Detailed Methods of the Multivariate Analyses

Supplementary Material

Supplementary Methods

Detailed methods of the multivariate analyses

In 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 between

OAC 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 in

176 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 patients

Entire 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 <0.0001

Age ≥75 years 3873 (30.5%) 477 (45.1%) 3396 (29.1%)

<0.0001

Male 9181 (72.2%) 752 (71.1%) 8429 (72.3%)

AF type

Paroxysmal ── 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%)

Acute myocardial infarction 4428 (34.8%) 392 (37.1%) 4036 (34.6%)

Hypertension 10473 (82.4%) 902 (85.3%) 9571 (82.1%)

Diabetes mellitus 4773 (37.5%) 362 (34.2%) 4411 (37.8%)

On insulin therapy 965 (7.6%) 60 (5.7%) 905 (7.8%)

Current smoker 4073 (32.0%) 237 (22.4%) 3836 (32.9%)

<0.0001

B Heart failure 2317 (18.2%) 417 (39.5%) 1900 (16.3%)

<0.0001

Shock at presentation 579 (4.6%) 98 (9.3%) 481 (4.1%)

<0.0001

Multivessel coronary artery disease 6980 (54.9%) 529 (50.0%) 6451 (55.3%)

Ejection fraction 58.8±12.9 55.4±14.1 59.1±12.8

<0.0001

Mitral regurgitation grade 3/4 489 (3.9%) 109 (10.3%) 380 (3.3%)

<0.0001

Prior myocardial infarction 1329 (10.5%) 128 (12.1%) 1201 (10.3%)

Prior stroke 1328 (10.4%) 196 (18.5%) 1132 (9.7%)

<0.0001

Prior intracranial bleeding 206 (1.6%) 27 (2.6%) 179 (1.5%)

Peripheral 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%)

0.0009

Dialysis 445 (3.5%) 48 (4.5%) 397 (3.4%)

Anemia (Hb <11.0 g/dl) 1420 (11.2%) 153 (14.5%) 1267 (10.9%)

0.0006

Platelet <100×109/L3 170 (1.3%) 30 (2.8%) 140 (1.2%)

<0.0001

Chronic obstructive pulmonary disease 461 (3.6%) 43 (4.1%) 418 (3.6%)

C 0.43

Liver cirrhosis 332 (2.6%) 30 (2.8%) 302 (2.6%)

Malignancy 1151 (9.1%) 108 (10.2%) 1043 (9.0%)

CHADS2 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%)

0.0009

Aspirin 12578 (98.9%) 1037 (98.1%) 11541 (99.0%)

Thienopyridine 12418 (97.7%) 1005 (95.1%) 11413 (97.9%)

<0.0001

DAPT 12300 (96.7%) 989 (93.6%) 11311 (97.0%)

<0.0001

Warfarin 1061 (8.3%) 506 (47.9%) 555 (4.8%)

<0.0001

Statins 6656 (52.3%) 430 (40.7%) 6226 (53.4%)

<0.0001

Beta-blockers 3949 (31.1%) 403 (38.1%) 3546 (30.4%)

<0.0001

ACE-I/ARB 7545 (59.3%) 646 (61.1%) 6899 (59.2%)

D 0.22

Proton pump inhibitors 3293 (25.9%) 310 (29.3%) 2983 (25.6%)

ACE-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 with

TTR≥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±8.8

Age ≥75 years 46 (29.9%) 115 (45.1%)

Male 127 (82.5%) 193 (75.7%)

AF type

Paroxysmal 75 (48.7%) 130 (51.0%)

Persistent / 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%)

Acute myocardial infarction 49 (31.8%) 80 (31.4%)

Hypertension 134 (87.0%) 221 (86.7%)

Diabetes mellitus 55 (35.7%) 93 (36.5%)

On insulin therapy 6 (3.9%) 14 (5.5%)

Current smoker 36 (23.4%) 67 (26.3%)

Heart failure 57 (37.0%) 99 (38.8%)

F Shock at presentation 9 (5.8%) 14 (5.5%) 0.88

Multivessel coronary artery disease 71 (46.1%) 124 (48.6%)

Ejection fraction (%) 54.4±14.2 53.9±15.2 0.75

Mitral regurgitation grade 3/4 14 (9.1%) 27 (10.6%)

Prior myocardial infarction 21 (13.6%) 32 (12.6%)

Prior stroke 35 (22.7%) 43 (16.9%)

Prior intracranial bleeding 2 (1.3%) 5 (2.0%)

Peripheral vascular disease 16 (10.4%) 28 (11.0%)

0.85 eGFR<30, not on dialysis 3 (2.0%) 18 (7.1%)

Dialysis 6 (3.9%) 6 (2.4%) 0.38

Anemia (Hb <11.0 g/dl) 12 (7.8%) 26 (10.2%)

Platelet <100×109/L3 2 (1.3%) 7 (2.8%) 0.49

Chronic obstructive pulmonary disease 6 (3.9%) 10 (3.9%)

Liver cirrhosis 4 (2.6%) 12 (4.7%)

Malignancy 11 (7.1%) 25 (9.8%)

CHADS2 score 2.4±1.3 2.4±1.2

CHADS2 score ≥2 112 (72.7%) 199 (78.0%)

G CHA2DS2-VASc score 4.3±1.6 4.5±1.5

Stent use 138 (89.6%) 228 (89.4%)

DES use 82 (53.3%) 139 (54.5%)

Aspirin 148 (96.1%) 251 (98.4%)

Thienopyridine 146 (94.8%) 242 (94.9%)

DAPT 142 (92.2%) 238 (93.3%)

Statins 69 (44.8%) 107 (42.0%) 0.57

Beta-blockers 74 (48.1%) 116 (45.5%)

ACE-I/ARB 101(65.6%) 169 (66.3%)

Proton pump inhibitors 42 (27.3%) 62 (24.3%)

ACE-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 0.09

Age ≥75 years 109 (38.1%) 79 (45.7%) 0.11

Male 229 (80.1%) 127 (73.4%)

AF type

Paroxysmal 146 (51.1%) 79 (45.7%) 0.53

Persistent / 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%)

Acute myocardial infarction 70 (24.5%) 77 (44.5%)

<0.001

Hypertension 246 (86.0%) 152 (87.9%) 0.57

Diabetes mellitus 120 (42.0%) 43 (24.9%)

0.0002

On insulin therapy 16 (5.6%) 4 (2.3%)

Current smoker 70 (24.5%) 37 (21.4%)

Heart failure 110 (38.5%) 65 (37.6%)

Shock at presentation 13 (4.6%) 12 (6.9%) 0.28

Multivessel coronary artery disease 154 (53.9%) 59 (34.1%)

<0.0001

I Ejection fraction (%) 54.1±14.7 55.0±13.8 0.53

Mitral regurgitation grade 3/4 19 (6.6%) 28 (16.2%)

Prior myocardial infarction 37 (12.9%) 21 (12.1%) 0.8

Prior stroke 59 (20.6%) 22 (12.7%) 0.03

Prior intracranial bleeding 2 (0.7%) 2 (1.2%) 0.63

Peripheral vascular disease 28 (9.8%) 14 (8.1%)

0.54 eGFR<30, not on dialysis 13 (4.6%) 9 (5.2%)

Dialysis 14 (4.9%) 3 (1.7%) 0.07

Anemia (Hb <11.0 g/dl) 29 (10.1%) 20 (11.6%) 0.63

Platelet <100×109/L3 6 (2.1%) 5 (2.9%) 0.75

Chronic obstructive pulmonary disease 10 (3.5%) 6 (3.5%) 0.99

Liver cirrhosis 10 (3.5%) 5 (2.9%) 0.72

Malignancy 23 (8.0%) 18 (10.4%) 0.39

CHADS2 score 2.5±1.2 2.2±1.2 0.04

CHADS2 score ≥2 225 (78.7%) 123 (71.1%) 0.07

CHA2DS2-VASc score 4.5±1.5 4.3±1.5 0.17

Stent use 280 (97.9%) 127 (73.4%)

<0.0001

DES use 207 (72.4%) 37 (21.4%)

<0.0001

Aspirin 286 (100%) 163 (94.2%)

<0.0001

Thienopyridine 286 (100%) 143 (82.7%)

<0.0001

DAPT 286 (100%) 135 (78.0%)

<0.0001

Statins 125 (43.7%) 73 (42.2%) 0.75

Beta-blockers 128 (44.8%) 76 (43.9%) 0.86

J ACE-I/ARB 182 (63.6%) 117 (67.6%) 0.38

Proton pump inhibitors 70 (24.5%) 44 (25.4%)

ACE-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-DAPT

No. of Events P Unadjusted HR Adjusted HR P (5-year cumulative rate) Value (95%CI) (95%CI) Value

On-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) 0.33

Ischemic 32 (12.0%) 13 (5.6%) 0.12 1.66 (0.87-3.17) 1.88 (0.73-4.80)

Hemorrhagic 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)

Major bleeding 36 (14.7%) 14 (8.7%) 0.10 1.68 (0.91-3.12) 1.61 (0.68-3.84)

Myocardial 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 legends

Supplementary Figure 1.

(A) Distributions of CHADS2 score in the OAC and no-OAC groups.

(A) Maintenance of OAC in the OAC group.

(B) Initiation of OAC in the no-OAC group.

Maintenance of DAPT in AF patients comparing OAC versus no-OAC groups.

Cumulative incidence of stroke comparing (A) TTR<60% versus TTR≥60% and (B) TTR<70% versus

TTR≥70% groups.

R Supplementary References

1. 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 Interv

2012;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 Cardiovasc

Interv 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-2

Kyoto University Graduate School of Medicine: Takeshi Kimura

Kishiwada City Hospital: Mitsuo Matsuda, Hirokazu Mitsuoka

Tenri Hospital: Yoshihisa Nakagawa

Hyogo Prefectural Amagasaki Hospital: Hisayoshi Fujiwara, Yoshiki Takatsu, Ryoji Taniguchi

Kitano Hospital: Ryuji Nohara

Koto Memorial Hospital: Tomoyuki Murakami, Teruki Takeda

Kokura Memorial Hospital: Masakiyo Nobuyoshi, Masashi Iwabuchi

Maizuru Kyosai Hospital: Ryozo Tatami

Nara Hospital, Kinki University Faculty of Medicine: Manabu Shirotani

Kobe City Medical Center General Hospital: Toru Kita, Yutaka Furukawa, Natsuhiko Ehara

Nishi-Kobe Medical Center: Hiroshi Kato, Hiroshi Eizawa

Kansai Electric Power Hospital: Katsuhisa Ishii

Osaka Red Cross Hospital: Masaru Tanaka

University of Fukui Hospital: Jong-Dae Lee, Akira Nakano

Shizuoka City Shizuoka Hospital: Akinori Takizawa, Tomoya Onodera, Kouichirou Murata

Hamamatsu Rosai Hospital: Masaaki Takahashi

Shiga University of Medical Science: Minoru Horie, Hiroyuki Takashima

Japanese Red Cross Wakayama Medical Center: Takashi Tamura

Shimabara Hospital: Mamoru Takahashi

Kagoshima University: Chuwa Tei, Shuichi Hamasaki

Shizuoka General Hospital: Hirofumi Kambara, Osamu Doi, Satoshi Kaburagi

Kurashiki Central Hospital: Kazuaki Mitsudo, Kazushige Kadota

Mitsubishi Kyoto Hospital: Shinji Miki, Tetsu Mizoguchi

Kumamoto University: Hisao Ogawa, Seigo Sugiyama

Shimada Municipal Hospital: Ryuichi Hattori, Takeshi Aoyama, Makoto Araki

Juntendo University Shizuoka Hospital: Satoru Suwa

T Supplementary Appendix B: List of clinical research coordinators

Research Institute for Production Development

Kumiko Kitagawa, Misato Yamauchi, Naoko Okamoto, Yumika Fujino, Saori Tezuka, Asuka Saeki, Miya

Hanazawa,

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 Kinoshita

Supplementary Appendix C: List of the clinical events committee members

Mitsuru Abe (Kyoto Medical Center), Hiroki Shiomi (Kyoto University Hospital), Tomohisa Tada (Deutsches

Herzzentrum), Junichi Tazaki (Kyoto University Hospital), Yoshihiro Kato (Saiseikai Noe Hospital), Mamoru

Hayano (Kyoto University Hospital), Akihiro Tokushige (Kagoshima University Hospital), Masahiro Natsuaki

(Kyoto University Hospital), Tetsu Nakajima (Kyoto University Hospital), Mitsuhiko Yahata (Kyoto University

Hospital), Erika Yamamoto (Kyoto University Hospital), Hirooki Higami (Kyoto University Hospital), Kentaro

Nakai (Kyoto University Hospital), Koji Goto (Kyoto University Hospital), Reiko Hozo (Kyoto University

Hospital), Yuko Morikami (Kyoto University Hospital).