TY - JOUR
AU - on behalf of the BASKET-PROVE Investigators
AB - Abstract Aims Rheumatologic disorders are characterised by inflammation and an increased risk of coronary artery disease (CAD). However, the association between rheumatologic disorders and long-term prognosis in CAD patients undergoing percutaneous coronary intervention (PCI) is unknown. Thus, we aimed to examine the association between rheumatologic disorders and long-term prognosis in CAD patients undergoing PCI. Methods and results A post-hoc analysis was performed in 4605 patients (age: 63.3 ± 11.0 years; male: 76.6%) with ST-segment elevation myocardial infarction (STEMI; n = 1396), non-STEMI (n = 1541), and stable CAD (n = 1668) from the all-comer stent trials, the BAsel Stent Kosten-Effektivitäts Trial-PROspective Validation Examination (BASKET-PROVE) I and II trials. We evaluated the association between rheumatologic disorders and 2-year major adverse cardiac events (MACEs; cardiac death, nonfatal myocardial infarction (MI), and target vessel revascularisation (TVR)) by Cox regression analysis. Patients with rheumatologic disorders (n = 197) were older, more often female, had a higher prevalence of renal disease, multi-vessel coronary disease, and bifurcation lesions, and had longer total stent lengths. During the 2-year follow-up, the MACE rate was 8.6% in the total cohort. After adjustment for potential confounders, rheumatologic disorders were associated with MACEs in the total cohort (adjusted hazard ratio: 1.55; 95% confidence interval (CI): 1.04–2.31) driven by the STEMI subgroup (adjusted hazard ratio: 2.38; 95% CI: 1.26–4.51). In all patients, rheumatologic disorders were associated with all-cause death (adjusted hazard ratio: 2.05; 95% CI: 1.14–3.70), cardiac death (adjusted hazard ratio: 2.63; 95% CI: 1.27–5.43), and non-fatal MI (adjusted hazard ratio: 2.64; 95% CI: 1.36–5.13), but not with TVR (adjusted hazard ratio: 0.81; 95% CI: 0.41–1.58). Conclusions The presence of rheumatologic disorders appears to be independently associated with worse outcome in CAD patients undergoing PCI. This calls for further studies and focus on this high-risk group of patients following PCI. Coronary artery disease, rheumatologic disorders, prognosis, revascularisation Introduction Inflammation is crucial at all stages of atherosclerotic plaque development, implying that coronary artery disease (CAD) is also an inflammatory disorder.1,2 Rheumatologic disorders are characterised by inflammation and are associated with an increased risk of cardiovascular events.1,3–5 In fact, patients with rheumatic disorders have a greater risk of CAD and stroke with an increased degree of inflammation.1,3–5 A recent meta-analysis showed that patients with systemic sclerosis had an 82% increased risk of CAD compared with matched non-systemic sclerosis subjects.6 However, few studies have assessed the prognostic impact of rheumatologic disorders in established CAD.7,8 A previous study has shown that 30-day cardiovascular mortality was 17.6% in patients after myocardial infarction (MI) or stroke with rheumatoid arthritis (RA) versus 10.8% in the patients without RA between 2001 and 2003 in Australia. However, there are limited data in terms of long-term prognosis in a contemporary population. Therefore, we sought to evaluate the association between rheumatologic disorders and long-term prognosis in patients with CAD in a real-world practice based on a sub-analysis of data from the all-comer stent trials, the BAsel Stent Kosten-Effektivitäts Trial-PROspective Validation Examination (BASKET-PROVE) I9,10 and II11,12 trials. Methods Data sources A pooled dataset of 4605 patients with acute or stable CAD from the BASKET-PROVE I and II trials were used in the study. The design and primary findings of these trials have been published previously.9–12 In brief, the BASKET-PROVE I trial (ISRCTN72444640) was performed in order to investigate the relative efficacy of first-generation drug-eluting stents (DESs) and bare-metal stents (BMSs) placed in large coronary arteries as a large, prospective, randomised, multicentre trial (n = 2314) in Switzerland, Denmark, Austria, and Italy from 2007 to 2010. The trial also compared the risk–benefit balance of first-generation and second-generation DESs. Eligible patients were those with chronic or acute coronary disease who underwent angioplasty with stenting and required only stents of ⩾3.0 mm in diameter. Exclusion criteria were cardiogenic shock, in-stent restenosis or thrombosis of stents placed before the study, unprotected left main coronary artery (i.e., with no functioning bypass graft) or substantial stenosis in a bypass graft, plans for any surgery within 12 months, a need for oral anticoagulation, an increased risk of bleeding, known intolerance to or suspected non-compliance with long-term antiplatelet therapy, or circumstances that would have made follow-up impossible. In addition, patients requiring stents larger than 4.0 mm in diameter were excluded, as no sirolimus-eluting stents of this size were available.9,10 The BASKET-PROVE II trial (NCT01166685) was a large, prospective, randomised, multicentre trial (n = 2291) in Switzerland, Denmark, Austria, and Germany from 2012 and 2014. The trial was performed to evaluate the long-term efficacy and safety of a biodegradable-polymer DES (BP-DES) compared with the most widely used durable-polymer DES (DP-DES) and a last-generation thin strut-coated BMS for late safety in patients with a background of dual antiplatelet therapy, including prasugrel. In the BASKET-PROVE II trial, patients with a history of transient ischaemic attack or stroke were excluded, in addition to those in BASKET-PROVE I in view of the use of prasugrel.11,12 Study procedures Angioplasty and stenting were performed using standard techniques chosen at the discretion of each interventional cardiologist. All BASKET-PROVE I and II patients were prescribed aspirin at a daily dose of 75–100 mg indefinitely. In the BASKET-PROVE I trial, patients received clopidogrel at a daily dose of 75 mg for 1 year, after a loading dose of 300 mg or 600 mg, regardless of stent type. In the BASKET-PROVE II trial, all patients received a loading dose of 60 mg prasugrel with a maintenance dose of 10 mg daily, risk adjusted to 5 mg in patients aged >75 years or with body weight <60 kg. Prasugrel was prescribed for 12 months after stenting with DESs and for patients with acute coronary syndrome, and for 4 weeks after elective stenting with BMSs. Prasugrel was not provided after 12 months. All other concomitant treatments were prescribed according to current guidelines. Definition of rheumatologic disorders and endpoints We defined rheumatologic disorders as the full spectrum of these disorders, including autoimmune diseases, such as systemic sclerosis, lupus, RA, and psoriatic arthritis, as well as other forms of arthritis. The presence of rheumatologic disorders was solely determined clinically based on history and clinical presentation by local investigators at the study enrolment and recorded as a rheumatologic disorder in the case report form at that time. No measures of inflammation status was recorded in the case record form. The primary outcome in the present study was major adverse cardiac events (MACE), a combination of cardiac death, nonfatal MI, and/or clinically driven non-MI-related target vessel revascularisation (TVR) within 2 years. Cardiac death was defined as any death without a clear extracardiac cause. MI required a clinical event with typical electrocardiographic or enzymatic changes.13 Stent thrombosis was defined according to the criteria of the Academic Research Consortium.14 We also evaluated outcome details of all-cause death, cardiac death, nonfatal MI, TVR, and stent thrombosis at 30 days and 2 years. The same independent critical events committee adjudicated all critical events in a blinded fashion as preciously described.10,12 Statistical analysis Descriptive statistics, including mean ± SD, median, and frequencies for continuous and categorical data, are presented for all patients and stratified by the presence of rheumatologic disorders. Wilcoxon rank sum and Pearson chi-square tests were used to compare characteristics among patients by the presence of rheumatologic disorders. Kaplan–Meier curves for the outcomes were stratified by rheumatologic disorders and evaluated with log-rank tests. We used the multivariable Cox proportional hazard models. We included rheumatologic disorders (variable of interest), age ⩾65 years, and female sex as confounders in all multivariable Cox models. We also included the following variables using a stepwise method with backward elimination: smoking, diabetes mellitus, arterial hypertension, family history of CAD, history of MI, history of percutaneous coronary intervention (PCI), history of coronary artery bypass grafting (CABG), heart failure, stroke or transient ischaemic attack, BMS use, aortic aneurysm, peripheral arterial occlusive disease, chronic obstructive pulmonary disease, liver disease, left main trunk disease, left anterior descending disease, multi-vessel disease, bifurcation lesions, serum creatinine level at baseline, stent length, and statin use at discharge. Since the dataset had 1245 missing values of serum creatinine (Supplemental Table 1) and there was no difference in the outcomes between patients with and without creatinine data (Supplemental Figure 1), we conducted multiple imputations for serum creatinine by Nelson–Aalen methods.15 All analyses were performed using STATA 13 (StataCorp). A two-sided p-value < 0.05 was considered to be significant. Results Baseline characteristics of patients The baseline characteristics of the 4605 patients (mean age: 63 ± 11 years; female: 23%) stratified by rheumatologic disorders are shown in Table 1. Patients with rheumatologic disorders (n = 197, 4.3% of all patients) were older and more commonly female, had a higher prevalence of renal disease and multi-vessel coronary disease, more treated bifurcation lesions, and a longer total stent length. Baseline parameters of the overall cohort of patients from the BASKET-PROVE I and II trials were very similar; the only significant differences were usage rates of a glycoprotein IIb/IIIa inhibitors, clopidogrel (BASKET-PROVE I), and prasugrel (BASKET-PROVE II) according to the corresponding protocols (Supplemental Table 2). Among the 4605 patients, 1396 (30.3%), 1541 (33.5%), and 1668 (36.2%) presented with ST-segment elevation MI (STEMI), non-STEMI, and stable CAD, respectively (Supplemental Table 3). Baseline characteristics in coronary artery disease patients after percutaneous coronary intervention by the presence of rheumatologic disorders Table 1. Baseline characteristics in coronary artery disease patients after percutaneous coronary intervention by the presence of rheumatologic disorders Characteristic . With rheumatologic disorders . Without rheumatologic disorders . p-value . Number of patients 197 4408 Age, years 68.7 ± 10.0 63.1 ± 11.0 <0.001 Female sex, n (%) 80 (41) 996 (23) <0.001 Smoking, n (%) 0.009  Never 84 (43) 1555 (35)  Current 48 (24) 1533 (35)  Former 65 (33) 1320 (30) Diabetes, n (%) 0.08  Non-insulin dependent 24 (12) 564 (13)  Insulin dependent 15 (8) 189 (4) Atrial hypertension, n (%) 139 (71) 2821 (64) 0.06 Dyslipidaemia, n (%) 125 (64) 2792 (63) 0.97 Family history, n (%) 70 (36) 1578 (36) 0.9 Renal disease, n (%) 27 (14) 238 (5) <0.001 Previous MI, n (%) 20 (10) 468 (11) 0.84 Previous PCI, n (%) 23 (12) 562 (13) 0.66 Previous CABG, n (%) 2 (1) 124 (3) 0.13 Heart failure, n (%) 14 (7) 236 (5) 0.29 Stroke or TIA, n (%) 0.62  TIA 4 (2) 55 (1)  Stroke 2 (1) 51 (1) STEMI, n (%) 63 (32) 1333 (30) 0.6 NSTEMI, n (%) 68 (35) 1473 (33) 0.75 Stable CAD, n (%) 66 (34) 1602 (36) 0.42 BMS allocation, n (%) 56 (28) 1470 (33) 0.15 DES allocation, n (%) 141 (72) 2938 (68) Aortic aneurysm, n (%) 1 (0.5) 32 (0.7) 0.72 PAOD, n (%) 12 (6) 187 (4) 0.21 COPD, n (%) 9 (5) 274 (6) 0.35 Liver disease, n (%) 2 (1) 92 (2) 0.3 Peptic ulcer disease, n (%) 10 (5) 111 (3) 0.028 Cancer, n (%) 0.22  None 183 (92.9) 4212 (95.6)  Metastasis 1 (0.5) 15 (0.3)  Non-metastatic within last 5 years 13 (6.6) 18 (4.1) Creatinine at baseline, µmol/L 83.4 ± 39.1 83.1 ± 27.0 0.92 Treated vessels, n (%)  Left main artery 0 47 (1) 0.15  Left anterior descending artery 138 (70) 2826 (64) 0.09  Left circumflex artery 83 (42) 1569 (36) 0.06  Right coronary artery 124 (63) 2296 (52) 0.003 Multi-vessel disease, n (%) 103 (52) 1764 (40) <0.001 Treated bifurcations, n (%) 28 (14) 282 (6) <0.001 Treated CTO, n (%) 8 (4) 186 (4) 0.91 Total stent length, mm 33.7 ± 23.3 28.2 ± 19.6 <0.001 Days of hospitalisation 6.0 ± 4.4 5.1 ± 4.2 0.003 Medication use at discharge, n (%)  Platelet inhibitors 196 (99.5) 4396 (99.7) 0.54  Clopidogrel 104 (53) 2301 (52) 0.87  Prasugrel 93 (47) 2142 (49)  Anticoagulation 6 (3) 162 (4) 0.64  Statin 182 (92) 4144 (95) 0.21 Characteristic . With rheumatologic disorders . Without rheumatologic disorders . p-value . Number of patients 197 4408 Age, years 68.7 ± 10.0 63.1 ± 11.0 <0.001 Female sex, n (%) 80 (41) 996 (23) <0.001 Smoking, n (%) 0.009  Never 84 (43) 1555 (35)  Current 48 (24) 1533 (35)  Former 65 (33) 1320 (30) Diabetes, n (%) 0.08  Non-insulin dependent 24 (12) 564 (13)  Insulin dependent 15 (8) 189 (4) Atrial hypertension, n (%) 139 (71) 2821 (64) 0.06 Dyslipidaemia, n (%) 125 (64) 2792 (63) 0.97 Family history, n (%) 70 (36) 1578 (36) 0.9 Renal disease, n (%) 27 (14) 238 (5) <0.001 Previous MI, n (%) 20 (10) 468 (11) 0.84 Previous PCI, n (%) 23 (12) 562 (13) 0.66 Previous CABG, n (%) 2 (1) 124 (3) 0.13 Heart failure, n (%) 14 (7) 236 (5) 0.29 Stroke or TIA, n (%) 0.62  TIA 4 (2) 55 (1)  Stroke 2 (1) 51 (1) STEMI, n (%) 63 (32) 1333 (30) 0.6 NSTEMI, n (%) 68 (35) 1473 (33) 0.75 Stable CAD, n (%) 66 (34) 1602 (36) 0.42 BMS allocation, n (%) 56 (28) 1470 (33) 0.15 DES allocation, n (%) 141 (72) 2938 (68) Aortic aneurysm, n (%) 1 (0.5) 32 (0.7) 0.72 PAOD, n (%) 12 (6) 187 (4) 0.21 COPD, n (%) 9 (5) 274 (6) 0.35 Liver disease, n (%) 2 (1) 92 (2) 0.3 Peptic ulcer disease, n (%) 10 (5) 111 (3) 0.028 Cancer, n (%) 0.22  None 183 (92.9) 4212 (95.6)  Metastasis 1 (0.5) 15 (0.3)  Non-metastatic within last 5 years 13 (6.6) 18 (4.1) Creatinine at baseline, µmol/L 83.4 ± 39.1 83.1 ± 27.0 0.92 Treated vessels, n (%)  Left main artery 0 47 (1) 0.15  Left anterior descending artery 138 (70) 2826 (64) 0.09  Left circumflex artery 83 (42) 1569 (36) 0.06  Right coronary artery 124 (63) 2296 (52) 0.003 Multi-vessel disease, n (%) 103 (52) 1764 (40) <0.001 Treated bifurcations, n (%) 28 (14) 282 (6) <0.001 Treated CTO, n (%) 8 (4) 186 (4) 0.91 Total stent length, mm 33.7 ± 23.3 28.2 ± 19.6 <0.001 Days of hospitalisation 6.0 ± 4.4 5.1 ± 4.2 0.003 Medication use at discharge, n (%)  Platelet inhibitors 196 (99.5) 4396 (99.7) 0.54  Clopidogrel 104 (53) 2301 (52) 0.87  Prasugrel 93 (47) 2142 (49)  Anticoagulation 6 (3) 162 (4) 0.64  Statin 182 (92) 4144 (95) 0.21 BMS: bare-metal stent; CABG: coronary artery bypass grafting; COPD: chronic obstructive pulmonary disease; CTO: chronic total occlusion; DES: drug-eluting stent; MI: myocardial infarction; NSTEMI: non-ST-segment elevation myocardial infarction; PAOD: peripheral artery occlusive disease; PCI: percutaneous coronary intervention; STEMI: ST-segment elevation myocardial infarction; TIA: transient ischaemic attack. Open in new tab Table 1. Baseline characteristics in coronary artery disease patients after percutaneous coronary intervention by the presence of rheumatologic disorders Characteristic . With rheumatologic disorders . Without rheumatologic disorders . p-value . Number of patients 197 4408 Age, years 68.7 ± 10.0 63.1 ± 11.0 <0.001 Female sex, n (%) 80 (41) 996 (23) <0.001 Smoking, n (%) 0.009  Never 84 (43) 1555 (35)  Current 48 (24) 1533 (35)  Former 65 (33) 1320 (30) Diabetes, n (%) 0.08  Non-insulin dependent 24 (12) 564 (13)  Insulin dependent 15 (8) 189 (4) Atrial hypertension, n (%) 139 (71) 2821 (64) 0.06 Dyslipidaemia, n (%) 125 (64) 2792 (63) 0.97 Family history, n (%) 70 (36) 1578 (36) 0.9 Renal disease, n (%) 27 (14) 238 (5) <0.001 Previous MI, n (%) 20 (10) 468 (11) 0.84 Previous PCI, n (%) 23 (12) 562 (13) 0.66 Previous CABG, n (%) 2 (1) 124 (3) 0.13 Heart failure, n (%) 14 (7) 236 (5) 0.29 Stroke or TIA, n (%) 0.62  TIA 4 (2) 55 (1)  Stroke 2 (1) 51 (1) STEMI, n (%) 63 (32) 1333 (30) 0.6 NSTEMI, n (%) 68 (35) 1473 (33) 0.75 Stable CAD, n (%) 66 (34) 1602 (36) 0.42 BMS allocation, n (%) 56 (28) 1470 (33) 0.15 DES allocation, n (%) 141 (72) 2938 (68) Aortic aneurysm, n (%) 1 (0.5) 32 (0.7) 0.72 PAOD, n (%) 12 (6) 187 (4) 0.21 COPD, n (%) 9 (5) 274 (6) 0.35 Liver disease, n (%) 2 (1) 92 (2) 0.3 Peptic ulcer disease, n (%) 10 (5) 111 (3) 0.028 Cancer, n (%) 0.22  None 183 (92.9) 4212 (95.6)  Metastasis 1 (0.5) 15 (0.3)  Non-metastatic within last 5 years 13 (6.6) 18 (4.1) Creatinine at baseline, µmol/L 83.4 ± 39.1 83.1 ± 27.0 0.92 Treated vessels, n (%)  Left main artery 0 47 (1) 0.15  Left anterior descending artery 138 (70) 2826 (64) 0.09  Left circumflex artery 83 (42) 1569 (36) 0.06  Right coronary artery 124 (63) 2296 (52) 0.003 Multi-vessel disease, n (%) 103 (52) 1764 (40) <0.001 Treated bifurcations, n (%) 28 (14) 282 (6) <0.001 Treated CTO, n (%) 8 (4) 186 (4) 0.91 Total stent length, mm 33.7 ± 23.3 28.2 ± 19.6 <0.001 Days of hospitalisation 6.0 ± 4.4 5.1 ± 4.2 0.003 Medication use at discharge, n (%)  Platelet inhibitors 196 (99.5) 4396 (99.7) 0.54  Clopidogrel 104 (53) 2301 (52) 0.87  Prasugrel 93 (47) 2142 (49)  Anticoagulation 6 (3) 162 (4) 0.64  Statin 182 (92) 4144 (95) 0.21 Characteristic . With rheumatologic disorders . Without rheumatologic disorders . p-value . Number of patients 197 4408 Age, years 68.7 ± 10.0 63.1 ± 11.0 <0.001 Female sex, n (%) 80 (41) 996 (23) <0.001 Smoking, n (%) 0.009  Never 84 (43) 1555 (35)  Current 48 (24) 1533 (35)  Former 65 (33) 1320 (30) Diabetes, n (%) 0.08  Non-insulin dependent 24 (12) 564 (13)  Insulin dependent 15 (8) 189 (4) Atrial hypertension, n (%) 139 (71) 2821 (64) 0.06 Dyslipidaemia, n (%) 125 (64) 2792 (63) 0.97 Family history, n (%) 70 (36) 1578 (36) 0.9 Renal disease, n (%) 27 (14) 238 (5) <0.001 Previous MI, n (%) 20 (10) 468 (11) 0.84 Previous PCI, n (%) 23 (12) 562 (13) 0.66 Previous CABG, n (%) 2 (1) 124 (3) 0.13 Heart failure, n (%) 14 (7) 236 (5) 0.29 Stroke or TIA, n (%) 0.62  TIA 4 (2) 55 (1)  Stroke 2 (1) 51 (1) STEMI, n (%) 63 (32) 1333 (30) 0.6 NSTEMI, n (%) 68 (35) 1473 (33) 0.75 Stable CAD, n (%) 66 (34) 1602 (36) 0.42 BMS allocation, n (%) 56 (28) 1470 (33) 0.15 DES allocation, n (%) 141 (72) 2938 (68) Aortic aneurysm, n (%) 1 (0.5) 32 (0.7) 0.72 PAOD, n (%) 12 (6) 187 (4) 0.21 COPD, n (%) 9 (5) 274 (6) 0.35 Liver disease, n (%) 2 (1) 92 (2) 0.3 Peptic ulcer disease, n (%) 10 (5) 111 (3) 0.028 Cancer, n (%) 0.22  None 183 (92.9) 4212 (95.6)  Metastasis 1 (0.5) 15 (0.3)  Non-metastatic within last 5 years 13 (6.6) 18 (4.1) Creatinine at baseline, µmol/L 83.4 ± 39.1 83.1 ± 27.0 0.92 Treated vessels, n (%)  Left main artery 0 47 (1) 0.15  Left anterior descending artery 138 (70) 2826 (64) 0.09  Left circumflex artery 83 (42) 1569 (36) 0.06  Right coronary artery 124 (63) 2296 (52) 0.003 Multi-vessel disease, n (%) 103 (52) 1764 (40) <0.001 Treated bifurcations, n (%) 28 (14) 282 (6) <0.001 Treated CTO, n (%) 8 (4) 186 (4) 0.91 Total stent length, mm 33.7 ± 23.3 28.2 ± 19.6 <0.001 Days of hospitalisation 6.0 ± 4.4 5.1 ± 4.2 0.003 Medication use at discharge, n (%)  Platelet inhibitors 196 (99.5) 4396 (99.7) 0.54  Clopidogrel 104 (53) 2301 (52) 0.87  Prasugrel 93 (47) 2142 (49)  Anticoagulation 6 (3) 162 (4) 0.64  Statin 182 (92) 4144 (95) 0.21 BMS: bare-metal stent; CABG: coronary artery bypass grafting; COPD: chronic obstructive pulmonary disease; CTO: chronic total occlusion; DES: drug-eluting stent; MI: myocardial infarction; NSTEMI: non-ST-segment elevation myocardial infarction; PAOD: peripheral artery occlusive disease; PCI: percutaneous coronary intervention; STEMI: ST-segment elevation myocardial infarction; TIA: transient ischaemic attack. Open in new tab Association between rheumatologic disorders and the primary outcome (MACEs) In the overall cohort, the crude 2-year event rates for MACEs (cardiac death, MI, and TVR) were 8.6% (394) in all patients and 6.9% (96), 9.4% (145), and 9.2% (153) in STEMI, NSTEMI, and stable CAD patients, respectively (log-rank p = 0.028). Figure 1 shows the 2-year cumulative event curves for the outcomes in patients with and without rheumatologic disorders. Patients with rheumatologic disorders had more frequent short-term events than those without rheumatologic disorders. Table 2 shows the results of the Cox models for the MACEs with multiple imputations in the overall cohort and stratified by STEMI, NSTEMI, and stable CAD. In the multivariable model, rheumatologic disorders were significantly associated with an increased rate of MACEs in all patients (hazard ratio (HR): 1.55; 95% confidence interval (CI): 1.04–2.31) and driven by events in patients with STEMI (HR: 2.38; 95% CI: 1.26–4.51). A sensitivity analysis including the complete case analysis excluding missing serum creatinine levels produced similar results (Supplemental Table 4). Cumulative event curves for the outcomes of a composite of cardiac death, myocardial infarction (MI), and target vessel revascularisation (TVR) by the presence of rheumatologic disorders Figure 1. Open in new tabDownload slide Results of the Cox proportional hazard models for the primary outcome of major adverse cardiac events (cardiac death, nonfatal myocardial infarction, and target vessel revascularisation) Table 2. Results of the Cox proportional hazard models for the primary outcome of major adverse cardiac events (cardiac death, nonfatal myocardial infarction, and target vessel revascularisation) Variable . Univariable models . Multivariable models . HR (95% CI) . z-score . p-value . Adjusted HR (95% CI) . z-score . p-value . Total (n = 4560)  BMS 1.83 (1.51–2.22) 6.11 <0.001 1.83 (1.51–2.23) 6.07 <0.001  Stent length (per 1-mm increase) 1.01 (1.006–1.014) 4.73 <0.001 1.01 (1.005–1.013) 4.45 <0.001  Statin use 0.48 (0.35–0.66) −4.48 <0.001 0.52 (0.38–0.72) −3.96 <0.001  COPD 1.92 (1.24–2.99) 4.10 <0.001 1.73 (1.26–2.39) 3.37 0.001  History of CABG 1.93 (1.24–2.99) 2.93 0.003 1.82 (1.17–2.85) 2.65 0.008  Rheumatologic disorders 1.64 (1.11–2.43) 2.49 0.013 1.55 (1.04–2.31) 2.16 0.031  Age >65 years 1.39 (1.14–1.68) 3.31 0.001 1.24 (1.01–1.52) 2.09 0.036  LAD lesion 1.30 (1.06–1.61) 2.46 0.014 1.20 (0.96–1.48) 1.63 0.103  Stroke or TIA 1.67 (1.01–2.76) 2.02 0.044 1.48 (0.89–2.45) 1.53 0.127  Diabetes mellitus 1.27 (1.00–1.61) 1.95 0.052 1.17 (0.92–1.49) 1.26 0.207  Female sex 0.99 (0.79–1.25) −0.05 0.964 0.90 (0.71–1.14) −0.85 0.393 STEMI (n = 1396)  Statin use 0.21 (0.11–0.38) −5.11 <0.001 0.25 (0.13–0.46) −4.43 <0.001  Rheumatologic disorders 2.70 (1.45–5.06) 3.12 0.002 2.38 (1.26–4.51) 2.67 0.008  COPD 2.40 (1.28–4.49) 2.74 0.006 1.74 (0.90–3.36) 1.64 0.101  History of MI 1.80 (0.91–3.57) 1.68 0.092 1.58 (0.79–3.15) 1.29 0.196  COPD 2.00 (1.36–2.95) 3.49 0.000 1.64 (1.10–2.47) 2.40 0.016  Age >65 years 1.76 (1.19–2.61) 2.85 0.004 1.59 (1.07–2.37) 2.29 0.022  Female sex 1.29 (0.83–1.99) 1.15 0.252 0.97 (0.62–1.53) −0.12 0.904 NSTEMI (n = 1541)  BMS 2.07 (1.50–2.86) 4.42 <0.001 2.10 (1.51–2.91) 4.44 <0.001  Statin use 0.42 (0.24–0.72) −3.11 0.002 0.42 (0.24–0.74) −3.04 0.002  LAD lesion 1.42 (1.00–2.01) 1.94 0.053 1.55 (1.08–2.22) 2.39 0.017  COPD 1.88 (1.13–3.11) 2.45 0.014 1.71 (1.02–2.86) 2.04 0.042  Family history of CAD 0.68 (0.47–0.97) −2.13 0.033 0.71 (0.49–1.03) −1.82 0.069  Age >65 years 1.42 (1.03–1.96) 2.13 0.033 1.32 (0.94–1.85) 1.60 0.110  Rheumatologic disorders 1.30 (0.64–2.66) 0.73 0.467 1.35 (0.65–2.79) 0.81 0.416  Female sex 0.82 (0.55–1.23) −0.94 0.346 0.81 (0.53–1.24) −0.97 0.331 Stable CAD (n = 1668)  Stent length (per 1-mm increase) 1.01 (1.008–1.020) 4.80 <0.001 1.014 (1.008–1.020) 4.72 <0.001  History of CABG 2.07 (1.20–3.59) 2.61 0.009 2.21 (1.27–3.84) 2.81 0.005  COPD 1.66 (0.99–2.79) 1.93 0.054 1.76 (1.05–2.98) 2.13 0.033  Smoking 0.84 (0.62–1.15) −1.07 0.287 0.78 (0.57–1.09) −1.46 0.143  Liver disease 1.83 (0.75–4.45) 1.32 0.185 1.89 (0.77–4.63) 1.40 0.162  Stroke or TIA 1.47 (0.69–3.13) 0.99 0.323 1.43 (0.67–3.05) 0.91 0.360  Rheumatologic disorders 1.29 (0.64–2.64) 0.71 0.476 1.27 (0.62–2.61) 0.65 0.517  Age >65 years 1.01 (0.74–1.37) 0.04 0.969 0.95 (0.68–1.31) −0.33 0.742  Female sex 0.98 (0.68–1.41) −0.12 0.902 0.99 (0.67–1.45) −0.08 0.94 Variable . Univariable models . Multivariable models . HR (95% CI) . z-score . p-value . Adjusted HR (95% CI) . z-score . p-value . Total (n = 4560)  BMS 1.83 (1.51–2.22) 6.11 <0.001 1.83 (1.51–2.23) 6.07 <0.001  Stent length (per 1-mm increase) 1.01 (1.006–1.014) 4.73 <0.001 1.01 (1.005–1.013) 4.45 <0.001  Statin use 0.48 (0.35–0.66) −4.48 <0.001 0.52 (0.38–0.72) −3.96 <0.001  COPD 1.92 (1.24–2.99) 4.10 <0.001 1.73 (1.26–2.39) 3.37 0.001  History of CABG 1.93 (1.24–2.99) 2.93 0.003 1.82 (1.17–2.85) 2.65 0.008  Rheumatologic disorders 1.64 (1.11–2.43) 2.49 0.013 1.55 (1.04–2.31) 2.16 0.031  Age >65 years 1.39 (1.14–1.68) 3.31 0.001 1.24 (1.01–1.52) 2.09 0.036  LAD lesion 1.30 (1.06–1.61) 2.46 0.014 1.20 (0.96–1.48) 1.63 0.103  Stroke or TIA 1.67 (1.01–2.76) 2.02 0.044 1.48 (0.89–2.45) 1.53 0.127  Diabetes mellitus 1.27 (1.00–1.61) 1.95 0.052 1.17 (0.92–1.49) 1.26 0.207  Female sex 0.99 (0.79–1.25) −0.05 0.964 0.90 (0.71–1.14) −0.85 0.393 STEMI (n = 1396)  Statin use 0.21 (0.11–0.38) −5.11 <0.001 0.25 (0.13–0.46) −4.43 <0.001  Rheumatologic disorders 2.70 (1.45–5.06) 3.12 0.002 2.38 (1.26–4.51) 2.67 0.008  COPD 2.40 (1.28–4.49) 2.74 0.006 1.74 (0.90–3.36) 1.64 0.101  History of MI 1.80 (0.91–3.57) 1.68 0.092 1.58 (0.79–3.15) 1.29 0.196  COPD 2.00 (1.36–2.95) 3.49 0.000 1.64 (1.10–2.47) 2.40 0.016  Age >65 years 1.76 (1.19–2.61) 2.85 0.004 1.59 (1.07–2.37) 2.29 0.022  Female sex 1.29 (0.83–1.99) 1.15 0.252 0.97 (0.62–1.53) −0.12 0.904 NSTEMI (n = 1541)  BMS 2.07 (1.50–2.86) 4.42 <0.001 2.10 (1.51–2.91) 4.44 <0.001  Statin use 0.42 (0.24–0.72) −3.11 0.002 0.42 (0.24–0.74) −3.04 0.002  LAD lesion 1.42 (1.00–2.01) 1.94 0.053 1.55 (1.08–2.22) 2.39 0.017  COPD 1.88 (1.13–3.11) 2.45 0.014 1.71 (1.02–2.86) 2.04 0.042  Family history of CAD 0.68 (0.47–0.97) −2.13 0.033 0.71 (0.49–1.03) −1.82 0.069  Age >65 years 1.42 (1.03–1.96) 2.13 0.033 1.32 (0.94–1.85) 1.60 0.110  Rheumatologic disorders 1.30 (0.64–2.66) 0.73 0.467 1.35 (0.65–2.79) 0.81 0.416  Female sex 0.82 (0.55–1.23) −0.94 0.346 0.81 (0.53–1.24) −0.97 0.331 Stable CAD (n = 1668)  Stent length (per 1-mm increase) 1.01 (1.008–1.020) 4.80 <0.001 1.014 (1.008–1.020) 4.72 <0.001  History of CABG 2.07 (1.20–3.59) 2.61 0.009 2.21 (1.27–3.84) 2.81 0.005  COPD 1.66 (0.99–2.79) 1.93 0.054 1.76 (1.05–2.98) 2.13 0.033  Smoking 0.84 (0.62–1.15) −1.07 0.287 0.78 (0.57–1.09) −1.46 0.143  Liver disease 1.83 (0.75–4.45) 1.32 0.185 1.89 (0.77–4.63) 1.40 0.162  Stroke or TIA 1.47 (0.69–3.13) 0.99 0.323 1.43 (0.67–3.05) 0.91 0.360  Rheumatologic disorders 1.29 (0.64–2.64) 0.71 0.476 1.27 (0.62–2.61) 0.65 0.517  Age >65 years 1.01 (0.74–1.37) 0.04 0.969 0.95 (0.68–1.31) −0.33 0.742  Female sex 0.98 (0.68–1.41) −0.12 0.902 0.99 (0.67–1.45) −0.08 0.94 Variables are listed according to z-scores in the multivariable Cox models. BMS: bare-metal stent; CABG: coronary artery bypass grafting; CAD: coronary artery disease; COPD: chronic obstructive pulmonary disease; CTO: chronic total occlusion; DES: drug-eluting stent; LAD: left anterior descending artery; MI: myocardial infarction; NSTEMI: non-ST-segment elevation myocardial infarction; PAOD: peripheral artery occlusive disease; PCI: percutaneous coronary intervention; STEMI: ST-segment elevation myocardial infarction; TIA: transient ischaemic attack. Open in new tab Table 2. Results of the Cox proportional hazard models for the primary outcome of major adverse cardiac events (cardiac death, nonfatal myocardial infarction, and target vessel revascularisation) Variable . Univariable models . Multivariable models . HR (95% CI) . z-score . p-value . Adjusted HR (95% CI) . z-score . p-value . Total (n = 4560)  BMS 1.83 (1.51–2.22) 6.11 <0.001 1.83 (1.51–2.23) 6.07 <0.001  Stent length (per 1-mm increase) 1.01 (1.006–1.014) 4.73 <0.001 1.01 (1.005–1.013) 4.45 <0.001  Statin use 0.48 (0.35–0.66) −4.48 <0.001 0.52 (0.38–0.72) −3.96 <0.001  COPD 1.92 (1.24–2.99) 4.10 <0.001 1.73 (1.26–2.39) 3.37 0.001  History of CABG 1.93 (1.24–2.99) 2.93 0.003 1.82 (1.17–2.85) 2.65 0.008  Rheumatologic disorders 1.64 (1.11–2.43) 2.49 0.013 1.55 (1.04–2.31) 2.16 0.031  Age >65 years 1.39 (1.14–1.68) 3.31 0.001 1.24 (1.01–1.52) 2.09 0.036  LAD lesion 1.30 (1.06–1.61) 2.46 0.014 1.20 (0.96–1.48) 1.63 0.103  Stroke or TIA 1.67 (1.01–2.76) 2.02 0.044 1.48 (0.89–2.45) 1.53 0.127  Diabetes mellitus 1.27 (1.00–1.61) 1.95 0.052 1.17 (0.92–1.49) 1.26 0.207  Female sex 0.99 (0.79–1.25) −0.05 0.964 0.90 (0.71–1.14) −0.85 0.393 STEMI (n = 1396)  Statin use 0.21 (0.11–0.38) −5.11 <0.001 0.25 (0.13–0.46) −4.43 <0.001  Rheumatologic disorders 2.70 (1.45–5.06) 3.12 0.002 2.38 (1.26–4.51) 2.67 0.008  COPD 2.40 (1.28–4.49) 2.74 0.006 1.74 (0.90–3.36) 1.64 0.101  History of MI 1.80 (0.91–3.57) 1.68 0.092 1.58 (0.79–3.15) 1.29 0.196  COPD 2.00 (1.36–2.95) 3.49 0.000 1.64 (1.10–2.47) 2.40 0.016  Age >65 years 1.76 (1.19–2.61) 2.85 0.004 1.59 (1.07–2.37) 2.29 0.022  Female sex 1.29 (0.83–1.99) 1.15 0.252 0.97 (0.62–1.53) −0.12 0.904 NSTEMI (n = 1541)  BMS 2.07 (1.50–2.86) 4.42 <0.001 2.10 (1.51–2.91) 4.44 <0.001  Statin use 0.42 (0.24–0.72) −3.11 0.002 0.42 (0.24–0.74) −3.04 0.002  LAD lesion 1.42 (1.00–2.01) 1.94 0.053 1.55 (1.08–2.22) 2.39 0.017  COPD 1.88 (1.13–3.11) 2.45 0.014 1.71 (1.02–2.86) 2.04 0.042  Family history of CAD 0.68 (0.47–0.97) −2.13 0.033 0.71 (0.49–1.03) −1.82 0.069  Age >65 years 1.42 (1.03–1.96) 2.13 0.033 1.32 (0.94–1.85) 1.60 0.110  Rheumatologic disorders 1.30 (0.64–2.66) 0.73 0.467 1.35 (0.65–2.79) 0.81 0.416  Female sex 0.82 (0.55–1.23) −0.94 0.346 0.81 (0.53–1.24) −0.97 0.331 Stable CAD (n = 1668)  Stent length (per 1-mm increase) 1.01 (1.008–1.020) 4.80 <0.001 1.014 (1.008–1.020) 4.72 <0.001  History of CABG 2.07 (1.20–3.59) 2.61 0.009 2.21 (1.27–3.84) 2.81 0.005  COPD 1.66 (0.99–2.79) 1.93 0.054 1.76 (1.05–2.98) 2.13 0.033  Smoking 0.84 (0.62–1.15) −1.07 0.287 0.78 (0.57–1.09) −1.46 0.143  Liver disease 1.83 (0.75–4.45) 1.32 0.185 1.89 (0.77–4.63) 1.40 0.162  Stroke or TIA 1.47 (0.69–3.13) 0.99 0.323 1.43 (0.67–3.05) 0.91 0.360  Rheumatologic disorders 1.29 (0.64–2.64) 0.71 0.476 1.27 (0.62–2.61) 0.65 0.517  Age >65 years 1.01 (0.74–1.37) 0.04 0.969 0.95 (0.68–1.31) −0.33 0.742  Female sex 0.98 (0.68–1.41) −0.12 0.902 0.99 (0.67–1.45) −0.08 0.94 Variable . Univariable models . Multivariable models . HR (95% CI) . z-score . p-value . Adjusted HR (95% CI) . z-score . p-value . Total (n = 4560)  BMS 1.83 (1.51–2.22) 6.11 <0.001 1.83 (1.51–2.23) 6.07 <0.001  Stent length (per 1-mm increase) 1.01 (1.006–1.014) 4.73 <0.001 1.01 (1.005–1.013) 4.45 <0.001  Statin use 0.48 (0.35–0.66) −4.48 <0.001 0.52 (0.38–0.72) −3.96 <0.001  COPD 1.92 (1.24–2.99) 4.10 <0.001 1.73 (1.26–2.39) 3.37 0.001  History of CABG 1.93 (1.24–2.99) 2.93 0.003 1.82 (1.17–2.85) 2.65 0.008  Rheumatologic disorders 1.64 (1.11–2.43) 2.49 0.013 1.55 (1.04–2.31) 2.16 0.031  Age >65 years 1.39 (1.14–1.68) 3.31 0.001 1.24 (1.01–1.52) 2.09 0.036  LAD lesion 1.30 (1.06–1.61) 2.46 0.014 1.20 (0.96–1.48) 1.63 0.103  Stroke or TIA 1.67 (1.01–2.76) 2.02 0.044 1.48 (0.89–2.45) 1.53 0.127  Diabetes mellitus 1.27 (1.00–1.61) 1.95 0.052 1.17 (0.92–1.49) 1.26 0.207  Female sex 0.99 (0.79–1.25) −0.05 0.964 0.90 (0.71–1.14) −0.85 0.393 STEMI (n = 1396)  Statin use 0.21 (0.11–0.38) −5.11 <0.001 0.25 (0.13–0.46) −4.43 <0.001  Rheumatologic disorders 2.70 (1.45–5.06) 3.12 0.002 2.38 (1.26–4.51) 2.67 0.008  COPD 2.40 (1.28–4.49) 2.74 0.006 1.74 (0.90–3.36) 1.64 0.101  History of MI 1.80 (0.91–3.57) 1.68 0.092 1.58 (0.79–3.15) 1.29 0.196  COPD 2.00 (1.36–2.95) 3.49 0.000 1.64 (1.10–2.47) 2.40 0.016  Age >65 years 1.76 (1.19–2.61) 2.85 0.004 1.59 (1.07–2.37) 2.29 0.022  Female sex 1.29 (0.83–1.99) 1.15 0.252 0.97 (0.62–1.53) −0.12 0.904 NSTEMI (n = 1541)  BMS 2.07 (1.50–2.86) 4.42 <0.001 2.10 (1.51–2.91) 4.44 <0.001  Statin use 0.42 (0.24–0.72) −3.11 0.002 0.42 (0.24–0.74) −3.04 0.002  LAD lesion 1.42 (1.00–2.01) 1.94 0.053 1.55 (1.08–2.22) 2.39 0.017  COPD 1.88 (1.13–3.11) 2.45 0.014 1.71 (1.02–2.86) 2.04 0.042  Family history of CAD 0.68 (0.47–0.97) −2.13 0.033 0.71 (0.49–1.03) −1.82 0.069  Age >65 years 1.42 (1.03–1.96) 2.13 0.033 1.32 (0.94–1.85) 1.60 0.110  Rheumatologic disorders 1.30 (0.64–2.66) 0.73 0.467 1.35 (0.65–2.79) 0.81 0.416  Female sex 0.82 (0.55–1.23) −0.94 0.346 0.81 (0.53–1.24) −0.97 0.331 Stable CAD (n = 1668)  Stent length (per 1-mm increase) 1.01 (1.008–1.020) 4.80 <0.001 1.014 (1.008–1.020) 4.72 <0.001  History of CABG 2.07 (1.20–3.59) 2.61 0.009 2.21 (1.27–3.84) 2.81 0.005  COPD 1.66 (0.99–2.79) 1.93 0.054 1.76 (1.05–2.98) 2.13 0.033  Smoking 0.84 (0.62–1.15) −1.07 0.287 0.78 (0.57–1.09) −1.46 0.143  Liver disease 1.83 (0.75–4.45) 1.32 0.185 1.89 (0.77–4.63) 1.40 0.162  Stroke or TIA 1.47 (0.69–3.13) 0.99 0.323 1.43 (0.67–3.05) 0.91 0.360  Rheumatologic disorders 1.29 (0.64–2.64) 0.71 0.476 1.27 (0.62–2.61) 0.65 0.517  Age >65 years 1.01 (0.74–1.37) 0.04 0.969 0.95 (0.68–1.31) −0.33 0.742  Female sex 0.98 (0.68–1.41) −0.12 0.902 0.99 (0.67–1.45) −0.08 0.94 Variables are listed according to z-scores in the multivariable Cox models. BMS: bare-metal stent; CABG: coronary artery bypass grafting; CAD: coronary artery disease; COPD: chronic obstructive pulmonary disease; CTO: chronic total occlusion; DES: drug-eluting stent; LAD: left anterior descending artery; MI: myocardial infarction; NSTEMI: non-ST-segment elevation myocardial infarction; PAOD: peripheral artery occlusive disease; PCI: percutaneous coronary intervention; STEMI: ST-segment elevation myocardial infarction; TIA: transient ischaemic attack. Open in new tab Notably, rheumatologic disorders did not modify the association between DESs and MACEs (p for interaction = 0.189). Likewise, rheumatologic disorders did not modify the association between first-generation DESs and DP- or BP-DESs and MACEs (p for interaction = 0.77). Association between rheumatologic disorders and outcome details Table 3 shows the outcome details of all-cause death, cardiac death, nonfatal MI, TVR, and stent thrombosis at 30 days and 2 years, stratified by the presence of rheumatologic disorders. In the multivariable Cox analysis with multiple imputations, rheumatologic disorders were significantly associated with all-cause death (HR: 2.05; 95% CI: 1.14–3.70), cardiac death (HR: 2.63; 95% CI: 1.27–5.43), and nonfatal MI (HR: 2.64; 95% CI: 1.36–5.13), but not with TVR (HR: 0.81; 95% CI: 0.41–1.58) at 2 years. Notably, during 2 years of follow-up, most nonfatal MI events occurred within 30 days in patients with rheumatologic disorders (40%; four out of ten events) compared to those without rheumatologic disorders (11%; nine out of 82 events). Outcome details Table 3. Outcome details Outcome . With rheumatologic disorders (n = 197) . Without rheumatologic disorders (n = 4408) . With rheumatologic disorder . 30 days . 2 years . 30 days . 2 years . Adjusted HR (95% CI) . p-value . Death, n (%)  All-cause 5 (2.5) 11 (5.6) 21 (0.5) 124 (2.8) 2.05 (1.14–3.70) 0.017  Cardiac 4 (2.0) 7 (3.6) 16 (0.4) 62 (1.4) 2.63 (1.27–5.43) 0.009 Nonfatal MI, n (%) 4 (2.0) 10 (5.1) 9 (0.2) 82 (1.9) 2.64 (1.36–5.13) 0.004 TVR, n (%) 1 (0.5) 8 (4.1) 13 (0.3) 252 (5.7) 0.81 (0.41–1.58) 0.529  Non-MI related 0 5 (2.5) 8 (0.2) 217 (4.9) 0.66 (0.29–1.49) 0.314  MI related 1 (0.5) 3 (1.5) 5 (0.1) 46 (1.0) 1.24 (0.38–4.02) 0.718 Stent thrombosis, n (%)  Definite 1 (0.5) 1 (0.5) 3 (0.07) 16 (0.4) 1.43 (0.18–11.1) 0.735  Definite/probable 2 (1.0) 2 (1.0) 7 (0.1) 24 (0.5) 2.04 (0.61–6.83) 0.248  Definite/probable/possible 2 (1.0) 4 (2.0) 7 (0.1) 42 (0.9) 2.26 (0.88–5.76) 0.088 Outcome . With rheumatologic disorders (n = 197) . Without rheumatologic disorders (n = 4408) . With rheumatologic disorder . 30 days . 2 years . 30 days . 2 years . Adjusted HR (95% CI) . p-value . Death, n (%)  All-cause 5 (2.5) 11 (5.6) 21 (0.5) 124 (2.8) 2.05 (1.14–3.70) 0.017  Cardiac 4 (2.0) 7 (3.6) 16 (0.4) 62 (1.4) 2.63 (1.27–5.43) 0.009 Nonfatal MI, n (%) 4 (2.0) 10 (5.1) 9 (0.2) 82 (1.9) 2.64 (1.36–5.13) 0.004 TVR, n (%) 1 (0.5) 8 (4.1) 13 (0.3) 252 (5.7) 0.81 (0.41–1.58) 0.529  Non-MI related 0 5 (2.5) 8 (0.2) 217 (4.9) 0.66 (0.29–1.49) 0.314  MI related 1 (0.5) 3 (1.5) 5 (0.1) 46 (1.0) 1.24 (0.38–4.02) 0.718 Stent thrombosis, n (%)  Definite 1 (0.5) 1 (0.5) 3 (0.07) 16 (0.4) 1.43 (0.18–11.1) 0.735  Definite/probable 2 (1.0) 2 (1.0) 7 (0.1) 24 (0.5) 2.04 (0.61–6.83) 0.248  Definite/probable/possible 2 (1.0) 4 (2.0) 7 (0.1) 42 (0.9) 2.26 (0.88–5.76) 0.088 The adjusted HR of rheumatologic disorders at 2 years = (adjusted hazard function of patients with a rheumatologic disorder):(adjusted hazard function of patients without a rheumatologic disorders) at 2 years. We adjusted the Cox models by age >65 years, female sex, bare-metal stent, stent length (per 1-mm increase), statin use, chronic obstructive pulmonary disease, history of coronary artery bypass grafting, LAD lesion, stroke or transient ischaemic attach, and diabetes mellitus with multiple imputation. CI: confidential interval; HR: hazard ratio; LAD: left anterior descending artery; MI: myocardial infarction; TVR: target vessel revascularisation. Open in new tab Table 3. Outcome details Outcome . With rheumatologic disorders (n = 197) . Without rheumatologic disorders (n = 4408) . With rheumatologic disorder . 30 days . 2 years . 30 days . 2 years . Adjusted HR (95% CI) . p-value . Death, n (%)  All-cause 5 (2.5) 11 (5.6) 21 (0.5) 124 (2.8) 2.05 (1.14–3.70) 0.017  Cardiac 4 (2.0) 7 (3.6) 16 (0.4) 62 (1.4) 2.63 (1.27–5.43) 0.009 Nonfatal MI, n (%) 4 (2.0) 10 (5.1) 9 (0.2) 82 (1.9) 2.64 (1.36–5.13) 0.004 TVR, n (%) 1 (0.5) 8 (4.1) 13 (0.3) 252 (5.7) 0.81 (0.41–1.58) 0.529  Non-MI related 0 5 (2.5) 8 (0.2) 217 (4.9) 0.66 (0.29–1.49) 0.314  MI related 1 (0.5) 3 (1.5) 5 (0.1) 46 (1.0) 1.24 (0.38–4.02) 0.718 Stent thrombosis, n (%)  Definite 1 (0.5) 1 (0.5) 3 (0.07) 16 (0.4) 1.43 (0.18–11.1) 0.735  Definite/probable 2 (1.0) 2 (1.0) 7 (0.1) 24 (0.5) 2.04 (0.61–6.83) 0.248  Definite/probable/possible 2 (1.0) 4 (2.0) 7 (0.1) 42 (0.9) 2.26 (0.88–5.76) 0.088 Outcome . With rheumatologic disorders (n = 197) . Without rheumatologic disorders (n = 4408) . With rheumatologic disorder . 30 days . 2 years . 30 days . 2 years . Adjusted HR (95% CI) . p-value . Death, n (%)  All-cause 5 (2.5) 11 (5.6) 21 (0.5) 124 (2.8) 2.05 (1.14–3.70) 0.017  Cardiac 4 (2.0) 7 (3.6) 16 (0.4) 62 (1.4) 2.63 (1.27–5.43) 0.009 Nonfatal MI, n (%) 4 (2.0) 10 (5.1) 9 (0.2) 82 (1.9) 2.64 (1.36–5.13) 0.004 TVR, n (%) 1 (0.5) 8 (4.1) 13 (0.3) 252 (5.7) 0.81 (0.41–1.58) 0.529  Non-MI related 0 5 (2.5) 8 (0.2) 217 (4.9) 0.66 (0.29–1.49) 0.314  MI related 1 (0.5) 3 (1.5) 5 (0.1) 46 (1.0) 1.24 (0.38–4.02) 0.718 Stent thrombosis, n (%)  Definite 1 (0.5) 1 (0.5) 3 (0.07) 16 (0.4) 1.43 (0.18–11.1) 0.735  Definite/probable 2 (1.0) 2 (1.0) 7 (0.1) 24 (0.5) 2.04 (0.61–6.83) 0.248  Definite/probable/possible 2 (1.0) 4 (2.0) 7 (0.1) 42 (0.9) 2.26 (0.88–5.76) 0.088 The adjusted HR of rheumatologic disorders at 2 years = (adjusted hazard function of patients with a rheumatologic disorder):(adjusted hazard function of patients without a rheumatologic disorders) at 2 years. We adjusted the Cox models by age >65 years, female sex, bare-metal stent, stent length (per 1-mm increase), statin use, chronic obstructive pulmonary disease, history of coronary artery bypass grafting, LAD lesion, stroke or transient ischaemic attach, and diabetes mellitus with multiple imputation. CI: confidential interval; HR: hazard ratio; LAD: left anterior descending artery; MI: myocardial infarction; TVR: target vessel revascularisation. Open in new tab Discussion In this sub-analysis of two all-comer stent trials with contemporary PCI treatment – the BASKET-PROVE I and II trials – we found that rheumatologic disorders were associated with an increased risk of cardiac death and MI in patients with acute or stable coronary disease, apparently driven by patients who had suffered a STEMI. To our knowledge, this is the first observation of such an association between rheumatologic disorders and long-term outcomes in a broad spectrum of patients with established acute or stable coronary disease after PCI. We observed the increased risk of MACEs over 2 years in patients with rheumatologic disorders in established CAD, especially in those with STEMI. In contrast, we observed no association between rheumatologic disorders and TVR. We speculated that the BASKET-PROVE I and II trials enrolled CAD patients who underwent stenting by skilled interventional cardiologists, and all lesions required stents of ⩾3.0 mm in diameter. In addition, during follow-up, patients received dual antiplatelet therapy and statins, which prevent coronary restenosis. These conditions might result in the observation of rheumatologic disorders not being predictive of TVR. In the general population, rheumatologic disorders have been considered to be risk factors for the development of MI.16–18 Accordingly, an observational study found that females aged 35–55 years with systemic lupus erythematosus without a history of CAD were 50-times more likely to have a MI compared to healthy women of the same age.19 Our results extend these findings to apply to patients with established CAD after PCI, and perhaps patients presenting with STEMI in particular. This may suggest a close relationship between rheumatologic disorders and the development of STEMI against a background of a systemic inflammatory state. Previous studies have shown that rheumatologic disorders accentuate traditional risk factors such as dyslipidaemia, smoking, hypertension, insulin resistance, physical inactivity, and obesity.4 Both shared and rheumatologic disorder-specific pathogenic mechanisms also contribute to accelerated atherogenesis by increasing TNF, IL-6, or fibrinogen, and by distorting arterial anatomy.4 Recently, Niccoli et al. reported the role of allergic inflammation in the pathogenesis of coronary instability, focusing on eosinophils and basophils.20 In addition, recent data suggested a link between eosinophilia and rheumatologic disorders. Eosinophilia in blood or tissue can be seen in some specific rheumatologic conditions (e.g., Chung–Strauss and IgG4-related disease), but in most rheumatologic disorders, eosinophilia is less common.21 Future basic and clinical research studies evaluating the associations between eosinophils, atherosclerosis, and rheumatologic disorders are needed. The role of immunosuppressive therapy in the prevention of restenosis after PCI remains controversial. Ribichini et al. reported that a short cycle of high-dose oral prednisone treatment after BMS stenting in non-diabetic patients with CAD improved the outcomes of patients receiving BMSs by reducing MACEs over 4 years.22 Recently, the same research group conducted a patient-level meta-analysis of randomised trials, including Ribichini et al.’s data, in order to evaluating the impact of the oral administration of prednisone or sirolimus for the prevention of restenosis.23 This group showed that, in CAD patients undergoing PCI, immunosuppressive therapy in addition to BMS reduces the risk of Target lesion revascularization (TLR) compared to BMSs alone, but not compared to DESs alone. They reported no differences in the composite endpoint of death and MI between therapies, and the beneficial effect of immunosuppressive therapy was driven by a lower risk of vessel narrowing as compared with BMSs alone. Immunosuppressive therapy for patients with rheumatologic disorders might have a beneficial impact not only in terms of lowering the risk of vessel narrowing, but also by controlling the underlying rheumatologic disease itself; however, further studies are needed in order to answer this question. Furthermore, a previous study reported that patients with rheumatologic disorders have more atherogenic lipid profiles, characterised by higher total cholesterol, triglyceride, and apolipoprotein B levels, and lower high-density lipoprotein C levels than age-, sex-, and storage time-matched controls.24 A previous study showed that rheumatologic disorders were associated with an increased risk of 30-day mortality (adjusted odds ratio: 1.6; 95% CI: 1.20–2.2) in 29,924 patients who experienced a first cardiovascular event (MI or stroke).8 In agreement with this, most nonfatal MI and stent thrombosis events in patients with rheumatologic disorders occurred within 30 days of PCI, calling for a strong focus on immediate intensive secondary prophylaxis following PCI in these patients. In terms of a follow-up strategy for CAD patients with rheumatologic disorders, biomarker-guided follow-up and non-invasive imaging assessments might be beneficial. Ruff et al. reported that baseline N-terminal pro-brain natriuretic peptide (NT pro-BNP) was a simple and robust non-invasive indicator of cardiovascular risk (cardiovascular death, MI, heart failure, or a composite of thrombotic events) in 6273 patients with RA and osteoarthritis taking long-term non-steroidal anti-inflammatory drugs.25 They also observed that high-sensitivity C-reactive protein (hs-CRP) was not associated with cardiovascular outcomes in this sample. In contrast, Wang et al. have shown that, in 60 patients with Takayasu arteritis with coronary artery involvement, hs-CRP was an independent predictor of MACEs. Hence, data support the notion that both NT pro-BNP- and hs-CRP-guided follow-up might be beneficial in CAD patients with rheumatologic disorders.26 In order to detect myocardial involvement in CAD patients with rheumatologic disorders, novel invasive imaging tools might also be useful. Tzelepis et al. showed that cardiac magnetic resonance imaging might be an important tool for detecting myocardial fibrosis in systemic sclerosis.27 Ciurzyński and colleagues showed that echocardiography was helpful for identifying both left and right ventricular diastolic dysfunction in patients with systemic sclerosis.28 The presented studies therefore support combining information obtained from both biomarkers and non-invasive imaging when assessing risk after PCI in patients with rheumatologic disorders. In accordance with our findings, in a recent observational study in 40,639 patients after CABG surgery, Lai et al.7 also found an association between rheumatologic disorders and poor prognosis by using data from the National Health Insurance Research Database of Taiwan. In particular, systemic lupus erythematosus was an independent predictor of operative mortality and overall mortality.7 This implies a focus on immediate intensive secondary prevention in patients with rheumatologic disorders following any coronary revascularisation. The strength of this observational study lies in the large sample size and the broad spectrum of patients included in two similar consecutive multicentre trials in Switzerland, Denmark, Austria, Germany, and Italy. Baseline characteristics, contemporary treatments (including stenting), and prospective long-term (2-year) prognostic data further support the generalisability of the results, with implications that are relevant to current daily practice. The lack of detailed information regarding diagnosis, disease status, and management of rheumatologic disorders is a limitation of the current report. The term ‘rheumatologic disorders’ encompasses a variety of heterogeneous disease entities, and the fact that the diagnosis of rheumatologic disorder was determined by the local investigators based on the clinical presentation of the patient might lead to a misclassification bias. The prevalence of rheumatologic disorders ranged from 0.9% to 6.1% between the different countries (Supplemental Table 5). Notably, the risk ratios (RRs) for rheumatologic disorders in terms of the risk of MACEs were similar, with RRs of 1.37–1.62 across the countries. Furthermore, data on rheumatologic disorders were collected prospectively at enrolment without knowledge of the outcomes of the patients; we therefore believe that rheumatologic disorder assignment bias has been avoided. In addition, no measures of inflammation status and anti-inflammatory medication were recorded in the case record forms, which would be an important factor for determining poor prognosis.16,17,29 Finally, the exclusion criteria in the BASKET-PROVE I and II trials excluded CAD patients with cardiogenic shock, in-stent restenosis or thrombosis of stents placed before the study, and unprotected left main coronary artery, which might result in an underestimation of the true risk of rheumatologic disorders for prognosis in CAD patients. Conclusions This observational study from two contemporary cohorts of randomised patients with established acute or stable CAD and PCI suggests that the clinical presence of rheumatologic disorders was associated with an adverse short- and long-term prognosis, and this may be particularly true of patients with STEMI. The findings are hypothesis generating and recommend a particular focus on future studies in this high-risk group of patients with CAD. Acknowledgement We thank all of the investigators of the BASKET-PROVE I and II trials. Conflict of interest The authors declare that there is no conflict of interest. Funding The BASKET-PROVE I and II trials were funded by the Basel Cardiovascular Research Foundation. The BASKET-PROVE I trial was also funded by the Swiss National Foundation. References 1 Libby P , Ridker P M, Hansson G K ; Leducq Transatlantic Network on Atherothrombosis . Inflammation in atherosclerosis: from pathophysiology to practice . J Am Coll Cardiol 2009 ; 54 ( 23 ): 2129 – 2138 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Roffi M , Patrono C, Collet J Pet al. . 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC) . Eur Heart J 2016 ; 37 ( 3 ): 267 – 315 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Berk B C , Weintraub W S, Alexander R W . Elevation of C-reactive protein in “active” coronary artery disease . Am J Cardiol 1990 ; 65 ( 3 ): 168 – 172 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Mason J C , Libby P . Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions . Eur Heart J 2015 ; 36 ( 8 ): 482 – 489c . Google Scholar Crossref Search ADS PubMed WorldCat 5 Lindhardsen J , Kristensen S L, Ahlehoff O . Management of cardiovascular risk in patients with chronic inflammatory diseases: current evidence and future perspectives . Am J Cardiovasc Drugs 2016 ; 16 ( 1 ): 1 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Ungprasert P , Charoenpong P, Ratanasrimetha Pet al. . Risk of coronary artery disease in patients with systemic sclerosis: a systematic review and meta-analysis . Clin Rheumatol 2014 ; 33 ( 8 ): 1099 – 1104 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 7 Lai C H , Lai W W, Chiou M Jet al. . Outcomes of coronary artery bypass grafting in patients with inflammatory rheumatic diseases: an 11-year nationwide cohort study . J Thorac Cardiovasc Surg 2015 ; 149 ( 3 ): 859 – 866 . e1 – 2 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 8 Van Doornum S , Brand C, King Bet al. . Increased case fatality rates following a first acute cardiovascular event in patients with rheumatoid arthritis . Arthritis Rheum 2006 ; 54 ( 7 ): 2061 – 2068 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 9 Pfisterer M , Bertel O, Bonetti P Oet al. .; BASKET-PROVE Investigators . Drug-eluting or bare-metal stents for large coronary vessel stenting? The BASKET-PROVE (PROspective Validation Examination) trial: study protocol and design . Am Heart J 2008 ; 155 ( 4 ): 609 – 614 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 10 Kaiser C , Galatius S, Erne Pet al. .; BASKET-PROVE Study Group . Drug-eluting versus bare-metal stents in large coronary arteries . N Engl J Med 2010 ; 363 ( 24 ): 2310 – 2319 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 11 Jeger R , Pfisterer M, Alber Het al. . Newest-generation drug-eluting and bare-metal stents combined with prasugrel-based antiplatelet therapy in large coronary arteries: the BAsel Stent Kosten Effektivitats Trial PROspective Validation Examination part II (BASKET-PROVE II) trial design . Am Heart J 2012 ; 163 ( 2 ): 136 – 141.e1 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 12 Kaiser C , Galatius S, Jeger Ret al. .; BASKET-PROVE II study group . Long-term efficacy and safety of biodegradable-polymer biolimus-eluting stents: main results of the Basel Stent Kosten-Effektivitats Trial-PROspective Validation Examination II (BASKET-PROVE II), a randomized, controlled noninferiority 2-year outcome trial . Circulation 2015 ; 131 ( 1 ): 74 – 81 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 13 Myocardial infarction redefined – a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction . Eur Heart J 2000 ; 21 ( 18 ): 1502 – 1513 . PubMed 14 Cutlip D E , Windecker S, Mehran Ret al. .; Academic Research Consortium . Clinical end points in coronary stent trials: a case for standardized definitions . Circulation 2007 ; 115 ( 17 ): 2344 – 2351 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 15 White I R , Royston P . Imputing missing covariate values for the Cox model . Stat Med 2009 ; 28 ( 15 ): 1982 – 1998 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 16 Gabriel S E . Heart disease and rheumatoid arthritis: understanding the risks . Ann Rheum Dis 2010 ; 69 ( Suppl. 1 ): i61 – i64 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 17 Kitas G D , Gabriel S E . Cardiovascular disease in rheumatoid arthritis: state of the art and future perspectives . Ann Rheum Dis 2011 ; 70 ( 1 ): 8 – 14 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 18 Linos E , Fiorentino D, Lingala Bet al. . Atherosclerotic cardiovascular disease and dermatomyositis: an analysis of the Nationwide Inpatient Sample survey . Arthritis Res Ther 2013 ; 15 ( 1 ): R7 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 19 Manzi S , Meilahn E N, Rairie J Eet al. . Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study . Am J Epidemiol 1997 ; 145 ( 5 ): 408 – 415 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 20 Niccoli G , Calvieri C, Flego Det al. . Allergic inflammation is associated with coronary instability and a worse clinical outcome after acute myocardial infarction . Circ Cardiovasc Interv 2015 ; 8 ( 8 ): e002554 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 21 Tamaki H , Chatterjee S, Langford C A . Eosinophilia in rheumatologic/vascular disorders . Immunol Allergy Clin North Am 2015 ; 35 ( 3 ): 453 – 476 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 22 Ribichini F , Tomai F, Pesarini Get al. .; CEREA-DES Investigators . Long-term clinical follow-up of the multicentre, randomized study to test immunosuppressive therapy with oral prednisone for the prevention of restenosis after percutaneous coronary interventions: Cortisone plus BMS or DES veRsus BMS alone to EliminAte Restenosis (CEREA-DES) . Eur Heart J 2013 ; 34 ( 23 ): 1740 – 1748 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 23 Cassese S , De Luca G, Ribichini Fet al. . ORAl iMmunosuppressive therapy to prevent in-Stent rEstenosiS (RAMSES) cooperation: a patient-level meta-analysis of randomized trials . Atherosclerosis 2014 ; 237 ( 2 ): 410 – 417 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 24 van Halm V P , Nielen M M, Nurmohamed M Tet al. . Lipids and inflammation: serial measurements of the lipid profile of blood donors who later developed rheumatoid arthritis . Ann Rheum Dis 2007 ; 66 ( 2 ): 184 – 188 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 25 Ruff C T , Morrow D A, Jarolim Pet al. . Evaluation of NT-proBNP and high sensitivity C-reactive protein for predicting cardiovascular risk in patients with arthritis taking longterm nonsteroidal antiinflammatory drugs . J Rheumatol 2011 ; 38 ( 6 ): 1071 – 1078 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 26 Wang X , Dang A, Lv Net al. . High-sensitivity C-reactive protein predicts adverse cardiovascular events in patients with Takayasu arteritis with coronary artery involvement . Clin Rheumatol 2016 ; 35 ( 3 ): 679 – 684 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 27 Tzelepis G E , Kelekis N L, Plastiras S Cet al. . Pattern and distribution of myocardial fibrosis in systemic sclerosis: a delayed enhanced magnetic resonance imaging study . Arthritis Rheum 2007 ; 56 ( 11 ): 3827 – 3236 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 28 Ciurzyński M , Bienias P, Irzyk Ket al. . Heart diastolic dysfunction in patients with systemic sclerosis . Arch Med Sci 2014 ; 10 ( 3 ): 445 – 454 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 29 Dixon W G , Watson K D, Lunt Met al. .; British Society for Rheumatology Biologics Register Control Centre Consortium; British Society for Rheumatology Biologics Register . Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register . Arthritis Rheum 2007 ; 56 ( 9 ): 2905 – 2912 . Google Scholar PubMed OpenURL Placeholder Text WorldCat © The European Society of Cardiology 2016 This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © The European Society of Cardiology 2016
TI - Long-term outcomes in patients with rheumatologic disorders undergoing percutaneous coronary intervention: a BAsel Stent Kosten-Effektivitäts Trial-PROspective Validation Examination (BASKET-PROVE) sub-study
JF - European Heart Journal. Acute Cardiovascular Care
DO - 10.1177/2048872616649860
DA - 2017-12-01
UR - https://www.deepdyve.com/lp/oxford-university-press/long-term-outcomes-in-patients-with-rheumatologic-disorders-undergoing-Shyt6KJ9xE
SP - 778
EP - 786
VL - 6
IS - 8
DP - DeepDyve
ER -