Introduction
Methods
Overview of the CHANCE trial and the imaging substudy
Data availability statement
Neuroimage analyses
Follow-up and study outcome assessment
Statistical analysis
Results
Demographics and baseline characteristics
Characteristics | No CSVD with NAI (n=58) | Slight CSVD with NAI (n=136) | Severe CSVD with NAI (n=89) | No CSVD with SAI (n=86) | Slight CSVD with SAI (n=171) | Severe CSVD with SAI (n=141) | No CSVD with MAIs (n=50) | Slight CSVD with MAIs (n=92) | Severe CSVD with MAIs (n=63) | p value |
---|---|---|---|---|---|---|---|---|---|---|
Age, years, median(IQR) | 56.5(48.1–62.3) | 63.2(56.4–71.5) | 69.2(63.0–74.9) | 57.1(50.3–63.1) | 59.4(52.7–68.3) | 67.7(61.1–73.5) | 58.6(51.7–67.5) | 63.6(55.5–74.2) | 68.2(60.0–74.2) | <0.001 |
BMI, kg/m2, median (IQR) | 24.6(22.4–26.8) | 24.1(22.0–26.7) | 24.2(22.5–25.7) | 24.3(23.0–26.4) | 24.8(22.9–26.2) | 24.2(22.1–26.0) | 25.1(22.9–26.7) | 23.9(21.3–25.9) | 24.2(21.8–26.6) | 0.23 |
Sex, male (%) | 34(58.6) | 82(60.3) | 67(75.3) | 59(68.6) | 114(66.7) | 97(68.8) | 35(70.0) | 65(70.7) | 37(58.7) | 0.25 |
Alcohol use, n (%) | 20(34.5) | 38(27.9) | 30(33.7) | 28(32.6) | 63(36.8) | 37(26.2) | 20(40.0) | 32(34.8) | 14(22.2) | 0.27 |
Tobacco use, n (%) | 25(43.1) | 55(40.4) | 33(37.1) | 43(50.0) | 78(45.6) | 58(41.1) | 24(48.00) | 48(52.2) | 24(38.1) | 0.43 |
History of disease, n (%) | ||||||||||
Ischaemic stroke | 2(3.5) | 20(14.7) | 20(22.5) | 8(9.3) | 24(14.0) | 36(25.5) | 7(14.0) | 15(16.3) | 14(22.2) | 0.002 |
TIA | 3(5.2) | 2(1.5) | 0(0) | 1(1.2) | 3(1.8) | 4(2.8) | 1(2.0) | 4(4.4) | 3(4.8) | 0.37 |
Myocardial infarction | 1(1.7) | 3(2.2) | 4(4.5) | 0(0) | 2(1.2) | 4(2.8) | 2(4.00) | 0(0) | 3(4.8) | 0.25 |
Congestive heart failure | 1(1.7) | 3(2.2) | 1(1.1) | 1(1.2) | 1(0.6) | 0(0) | 2(4.0) | 2(2.2) | 5(7.9) | 0.01 |
Atrial fibrillation | 1(1.7) | 5(3.7) | 3(3.4) | 1(1.2) | 1(0.6) | 4(2.8) | 1(2.0) | 3(3.3) | 2(3.2) | 0.75 |
Diabetes mellitus | 8(13.8) | 20(14.7) | 17(19.1) | 15(17.4) | 47(27.5) | 28(19.9) | 13(26.0) | 20(21.7) | 15(23.8) | 0.17 |
Hypertension | 25(43.1) | 92(67.6) | 66(74.2) | 39(45.6) | 112(65.5) | 103(73.1) | 29(58.0) | 53(57.6) | 50(79.8) | <0.001 |
Hyperlipidemia | 7(12.1) | 19(14.0) | 9(10.1) | 9(10.5) | 28(16.4) | 11(7.8) | 5(10.0) | 11(12.0) | 11(17.5) | 0.43 |
ICAS | 30(51.7) | 74(54.8) | 42(47.2) | 35(40.7) | 72(42.1) | 65(46.1) | 40(80.0) | 63(68.5) | 38(60.3) | <0.001 |
NIHSS score on admission, median(IQR) | 1(0–2) | 1(0–2) | 2(1–2) | 2(1–3) | 2(1–3) | 2(1–3) | 2(1–3) | 2(1–3) | 2(1–3) | <0.001 |
Mean time to randomization, hour, median(IQR) | 13.4(8.0–19.7) | 11.1(7.6–19.0) | 15.0(8.8–20.5) | 11.4(7.0–18.5) | 13.0(8.5–20.0) | 13.3(9.0–21.0) | 10.0(6.6–17.3) | 11.8(6.8–20.3) | 12.3(7.6–20.5) | 0.19 |
Qualifying event, N (%) | <0.001 | |||||||||
Minor stroke | 40(69.0) | 94(69.1) | 80(90.0) | 78(90.7) | 157(91.8) | 132(93.6) | 42(84.0) | 81(88.0) | 56(88.9) | |
TIA | 18(31.0) | 42(30.9) | 9(10.1) | 8(9.3) | 14(8.2) | 9(6.4) | 8(16.0) | 11(12.0) | 7(11.1) | |
Antiplatelet therapy, n (%) | 0.81 | |||||||||
Aspirin only | 28(48.3) | 66(48.5) | 50(56.2) | 40(46.5) | 95(55.6) | 71(50.4) | 27(54.0) | 43(46.7) | 31(49.2) | |
Clopidogrel+aspirin | 30(51.7) | 70(51.5) | 39(43.8) | 46(53.5) | 76(44.4) | 70(49.6) | 23(46.0) | 49(53.3) | 32(50.8) |
Characteristics | NAI(n=283) | SAI(n=398) | MAIs(n=205) | ||||||
---|---|---|---|---|---|---|---|---|---|
Non-CSVD (n=58) | CSVD (n=225) | p value | Non-CSVD (n=86) | CSVD (n=312) | p value | Non-CSVD (n=50) | CSVD (n=155) | p value | |
Age, years, median(IQR) | 56.5(48.1–62.3) | 66.1(59.5–73.3) | <0.001 | 57.1(50.3–63.1) | 62.9(55.3–71.2) | <0.001 | 58.6(51.7–67.5) | 64.9(56.8–74.2) | <0.001 |
BMI, kg/m2, median (IQR) | 24.6(22.4–26.8) | 24.2(22.0–26.3) | 0.26 | 24.3(23.0–26.4) | 24.5(22.5–26.1) | 0.50 | 25.1(22.9–26.7) | 24.1(21.5–26.0) | 0.04 |
Sex, male (%) | 34(66.2) | 149(66.2) | 0.28 | 59(68.6) | 211(67.6) | 0.86 | 35(70.7) | 102(65.8) | 0.58 |
Alcohol use, n (%) | 20(34.5) | 68(30.2) | 0.53 | 28(32.6) | 100(32.1) | 0.93 | 20(40.0) | 46(29.7) | 0.17 |
Tobacco use, n (%) | 25(43.1) | 88(39.1) | 0.58 | 43(50.0) | 136(43.6) | 0.29 | 24(48.0) | 72(46.5) | 0.85 |
History of disease, n (%) | |||||||||
Ischaemic stroke | 2(3.5) | 40(17.8) | 0.006 | 8(9.3) | 60(19.2) | 0.03 | 7(14.0) | 29(18.7) | 0.45 |
TIA | 3(5.2) | 2(0.89) | 0.03 | 1(1.2) | 7(2.2) | 0.53 | 1(2.0) | 7(4.5) | 0.42 |
Myocardial infarction | 1(1.7) | 7(3.1) | 0.57 | 0(0) | 6(1.9) | 0.20 | 2(4.0) | 3(1.9) | 0.41 |
Congestive heart failure | 1(1.7) | 4(1.8) | 0.98 | 1(1.2) | 1(0.3) | 0.33 | 2(4.0) | 7(4.5) | 0.88 |
Atrial fibrillation | 1(1.7) | 8(3.6) | 0.48 | 1(1.2) | 5(1.6) | 0.77 | 1(2.0) | 5(3.2) | 0.65 |
Diabetes mellitus | 8(13.8) | 37(16.4) | 0.62 | 15(17.4) | 75(24.0) | 0.20 | 13(26.0) | 35(22.6) | 0.62 |
Hypertension | 25(43.1) | 158(70.2) | 0.001 | 39(45.4) | 215(68.9) | <0.001 | 29(58.0) | 103(66.5) | 0.28 |
Hyperlipidemia | 7(12.1) | 28(12.4) | 0.94 | 9(10.5) | 39(12.5) | 0.61 | 5(10.0) | 22(14.2) | 0.45 |
ICAS | 30(51.7) | 116(51.8) | 0.99 | 35(340.7) | 137(43.9) | 0.59 | 40(80.0) | 101(65.2) | 0.05 |
NIHSS score on admission, median(IQR) | 1(0–1) | 1(0–2) | 0.45 | 2(1–3) | 2(1–3) | 0.37 | 2(1–3) | 2(1–3) | 0.17 |
Mean time to randomisation, hour, median(IQR) | 13.4(8.0–20.0) | 12.0(8.0–20.0) | 0.81 | 11.4(7.0–18.5) | 13.0(8.5–12.1) | 0.04 | 10.0(6.6–17.3) | 12.2(7.0–20.5) | 0.22 |
Qualifying event, N (%) | 0.19 | 0.55 | 0.42 | ||||||
Minor stroke | 40(69.0) | 18(31.0) | 78(90.7) | 289(92.6) | 42(84.0) | 137(88.4) | |||
TIA | 174(77.3) | 51(22.7) | 8(9.3) | 23(7.4) | 8(16.0) | 18(11.6) | |||
Antiplatelet therapy, n (%) | 0.66 | 0.27 | 0.44 | ||||||
Aspirin only | 28(48.3) | 116(51.6) | 40(46.5) | 166(53.2) | 27(54.0) | 74(47.7) | |||
Clopidogrel+aspirin | 30(51.7) | 109(48.4) | 46(53.4) | 146(46.8) | 23(46.0) | 81(52.3) |
Outcomes by CSVD and infarction number respectively
Outcomes | No. | Event, n (%) | Model 1 | Model 2 | |||
---|---|---|---|---|---|---|---|
Adjusted HR(95%CI) | p value | Adjusted HR(95%CI) | p value | ||||
Stroke | |||||||
Infarction number | NAI | 283 | 8(2.8) | Ref. | Ref. | ||
SAI | 398 | 51(12.1) | 4.88(2.31–10.29) | <0.001 | 4.65(2.17–10.00) | <0.001 | |
MAI | 205 | 34(16.6) | 6.34(2.94–13.70) | <0.001 | 5.92(2.70–13.00) | <0.001 | |
Total CSVD burden | 0 | 194 | 19(9.8) | Ref. | Ref. | ||
1–2 | 399 | 50(12.5) | 1.24(0.72–2.13) | 0.43 | 1.17(0.68–2.02) | 0.57 | |
3–4 | 293 | 24(8.2) | 0.77(0.41-1.46) | 0.43 | 0.67(0.35–1.30) | 0.24 | |
Presence of CSVD | None | 194 | 19(9.8) | Ref. | Ref. | ||
Presence | 692 | 74(10.7) | 1.07(0.63–1.81) | 0.80 | 1.00(0.58–1.71) | 0.99 | |
Ischaemic stroke | |||||||
Infarction number | NAI | 283 | 8(2.8) | Ref. | Ref. | ||
SAI | 398 | 51(12.8) | 4.90(2.32–10.32) | <0.001 | 4.76(2.22–10.22) | <0.001 | |
MAI | 205 | 37(18.1) | 6.94(3.23–14.90) | <0.001 | 6.65(3.05–14.50) | <0.001 | |
Total CSVD burden | 0 | 194 | 19(9.8) | Ref. | Ref. | ||
1–2 | 399 | 50(12.5) | 1.24(0.72–2.13) | 0.43 | 1.17(0.68–2.02) | 0.57 | |
3–4 | 293 | 24(8.2) | 0.77(0.41–1.46) | 0.43 | 0.67(0.35–1.30) | 0.24 | |
Presence of CSVD | None | 194 | 19(9.8) | Ref. | Ref. | ||
Presence | 692 | 74(10.7) | 1.07(0.63–1.81) | 0.80 | 1.00(0.58–1.71) | 0.99 | |
CVE | |||||||
Infarction number | NAI | 283 | 8(2.8) | Ref. | Ref. | ||
SAI | 398 | 51(12.8) | 4.90(2.32–10.32) | <0.001 | 4.76(2.22–10.22) | <0.001 | |
MAI | 205 | 37(18.1) | 6.94(3.23–14.90) | <0.001 | 6.65(3.05–14.50) | <0.001 | |
Total CSVD burden | 0 | 194 | 19(9.8) | Ref. | Ref. | ||
1–2 | 399 | 53(13.3) | 1.30(0.76–2.23) | 0.33 | 1.22(0.71–2.10) | 0.47 | |
3–4 | 293 | 24(8.2) | 0.76(0.40–1.43) | 0.39 | 0.66(0.34–1.26) | 0.20 | |
Presence of CSVD | None | 194 | 19(9.8) | Ref. | Ref. | ||
Presence | 692 | 77(11.1) | 1.10(0.66–1.86) | 0.71 | 1.02(0.60–1.75) | 0.93 | |
TIA | |||||||
Infarction number | NAI | 283 | 12(4.2) | Ref. | Ref. | ||
SAI | 398 | 5(1.3) | 0.30(0.11–0.86) | 0.025 | 0.46(0.16–1.35) | 0.16 | |
MAI | 205 | 7(3.4) | 0.81(0.32–2.06) | 0.660 | 1.08(0.40–2.91) | 0.88 | |
Total CSVD burden | 0 | 194 | 7(3.6) | Ref. | Ref. | ||
1–2 | 399 | 10(2.5) | 0.65(0.24–1.73) | 0.38 | 0.6899.24–1.96) | 0.49 | |
3–4 | 293 | 7(2.4) | 0.57(0.19–1.76) | 0.33 | 0.90(0.26–3.07) | 0.86 | |
Presence of CSVD | None | 194 | 7(3.6) | Ref. | Ref. | ||
Presence | 692 | 17(2.5) | 0.62(0.25–1.56) | 0.31 | 0.74(0.28–2.00) | 0.56 |
Outcome by the status of CSVD and infarction pattern
Outcomes | No. | Event, n (%) | Model 1 | Model 2 | ||
---|---|---|---|---|---|---|
Adjusted HR(95%CI) | p value | Adjusted HR(95%CI) | p value | |||
Stroke | ||||||
No CSVD with NAI | 58 | 1(1.7) | Ref. | Ref. | ||
CSVD with NAI | 225 | 7(3.1) | 1.78(0.22–14.59) | 0.59 | 1.73(0.21–14.33) | 0.61 |
No CSVD with SAI | 86 | 11(12.8) | 8.03(1.04–62.20) | 0.05 | 7.86(1.00–61.50) | 0.05 |
CSVD with SAI | 312 | 40(12.8) | 7.88(1.08–57.55) | 0.04 | 7.27(0.98–54.09) | 0.05 |
No CSVD with MAIs | 50 | 7(14.0) | 9.10(1.12–74.04) | 0.04 | 8.86(1.08–72.69) | 0.04 |
CSVD with MAIs | 155 | 27(17.4) | 10.66(1.44–78.98) | 0.02 | 9.56(1.27–71.79) | 0.03 |
Ischaemic stroke | ||||||
No CSVD with NAI | 58 | 1(1.7) | Ref. | Ref. | ||
CSVD with NAI | 225 | 7(3.1) | 1.78(0.22–14.59) | 0.59 | 1.73(0.21–14.33) | 0.61 |
No CSVD with SAI | 86 | 11(12.8) | 8.03(1.04–62.20) | 0.05 | 7.86(1.00–61.50) | 0.05 |
CSVD with SAI | 312 | 40(12.8) | 7.88(1.08–57.55) | 0.04 | 7.27(0.98–54.09) | 0.05 |
No CSVD with MAIs | 50 | 7(14.0) | 9.10(1.12–74.04) | 0.04 | 8.86(1.08–72.69) | 0.04 |
CSVD with MAIs | 155 | 27(17.4) | 10.66(1.44–78.98) | 0.02 | 9.56(1.27–71.79) | 0.03 |
CVE | ||||||
No CSVD with NAI | 58 | 1(1.7) | Ref. | Ref. | ||
CSVD with NAI | 225 | 7(3.1) | 1.76(0.22–14.44) | 0.60 | 1.70(0.21–14.06) | 0.62 |
No CSVD with SAI | 86 | 11(12.8) | 8.03(1.04–62.17) | 0.05 | 8.00(1.02–62.63) | 0.05 |
CSVD with SAI | 312 | 40(12.8) | 7.82(1.07–57.15) | 0.04 | 7.32(0.99–54.42) | 0.05 |
No CSVD with MAIs | 50 | 7(14.0) | 9.08(1.12–73.85) | 0.04 | 9.02(1.10–73.93) | 0.04 |
CSVD with MAIs | 155 | 30(19.4) | 11.81(1.60–87.17) | 0.02 | 10.84(1.45–81.04) | 0.02 |
TIA | ||||||
No CSVD with NAI | 58 | 5(8.6) | Ref. | Ref. | ||
CSVD with NAI | 225 | 7(3.1) | 0.32(0.10–1.07) | 0.06 | 0.36(0.10–1.28) | 0.11 |
No CSVD with SAI | 86 | 1(1.2) | 0.13(0.02–1.15) | 0.07 | 0.18(0.02–1.64) | 0.18 |
CSVD with SAI | 312 | 4(1.3) | 0.14(0.04–0.53) | 0.004 | 0.24(0.06–1.01) | 0.05 |
No CSVD with MAIs | 50 | 1(2.0) | 0.22(0.03–1.93) | 0.17 | 0.30(0.03–2.64) | 0.28 |
CSVD with MAIs | 155 | 6(3.9) | 0.40(0.12–1.39) | 0.15 | 0.63(0.17–2.40) | 0.50 |
Outcome by the presence of CSVD in different infarction pattern
Outcomes | Non-acute infarction (n=283) | Single acute infarction (n=398) | Multiple acute infarctions (n=205) | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Non-CSVD | CSVD | Adjusted HR (95%CI) | p value | Non-CSVD | CSVD | Adjusted HR (95%CI) | p value | Non-CSVD | CSVD | Adjusted HR (95%CI) | p value | |
Stroke | 1(1.7) | 7(3.1) | 1.59(0.15–17.28) | 0.70 | 11(12.8) | 40(12.8) | 0.98(0.48–2.04) | 0.96 | 7(14.0) | 27(17.4) | 1.03(0.42–2.52) | 0.95 |
Ischaemic stroke | 1(1.7) | 7(3.1) | 1.59(0.15–17.28) | 0.70 | 11(12.8) | 40(12.8) | 0.98(0.48-2.04) | 0.96 | 7(14.0) | 27(17.4) | 1.03(0.42–2.52) | 0.95 |
CVE | 1(1.7) | 7(3.1) | 1.59(0.15–17.28) | 0.70 | 11(12.8) | 40(12.8) | 0.98(0.48–2.04) | 0.96 | 7(14.0) | 30(19.4) | 1.23(0.46–2.73) | 0.79 |
TIA | 5(8.6) | 7(3.1) | 0.15(0.03–0.71) | 0.02 | 1(1.2) | 4(1.3) | 0.90(0.06–12.68) | 0.94 | 1(2.0) | 6(3.9) | 1.68(0.16–18.3) | 0.67 |