ONLINE APPENDIX

Expanded biomarker methods

The biomarkers used had the following performance characteristics: hs-cTnT:

Limit of quantification (LOQ): 3 ng/L Local Coefficient of variation (CV): 2% at 28.7 ng/L; 2% at 2155 ng/L

NT-proBNP:LOQ: 5 ng/LLocal CV: 2% at 133 ng/L; 2% at 4463 ng/L

IL-6:LOQ: 0.039 ng/LLocal CV: 6% at 1.4 ng/L; 6% at 5.64 ng/L

hs-CRP:LOQ: 0.15 mg/LLocal CV: 3% at 3.96 mg/L; 2% at 11.5 ng/L

Cystatin C:LOQ: 0.4 mg/LLocal CV: 3% at 1.11 mg/L; 3% at 4.35 ng/L

GDF-15:LOQ: 400 ng/LLocal CV: 2% at 1450 ng/L; 2% at 5750 ng/L

Online Table 1: Eligibility criteria in the STABILITY trial

Inclusion criteria Exclusion criteria Signed written informed consent Male of female aged ≥18 y, inclusive, at screening.

Female patients must be postmenopausal or using a highly effective method for avoidance of pregnancy

Current treatment with statin therapy unless not indicated according to treatment guidelines or contraindicated in the opinion of the investigator

Chronic CHD documented by at least one of the following:

o Prior MI (>1 m before randomization)o Prior coronary revascularization procedure (PCI

>1m before randomization or CABG >3m before randomization)

o Multivessel CHD involving major epicardial coronary arteries confirmed by coronary angiography at any time (without revascularization)

Planned coronary revascularization (PCI or CABG) or any other major surgical procedure

Current liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) or evidence of abnormal liver function tests (total bilirubin or alkaline phosphatase >1.5x upper limit of normal or ALT or AST >2.5x upper limit of normal).

Severe renal impairment (eGFR <30 mL/min/1.73 m2 or chronic dialysis), history of nephrectomy or kidney transplant (regardless of renal function).

Current New York Heart Association class III or IV heart failure.

Poorly controlled hypertension despite lifestyle modifications and pharmacotherapy.

Any life-threatening condition with life expectancy <2y, other than vascular disease, that might prevent the subject from completing the study.

Severe asthma that is poorly controlled on pharmacotherapy.

Positive pregnancy test. History of anaphylaxis, anaphylactoid (resembling

anaphylaxis) reactions, or severe allergic responses. Alcohol or drug abuse within the past 6 m, or current

mental condition (psychiatric disorder, senility, or dementia), which may affect study compliance.

Current or planned chronic administration of strong oral or injectable cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors.

Patients with both parents of Japanese, Chinese, or Korean ancestry must have a blood sample collected for assessment of Lp-PLA2 activity by the central laboratory before randomization. Those with Lp-PLA2 activity ≤20 nmol/min/mL will be excluded from participation in the study.

Previous exposure to darapladib. Use of another investigational product within 30 d or 5

half-lives (whichever is the longer) preceding the first dose of darapladib or matching placebo.

Currently in a study of an investigational device.

Online Table 2: Enrichment criteria in the STABILITY trial

Enrichment criteria Age ≥60 y at randomization Diabetes mellitus requiring pharmacotherapy. High-density lipoprotein cholesterol <40 mg/dL (1.03 mmol/L). Smoker (defined as ≥5 cigarettes per day on average) or a previous smoker

(defined as ≥5 cigarettes per day on average when smoking) who discontinued within the past 3 months.

Renal dysfunction (defined as eGFR ≥30 and ≤59 mL/min per 1.73 m2 OR urine ACR ≥30 mg albumin/g creatinine).

Polyvascular disease manifested as coexistent clinically diagnosed arterial disease in ≥2 arterial territories, defined as:

o Chronic CHD and cerebrovascular disease defined as carotid artery disease or prior ischemic stroke

ORo Chronic CHD and peripheral arterial disease

Online Table 3: Extended baseline characteristics in relation to quartiles of hs-cTnT and NT-proBNPhs-cTnT by quartile NT-proBNP by quartile

<6.2 6.2-9.3 9.3-14.2 >=14.2P-value

<83 83-173 173-380 >=380P-value

N=3256 N=3311 N=3257 N=3340 N=3278 N=3334 N=3309 N=3243

Age at randomization (years)

n 3256 3311 3257 3340 <.0001

Age at randomization (years)

n 3278 3334 3309 3243 <.0001

Mean (SD) 59.6 (8.8) 63.6 (8.4) 66.5 (8.5) 68.4 (9.0) Mean (SD) 60.2 (8.8) 64.0 (8.7) 66.0 (8.8) 68.0 (9.0)

Median (Min, Max) 61.0 (29, 86) 64.0 (29, 87) 67.0 (30, 89) 69.0 (33, 92) Median (Min, Max) 61.0 (29, 87) 64.0 (29, 87) 67.0 (30, 90) 69.0 (31, 92)

(Q1, Q3) (54.0, 66.0) (59.0, 70.0) (61.0, 72.0) (63.0, 75.0) (Q1, Q3) (54.0, 66.0) (59.0, 70.0) (61.0, 72.0) (62.0, 74.0)

SexFemale 934 (28.7%) 586 (17.7%) 472 (14.5%) 416 (12.5%) <.0001

SexFemale 389 (11.9%) 558 (16.7%) 673 (20.3%) 788 (24.3%) <.0001

Male 2322 (71.3%) 2725 (82.3%) 2785 (85.5%) 2924 (87.5%) Male 2889 (88.1%) 2776 (83.3%) 2636 (79.7%) 2455 (75.7%)

BMI

n 3256 3311 3257 3340 <.0001

BMI

n 3278 3334 3309 3243 <.0001

Mean (SD) 28.5 (4.7) 28.8 (4.9) 29.1 (5.0) 29.8 (5.4) Mean (SD) 29.5 (5.0) 29.1 (4.9) 29.0 (4.9) 28.5 (5.2)

Median (Min, Max) 28.0 (17, 61) 28.2 (16, 60) 28.4 (16, 57) 29.0 (13, 61) Median (Min, Max) 28.9 (17, 61) 28.6 (17, 61) 28.4 (15, 57) 27.8 (13, 56)

(Q1, Q3) (25.2, 31.1) (25.5, 31.5) (25.7, 31.9) (26.1, 32.7) (Q1, Q3) (26.0, 32.2) (25.8, 31.7) (25.6, 31.9) (25.1, 31.4)

Diagnosis of hypertension

No 1192 (36.6%) 1008 (30.4%) 848 (26.0%) 698 (20.9%) <.0001Diagnosis of hypertension

No 1041 (31.8%) 952 (28.6%) 931 (28.1%) 822 (25.3%) <.0001

Yes 2064 (63.4%) 2303 (69.6%) 2409 (74.0%) 2642 (79.1%) Yes 2237 (68.2%) 2382 (71.4%) 2378 (71.9%) 2421 (74.7%)

LDL-C (mmol/L)

n 3256 3311 3257 3340 <.0001

LDL-C (mmol/L)

n 3278 3334 3309 3243 0.6031

Mean (SD) 2.3 (0.9) 2.2 (0.8) 2.2 (0.8) 2.1 (0.8) Mean (SD) 2.2 (0.8) 2.2 (0.8) 2.2 (0.9) 2.2 (0.9)

Median (Min, Max) 2.2 (0, 9) 2.1 (0, 8) 2.1 (0, 15) 2.0 (0, 9) Median (Min, Max) 2.1 (0, 7) 2.1 (0, 9) 2.1 (0, 15) 2.1 (0, 9)

(Q1, Q3) (1.7, 2.7) (1.7, 2.6) (1.6, 2.6) (1.6, 2.5) (Q1, Q3) (1.7, 2.7) (1.6, 2.6) (1.6, 2.6) (1.6, 2.6)

HDL-C (mmol/L)

n 3256 3311 3257 3340 <.0001

HDL-C (mmol/L)

n 3278 3334 3309 3243 <.0001

Mean (SD) 1.2 (0.3) 1.2 (0.3) 1.2 (0.3) 1.2 (0.3) Mean (SD) 1.2 (0.3) 1.2 (0.3) 1.2 (0.3) 1.2 (0.3)

Median (Min, Max) 1.2 (0, 5) 1.2 (0, 3) 1.2 (0, 4) 1.2 (0, 3) Median (Min, Max) 1.1 (0, 3) 1.2 (0, 4) 1.2 (0, 5) 1.2 (0, 4)

(Q1, Q3) (1.0, 1.4) (1.0, 1.4) (1.0, 1.4) (1.0, 1.4) (Q1, Q3) (1.0, 1.3) (1.0, 1.4) (1.0, 1.4) (1.0, 1.4)

Triglycerides (mmol/L)

n 3256 3311 3257 3340 <.0001

Triglycerides (mmol/L)

n 3278 3334 3309 3243 <.0001

Mean (SD) 1.8 (1.2) 1.8 (1.2) 1.7 (1.1) 1.8 (1.2) Mean (SD) 2.0 (1.3) 1.8 (1.2) 1.8 (1.1) 1.6 (0.9)

Median (Min, Max) 1.6 (0, 19) 1.5 (0, 17) 1.5 (0, 22) 1.5 (0, 16) Median (Min, Max) 1.7 (0, 22) 1.5 (0, 19) 1.5 (0, 17) 1.4 (0, 15)

(Q1, Q3) (1.1, 2.2) (1.1, 2.1) (1.1, 2.0) (1.1, 2.2) (Q1, Q3) (1.2, 2.3) (1.1, 2.1) (1.1, 2.1) (1.0, 1.9)

eGFR (CKD-EPI)

n 3256 3311 3257 3340 <.0001

eGFR (CKD-EPI)

n 3278 3334 3309 3243 <.0001

Mean (SD) 82.3 (14.5) 76.5 (15.1) 71.3 (16.1) 64.1 (18.4) Mean (SD) 80.7 (15.3) 75.7 (15.8) 71.8 (16.9) 65.6 (18.2)

Median (Min, Max) 83.0 (27, 128) 77.1 (26, 125) 71.7 (17, 132) 63.4 (16, 182) Median (Min, Max) 81.6 (27, 128) 76.5 (19, 125) 72.1 (17, 182) 65.1 (16, 132)

(Q1, Q3) (72.3, 93.0) (65.6, 87.5) (59.8, 83.2) (50.6, 77.4) (Q1, Q3) (70.4, 91.9) (64.8, 87.9) (60.3, 84.3) (52.3, 79.1)

Creatinine n 3256 3311 3257 3340 <.0001 Creatinine n 3278 3334 3309 3243 <.0001

Mean (SD) 83.6 (15.1) 89.8 (16.6) 95.4 (19.8) 106.4 (28.1) Mean (SD) 88.6 (16.9) 91.1 (19.4) 94.3 (21.9) 101.5 (27.2)

Median (Min, Max) 82.0 (38, 221) 88.0 (44, 235) 92.0 (47, 298) 100.0 (17, 308) Median (Min, Max) 88.0 (44, 203) 88.0 (44, 256) 90.0 (17, 298) 97.0 (44, 308)

(Q1, Q3) (73.0, 92.0) (80.0, 98.0) (82.0, 106.0) (88.0, 121.5) (Q1, Q3) (79.0, 97.0) (80.0, 99.0) (80.0, 106.0) (83.0, 115.0)

Significant renal dysfunction

No 2806 (86.2%) 2594 (78.3%) 2155 (66.2%) 1621 (48.5%) <.0001Significant renal dysfunction

No 2680 (81.8%) 2508 (75.2%) 2277 (68.8%) 1711 (52.8%) <.0001

Yes 450 (13.8%) 717 (21.7%) 1102 (33.8%) 1719 (51.5%) Yes 598 (18.2%) 826 (24.8%) 1032 (31.2%) 1532 (47.2%)

Hemoglobin (g/L)

n 3256 3311 3257 3340 <.0001

Hemoglobin (g/L)

n 3278 3334 3309 3243 <.0001

Mean (SD) 143.7 (12.8) 144.2 (13.4) 142.8 (13.5) 139.6 (15.0) Mean (SD) 147.0 (12.2) 143.7 (12.9) 141.3 (13.4) 138.3 (15.3)

Median (Min, Max) 144.0 (69, 186) 145.0 (72, 205) 144.0 (93, 187) 140.0 (51, 193) Median (Min, Max) 147.0 (80, 186) 145.0 (75, 187) 142.0 (69, 193) 138.0 (51, 205)

(Q1, Q3) (136.0, 152.0) (136.0, 153.0) (135.0, 152.0) (130.0, 150.0) (Q1, Q3) (140.0, 155.0) (136.0, 152.0) (133.0, 150.0) (129.0, 149.0)

WBC (GI/L)

n 3256 3311 3257 3340 <.0001

WBC (GI/L)

n 3278 3334 3309 3243 <.0001

Mean (SD) 6.8 (1.9) 6.7 (1.7) 6.7 (1.8) 7.0 (2.1) Mean (SD) 6.7 (1.7) 6.7 (1.8) 6.7 (1.9) 7.0 (2.1)

Median (Min, Max) 6.6 (2, 18) 6.5 (3, 21) 6.5 (2, 24) 6.7 (3, 53) Median (Min, Max) 6.5 (3, 18) 6.4 (2, 20) 6.5 (3, 32) 6.8 (2, 53)

(Q1, Q3) (5.5, 7.9) (5.5, 7.6) (5.5, 7.7) (5.7, 7.9) (Q1, Q3) (5.5, 7.8) (5.4, 7.6) (5.5, 7.7) (5.7, 8.0)

Prior MINo 1308 (40.2%) 1337 (40.4%) 1377 (42.3%) 1394 (41.7%) 0.2326

Prior MINo 1478 (45.1%) 1432 (43.0%) 1368 (41.3%) 1138 (35.1%) <.0001

Yes 1948 (59.8%) 1974 (59.6%) 1880 (57.7%) 1946 (58.3%) Yes 1800 (54.9%) 1902 (57.0%) 1941 (58.7%) 2105 (64.9%)

Prior PCI or CABGNo 872 (26.8%) 855 (25.8%) 770 (23.6%) 807 (24.2%) 0.0114

Prior PCI or CABGNo 810 (24.7%) 824 (24.7%) 781 (23.6%) 889 (27.4%) 0.0033

Yes 2384 (73.2%) 2456 (74.2%) 2487 (76.4%) 2533 (75.8%) Yes 2468 (75.3%) 2510 (75.3%) 2528 (76.4%) 2354 (72.6%)

Multivessel CHDNo 2856 (87.7%) 2877 (86.9%) 2800 (86.0%) 2812 (84.2%) 0.0003

Multivessel CHDNo 2887 (88.1%) 2875 (86.2%) 2843 (85.9%) 2740 (84.5%) 0.0005

Yes 400 (12.3%) 434 (13.1%) 457 (14.0%) 528 (15.8%) Yes 391 (11.9%) 459 (13.8%) 466 (14.1%) 503 (15.5%)

Diabetes MellitusNo 2295 (70.5%) 2157 (65.1%) 1985 (60.9%) 1586 (47.5%) <.0001

Diabetes MellitusNo 1963 (59.9%) 2090 (62.7%) 2038 (61.6%) 1932 (59.6%) 0.0301

Yes 961 (29.5%) 1154 (34.9%) 1272 (39.1%) 1754 (52.5%) Yes 1315 (40.1%) 1244 (37.3%) 1271 (38.4%) 1311 (40.4%)

Smoking status

Never smoked 912 (28.0%) 959 (29.0%) 1042 (32.0%) 1070 (32.0%) <.0001

Smoking status

Never smoked 837 (25.5%) 999 (30.0%) 1061 (32.1%) 1086 (33.5%) <.0001

Current smoker 856 (26.3%) 652 (19.7%) 483 (14.8%) 404 (12.1%) Current smoker 788 (24.0%) 603 (18.1%) 538 (16.3%) 466 (14.4%)

Former smoker 1488 (45.7%) 1700 (51.3%) 1732 (53.2%) 1866 (55.9%) Former smoker 1653 (50.4%) 1732 (51.9%) 1710 (51.7%) 1691 (52.1%)

Polyvascular disease

No 2884 (88.6%) 2871 (86.7%) 2776 (85.2%) 2635 (78.9%) <.0001Polyvascular disease

No 2921 (89.1%) 2896 (86.9%) 2765 (83.6%) 2584 (79.7%) <.0001

Yes 372 (11.4%) 440 (13.3%) 481 (14.8%) 705 (21.1%) Yes 357 (10.9%) 438 (13.1%) 544 (16.4%) 659 (20.3%)

Aspirin at Randomization

No 139 (4.3%) 229 (6.9%) 247 (7.6%) 386 (11.6%) <.0001Aspirin at Randomization

No 180 (5.5%) 191 (5.7%) 225 (6.8%) 405 (12.5%) <.0001

Yes 3117 (95.7%) 3082 (93.1%) 3010 (92.4%) 2954 (88.4%) Yes 3098 (94.5%) 3143 (94.3%) 3084 (93.2%) 2838 (87.5%)

ACE inhibitor or ARB at randomization

No 940 (28.9%) 792 (23.9%) 638 (19.6%) 586 (17.5%) <.0001 ACE inhibitor or ARB at randomization

No 824 (25.1%) 826 (24.8%) 703 (21.2%) 603 (18.6%) <.0001

Yes 2316 (71.1%) 2519 (76.1%) 2619 (80.4%) 2754 (82.5%) Yes 2454 (74.9%) 2508 (75.2%) 2606 (78.8%) 2640 (81.4%)

Statin at randomization

No 80 (2.5%) 82 (2.5%) 79 (2.4%) 119 (3.6%) 0.0091Statin at randomization

No 95 (2.9%) 91 (2.7%) 91 (2.8%) 83 (2.6%) 0.8715

Yes 3176 (97.5%) 3229 (97.5%) 3178 (97.6%) 3221 (96.4%) Yes 3183 (97.1%) 3243 (97.3%) 3218 (97.2%) 3160 (97.4%)

Beta blocker at randomization

No 657 (20.2%) 681 (20.6%) 702 (21.6%) 716 (21.4%) 0.4474Beta blocker at randomization

No 982 (30.0%) 745 (22.3%) 554 (16.7%) 475 (14.6%) <.0001

Yes 2599 (79.8%) 2630 (79.4%) 2555 (78.4%) 2624 (78.6%) Yes 2296 (70.0%) 2589 (77.7%) 2755 (83.3%) 2768 (85.4%)

P2Y12 at randomization

No 2116 (65.0%) 2159 (65.2%) 2241 (68.8%) 2265 (67.8%) 0.0011P2Y12 at randomization

No 2099 (64.0%) 2264 (67.9%) 2250 (68.0%) 2168 (66.9%) 0.0016

Yes 1140 (35.0%) 1152 (34.8%) 1016 (31.2%) 1075 (32.2%) Yes 1179 (36.0%) 1070 (32.1%) 1059 (32.0%) 1075 (33.1%)

hsCRP

n 3256 3311 3257 3340 <.0001

hsCRP

n 3278 3334 3309 3243 <.0001

Mean (SD) 2.5 (4.3) 2.5 (4.6) 2.9 (6.7) 4.0 (9.2) Mean (SD) 2.3 (4.1) 2.5 (4.3) 2.6 (4.2) 4.5 (10.8)

Median (Min, Max) 1.2 (0, 71) 1.2 (0, 78) 1.3 (0, 188) 1.7 (0, 164) Median (Min, Max) 1.2 (0, 72) 1.2 (0, 102) 1.4 (0, 79) 1.7 (0, 188)

(Q1, Q3) (0.6, 2.7) (0.6, 2.8) (0.6, 3.0) (0.8, 3.9) (Q1, Q3) (0.6, 2.7) (0.6, 2.7) (0.7, 2.9) (0.8, 4.3)

hsTroponin T

n 3256 3311 3257 3340 <.0001

hsTroponin T

n 3278 3334 3309 3243 <.0001

Mean (SD) 4.4 (1.4) 7.6 (0.9) 11.4 (1.4) 26.1 (30.0) Mean (SD) 7.8 (5.7) 10.0 (10.1) 12.4 (13.2) 19.7 (28.7)

Median (Min, Max) 4.7 (2, 6) 7.6 (6, 9) 11.3 (9, 14) 19.7 (14, 783) Median (Min, Max) 6.6 (2, 125) 8.3 (2, 350) 10.1 (2, 399) 14.2 (2, 783)

(Q1, Q3) (3.7, 5.4) (6.9, 8.4) (10.2, 12.5) (16.4, 26.1) (Q1, Q3) (4.7, 9.4) (5.8, 12.0) (7.0, 14.5) (9.6, 21.7)

NT-proBNP

n 3256 3311 3257 3340 <.0001

NT-proBNP

n 3278 3334 3309 3243 <.0001

Mean (SD) 150.9 (203.8) 222.4 (274.2) 333.5 (410.2) 749.8 (1344.5) Mean (SD) 48.3 (20.1) 123.2 (25.5) 255.5 (57.2) 1049.6 (1312.5)

Median (Min, Max) 92.0 (3, 4102) 140.0 (3, 3429) 201.0 (3, 5743) 365.0 (3, 25770) Median (Min, Max) 49.0 (3, 82) 121.0 (83, 172) 246.0 (173, 379) 686.0 (380, 25770)

(Q1, Q3) (48.0, 173.5) (72.0, 264.0) (105.0, 398.0) (174.0, 824.5) (Q1, Q3) (32.0, 65.0) (101.0, 145.0) (206.0, 301.0) (495.0, 1121.0)

IL-6

n 3256 3311 3257 3340 <.0001

IL-6

n 3278 3334 3309 3243 <.0001

Mean (SD) 2.4 (2.2) 2.5 (2.7) 2.8 (2.4) 3.6 (3.8) Mean (SD) 2.3 (2.5) 2.5 (2.2) 2.7 (2.3) 3.7 (4.0)

Median (Min, Max) 1.8 (0, 33) 1.9 (0, 88) 2.1 (0, 36) 2.6 (0, 75) Median (Min, Max) 1.8 (0, 88) 2.0 (0, 35) 2.1 (0, 37) 2.6 (0, 75)

(Q1, Q3) (1.3, 2.7) (1.3, 2.9) (1.5, 3.1) (1.8, 4.0) (Q1, Q3) (1.2, 2.7) (1.4, 2.8) (1.5, 3.2) (1.7, 4.2)

Cystatin C

n 3255 3309 3257 3335 <.0001

Cystatin C

n 3278 3334 3304 3240 <.0001

Mean (SD) 0.9 (0.2) 1.0 (0.2) 1.1 (0.3) 1.2 (0.4) Mean (SD) 0.9 (0.2) 1.0 (0.2) 1.1 (0.3) 1.2 (0.3)

Median (Min, Max) 0.9 (0, 4) 1.0 (0, 3) 1.0 (0, 3) 1.2 (0, 3) Median (Min, Max) 0.9 (0, 3) 1.0 (0, 3) 1.0 (0, 4) 1.2 (0, 3)

(Q1, Q3) (0.8, 1.0) (0.9, 1.1) (0.9, 1.2) (1.0, 1.4) (Q1, Q3) (0.8, 1.0) (0.9, 1.1) (0.9, 1.2) (1.0, 1.4)

GDF-15 n 3256 3311 3257 3340 <.0001 GDF-15 n 3278 3334 3309 3243 <.0001

Mean (SD) 1160.6 (669.2) 1361.0 (898.1) 1599.5 (947.7) 2142.6 (1575.1) Mean (SD) 1274.7 (833.6) 1423.2 (954.2) 1600.4 (1148.1) 1983.2 (1420.1)

Median (Min, Max) 981.0 (200, 11682)

1153.0 (200, 20000)

1319.0 (200, 10692)

1706.5 (200, 20000) Median (Min, Max) 1062.0 (200,

18280)1165.0 (200, 19303)

1299.0 (200, 20000)

1587.0 (200, 20000)

(Q1, Q3) (765.5, 1347.0) (875.0, 1574.0) (990.0, 1888.0) (1218.0, 2587.0) (Q1, Q3) (804.0, 1490.0) (880.0, 1652.0) (967.0, 1869.0) (1124.0, 2355.0)

LpPLA2

n 3223 3266 3219 3305 0.0006

LpPLA2

n 3227 3300 3277 3209 0.0003

Mean (SD) 173.8 (48.3) 175.4 (47.0) 175.4 (47.3) 179.3 (48.3) Mean (SD) 177.6 (47.8) 174.3 (47.2) 174.2 (47.7) 178.0 (48.2)

Median (Min, Max) 171.5 (20, 426) 172.1 (1, 376) 172.3 (1, 389) 175.3 (1, 376) Median (Min, Max) 175.4 (2, 372) 172.3 (1, 384) 170.0 (1, 426) 173.2 (2, 376)

(Q1, Q3) (140.1, 204.5) (143.9, 203.7) (144.1, 202.0) (146.6, 207.4) (Q1, Q3) (144.8, 208.0) (142.9, 202.0) (142.2, 202.0) (144.5, 206.6)

Online Table 4: Multivariable effect of baseline characteristics on NT-proBNP and C-TnT-hs levels at baseline.

NT-proBNP cTnT-hsBackground characteristic

Relative increase 95% C.I. P-value Relative increase 95% C.I. P-value

Female vs Male 1.0630 (1.0099 ; 1.1189) 0.0195 0.6204 (0.6020 ; 0.6394) <.0001

Eastern Europe vs North America 1.3569 (1.2878 ; 1.4296) <.0001 1.0097 (0.9792 ; 1.0412) 0.5380

Western Europe vs North America 1.0127 (0.9634 ; 1.0645) 0.6207 0.9704 (0.9423 ; 0.9993) 0.0446

South America vs North America 1.3198 (1.2172 ; 1.4309) <.0001 1.0271 (0.9794 ; 1.0771) 0.2707

Asia/Pacific vs North America 0.8666 (0.8184 ; 0.9177) <.0001 0.9483 (0.9169 ; 0.9808) 0.0020

Diagnosis of hypertension 0.9924 (0.9532 ; 1.0332) 0.7099 1.0545 (1.0298 ; 1.0798) <.0001

Previous MI 1.3177 (1.2682 ; 1.3691) <.0001 1.0916 (1.0673 ; 1.1164) <.0001

Previous PCI or CABG 1.0477 (1.0030 ; 1.0944) 0.0363 0.9936 (0.9685 ; 1.0194) 0.6256

Multivessel CHD 1.1303 (1.0737 ; 1.1899) <.0001 1.0477 (1.0166 ; 1.0799) 0.0025

Diabetes mellitus 1.0040 (0.9668 ; 1.0427) 0.8365 1.2223 (1.1954 ; 1.2498) <.0001

Former smoker vs never smoked 1.0164 (0.9753 ; 1.0593) 0.4388 0.9693 (0.9460 ; 0.9931) 0.0118

Current smoker vs never smoked 0.9925 (0.9379 ; 1.0503) 0.7950 0.9544 (0.9231 ; 0.9867) 0.0060

Polyvascular disease 1.1822 (1.1256 ; 1.2416) <.0001 1.1038 (1.0724 ; 1.1361) <.0001

Age, 10 year increase 1.2448 (1.2147 ; 1.2756) <.0001 1.1725 (1.1558 ; 1.1895) <.0001

BMI, 1 kg/m2 increase 0.9829 (0.9791 ; 0.9868) <.0001 1.0099 (1.0076 ; 1.0122) <.0001

Systolic blood pressure, 10 mmHg increase 1.0320 (1.0206 ; 1.0435) <.0001 1.0136 (1.0070 ; 1.0203) <.0001

eGFR (CKD-EPI), 10 mL/min/1.73m2 unit increase

0.8695 (0.8590 ; 0.8800) <.0001 0.8955 (0.8891 ; 0.9018) <.0001

Hb, 10 g/L increase 0.8600 (0.8478 ; 0.8723) <.0001 0.9522 (0.9443 ; 0.9602) <.0001

WBC, 1 GI/L increase 1.0670 (1.0568 ; 1.0774) <.0001 1.0240 (1.0182 ; 1.0298) <.0001

LDL-C, 0.1 mmol/L increase 1.0018 (0.9997 ; 1.0040) 0.0985 1.0012 (0.9999 ; 1.0025) 0.0671

HDL-C, 0.1 mmol/L increase 0.9885 (0.9824 ; 0.9945) 0.0002 0.9996 (0.9960 ; 1.0032) 0.8236

TG, 0.1 mmol/L increase 0.9919 (0.9902 ; 0.9936) <.0001 0.9995 (0.9985 ; 1.0005) 0.3514

Online Table 5: Pearson correlation coefficients (r) between biomarkers (all biomarker levels except Lp-PLA2 log transformed)

NT-proBNP (log) cTnT-hs (log)r p-value r p-value

NT-proBNP (log) 1.0000 - 0.4722 <0.0001cTnT-hs (log) 0.4722 <0.0001 1.0000 -hsCRP (log) 0.1549 <0.0001 0.1192 <0.0001IL-6 (log) 0.2495 <0.0001 0.2222 <0.0001Cystatin C (log) 0.4409 <0.0001 0.4654 <0.0001GDF-15 (log) 0.3044 <0.0001 0.3925 <0.0001LpPLA2 0.0096 0.2759 0.0475 <0.0001

Online Table 6: Incidence rates

Outcome No at risk No of events Person-years Incidence rate* 95% CIMACE 13164 1305 45178 2.89 [2.73, 3.05]MCE 13164 1268 45088 2.81 [2.66, 2.97]Death 13164 958 46610 2.06 [1.93, 2.19]CV death 13164 591 46558 1.27 [1.17, 1.38]Non-CV death 13164 291 46558 0.63 [0.56, 0.70]MI 13164 640 45511 1.41 [1.30, 1.52]Stroke 13164 255 46200 0.55 [0.49, 0.62]HF hosp 13164 296 46121 0.64 [0.57, 0.72]CVD/HF hosp 13164 809 46121 1.75 [1.63, 1.88]MACE/HF hosp 13164 1485 44808 3.31 [3.15, 3.49]Death/MACE 13164 1565 45178 3.46 [3.29, 3.64]Cancer death 13164 154 46558 0.33 [0.28, 0.39]* = per 100 person-years

Online Table 7: C indices for other endpoints using the model derived for prediction of CV death

Online Table 8: Summary of the decision curve analysis

Online Figure 1: Selection of patients in the development cohort

Online Figure 2. NT-proBNP and cTnT-hs by quartile in relation to MACE and CV death.

Online Figure 3. Example of a web-based application implementing the ABC-CHD score

TRIPOD Checklist: Prediction Model Development and Validation

Section/TopicItem Checklist Item PageTitle and abstract

Title 1 D;V Identify the study as developing and/or validating a multivariable prediction model, the target population, and the outcome to be predicted. 1

Abstract 2 D;VProvide a summary of objectives, study design, setting, participants, sample size, predictors, outcome, statistical analysis, results, and conclusions.

1

Introduction

Background and objectives

3a D;VExplain the medical context (including whether diagnostic or prognostic) and rationale for developing or validating the multivariable prediction model, including references to existing models.

2-3

3b D;V Specify the objectives, including whether the study describes the development or validation of the model or both. 3

Methods

Source of data4a D;V Describe the study design or source of data (e.g., randomized trial, cohort, or registry

data), separately for the development and validation data sets, if applicable.3 &

Suppl

4b D;V Specify the key study dates, including start of accrual; end of accrual; and, if applicable, end of follow-up.

3 & Suppl

Participants

5a D;V Specify key elements of the study setting (e.g., primary care, secondary care, general population) including number and location of centres. 3

5b D;V Describe eligibility criteria for participants.Online Table 1

& 25c D;V Give details of treatments received, if relevant. 3

Outcome 6a D;V Clearly define the outcome that is predicted by the prediction model, including how and when assessed. 4

6b D;V Report any actions to blind assessment of the outcome to be predicted. 4

Predictors7a D;V Clearly define all predictors used in developing or validating the multivariable

prediction model, including how and when they were measured. 4

7b D;V Report any actions to blind assessment of predictors for the outcome and other predictors. 4

Sample size 8 D;V Explain how the study size was arrived at. 5

Missing data 9 D;V Describe how missing data were handled (e.g., complete-case analysis, single imputation, multiple imputation) with details of any imputation method. 4

Statistical analysis methods

10a D Describe how predictors were handled in the analyses. 4-5

10b D Specify type of model, all model-building procedures (including any predictor selection), and method for internal validation. 4-5

10c V For validation, describe how the predictions were calculated. 5

10d D;V Specify all measures used to assess model performance and, if relevant, to compare multiple models. 5

10e V Describe any model updating (e.g., recalibration) arising from the validation, if done. -Risk groups 11 D;V Provide details on how risk groups were created, if done. -Development vs. validation 12 V For validation, identify any differences from the development data in setting, eligibility

criteria, outcome, and predictors. 3, 7

Results

Participants

13a D;VDescribe the flow of participants through the study, including the number of participants with and without the outcome and, if applicable, a summary of the follow-up time. A diagram may be helpful.

Online Fig 1

13b D;VDescribe the characteristics of the participants (basic demographics, clinical features, available predictors), including the number of participants with missing data for predictors and outcome.

Online Table 7

13c V For validation, show a comparison with the development data of the distribution of important variables (demographics, predictors and outcome).

Online Table

7

Model development

14a D Specify the number of participants and outcome events in each analysis.Online Table

5

14b D If done, report the unadjusted association between each candidate predictor and outcome. -

Model specification

15a D Present the full prediction model to allow predictions for individuals (i.e., all regression coefficients, and model intercept or baseline survival at a given time point). Fig 4

15b D Explain how to the use the prediction model. Fig 4

Model performance 16 D;V Report performance measures (with CIs) for the prediction model.

7-8, Online Table 6

Model-updating 17 V If done, report the results from any model updating (i.e., model specification, model performance). -

Discussion

Limitations 18 D;V Discuss any limitations of the study (such as nonrepresentative sample, few events per predictor, missing data). 12

Interpretation19a V For validation, discuss the results with reference to performance in the development

data, and any other validation data. 8-12

19b D;V Give an overall interpretation of the results, considering objectives, limitations, results from similar studies, and other relevant evidence. 8-12

Implications 20 D;V Discuss the potential clinical use of the model and implications for future research. 8-12Other information

Supplementary information 21 D;V Provide information about the availability of supplementary resources, such as study

protocol, Web calculator, and data sets. 14

Funding 22 D;V Give the source of funding and the role of the funders for the present study. 2

TRIPOD Checklist: Prediction Model Development and Validation

*Items relevant only to the development of a prediction model are denoted by D, items relating solely to a validation of a prediction model are denoted by V, and items relating to both are denoted D;V. We recommend using the TRIPOD Checklist in conjunction with the TRIPOD Explanation and Elaboration document.