Introduction
Methods
Study design, patients, and definitions
Biomarker measurements
Statistical analysis
Results
Patients
Unmatched cohort | Propensity-matched cohort | |||||
---|---|---|---|---|---|---|
Antiplatelet therapy
N = 267 | No antiplatelet therapy
N = 705 |
p
| Antiplatelet therapy
N = 150 | No antiplatelet therapy
N = 150 |
p
| |
Demographics | ||||||
Age, years, mean [SD] | 67.6 [10.4] | 58.8 [15.4] | <0.0001 | 66.1 [10.5] | 65.7 [10.7] | 0.66 |
Gender, male (%) | 184 (68.9) | 402 (57) | <0.001 | 91 (60.7) | 96 (64) | 0.61 |
Race, white (%) | 242 (90.6) | 617 (87.5) | 0.15 | 140 (93.3) | 137 (91.3) | 0.65 |
BMI, kg/m2, mean [SD] | 26.2 [6.2] | 25.8 [6.1] | 0.40 | 26.3 [6.7] | 26.2 [5.9] | 0.97 |
Admission type, medical (%) | 220 (82.4) | 564 (80) | 0.41 | 124 (82.7) | 128 (85.3) | 0.64 |
Comorbidities | ||||||
Charlson score, median [IQR]a
| 2 [1–3] | 1 [0–2] | <0.001 | 2 [1–3] | 2 [1–2] | 0.31 |
Cerebrovascular disease (%) | 54 (20.2) | 37 (5.2) | <0.001 | 27 (18) | 21 (14) | 0.38 |
Chronic cardiovascular insufficiency (%) | 18 (6.7) | 20 (2.8) | 0.0065 | 8 (5.3) | 9 (6) | 1 |
Chronic renal insufficiency (%) | 63 (23.6) | 83 (11.8) | <0.001 | 33 (22) | 31 (20.7) | 0.88 |
Congestive heart failure (%) | 25 (9.4) | 21 (3) | <0.001 | 11 (7.3) | 11 (7.3) | 1 |
COPD (%) | 62 (23.2) | 88 (12.5) | <0.001 | 30 (20) | 37 (24.7) | 0.39 |
Diabetes mellitus (%) | 96 (36) | 109 (15.5) | <0.001 | 45 (30) | 46 (30.7) | 1 |
Hematologic malignancy (%) | 13 (4.9) | 65 (9.2) | 0.037 | 10 (6.7) | 8 (5.3) | 0.81 |
Hypertension (%) | 127 (47.6) | 175 (24.8) | <0.001 | 60 (40) | 55 (36.7) | 0.63 |
Immune deficiency (%) | 47 (17.6) | 167 (23.7) | 0.05 | 34 (22.7) | 30 (20) | 0.65 |
Liver cirrhosis (%) | 6 (2.2) | 16 (2.3) | 1 | 4 (2.7) | 3 (2) | 1 |
Metastatic malignancy (%) | 4 (1.5) | 35 (5) | 0.012 | 3 (2) | 0 (0) | 0.25 |
Myocardial infarction (history of) (%) | 72 (27) | 20 (2.8) | <0.001 | 15 (10) | 17 (11.3) | 0.81 |
Non-metastatic malignancy (%) | 44 (16.5) | 88 (12.5) | 0.11 | 24 (16) | 20 (13.3) | 0.63 |
Peripheral vascular disease (%) | 68 (25.5) | 45 (6.4) | <0.001 | 22 (14.7) | 20 (13.3) | 0.87 |
Chronic medication | ||||||
ACE inhibitors and ARBs (%) | 131 (49.1) | 157 (22.3) | <0.001 | 66 (44) | 66 (44) | 1 |
Anticoagulants (%) | 33 (12.4) | 123 (17.4) | 0.06 | 22 (14.7) | 26 (17.3) | 0.63 |
Beta-blockers (%) | 152 (56.9) | 166 (23.5) | <0.001 | 71 (47.3) | 65 (43.3) | 0.50 |
Calcium channel blockers (%) | 83 (31.5) | 93 (13.2) | <0.001 | 42 (28) | 36 (24) | 0.50 |
Corticosteroids (%) | 38 (14.2) | 114 (16.2) | 0.47 | 27 (18) | 29 (19.3) | 0.87 |
Diuretics (%) | 90 (33.7) | 160 (22.7) | 0.001 | 47 (31.3) | 48 (32) | 1 |
Insulin (%) | 57 (21.3) | 62 (8.8) | <0.001 | 29 (19.3) | 29 (19.3) | 1 |
NSAIDs and COX II inhibitors (%) | 23 (8.6) | 89 (12.6) | 0.10 | 13 (8.7) | 11 (7.3) | 0.84 |
Oral antidiabetic drugs (%) | 62 (23.2) | 66 (9.4) | <0.001 | 26 (17.3) | 30 (20) | 0.66 |
Other antiarrhythmic drugs (%) | 13 (4.9) | 37 (5.2) | 0.87 | 6 (4) | 8 (5.3) | 0.79 |
Statins (%) | 182 (68.2) | 129 (18.3) | <0.001 | 84 (56) | 86 (57.3) | 0.87 |
Antiplatelet therapy | ||||||
Acetylsalicylic acid (%) | 256 (95.9) | 141 (94) | ||||
Clopidogrel (%) | 43 (16.1) | 20 (13.3) | ||||
Dipyridamole (%) | 33 (12.4) | 19 (12.7) | ||||
Prasugrel (%) | 2 (0.7) | 1 (0.7) | ||||
Severity of disease in first 24 h | ||||||
APACHE IV score, median [IQR] | 83 [67–107] | 80 [63–102] | 0.06 | 83 [66–105] | 83 [64–104] | 0.96 |
APACHE IV APS, median [IQR] | 67 [52–90] | 68 [51–86] | 0.57 | 66 [51–88] | 68 [49–87] | 0.85 |
SOFA score, median [IQR]b
| 7 [5–9] | 7 [5–9] | 0.31 | 7 [5–10] | 8 [5–9] | 0.55 |
Organ failure (%) | 228 (85.4) | 595 (84.4) | 0.50 | 130 (86.7) | 125 (83.3) | 0.79 |
Shock (%) | 86 (32.2) | 239 (33.9) | 0.67 | 47 (31.3) | 52 (34.7) | 0.60 |
Treatment during first 24 h | ||||||
Mechanical ventilation (%) | 209 (78.3) | 545 (77.3) | 0.80 | 117 (78) | 113 (75.3) | 0.70 |
Renal replacement therapy (%) | 34 (12.7) | 68 (9.6) | 0.19 | 16 (10.7) | 19 (12.7) | 0.72 |
Sepsis severity on admission
Sepsis outcomes
Unmatched cohort | Propensity-matched cohort | |||||
---|---|---|---|---|---|---|
Antiplatelet therapy
N = 267 | No antiplatelet therapy
N = 705 |
p
| Antiplatelet therapy
N = 150 | No antiplatelet therapy
N = 150 |
p
| |
Length of stay ICU, median, days [IQR] | 4 [2–9] | 5 [2–10] | 0.23 | 4 [2–9] | 4 [1–10] | 0.69 |
Organ failure during admission (%) | 228 (85.4) | 595 (84.4) | 0.50 | 137 (91.3) | 132 (88) | 0.34 |
Shock during admission (%) | 86 (32.2) | 239 (33.9) | 0.67 | 59 (39.3) | 65 (43.3) | 0.54 |
Mortality | ||||||
ICU mortality (%) | 52 (19.5) | 150 (21.3) | 0.60 | 31 (20.7) | 29 (19.3) | 0.88 |
30-day mortality (%) | 82 (30.7) | 196 (27.8) | 0.44 | 47 (31.3) | 41 (27.3) | 0.63 |
60-day mortality (%) | 94 (35.2) | 237 (33.6) | 0.71 | 52 (34.7) | 50 (33.3) | 1 |
90-day mortality (%) | 98 (36.7) | 263 (37.3) | 0.83 | 55 (36.7) | 61 (40.7) | 0.54 |
Unmatched cohort | Propensity-matched cohort | Unmatched cohort adjusted for propensity | |||||||
---|---|---|---|---|---|---|---|---|---|
HR | 95 % CI |
p
| HR | 95 % CI |
p
| HR | 95 % CI |
p
| |
Antiplatelet therapy | 1.05 | 0.81–1.36 | 0.69 | 1.21 | 0.79–1.84 | 0.38 | 1.22 | 0.88–1.70 | 0.23 |
APS | 1.02 | 1.02–1.03 | <0.0001 | 1.02 | 1.01–1.02 | <0.0001 | 1.02 | 1.02–1.03 | <0.0001 |
Subgroup and sensitivity analyses
Host response biomarkers
Days 0, 2, 4 | Admission (day 0) | Day 2 | Day 4 | |||||||
---|---|---|---|---|---|---|---|---|---|---|
p
a
| Antiplatelet therapy
N = 132b
| No antiplatelet therapy
N = 125 |
p
| Antiplatelet therapy
N = 110 | No antiplatelet therapy
N = 103 |
p
| Antiplatelet therapy
N = 71 | No antiplatelet therapy
N = 75 |
p
| |
Coagulation | ||||||||||
Platelets (×109/l) | 0.62 | 189 [124–268] | 178 [123–274] | 0.76 | 179 [128–244] | 168 [109–280] | 0.65 | 173.5 [88–249] | 164 [85–314] | 0.74 |
D-dimer (µg/ml) | 0.08 | 11.7 [6–19.1] | 9.2 [3.8–17.5] | 0.09 | 10.8 [5.4–18.4] | 9.4 [3.9–18.5] | 0.28 | 13.5 [7.7–20] | 11.5 [6.3–17.5] | 0.25 |
Protein C (ng/ml) | 0.71 | 116.3 [93.9–150.1] | 113.7 [81.9–164.3] | 0.99 | 115.8 [90.6–161.6] | 117.5 [88.5–172.7] | 0.50 | 126.5 [94.2–182.4] | 145.4 [106.9–191] | 0.09 |
Antithrombin (ng/ml) | 0.59 | 726 [493.8–1127.8] | 748.6 [549.3–1031.5] | 0.71 | 690.9 [428.7–1037.6] | 699.1 [462.1–1048] | 0.59 | 827.8 [566.1–1383.9] | 930.6 [587.4–1392.6] | 0.55 |
Endothelial cell activation | ||||||||||
sE-selectin (ng/ml) | 0.91 | 11.2 [5–26.5] | 11.7 [5–25.3] | 0.79 | 12.1 [5.3–22] | 10.9 [4.6–19.8] | 0.47 | 7.6 [4.4–16.4] | 9 [4.2–16.5] | 0.83 |
sICAM-1 (ng/ml)c
| 0.32 | 193.3 [116.4–334.5] | 167.5 [100.3–275.7] | 0.43 | 213 [114.9–364.1] | 201.3 [107.9–337.8] | 0.50 | 223.2 [139–355.1] | 202.6 [117–334.4] | 0.39 |
Ang-1 (ng/ml) | 0.35 | 1.6 [0.8–4.7] | 2.6 [1.1–5.3] | 0.07 | 1.7 [0.8–4] | 1.6 [0.8–3.5] | 0.72 | 1.3 [0.5–3.5] | 1.4 [0.7–3.8] | 0.46 |
Ang-2 (ng/ml) | 0.80 | 7.7 [3.4–16.1] | 7.7 [3.3–13.9] | 0.71 | 8.3 [3.7–20] | 7.3 [3.6–14.7] | 0.30 | 5.6 [2.5–10.8] | 6.2 [3–17.6] | 0.24 |
Ang-2/Ang-1 ratio | 0.44 | 4 [0.9–16.8] | 2.6 [1–9.2] | 0.17 | 4.5 [1.4–23.5] | 4.4 [1.8–15.3] | 0.76 | 4 [0.9–16.3] | 4.8 [1.6–17.2] | 0.69 |
Metalloproteinases | ||||||||||
MMP-8 (ng/ml) | 0.30 | 4.3 [1.4–11.3] | 2.6 [1–8.5] | 0.12 | 3.8 [1.3–8.3] | 2 [0.7–4.8] | 0.01 | 1.8 [0.7–5] | 1.3 [0.7–4] | 0.36 |
TIMP-1 (ng/ml) | 0.81 | 631 [322.8–1027.8] | 580.1 [306.8–1129.5] | 0.94 | 517.6 [295–876.4] | 507.2 [276.1–851.4] | 0.51 | 364.9 [222.2–766.4] | 424.9 [220.2–693] | 0.88 |
Pro-inflammatory cytokines | ||||||||||
TNF-α (pg/ml) | 0.58 | 1 [0.7–1.7] | 1.2 [0.7–1.9] | 0.21 | 1 [0.7–1.7] | 1 [0.7–1.7] | 0.96 | 0.7 [0.7–1.7] | 1.1 [0.2–1.7] | 0.21 |
IL1-β (pg/ml) | 0.89 | 2.2 [1.1–4.5] | 2.6 [1.1–5] | 0.56 | 2.3 [1.1–3.4] | 1.8 [1–3.1] | 0.50 | 1.8 [1–3.2] | 2.6 [1.3–3.4] | 0.12 |
IL-6 (pg/ml) | 0.98 | 175.3 [51.7–854.1] | 133.7 [32.4–1393.7] | 0.32 | 59.1 [22.3–145.9] | 64.3 [24.5–246.1] | 0.65 | 40 [13.1–100.1] | 33.9 [13.2–96.5] | 0.94 |
IL-8 (pg/ml) | 0.81 | 124.6 [51.7–528.5] | 107.9 [52.1–446.2] | 0.43 | 75.7 [28.9–181.7] | 65.5 [32.1–153] | 0.98 | 58 [18.3–180.4] | 52.3 [20.2–130.4] | 0.70 |
Anti-inflammatory cytokinesd
| ||||||||||
IL-10 (pg/ml) | 0.29 | 13.8 [4–56.7] | 13.5 [5.1–49.9] | 0.90 | 6.3 [2.9–13.8] | 8.1 [3.5–17.3] | 0.13 | 3.9 [1.9–9.2] | 5.1 [2–14.2] | 0.28 |
Renal injury | ||||||||||
Creatinine (µmol/l) | 0.74 | 140 [83–234] | 126 [79–230] | 0.38 | 115 [75–191] | 111 [70–228] | 0.67 | 106 [66.8–167] | 99 [71–158] | 0.81 |
NGAL (ng/ml)e
| 0.54 | 306.5 [178.4–535] | 302.3 [155.7–562] | 0.91 | 271 [167.8–499.6] | 240.7 [121.9–569.6] | 0.43 | 201.6 [131.8–403.2] | 209 [117.4–395.2] | 0.81 |
Cystatin C (µg/ml) | 0.72 | 1.7 [1.1–2.5] | 1.6 [1.1–2.9] | 0.66 | 1.7 [1.1–2.6] | 1.4 [1–2.8] | 0.91 | 1.6 [1–2.4] | 1.7 [1.3–3] | 0.47 |