Detailed Methods of the Multivariate Analyses

Supplementary MaterialSupplementary MethodsDetailed methods of the multivariate analysesIn line with our previous reports,1, 2, 3 we chose 37 clinically relevant factors as risk-adjusting variables; age ≥75 years, male, body mass index <25.0, acute myocardial infarction, hypertension, diabetes mellitus on insulin therapy, current smoking, heart failure, shock at presentation, multivessel disease, mitral regurgitation grade 3 or 4, prior myocardial infarction, prior stroke, peripheral vascular disease, eGFR<30 (not on dialysis), dialysis, anemia (hemoglobin <11.0 g/dl), thrombocytemia (platelet <100×10 9/L3), chronic obstructive pulmonary disease, liver cirrhosis, malignancy, target of proximal left anterior descending coronary artery, target of unprotected left main coronary artery, target of chronic total occlusion, target of bifurcation, side- branch stenting, total stent length >28 mm, minimum stent size <3.0mm, and usage of cilostazol, statins, beta- blockers, angiotensin converting enzyme inhibitor or angiotensin receptor blocker, nitrates, calcium channel blockers, nicorandil, proton pump inhibitors, or histamine type 2 receptor blockers. In comparisons betweenOAC versus no-OAC, TTR≥65% versus TTR<65%, and on-DAPT versus off-DAPT groups, CHADS2 score≥2 was also included as co-variable in the multivariate models.The continuous variables were dichotomized by clinically meaningful reference values or median values. Values were missing for body-mass index (BMI) in 374 patients, for eGFR in 160 patients, for anemia in176 patients, for thrombocytopenia in 86 patients, and for cilostazol use in 1 patient. Those patients with missing values were regarded as having BMI <25.0 kg/m2, not having renal failure, anemia, and thrombocytopenia, and not on cilostazol. Proportional hazard assumption for the comparison between the groups was assessed on the plots of log (time) versus log [-log (survival)]. A Supplementary Table 1. Baseline characteristics of entire study population comparing AF versus no-AF patientsEntire Population AF no-AF P value (N=12716) (N=1057) (N=11659) Age (years) 68.0±11.0 72.5±9.3 67.6±11.1 <0.0001Age ≥75 years 3873 (30.5%) 477 (45.1%) 3396 (29.1%)<0.0001Male 9181 (72.2%) 752 (71.1%) 8429 (72.3%)0.43AF typeParoxysmal ── 652 (61.7%) ── ──Persistent / Permanent ── 302 (28.6%) ── ──Unknown ── 103 (9.7%) ── ──Body mass index < 25.0 kg/m2 8655 (68.1%) 766 (72.5%) 7889 (67.7%)0.001Acute myocardial infarction 4428 (34.8%) 392 (37.1%) 4036 (34.6%)0.11Hypertension 10473 (82.4%) 902 (85.3%) 9571 (82.1%)0.007Diabetes mellitus 4773 (37.5%) 362 (34.2%) 4411 (37.8%)0.02On insulin therapy 965 (7.6%) 60 (5.7%) 905 (7.8%)0.01Current smoker 4073 (32.0%) 237 (22.4%) 3836 (32.9%)<0.0001B Heart failure 2317 (18.2%) 417 (39.5%) 1900 (16.3%)<0.0001Shock at presentation 579 (4.6%) 98 (9.3%) 481 (4.1%)<0.0001Multivessel coronary artery disease 6980 (54.9%) 529 (50.0%) 6451 (55.3%)0.001Ejection fraction 58.8±12.9 55.4±14.1 59.1±12.8<0.0001Mitral regurgitation grade 3/4 489 (3.9%) 109 (10.3%) 380 (3.3%)<0.0001Prior myocardial infarction 1329 (10.5%) 128 (12.1%) 1201 (10.3%)0.07Prior stroke 1328 (10.4%) 196 (18.5%) 1132 (9.7%)<0.0001Prior intracranial bleeding 206 (1.6%) 27 (2.6%) 179 (1.5%)0.02Peripheral vascular disease 932 (7.3%) 87 (8.2%) 845 (7.3%)0.25 eGFR<30, not on dialysis 462 (3.6%) 59 (5.6%) 403 (3.5%)0.0009Dialysis 445 (3.5%) 48 (4.5%) 397 (3.4%)0.06Anemia (Hb <11.0 g/dl) 1420 (11.2%) 153 (14.5%) 1267 (10.9%)0.0006Platelet <100×109/L3 170 (1.3%) 30 (2.8%) 140 (1.2%)<0.0001Chronic obstructive pulmonary disease 461 (3.6%) 43 (4.1%) 418 (3.6%)C 0.43Liver cirrhosis 332 (2.6%) 30 (2.8%) 302 (2.6%)0.63Malignancy 1151 (9.1%) 108 (10.2%) 1043 (9.0%)0.17CHADS2 score ── 2.4±1.3 ── ──CHADS2 score ≥2 ── 795 (75.2%) ── ──CHA2DS2-VASc score ── 4.5±1.5 ── ──Stent use 11889 (93.5%) 959 (90.7%) 10930 (93.8%)0.0003 DES use 6710 (52.8%) 506 (47.9%) 6204 (53.2%)0.0009Aspirin 12578 (98.9%) 1037 (98.1%) 11541 (99.0%)0.02Thienopyridine 12418 (97.7%) 1005 (95.1%) 11413 (97.9%)<0.0001DAPT 12300 (96.7%) 989 (93.6%) 11311 (97.0%)<0.0001Warfarin 1061 (8.3%) 506 (47.9%) 555 (4.8%)<0.0001 Statins 6656 (52.3%) 430 (40.7%) 6226 (53.4%)<0.0001Beta-blockers 3949 (31.1%) 403 (38.1%) 3546 (30.4%)<0.0001ACE-I/ARB 7545 (59.3%) 646 (61.1%) 6899 (59.2%)D 0.22Proton pump inhibitors 3293 (25.9%) 310 (29.3%) 2983 (25.6%)0.009ACE-I=angiotensin converting enzyme inhibitor, AF=atrial fibrillation, ARB=angiotensin receptor blocker,DES=drug-eluting stent, DAPT=dual antiplatelet therapy, and eGFR=estimated glomerular filtration rate.E Supplementary Table 2. Comparison of baseline characteristics between patients withTTR≥65% and TTR<65% in the OAC group.TTR≥65% TTR<65% P value (N=154) (N=255) Age (years) 69.8±8.4 72.3±8.80.004Age ≥75 years 46 (29.9%) 115 (45.1%)0.002Male 127 (82.5%) 193 (75.7%)0.10AF typeParoxysmal 75 (48.7%) 130 (51.0%)0.90Persistent / Permanent 62 (40.3%) 99 (38.8%)Unknown 17 (11.0%) 26 (10.2%)Body mass index < 25.0 kg/m2 107 (69.5%) 178 (69.8%)0.95Acute myocardial infarction 49 (31.8%) 80 (31.4%)0.93Hypertension 134 (87.0%) 221 (86.7%)0.92Diabetes mellitus 55 (35.7%) 93 (36.5%) 0.88On insulin therapy 6 (3.9%) 14 (5.5%)0.46Current smoker 36 (23.4%) 67 (26.3%)0.51Heart failure 57 (37.0%) 99 (38.8%)0.71F Shock at presentation 9 (5.8%) 14 (5.5%) 0.88Multivessel coronary artery disease 71 (46.1%) 124 (48.6%)0.62Ejection fraction (%) 54.4±14.2 53.9±15.2 0.75Mitral regurgitation grade 3/4 14 (9.1%) 27 (10.6%)0.62Prior myocardial infarction 21 (13.6%) 32 (12.6%)0.75Prior stroke 35 (22.7%) 43 (16.9%)0.15Prior intracranial bleeding 2 (1.3%) 5 (2.0%) 0.72Peripheral vascular disease 16 (10.4%) 28 (11.0%)0.85 eGFR<30, not on dialysis 3 (2.0%) 18 (7.1%)0.02Dialysis 6 (3.9%) 6 (2.4%) 0.38Anemia (Hb <11.0 g/dl) 12 (7.8%) 26 (10.2%)0.41Platelet <100×109/L3 2 (1.3%) 7 (2.8%) 0.49Chronic obstructive pulmonary disease 6 (3.9%) 10 (3.9%)0.99Liver cirrhosis 4 (2.6%) 12 (4.7%)0.27Malignancy 11 (7.1%) 25 (9.8%)0.35CHADS2 score 2.4±1.3 2.4±1.20.65CHADS2 score ≥2 112 (72.7%) 199 (78.0%)0.23G CHA2DS2-VASc score 4.3±1.6 4.5±1.50.17Stent use 138 (89.6%) 228 (89.4%)0.95DES use 82 (53.3%) 139 (54.5%)0.80Aspirin 148 (96.1%) 251 (98.4%)0.19Thienopyridine 146 (94.8%) 242 (94.9%)0.97DAPT 142 (92.2%) 238 (93.3%)0.67Statins 69 (44.8%) 107 (42.0%) 0.57Beta-blockers 74 (48.1%) 116 (45.5%)0.61ACE-I/ARB 101(65.6%) 169 (66.3%)0.89Proton pump inhibitors 42 (27.3%) 62 (24.3%)0.51ACE-I=angiotensin converting enzyme inhibitor, AF=atrial fibrillation, ARB=angiotensin receptor blocker, DES=drug-eluting stent, DAPT=dual antiplatelet therapy, eGFR=estimated glomerular filtration rate OAC=oral anticoagulation, and TTR=time in therapeutic range.H Supplementary Table 3. Baseline characteristics of AF patients with OAC at hospital discharge in the 4-month landmark analysis: On- versus Off-DAPT On-DAPT Off-DAPT P value (N=286) (N=173)Age (years) 71.4±8.6 72.8±9.0 0.09Age ≥75 years 109 (38.1%) 79 (45.7%) 0.11Male 229 (80.1%) 127 (73.4%)0.10AF typeParoxysmal 146 (51.1%) 79 (45.7%) 0.53Persistent / Permanent 111 (38.8%) 74 (42.8%)Unknown 29 (10.1%) 20 (11.6%)Body mass index < 25.0 kg/m2 198 (69.2%) 118 (68.2%)0.82Acute myocardial infarction 70 (24.5%) 77 (44.5%)<0.001Hypertension 246 (86.0%) 152 (87.9%) 0.57Diabetes mellitus 120 (42.0%) 43 (24.9%) 0.0002On insulin therapy 16 (5.6%) 4 (2.3%)0.08Current smoker 70 (24.5%) 37 (21.4%)0.45Heart failure 110 (38.5%) 65 (37.6%)0.85Shock at presentation 13 (4.6%) 12 (6.9%) 0.28Multivessel coronary artery disease 154 (53.9%) 59 (34.1%)<0.0001I Ejection fraction (%) 54.1±14.7 55.0±13.8 0.53Mitral regurgitation grade 3/4 19 (6.6%) 28 (16.2%)0.001Prior myocardial infarction 37 (12.9%) 21 (12.1%) 0.8Prior stroke 59 (20.6%) 22 (12.7%) 0.03Prior intracranial bleeding 2 (0.7%) 2 (1.2%) 0.63Peripheral vascular disease 28 (9.8%) 14 (8.1%)0.54 eGFR<30, not on dialysis 13 (4.6%) 9 (5.2%)0.75Dialysis 14 (4.9%) 3 (1.7%) 0.07Anemia (Hb <11.0 g/dl) 29 (10.1%) 20 (11.6%) 0.63Platelet <100×109/L3 6 (2.1%) 5 (2.9%) 0.75Chronic obstructive pulmonary disease 10 (3.5%) 6 (3.5%) 0.99Liver cirrhosis 10 (3.5%) 5 (2.9%) 0.72Malignancy 23 (8.0%) 18 (10.4%) 0.39CHADS2 score 2.5±1.2 2.2±1.2 0.04CHADS2 score ≥2 225 (78.7%) 123 (71.1%) 0.07CHA2DS2-VASc score 4.5±1.5 4.3±1.5 0.17Stent use 280 (97.9%) 127 (73.4%)<0.0001DES use 207 (72.4%) 37 (21.4%)<0.0001Aspirin 286 (100%) 163 (94.2%)<0.0001Thienopyridine 286 (100%) 143 (82.7%)<0.0001DAPT 286 (100%) 135 (78.0%)<0.0001Statins 125 (43.7%) 73 (42.2%) 0.75Beta-blockers 128 (44.8%) 76 (43.9%) 0.86J ACE-I/ARB 182 (63.6%) 117 (67.6%) 0.38Proton pump inhibitors 70 (24.5%) 44 (25.4%)0.82ACE-I=angiotensin converting enzyme inhibitor, AF=atrial fibrillation, ARB=angiotensin receptor blocker, DES=drug-eluting stent, DAPT=dual antiplatelet therapy, eGFR=estimated glomerular filtration rate, and OAC=oral anticoagulation.K Supplementary Table 4. Unadjusted and adjusted clinical outcomes in the 4-month landmark analysis among AF patients with OAC: On- versus Off-DAPTNo. of Events P Unadjusted HR Adjusted HR P (5-year cumulative rate) Value (95%CI) (95%CI) ValueOn-DAPT Off-DAPT (N=286) (N=173) ) Stroke* 40 (15.1%) 15 (6.7%) 0.052 1.79 (0.99-3.24) 1.50 (0.67-3.39) 0.33Ischemic 32 (12.0%) 13 (5.6%) 0.12 1.66 (0.87-3.17) 1.88 (0.73-4.80)0.19Hemorrhagic 10 (4.3%) 2 (1.2%) 0.12 3.15 (0.69-14.4) ─ ‡─All-caused death 81 (25.2%) 39 (20.4%) 0.10 1.38 (0.94-2.02) 1.35 (0.81-2.25)0.25Major bleeding 36 (14.7%) 14 (8.7%) 0.10 1.68 (0.91-3.12) 1.61 (0.68-3.84)0.28Myocardial infarction 7 (3.4%) 6 (4.7%) 0.57 0.73 (0.25-2.18) ─ ‡─Stent thrombosis† 1 (0.5%) 1 (0.7%) 0.75 0.64 (0.04-10.2) ─ ‡─AF=atrial fibrillation, CI=confidence interval, DAPT=dual antiplatelet therapy, HR=hazard ratio, and OAC=oral anticoagulation.* The sum of the numbers of ischemic and hemorrhagic stroke events is not necessarily equal to the number of overall stroke events because of patients with multiple events.†Academic Research Consortium definite. ‡ Not available because of small number of events.L Supplementary Figure 1.M Supplementary Figure 2.N O Supplementary Figure 3.P Supplementary Figure 4.Q Supplementary Figure legendsSupplementary Figure 1.(A) Distributions of CHADS2 score in the OAC and no-OAC groups. Supplementary Figure 2.(A) Maintenance of OAC in the OAC group. (B) Initiation of OAC in the no-OAC group.Supplementary Figure 3.Maintenance of DAPT in AF patients comparing OAC versus no-OAC groups.Supplementary Figure 4.Cumulative incidence of stroke comparing (A) TTR<60% versus TTR≥60% and (B) TTR<70% versusTTR≥70% groups.R Supplementary References1. Kimura T, Morimoto T, Furukawa Y, et al. Long-term outcomes of coronary-artery bypass graft surgery versus percutaneous coronary intervention for multivessel coronary artery disease in the bare-metal stent era. Circulation 2008;118:S199-S209.2. Tokushige A, Shiomi H, Morimoto T, et al; CREDO-Kyoto PCI/CABG registry cohort-2 investigators.Incidence and outcome of surgical procedures after coronary bare-metal and drug-eluting stent implantation: a report from the CREDO-Kyoto PCI/CABG registry cohort-2. Circ Cardiovasc Interv2012;5:237-246.3. Tada T, Natsuaki M, Morimoto T, et al; CREDO-Kyoto PCI/CABG Registry Cohort-2 Investigators.Duration of dual antiplatelet therapy and long-term clinical outcome after coronary drug-eluting stent implantation: landmark analyses from the CREDO-Kyoto PCI/CABG Registry Cohort-2. Circ CardiovascInterv 2012;5:381-391.S Supplementary Appendix A: List of participating centers and investigators for the CREDO-Kyoto (Coronary REvascularization Demonstrating Outcome Study in Kyoto) Registry Cohort-2Kyoto University Graduate School of Medicine: Takeshi KimuraKishiwada City Hospital: Mitsuo Matsuda, Hirokazu MitsuokaTenri Hospital: Yoshihisa NakagawaHyogo Prefectural Amagasaki Hospital: Hisayoshi Fujiwara, Yoshiki Takatsu, Ryoji TaniguchiKitano Hospital: Ryuji NoharaKoto Memorial Hospital: Tomoyuki Murakami, Teruki TakedaKokura Memorial Hospital: Masakiyo Nobuyoshi, Masashi IwabuchiMaizuru Kyosai Hospital: Ryozo TatamiNara Hospital, Kinki University Faculty of Medicine: Manabu ShirotaniKobe City Medical Center General Hospital: Toru Kita, Yutaka Furukawa, Natsuhiko EharaNishi-Kobe Medical Center: Hiroshi Kato, Hiroshi EizawaKansai Electric Power Hospital: Katsuhisa IshiiOsaka Red Cross Hospital: Masaru TanakaUniversity of Fukui Hospital: Jong-Dae Lee, Akira NakanoShizuoka City Shizuoka Hospital: Akinori Takizawa, Tomoya Onodera, Kouichirou MurataHamamatsu Rosai Hospital: Masaaki TakahashiShiga University of Medical Science: Minoru Horie, Hiroyuki TakashimaJapanese Red Cross Wakayama Medical Center: Takashi TamuraShimabara Hospital: Mamoru TakahashiKagoshima University: Chuwa Tei, Shuichi HamasakiShizuoka General Hospital: Hirofumi Kambara, Osamu Doi, Satoshi KaburagiKurashiki Central Hospital: Kazuaki Mitsudo, Kazushige KadotaMitsubishi Kyoto Hospital: Shinji Miki, Tetsu MizoguchiKumamoto University: Hisao Ogawa, Seigo SugiyamaShimada Municipal Hospital: Ryuichi Hattori, Takeshi Aoyama, Makoto ArakiJuntendo University Shizuoka Hospital: Satoru SuwaT Supplementary Appendix B: List of clinical research coordinatorsResearch Institute for Production DevelopmentKumiko Kitagawa, Misato Yamauchi, Naoko Okamoto, Yumika Fujino, Saori Tezuka, Asuka Saeki, MiyaHanazawa,Yuki Sato, Chikako Hibi, Hitomi Sasae, Emi Takinami, Yuriko Uchida,Yuko Yamamoto, Satoko Nishida,Mai Yoshimoto, Sachiko Maeda, Izumi Miki, Saeko Minematsu, Asuka Takahashi, Yui KinoshitaSupplementary Appendix C: List of the clinical events committee membersMitsuru Abe (Kyoto Medical Center), Hiroki Shiomi (Kyoto University Hospital), Tomohisa Tada (DeutschesHerzzentrum), Junichi Tazaki (Kyoto University Hospital), Yoshihiro Kato (Saiseikai Noe Hospital), MamoruHayano (Kyoto University Hospital), Akihiro Tokushige (Kagoshima University Hospital), Masahiro Natsuaki(Kyoto University Hospital), Tetsu Nakajima (Kyoto University Hospital), Mitsuhiko Yahata (Kyoto UniversityHospital), Erika Yamamoto (Kyoto University Hospital), Hirooki Higami (Kyoto University Hospital), KentaroNakai (Kyoto University Hospital), Koji Goto (Kyoto University Hospital), Reiko Hozo (Kyoto UniversityHospital), Yuko Morikami (Kyoto University Hospital).U

Detailed Methods of the Multivariate Analyses

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