Recently, one observational study showed that patients with ST-segment elevation myocardial infarction (STEMI) without standard cardiovascular risk factors were associated with increased mortality compared with patients with risk factors. This unexpected result should be evaluated in other populations including those with non–ST-segment elevation acute coronary syndrome (NSTE-ACS) and chronic coronary syndrome (CCS). Among 30,098 consecutive patients undergoing first coronary revascularization in the CREDO-Kyoto PCI/CABG (Coronary Revascularization Demonstrating Outcome Study in Kyoto Percutaneous Coronary Intervention/Coronary Artery Bypass Grafting) registry cohort-2 and 3, we compared clinical characteristics and outcomes between patients with and without risk factors stratified by their presentation (STEMI n = 8,312, NSTE-ACS n = 3,386, and CCS n = 18,400). Patients with risk factors were defined as having at least one of the following risk factors: hypertension, dyslipidemia, diabetes, and current smoking. The proportion of patients without risk factors was low (STEMI: 369 patients [4.4%], NSTE-ACS: 110 patients [3.2%], and CCS: 462 patients [2.5%]). Patients without risk factors compared with those with risk factors more often had advanced age, low body weight, and malignancy and less often had history of atherosclerotic disease and prescription of optimal medical therapy. In patients with STEMI, patients without risk factors compared with those with risk factors were more often women and more often had atrial fibrillation, long door-to-balloon time, and severe hemodynamic compromise. During a median of 5.6 years follow-up, patients without risk factors compared with those with risk factors had higher crude incidence of all-cause death. After adjusting confounders, the mortality risk was significant in patients with CCS (hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.01 to 1.49, p = 0.04) but not in patients with STEMI (HR 1.06, 95% CI 0.89 to 1.27, p = 0.52) and NSTE-ACS (HR 1.07, 95% CI, 0.74 to 1.54, p = 0.73). In conclusion, among patients undergoing coronary revascularization, patients without standard cardiovascular risk factors had higher crude incidence of all-cause death compared with those with at least one risk factor. After adjusting confounders, the mortality risk was significant in patients with CCS but not in patients with STEMI and NSTE-ACS.
Hypertension, dyslipidemia, diabetes, and smoking have been well-known as the standard cardiovascular risk factors. Interventions for these risk factors are standard practice for the primary and secondary prevention of coronary artery disease (CAD), resulting in improved clinical outcomes of patients with CAD. , In contrast, there have been patients with CAD who do not have any standard cardiovascular risk factors in real-world practice and their clinical characteristics and outcomes have not been adequately evaluated. Recently, an observational study from the SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) registry showed that patients with ST-segment elevation myocardial infarction (STEMI) without standard cardiovascular risk factors were associated with higher short-term and long-term mortality compared with those with at least one risk factor. However, the mechanisms of CAD development and higher mortality risk in this population have not been clearly demonstrated. In addition, this unexpected result should be evaluated in other populations including patients with non–ST-segment elevation acute coronary syndrome (NSTE-ACS) and chronic coronary syndrome (CCS). Understanding clinical characteristics and outcomes in patients without standard risk factors might be important to unveil residual risks and achieve further improvement of clinical outcomes in patients with CAD. Therefore, we sought to evaluate clinical characteristics and comparative long-term clinical outcomes between patients with and without standard cardiovascular risk factors using a pooled population of 2 large-scale, all-comer registries of patients undergoing first coronary revascularization in Japan (CREDO-Kyoto PCI/CABG [Coronary Revascularization Demonstrating Outcome Study in Kyoto Percutaneous Coronary Intervention/Coronary Artery Bypass Grafting] registry cohort-2 and cohort-3).
Methods
The CREDO-Kyoto PCI/CABG registry cohort-2 and cohort-3 are physician-initiated, noncompany-sponsored, multicenter registries enrolling consecutive patients undergoing first coronary revascularization with percutaneous coronary intervention or isolated coronary artery bypass grafting without combined noncoronary surgery in the first-generation drug-eluting stents era (January 2005 to December 2007) for cohort-2 and in the new-generation drug-eluting stents era (January 2011 to December 2013) for cohort-3 (Supplementary Appendix). Of a total of 30,257 patients enrolled in the registries (cohort-2 n = 15,330, and cohort-3 n = 14,927), we excluded patients who refused study participation (cohort-2 n = 99 and cohort-3 n = 60), and the current study population consisted of 30,098 patients. In the present study, we compared long-term clinical outcomes between patients with and without standard cardiovascular risk factors stratified by their clinical presentation (STEMI n = 8,312, NSTE-ACS n = 3,386, and CCS n = 18,400) ( Figure 1 ).
The relevant ethics committees in all the participating centers approved the study protocol. Because of the retrospective enrollment, written informed consents from the patients were waived; however, we excluded those patients who refused participation in the study when contacted for follow-up.
Patients with risk factors were defined as those who had at least one of the following risk factors such as hypertension, dyslipidemia, diabetes, and current smoking, in accordance with the previous reports. , Hypertension was defined as prior diagnosis, or a new diagnosis during the index hospitalization. Dyslipidemia was defined as taking statins at the admission of the index hospitalization, low-density lipoprotein cholesterol (LDL-C) level ≥140 mg/dl, non-high density lipoprotein cholesterol (HDL-C) level ≥170 mg/dl, or HDL-C level <40 mg/dl, in accordance with the definition of Japan Atherosclerosis Society guideline. LDL-C level was calculated by the Friedewald formula. Diabetes was defined as prior diagnosis, glycated hemoglobin level ≥6.5%, or nonfasting blood glucose level ≥200 mg/dl. Current smoking was defined as regularly smoking within the last 1 month before the index hospitalization. Other definitions for baseline characteristics were described previously. ,
The primary outcome measure of this study was all-cause death. The secondary outcome measures included cardiovascular death, noncardiovascular death, myocardial infarction, stroke, hospitalization for heart failure, and any coronary revascularization. Definitions of the outcome measures were described in the Supplementary Appendix.
Clinical, angiographic, and procedural data were collected from hospital charts or hospital databases according to the prespecified definitions by the experienced clinical research coordinators belonging to an independent clinical research organization (Research Institute for Production Development, Kyoto, Japan) (Supplementary Appendix). Follow-up data were collected from the hospital charts and/or obtained by contacting patients, their relatives or referring physicians. The clinical event committee adjudicated those events such as death, myocardial infarction, and stroke (Supplementary Appendix).
Categorical variables were presented as number and percentage, and compared with the chi-square test. Continuous variables were expressed as mean ± SD or median and interquartile range (IQR). Continuous variables were compared using t test or Wilcoxon rank sum test based on their distributions. Cumulative incidence of the outcome measures was estimated by the Kaplan-Meier method and the differences were assessed with the log-rank test. The effects of patients without risk factors relative to those with risk factors for the outcome measures were estimated by the Cox proportional hazard models throughout the entire follow-up period, and were expressed as hazard ratios (HRs) and their 95% confidence intervals (CIs). The adjusted HRs were estimated by the multivariable Cox proportional hazard models adjusting for the 25 clinically relevant factors listed in Table 1 including clinical and procedural characteristics, medications, and “study” (cohort-2 vs cohort-3). Continuous variables were dichotomized by clinically meaningful reference values to make proportional hazard assumptions robust and to be consistent with our previous reports. , In the subgroup analysis, all-cause death was compared between patients with and without risk factors in the subgroup stratified by gender.
| Patients with STEMI (N=8312) | Patients with NSTE-ACS (N=3386) | Patients with CCS (N=18,400) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Without risk factor | With risk factor | P value | Without risk factor | With risk factor | P value | Without risk factor | With risk factor | P value | |
| (N=369) | (N=7943) | (N=110) | (N=3276) | (N=462) | (N=17,938) | ||||
| (A) Risk factor | |||||||||
| Number of risk factors | – | 2 (1-3) | – | – | 2 (2-3) | – | – | 2 (2-3) | – |
| Hypertension | – | 6480 (81.6%) | – | – | 2798 (85.4%) | – | – | 15478 (86.3%) | – |
| on medication | – | 3831 (48.2%) | – | – | 1936 (59.1%) | – | – | 13537 (75.5%) | – |
| Dyslipidemia † | – | 4638 (58.4%) | – | – | 1984 (60.6%) | – | – | 13012 (72.5%) | – |
| on statin | – | 1275 (16.1%) | – | – | 937 (28.6%) | – | – | 9410 (52.5%) | – |
| Diabetes | – | 2771 (34.9%) | – | – | 1269 (38.7%) | – | – | 7820 (43.6%) | – |
| on insulin or medication | – | 1837 (23.1%) | – | – | 866 (26.4%) | – | – | 6311 (35.2%) | – |
| on insulin | – | 398 (5.0%) | – | – | 229 (7.0%) | – | – | 2112 (11.8%) | – |
| Current smoker | – | 3281 (41.3%) | – | – | 1125 (34.3%) | – | – | 4256 (23.7%) | – |
| Prior smoker | 129 (35.0%) | 1885 (23.7%) | <0.001 | 41 (37.3%) | 918 (28.0%) | 0.03 | 218 (47.2%) | 6406 (35.7%) | <0.001 |
| (B) Presentation | |||||||||
| STEMI | 369 (100%) | 7943 (100%) | – | – | – | – | – | – | – |
| NSTEMI | – | – | – | 70 (63.6%) | 2020 (61.7%) | 0.68 | – | – | – |
| Cardiogenic shock * | 77 (20.9%) | 1153 (14.5%) | 0.001 | 9 (8.2%) | 236 (7.2%) | 0.7 | – | – | – |
| Cardiopulmonary arrest | 24 (6.5%) | 288 (3.6%) | 0.005 | 2 (1.8%) | 65 (2.0%) | 0.9 | – | – | – |
| Unstable angina | – | – | – | 40 (36.4%) | 1256 (38.3%) | 0.68 | – | – | – |
| CCS | – | – | – | – | – | – | 462 (100%) | 17938 (100%) | – |
| (C) Clinical characteristics | |||||||||
| Age (years) | 73.0±12.1 | 67.7±12.4 | <0.001 | 70.0±13.0 | 69.3±11.4 | 0.57 | 70.6±12.1 | 69.1±10.0 | 0.001 |
| >=75 * | 179 (48.5%) | 2545 (32.0%) | <0.001 | 47 (42.7%) | 1189 (36.3%) | 0.17 | 198 (42.9%) | 5750 (32.1%) | <0.001 |
| Men * | 230 (62.3%) | 5870 (73.9%) | <0.001 | 72 (65.5%) | 2395 (73.1%) | 0.08 | 343 (74.2%) | 13032 (72.7%) | 0.45 |
| Body mass index (kg/m 2 ) | 21.8±3.1 | 23.7±3.6 | <0.001 | 22.3±3.4 | 23.6±3.5 | <0.001 | 22.0±3.1 | 23.9±3.5 | <0.001 |
| <25.0 * | 320 (86.7%) | 5537 (69.7%) | <0.001 | 88 (80.0%) | 2275 (69.4%) | 0.02 | 391 (84.6%) | 11879 (66.2%) | <0.001 |
| Heart failure * | 140 (37.9%) | 2498 (31.4%) | 0.009 | 26 (23.6%) | 815 (24.9%) | 0.77 | 54 (11.7%) | 3166 (17.6%) | 0.001 |
| LVEF (%) | 52.1±13.6 | 53.6±12.5 | 0.046 | 59.0±12.8 | 57.8±13.1 | 0.41 | 62.2±11.8 | 60.7±13.0 | 0.03 |
| <=40 | 45 (16.3%) | 986 (14.6%) | 0.44 | 6 (8.0%) | 276 (11.2%) | 0.39 | 24 (6.2%) | 1409 (8.9%) | 0.06 |
| Mitral regurgitation grade >=3/4 | 27 (7.7%) | 446 (5.8%) | 0.13 | 10 (9.9%) | 175 (5.7%) | 0.08 | 23 (5.4%) | 924 (5.5%) | 0.91 |
| Prior myocardial infarction * | 15 (4.1%) | 217 (2.7%) | 0.13 | 2 (1.8%) | 198 (6.0%) | 0.06 | 50 (10.8%) | 3143 (17.5%) | <0.001 |
| Prior stroke * | 36 (9.8%) | 767 (9.7%) | 0.95 | 9 (8.2%) | 436 (13.3%) | 0.12 | 37 (8.0%) | 2383 (13.3%) | 0.001 |
| Peripheral vascular disease * | 4 (1.1%) | 251 (3.2%) | 0.02 | 3 (2.7%) | 155 (4.7%) | 0.33 | 39 (8.4%) | 2183 (12.2%) | 0.02 |
| eGFR <30 mL/min/1.73m 2 , without hemodialysis * | 17 (4.6%) | 414 (5.2%) | 0.61 | 4 (3.6%) | 190 (5.8%) | 0.34 | 7 (1.5%) | 736 (4.1%) | 0.005 |
| Hemodialysis * | 6 (1.6%) | 146 (1.8%) | 0.77 | 4 (3.6%) | 129 (3.9%) | 0.87 | 34 (7.4%) | 1020 (5.7%) | 0.13 |
| Atrial fibrillation * | 46 (12.5%) | 698 (8.8%) | 0.02 | 10 (9.1%) | 312 (9.5%) | 0.88 | 53 (11.5%) | 1786 (10.0%) | 0.28 |
| Hemoglobin <11.0 g/dL * | 68 (18.4%) | 795 (10.0%) | <0.001 | 12 (10.9%) | 471 (14.4%) | 0.31 | 67 (14.5%) | 2442 (13.6%) | 0.58 |
| Platelet <100 × 10 9 /L * | 13 (3.5%) | 153 (1.9%) | 0.03 | 3 (2.7%) | 67 (2.0%) | 0.62 | 17 (3.7%) | 305 (1.7%) | 0.001 |
| CRP (mg/dL) | 0.16 (0.07-0.57) | 0.20 (0.10-0.60) | 0.002 | 0.20 (0.10-0.89) | 0.20 (0.10-0.70) | 0.98 | 0.12 (0.05-0.36) | 0.16 (0.07-0.40) | 0.02 |
| Chronic obstructive pulmonary disease * | 17 (4.6%) | 266 (3.3%) | 0.19 | 6 (5.5%) | 127 (3.9%) | 0.4 | 26 (5.6%) | 695 (3.9%) | 0.06 |
| Liver cirrhosis * | 13 (3.5%) | 178 (2.2%) | 0.11 | 4 (3.6%) | 79 (2.4%) | 0.41 | 16 (3.5%) | 496 (2.8%) | 0.37 |
| Malignancy * | 49 (13.3%) | 705 (8.9%) | 0.004 | 12 (10.9%) | 318 (9.7%) | 0.68 | 76 (16.5%) | 2108 (11.8%) | 0.002 |
| Family history of coronary artery disease ‡ | 20 (11.8%) | 488 (12.2%) | 0.89 | 6 (12.0%) | 182 (11.9%) | 0.98 | 20 (10.4%) | 900 (10.1%) | 0.9 |
| Family history of sudden death ‡ | 0 (0%) | 32 (0.8%) | 0.24 | 1 (2.0%) | 14 (0.9%) | 0.44 | 1 (0.5%) | 89 (1.0%) | 0.51 |
| (D) Angiographic and procedural characteristics | |||||||||
| Infarct related coronary artery location | |||||||||
| LAD | 190 (51.5%) | 3771 (47.5%) | 0.13 | 23 (32.9%) | 791 (39.2%) | 0.29 | – | – | – |
| LCX | 34 (9.2%) | 796 (10.0%) | 0.61 | 14 (20.0%) | 618 (30.6%) | 0.06 | – | – | – |
| Right | 129 (35.0%) | 3126 (39.4%) | 0.09 | 23 (32.9%) | 483 (23.9%) | 0.09 | – | – | – |
| LM | 16 (4.3%) | 239 (3.0%) | 0.15 | 10 (14.3%) | 122 (6.0%) | 0.005 | – | – | – |
| Maximum CK | 2059 (1003-3698) | 2020 (902-3959) | 0.64 | 718 (356-1706) | 664 (239-1571) | 0.32 | – | – | – |
| Onset-to-balloon time (hours) § | 4.6 (3.0-7.4) | 4.1 (2.8-7.0) | 0.11 | – | – | – | – | – | – |
| Door-to-balloon time (min) § | 90 (61-131) | 84 (60-120) | 0.04 | – | – | – | – | – | – |
| IABP use | 77 (20.9%) | 1493 (18.8%) | 0.32 | 15 (21.4%) | 363 (18.0%) | 0.46 | – | – | – |
| VA ECMO use | 21 (5.7%) | 222 (2.8%) | 0.001 | 4 (5.7%) | 56 (2.8%) | 0.15 | – | – | – |
| Number of target lesions or anastomoses | 1.3±0.7 | 1.5±0.8 | 0.002 | 1.5±0.9 | 1.7±1.0 | 0.06 | 1.5±0.9 | 1.8±1.1 | <0.001 |
| Target of proximal LAD * | 208 (56.4%) | 4582 (57.7%) | 0.62 | 58 (52.7%) | 1881 (57.4%) | 0.33 | 292 (63.2%) | 11742 (65.5%) | 0.31 |
| Target of chronic total occlusion * | 16 (4.3%) | 314 (4.0%) | 0.71 | 8 (7.3%) | 340 (10.4%) | 0.29 | 71 (15.4%) | 3609 (20.1%) | 0.01 |
| PCI | 359 (97.3%) | 7766 (97.8%) | 0.54 | 96 (87.3%) | 2898 (88.5%) | 0.7 | 396 (85.7%) | 14801 (82.5%) | 0.07 |
| Stent use | 306 (85.2%) | 7222 (93.0%) | <0.001 | 90 (93.8%) | 2714 (93.7%) | 0.97 | 375 (94.7%) | 14164 (95.7%) | 0.33 |
| DES use | 136 (44.4%) | 3511 (48.6%) | <0.001 | 49 (54.4%) | 1662 (61.2%) | 0.19 | 265 (70.7%) | 11499 (81.2%) | <0.001 |
| New-generation DES use | 85 (27.8%) | 2360 (32.7%) | 0.07 | 30 (33.3%) | 997 (36.7%) | 0.51 | 144 (38.4%) | 6567 (46.4%) | 0.002 |
| Total number of stents | 1.6±1.0 | 1.7±1.2 | 0.02 | 1.6±1.1 | 1.9±1.4 | 0.03 | 1.5±0.8 | 2.0±1.3 | <0.001 |
| Total stent length (mm) | 24 (18-38) | 26 (18-44) | 0.003 | 24 (18-36) | 28 (18-49) | 0.07 | 23 (18-40) | 32 (18-56) | <0.001 |
| IVUS use | 139 (38.7%) | 3816 (49.1%) | <0.001 | 32 (33.3%) | 1493 (51.5%) | 0.001 | 228 (57.6%) | 9423 (63.7%) | 0.01 |
| CABG | 10 (2.7%) | 177 (2.2%) | 0.54 | 14 (12.7%) | 378 (11.5%) | 0.7 | 66 (14.3%) | 3137 (17.5%) | 0.07 |
| Internal thoracic artery graft use | 7 (70.0%) | 149 (84.2%) | 0.24 | 10 (71.4%) | 357 (94.4%) | 0.001 | 61 (92.4%) | 3070 (97.9%) | 0.003 |
| Off pump surgery | 4 (40.0%) | 67 (37.9%) | 0.89 | 5 (35.7%) | 196 (51.9%) | 0.24 | 36 (54.5%) | 1974 (62.9%) | 0.16 |
| (E) Medications at hospital discharge | |||||||||
| Thienopyridine | 324 (87.8%) | 7531 (94.8%) | <0.001 | 97 (88.2%) | 2908 (88.8%) | 0.85 | 391 (84.6%) | 15071 (84.0%) | 0.72 |
| Aspirin | 348 (94.3%) | 7820 (98.5%) | <0.001 | 107 (97.3%) | 3228 (98.5%) | 0.29 | 456 (98.7%) | 17728 (98.8%) | 0.8 |
| Cilostazol | 63 (17.1%) | 1471 (18.5%) | 0.48 | 15 (13.6%) | 448 (13.7%) | 0.99 | 35 (7.6%) | 1052 (5.9%) | 0.12 |
| Statins * | 170 (46.1%) | 5414 (68.2%) | <0.001 | 53 (48.2%) | 2036 (62.1%) | 0.003 | 92 (19.9%) | 10817 (60.3%) | <0.001 |
| Beta-blockers * | 126 (34.1%) | 3756 (47.3%) | <0.001 | 21 (19.1%) | 1187 (36.2%) | <0.001 | 42 (9.1%) | 5450 (30.4%) | <0.001 |
| ACE-I/ARB * | 154 (41.7%) | 5928 (74.6%) | <0.001 | 38 (34.5%) | 2054 (62.7%) | <0.001 | 30 (6.5%) | 9092 (50.7%) | <0.001 |
| Calcium antagonists * | 28 (7.6%) | 1591 (20.0%) | <0.001 | 12 (10.9%) | 1241 (37.9%) | <0.001 | 113 (24.5%) | 9155 (51.0%) | <0.001 |
| Oral anticoagulants * | 52 (14.1%) | 968 (12.2%) | 0.28 | 15 (13.6%) | 349 (10.7%) | 0.32 | 63 (13.6%) | 2632 (14.7%) | 0.53 |
| Warfarin | 48 (13.0%) | 916 (11.5%) | 13 (11.8%) | 328 (10.0%) | 62 (13.4%) | 2519 (14.0%) | |||
| DOAC | 4 (1.1%) | 52 (0.7%) | 2 (1.8%) | 22 (0.7%) | 1 (0.2%) | 114 (0.6%) | |||
| PPI or H2 blockers * | 257 (69.6%) | 6120 (77.0%) | 0.001 | 73 (66.4%) | 2351 (71.8%) | 0.22 | 261 (56.5%) | 11002 (61.3%) | 0.04 |
| PPI | 177 (48.0%) | 4358 (54.9%) | 48 (43.6%) | 1663 (50.8%) | 178 (38.5%) | 7832 (43.7%) | |||
| H2 blockers | 81 (22.0%) | 1786 (22.5%) | 25 (22.7%) | 702 (21.4%) | 84 (18.2%) | 3240 (18.1%) | |||
| (F) Study * | |||||||||
| Cohort-2 | 200 (54.2%) | 3938 (49.6%) | 0.08 | 60 (54.5%) | 1747 (53.3%) | 0.8 | 269 (58.2%) | 9017 (50.3%) | 0.001 |
| Cohort-3 | 169 (45.8%) | 4005 (50.4%) | 50 (45.5%) | 1529 (46.7%) | 193 (41.8%) | 8921 (49.7%) | |||
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