overall mortality (HR=1.55, 95% CI 1.35 to 1.79), ischaemic events (HR=1.18, 95% CI 1.01 to 1.39) and MACE (HR=1.20, 95% CI 1.07 to 1.34) during long-term follow-up, whereas SLE was independently associated with overall mortality (HR=2.20, 95% CI 1.74 to 2.78), repeat revascularisation (HR=1.27, 95% CI 1.02 to 1.58) and MACE (HR=1.47, 95% CI 1.24 to 1.75). Compared with patients without autoimmune diseases, patients with more recent SLE-related hospitalisations prior to PCI were at higher risk of inhospital mortality (p for trend <0.0001).

Conclusions This study recognises the inherent risks associated with RA and SLE in patients undergoing PCI and highlights the necessity to improve the caring and secondary prevention strategies for these high-risk patients.

• Cardiovascular Disease
• Rheumatoid Arthritis
• Systemic Lupus Erythematosus
• Outcomes research

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## Introduction

Atherosclerosis has been traditionally considered a lipid-driven disorder affecting the arterial system. Over the past two decades, however, this theory has been substantially modified based on increased knowledge of the pathophysiology of atherosclerosis.1–4 Recent evidence supports an essential role of chronic inflammation in the development and propagation of systemic atherosclerosis.1–4 Autoimmune diseases, a group of disorders arising from abnormal autoimmunity, can involve different organ systems with a wide spectrum of clinical manifestations. These inflammatory rheumatic disorders can lead to chronic, relapsing and systemic inflammatory responses that increase cardiovascular risks in affected patients. A number of autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), polymyositis-dermatomyositis (PM-DM), systemic sclerosis (SSc) and inflammatory bowel diseases (IBD), have been associated with the development of coronary artery disease (CAD), myocardial infarction and cardiovascular death.1–8

The high burden of cardiovascular diseases in patients with autoimmune diseases has drawn attention to whether autoimmune diseases might worsen the prognosis for CAD. Outcomes after myocardial infarction/acute coronary syndrome (ACS) have been compared in patients with autoimmune diseases, such as RA and SLE, and the general populations in several studies.7–14 Although some patients undergo coronary revascularisation with percutaneous coronary intervention (PCI), the most frequently used revascularisation procedure for CAD in contemporary practice, early and late outcomes have rarely been specified for this subgroup. Several studies have focused on the outcomes of PCI in patients with autoimmune diseases.15–18 However, the outcomes in patients with RA versus patients without RA are inconsistent in the literature,15–17 and available data for SLE are based on a small number of patients with a limited duration of follow-up.18 In the modern era of widespread use of intervention therapy, the outcomes of PCI in patients with autoimmune diseases remain largely underdetermined. The impact of autoimmune diseases on patients undergoing PCI requires further elucidation.

The National Health Insurance Research Database (NHIRD) of Taiwan contains a large sample size and high validity of diagnosis for catastrophic illnesses (eg, autoimmune diseases, cancers, congenital heart diseases and end-stage renal disease (ESRD)), and thus may be suitable to appraise the outcomes following certain procedures in patients with rare diseases. In addition, this database has provided a valuable real-world platform for elucidating various clinical facets of autoimmune diseases.19–22 In studies presented here we attempted, through the NHIRD of Taiwan, to describe the characteristics and outcomes of patients with autoimmune diseases undergoing PCI and to investigate whether autoimmune diseases might be associated with increased risks of inhospital mortality after PCI and of adverse outcomes during long-term follow-up.

## Patients and methods

### The PCI cohort

This retrospective cohort study was conducted using the NHIRD of Taiwan (see online supplementary text 1). In this database, the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) is used to define diseases and procedures.19–22 The ICD-9-CM codes of procedures and diseases described in this study are listed in online supplementary table S1. Our access to NHIRD was approved by the Review Committee of the National Health Research Institutes.

The study cohort was identified from the inpatient hospital claims of the NHIRD, which provides data for all hospitalised patients undergoing PCI. The procedures used to establish the study cohort are summarised in figure 1. We selected hospitalisations with procedure codes for PCI, including percutaneous transluminal coronary angioplasty and coronary artery stenting, from 1 January 2000 to 31 December 2010. There were 271 711 hospitalisations for PCI during the study period. Among these hospitalisations, 171 547 adult patients who underwent first-time PCI were identified as the study cohort. Using the catastrophic illness database, we identified 525 patients with RA (0.31%) and 211 patients with SLE (0.12%) in the PCI cohort. Patients with PM-DM (25 patients), SSc (21 patients) and IBD (16 patients) were few in number and therefore not analysed in this study.

Figure 1

Study flow chart: cohort assembly of 171 547 adult patients undergoing first-time percutaneous coronary intervention between 2000 and 2010 in the National Health Insurance Research Database of Taiwan. PCI, percutaneous coronary intervention; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; PM-DM, polymyositis-dermatomyositis; IBD, inflammatory bowel diseases.

### Comorbidities and outcome measurements

Based on the hospital care data and prior hospitalisations of each patient, we identified baseline medical comorbidities, including hypertension, diabetes mellitus (DM), hyperlipidaemia, congestive heart failure (CHF), chronic kidney disease (CKD), peripheral artery disease (PAD), prior stroke, chronic obstructive pulmonary disease (COPD), dementia and Parkinson's disease. Patients with ESRD were further recognised from patients with CKD if they were registered with dialysis catastrophic illness certificates. We also identified whether the patients were hospitalised with a diagnosis of ACS. In addition, we distinguished the accreditation levels of the hospitals at which the PCI procedures were conducted (ie, medical centres, regional hospitals or district hospitals). The use of stenting during the PCI procedures was also recorded.

Inhospital mortality was measured. Overall mortality and adverse cardiac outcomes during long-term follow-up, including ischaemic events, repeat revascularisation and major adverse cardiac events (MACE) after PCI, were also evaluated and analysed. Ischaemic events were defined as rehospitalisations due to ACS after PCI. Repeat revascularisation was defined as rehospitalisations for either re-PCI or coronary artery bypass grafting after PCI. Finally, MACE was a composite end point, defined as any occurrence of all-cause mortality, myocardial infarction and repeat revascularisation.23 ,24 The three selected adverse cardiac outcomes that occurred prior to censoring events, including mortality, withdrawal from the insurance programme or 31 December 2011, were recorded. The first episode of each outcome was counted when a patient experienced more than one episode.

### Statistical analysis

The control group comprised patients who did not have any of the abovementioned autoimmune diseases. Patients with RA and SLE were compared separately with the control group to describe the differences in baseline characteristics and outcomes. Categorical variables, expressed as numbers and percentages, were compared using the χ2 test or Fisher's exact test. Continuous variables, expressed as mean±SD, were compared using the Student's t test. Kaplan-Meier estimates of overall survival and freedom from ischaemic events, repeat revascularisation and any MACE were plotted. Logistic regression analysis was performed to estimate the ORs of inhospital mortality associated with RA and SLE, with adjustment for potential confounding variables considered in relevant cardiovascular studies,24–26 including patient characteristics (ie, age, sex, hypertension, DM, hyperlipidaemia, CHF, CKD, PAD, prior stroke, COPD, dementia, Parkinson's disease and ACS), stenting and hospital levels. A Cox proportional hazards regression model with adjustment for potential confounding variables was performed to estimate the HRs of overall mortality, ischaemic events, repeat revascularisation and any MACE after PCI associated with RA and SLE. To evaluate the potential impact of recent RA-related and SLE-related hospitalisations on the inhospital outcomes of PCI, the patients were divided into three categories: (1) patients without a history of recent hospitalisations within 2 years prior to PCI, (2) patients with a history of recent hospitalisations between 2 years and 2 months prior to PCI, and (3) patients with a history of recent hospitalisations within 2 months. The adjusted ORs of inhospital mortality were then estimated. Additionally, to evaluate the potential impact of disease duration of RA and SLE prior to PCI on inhospital outcomes of PCI, the patients were divided into two categories: (1) patients with disease duration of 3 years or less and (2) patients with disease duration of longer than 3 years, and the adjusted ORs of inhospital mortality were estimated. Statistical analyses were performed using SAS, version 9.3 (SAS Institute, Cary, North Carolina, USA) and Stata/SE 12.0 for Windows (StataCorp; College Station, Texas). A p value less than 0.05 was considered statistically significant.

## Results

### Baseline characteristics and procedures

The comparisons of baseline characteristics and operative data for patients without autoimmune diseases (the control group), patients with RA and patients with SLE in the PCI cohort are summarised in table 1. Among the 170 762 patients without autoimmune diseases, the mean age was 65.3 years, with a male-to-female ratio of 2.56. Hypertension (65.9%) was the most common underlying medical comorbidity. The average total hospital cost was NT$160 421 per hospitalisation, equivalent to approximately US$5416 or €4124.

Table 1

Comparison of patient characteristics between patients without autoimmune diseases (control group), patients with RA and patients with SLE in the PCI cohort of Taiwan, 2000–2010

Compared with the control group, the 525 patients with RA were significantly older and predominantly female. The patients with RA had a lower proportion of hyperlipidaemia and higher proportions of CHF and COPD and more frequently underwent stenting during PCI. Among the 211 patients with SLE, the mean age was significantly lower than that of the control group. The patients with SLE were predominantly female. Although the patients with SLE had significantly lower proportions of DM and hyperlipidaemia, these patients were much more likely to have CKD and ESRD. The PCI procedures for patients with SLE were primarily conducted in medical centres (p<0.0001, the distribution of hospital levels). Moreover, the average total hospital costs per hospitalisation of patients with RA and SLE were significantly higher than the costs for patients without autoimmune diseases.

### Inhospital outcomes

The inhospital mortality rates following PCI procedures in the control group, in patients with RA and in patients with SLE were 2.0%, 4.2% and 5.2%, respectively (table 2). RA and SLE were associated with increased odds of inhospital mortality. After adjustment for potential confounding variables, RA (adjusted OR 1.73, 95% CI 1.11 to 2.68, p=0.01) and SLE (adjusted OR 3.81, 95% CI 2.02 to 7.16, p<0.0001) were independent predictors of inhospital mortality.

Table 2

ORs of inhospital mortality and HRs of overall mortality and adverse cardiac outcomes associated with RA and SLE

### Long-term follow-up

The Kaplan-Meier estimates of overall survival, freedom from ischaemic events, freedom from repeat revascularisation and freedom from any MACE are depicted in figure 2A–D, respectively. The HRs of overall mortality, ischaemic events, repeat revascularisation and MACE associated with RA and SLE are presented in table 2. RA and SLE were associated with an increased risk of overall mortality during the follow-up period. After controlling for potential confounding variables, RA (adjusted HR 1.55, 95% CI 1.35 to 1.79, p<0.0001) and SLE (adjusted HR 2.20, 95% CI 1.74 to 2.78, p<0.0001) remained independent predictors of overall mortality after PCI.

Figure 2

Kaplan–Meier estimates of (A) overall survival, (B) freedom from ischaemic events, (C) freedom from repeat revascularisation and (D) freedom from any MACE in patients without autoimmune diseases (control group), patients with RA and patients with SLE in the PCI cohort of Taiwan, 2000–2010. RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; PCI, percutaneous coronary intervention; MACE, major adverse cardiac events.

During the follow-up period, RA was significantly associated with an increased risk of ischaemic events, whereas SLE was not. After adjustment for potential confounding variables, RA remained an independent predictor of ischaemic events after PCI (adjusted HR 1.18, 95% CI 1.01 to 1.39, p=0.04).

During the follow-up period, SLE was marginally associated with an increased risk of repeat revascularisation (crude HR 1.23, 95% CI 0.99 to 1.52, p=0.06), whereas RA was not. After adjustment for potential confounding variables, SLE was an independent predictor of repeat revascularisation after PCI (adjusted HR 1.27, 95% CI 1.02 to 1.58, p=0.03). As shown in figure 2C, the risks of repeat revascularisation associated with SLE before and after 4 years since PCI were somewhat different and thus were further estimated. SLE was not significantly associated with repeat revascularisation within 4 years (adjusted HR 1.18, 95% CI 0.93 to 1.49, p=0.18) but was associated with an increased risk of repeat revascularisation beyond 4 years after PCI (adjusted HR 2.28, 95% CI 1.29 to 4.03, p=0.005).

During the follow-up period, RA and SLE were associated with an increased risk of MACE. After controlling for potential confounding variables, RA (adjusted HR 1.20, 95% CI 1.07 to 1.34, p=0.001) and SLE (adjusted HR 1.47, 95% CI 1.24 to 1.75, p<0.0001) were independent predictors of MACE.

### The impact of recent hospitalisations and disease duration on inhospital outcomes

The impact of recent RA-related and SLE-related hospitalisations prior to PCI on the inhospital outcome of PCI was evaluated (table 3). Compared with the control group, patients with recent SLE-related hospitalisations prior to PCI were associated with an increase in adjusted ORs of inhospital mortality (p for trend <0.0001), whereas those with recent RA-related hospitalisations were not. We also evaluated the impact of the disease duration of RA and SLE prior to PCI on the inhospital outcome of PCI (see online supplementary table S2). Compared with the control group, patients with RA and SLE with disease duration of longer than 3 years were associated with an increase in adjusted ORs of inhospital mortality.

Table 3

Adjusted ORs of inhospital mortality associated with recent RA-related and SLE-related hospitalisations prior to PCI

## Discussion

Whereas most relevant studies have primarily focused on RA, the present study extended the scope to demonstrate the impact of SLE on patients undergoing PCI. Using a nationwide database, we found that PCI procedures for patients with SLE in this cohort were primarily conducted in medical centres. Despite younger age and a lower prevalence of traditional risk factors for CAD (eg, DM and hyperlipidaemia), patients with SLE had a much higher prevalence of CKD and ESRD. Even after adjustment for potential confounding factors, SLE remained an independent predictor of inhospital mortality, overall mortality, repeat revascularisation and MACE after PCI (table 2). Using the National Heart, Lung and Blood Institute Dynamic Registry across 23 clinical centres in North America, Maksimowicz-McKinnon et al18 examined the outcomes of 28 patients with SLE and 3385 patients without SLE undergoing PCI. Probably in association with a hypercoagulable state and low frequency of aspirin therapy, patients with SLE required repeat PCI more often than patients without SLE within 1 year. In the present study, the risk of repeat revascularisation was higher in patients with SLE. However, this effect was not apparent until 4 years after PCI. In addition, we found that recent SLE-related hospitalisations might affect inhospital mortality after PCI, consistent with the observation by Lin et al22 that a recent history of hospitalisations due to SLE prior to major surgery may increase risks of postoperative 30-day inhospital overall complications and mortality. The choice of optimal timing for PCI warrants further investigation to improve the early outcomes of these patients (see online supplementary text 2).

Our study has some limitations. First, the numbers of patients with PM-DM, SSc and IBD were insufficient for analyses in this nationwide study. Further studies using larger databases including these diagnoses as data collection items would likely overcome this problem. Second, large reimbursement cuts in Taiwan, evidenced as low total hospital costs in the cohort, might reduce the quality of cardiac care.42 This economic factor could possibly bring more negative impacts on patients with autoimmune diseases who underwent PCI as these patients inevitably are in need of multidisciplinary care (see online supplementary text 3). Validation of our findings in other healthcare systems and countries is required. Third, some variables of interest were unavailable from the medical claims, such as the extent and distribution of CAD, choice of coronary stents (bare metal stents or drug-eluting stents), details of immunosuppressants and causes of death; thus, these variables cannot be considered in the analyses. Finally, a relatively small percentage of missing data or miscoded diagnoses is inherent in studies using large databases. However, such coding errors are likely random and should not be a valid argument for the observed findings of the present study because non-differential disease misclassification tends to bias the results towards the null.

In summary, our study may help rheumatologists and cardiologists recognise the inherent risks associated with RA and SLE in patients undergoing PCI. Previous investigators have clearly demonstrated that patients with RA and SLE are at increased risk for the development of CAD and associated morbidity and mortality. The present study further demonstrates that following coronary revascularisation with PCI, the risks of mortality and adverse cardiac outcomes remain higher in patients with RA and SLE. These findings highlight the urgent need to improve the caring and secondary prevention strategies after PCI for these high-risk patients.

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• ## Supplementary Data

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

## Footnotes

• Handling editor Tore K Kvien

• C-YL and L-MT contributed equally.

• Contributors Study conception and design: C-HL, W-WL, Y-JY, C-YL, L-MT. Acquisition of data: C-HL, M-JC, W-CL. Analysis and interpretation of data: C-HL, M-JC, W-CL, C-YL, L-MT. Manuscript drafting and critical review: All authors. Final approval of the manuscript: All authors.

• Funding This work was supported by a grant from the National Cheng Kung University Hospital, Tainan, Taiwan (NCKUH-10403012 to C-HL).

• Competing interests None declared.

• Disclaimer The present study was based on data from the NHIRD provided by the National Health Insurance (NHI) administration, Ministry of Health and Welfare of Taiwan and the National Health Research Institutes (NHRI) of Taiwan. However, the interpretation and conclusions contained herein do not represent those of the NHI administration, Ministry of Health and Welfare of Taiwan or the NHRI of Taiwan.

• Ethics approval The study protocol was approved by the Institutional Review Board of National Cheng Kung University Hospital (approval number: A-EX-102-010).

• Provenance and peer review Not commissioned; externally peer reviewed.