Thromboembolicconditions constitute a significant global disease burden, causing 1 in 4 deaths worldwide.1,2Antithrombotic therapy (ATT), including antiplatelet (AP) and anticoagulant (AC) medications, is essential for treating and preventing end-organ ischemia and is increasingly encountered in neurosurgical practice.3- - - - - -7However, antithrombotics inherently increase the risk of spontaneous intracranial hemorrhage (ICH) and secondary hematoma expansion and challenge hemostasis during invasive procedures.8,9For patients receiving ATT who sustain ICH, the Neurocritical Care Society recommends reversal therapy regardless of neurosurgical intervention.10Current strategies emphasize rapid restoration of functional platelets and/or coagulation factors through blood product replacement, often lacking specific ATT inhibitors that only exist for heparins and two direct-acting oral ACs (DOACs) to date.2,11- - - - - -14Furthermore, their timely use is dependent on accurate medication history and resource availability.12,13
Despite current guidelines, the evidence for ATT reversal is of very low quality and unclear when considering operative management.9,10,15Its use and safety specifically for subdural hematoma (SDH) evacuation have been insufficiently investigated in comparison with intraparenchymal hemorrhage.16Furthermore, reversal incurs its own risk of serious adverse events, including thrombosis, anaphylaxis, and potential delays in care.9,12,15,17At our institution, ATT reversal for neurosurgical trauma patients follows multidisciplinary institutional guidelines that direct the use of reversal agents for all patients with active ATT use and operative neurotrauma immediately prior to neurosurgical intervention with the following exceptions: 1) hematological assays that do not correlate with a therapeutic response relevant to mechanism of action, 2) stable neurological examination precluding the need for urgent neurosurgery, and 3) a risk-benefit analysis for patients with a vague medication history or significant thrombophilic disorders.
Given the limited understanding of the impact of ATT and reversal agents in nonelective neurosurgical intervention, the purpose of this study was to report our center’s experience with perioperative antithrombotic management in urgent SDH evacuation. We hypothesized that patients on preoperative ATT would sustain poor neurological outcomes, increased hematoma expansion, and increased mortality regardless of reversal. Furthermore, we delineate the risks associated with ATT reversal and practice patterns concerning ATT reinitiation in this population, highlighting the ongoing challenges in perioperative management for these high-risk patients.
开云体育世界杯赔率
Institutional review board approval was obtained from the Inova Hospital System to conduct this retrospective study. All patients admitted to our level I trauma center between March 1, 2020, and May 1, 2021, who underwent SDH evacuation were included. Exclusion criteria comprised patients receiving medical management only or those with undocumented ATT history. For patients with multiple admissions and surgeries, data were collected only for their first intervention. Bilateral SDH cases were treated as a single entity to avoid data overrepresentation. To account for surgical technique variation, changes in SDH thickness and midline shift (MLS) were measured via a 24-hour postoperative CT study to assess the extent of evacuation accomplished with each intervention. Inclusion criteria did not restrict according to SDH chronicity or additional intracranial injury, as long as no further surgical intervention was required beyond the planned SDH evacuation, to accurately reflect our modern-day, urban neurotrauma patient population. Informed consent was obtained from all individual participants included in the study.
患者首先分为两组based on ATT use within 7 days of admission. Within the antithrombotic cohort, further stratification was performed based on ATT reversal by the time of incision. The primary outcome evaluated was 30-day all-cause mortality. Secondary endpoints included improvement of preoperative neurological deficit, radiographic hematoma expansion ≥ 2 mm at 24 hours, and revision evacuation. A crossover analysis was conducted to assess the impact of antithrombotic interruption in patients with safely delayed surgery. Patients were crossed over to the nonantithrombotic cohort if AC medications were withheld for a minimum duration of 4.5 half-lives and/or AP medications were withheld for 3–7 days to ensure functional platelet recovery and turnover, following CHEST (American College of Chest Physicians) guidelines.18
Statistical analysis was performed using R software (version 4.2.1, The R Foundation for Statistical Computing) and RStudio (posit.co). In rare instances of missing data, patients were excluded from the analysis for that specific variable. Cohort comparison used the chi-square test for ordinal variables, corrected for continuity, and the Welch two-sample t-test for scaled variables. Binary multivariate logistic regression was performed to predict the primary and secondary outcomes based on preoperative ATT use, category type, and reversal as featured variables. Potential confounders included as covariates were age, sex, SDH chronicity, thickness, MLS, extent of evacuation denoted by changes in SDH thickness and MLS, and additional ICH. Type 1 error was set at 0.05 for all tests.
Results
Of 105 screened patients, 5 were excluded due to unreliable ATT history. Thus, 100 patients were included, of whom 48 (48%) were prescribed 1 of 4 AP regimens (54.2%), 1 of 3 ACs (39.6%), or both APs and ACs (6.3%) upon admission. Twenty-six patients (54.2%) received reversal agents by the time of intervention, while 22 patients (45.8%) did not receive reversal based on institutional guidelines. Reversal of AP agents involved desmopressin and/or platelet transfusion, while targeted reversal with idarucizumab was used for 1 patient on dabigatran. AC reversal methods included 4-factor prothrombin-complex concentrate, fresh-frozen plasma (FFP), cryoprecipitate, and/or vitamin K. Among patients who underwent reversal, 38.5% demonstrated laboratory evidence of hematological restoration without identifiable rebound effects for warfarin users.
Original Cohort Comparison Stratified by ATT and Reversal
Table 1presents each cohort’s demographics and neurosurgical presentation. The groups were well matched with few differences. The antithrombotic cohort had a median age of 76 years, which was significantly higher than that of the nonantithrombotic cohort (p = 0.004), indicating a higher prevalence of thromboembolic disease with advancing age. An increased incidence of atraumatic SDH etiology in the antithrombotic cohort trended toward significance, aligning with an increased propensity for spontaneous ICH secondary to ATT use. Patients receiving reversal agents were more likely to harbor unilateral dominant-side pathology (p < 0.00001), increased preoperative MLS (p = 0.014), and decreased preoperative total Glasgow Coma Scale (GCS) score (p = 0.017) than those who did not receive reversal.
Characterization of patient demographics and neurosurgical presentation for each patient cohort
| Variable | Total Cohort (n = 100) | Non-ATT Cohort (n = 52) | ATT Cohort (n = 48) | p Value | Nonreversal Cohort (n = 22) | Reversal Cohort (n = 26) | p Value |
|---|---|---|---|---|---|---|---|
| Demographics | |||||||
| Age, yrs | 73 [63, 82] | 70 [57, 81.3] | 76 [69.8, 84] | 0.004* | 77 [73.3, 83.8] | 72.5 [66, 84.3] | 0.33 |
| Female sex | 37 (37.0) | 22 (42.3) | 15 (31.3) | 0.35 | 7 (31.8) | 8 (30.8) | >0.99 |
| Neurosurgical presentation | |||||||
| Etiology–trauma | 78 (78.0) | 44 (84.6) | 34 (70.8) | 0.25 | 15 (68.2) | 19 (73.1) | 0.29 |
| SDH laterality | |||||||
| Unilat–unknown | 49 (49.0) | 22 (42.3) | 27 (56.3) | — | 9 (40.9) | 18 (69.2) | — |
| Unilat–dominant | 20 (20.0) | 14 (26.9) | 6 (12.5) | 0.42 | 2 (9.1) | 4 (15.4) | <0.00001* |
| Unilat–nondominant | 16 (16.0) | 8 (15.4) | 8 (16.7) | 6 (27.3) | 2 (7.7) | ||
| Bilat | 15 (15.0) | 8 (15.4) | 7 (14.6) | 5 (22.7) | 2 (7.7) | ||
| SDH chronicity | |||||||
| Acute | 32 (32.0) | 15 (28.8) | 17 (35.4) | 0.69 | 5 (22.7) | 12 (46.2) | 0.23 |
| Subacute/chronic | 33 (33.0) | 19 (36.5) | 14 (29.2) | 8 (36.4) | 6 (23.1) | ||
| Mixed density | 35 (35.0) | 18 (34.6) | 17 (35.4) | 9 (40.9) | 8 (30.8) | ||
| Presence of additional ICH | 26 (26.0) | 15 (28.8) | 11 (22.9) | 0.65 | 5 (22.7) | 6 (23.1) | >0.99 |
| SDH thickness, mm | 20 [14, 25] | 21 [14.8, 25] | 19 [14, 25] | 0.97 | 18 [13.3, 25.3] | 20 [16, 25] | 0.57 |
| MLS, mm | 9.5 [6, 13] | 10 [7, 13] | 9 [5.4, 13] | 0.71 | 6.5 [3.3, 10.5] | 11.5 [8.1, 15.8] | 0.014* |
| Preop total GCS score | 14 [10, 15] | 14 [12.5, 15] | 14 [8, 15] | 0.59 | 15 [13.3, 15] | 12 [6, 15] | 0.017* |
Values are given as median [IQR] or number of patients (%) unless otherwise indicated.
p < 0.05.
Characterizations of each cohort’s operative course, postoperative outcomes, and disposition are presented inTables 2和3. SDH evacuation was performed by 10 neurosurgeons, without standardized operating protocols for trepanation or surgical drain placement; however, the cohorts were well matched with no significant differences. Variables substituting perceived hemostatic dysfunction, including operative duration, estimated blood loss (EBL), and surgical drain duration, likewise revealed no significant differences between cohorts. ATT use was associated with less SDH evacuation, increased incidence of SDH expansion with or without revision evacuation, and statistically significantly lower rates of neurological improvement (p = 0.008). ATT reversal contributed no difference in these secondary endpoints. Overall, 11 patients required revision evacuation with a median time to surgery of 8 days.
Characterization of operative course and postoperative outcomes for each patient cohort
| Variable | Total Cohort (n = 100) | Non-ATT Cohort (n = 52) | ATT Cohort (n = 48) | p Value | Nonreversal Cohort (n = 22) | Reversal Cohort (n = 26) | p Value |
|---|---|---|---|---|---|---|---|
| Op course | |||||||
| Neurosurgical intervention type | |||||||
| Burr holes only | 32 (32.0) | 20 (38.5) | 12 (25.0) | 0.38 | 5 (22.7) | 7 (26.9) | 0.17 |
| Craniotomy only | 53 (53.0) | 25 (48.1) | 28 (58.3) | 13 (59.1) | 15 (57.7) | ||
| Burr holes & craniotomy | 4 (4.0) | 1 (1.9) | 3 (6.3) | 3 (13.6) | 0 (0) | ||
| Decompressive craniectomy | 11 (11.0) | 6 (11.5) | 5 (10.4) | 1 (4.5) | 4 (15.4) | ||
| Op duration, mins | 74.5 [55, 107.3] | 75.5 [59.3, 106.5] | 74.5 [53.5, 109.3] | 0.49 | 73 [51, 106.5] | 77 [54.3, 113] | 0.63 |
| EBL, mL | 100 [25, 200] | 100 [21.3, 187.5] | 100 [50, 200] | 0.97 | 100 [43.8, 200] | 100 [50, 150] | 0.88 |
| No. of surgical drains | |||||||
| 1 drain/side | 62 (66.7) | 31 (66.0) | 31 (67.4) | >0.99 | 11 (52.4) | 20 (80.0) | 0.063 |
| >1 drain/side | 31 (33.3) | 16 (34.0) | 15 (32.6) | 10 (47.6) | 5 (20.0) | ||
| Surgical drain location | |||||||
| Subgaleal/epidural | 38 (40.1) | 19 (40.4) | 19 (41.3) | 0.33 | 7 (33.3) | 12 (48.0) | 0.38 |
| Subdural | 30 (32.3) | 18 (38.3) | 12 (26.1) | 5 (23.8) | 7 (28.0) | ||
| Both subgaleal & subdural | 25 (26.9) | 10 (21.3) | 15 (32.6) | 9 (42.9) | 6 (24.0) | ||
| Duration of surgical drain placement, days | 3 [2, 4] | 3 [2, 4] | 2.5 [2, 3] | 0.37 | 3 [2, 4] | 2 [2, 3] | 0.31 |
| Postop outcomes | |||||||
| Change in SDH thickness, mm | 9 [5, 14] | 10 [6, 17] | 7 [4, 12] | 0.13 | 7 [4, 11.8] | 8 [5, 12] | 0.95 |
| Change in MLS, mm | 5 [1, 8] | 6 [2, 8] | 3 [1, 7.5] | 0.30 | 2.5 [1, 5.8] | 5 [2, 8] | 0.20 |
| SDH expansion >2 mm | 35 (35.0) | 14 (26.9) | 21 (43.8) | 0.138 | 10 (45.5) | 11 (42.3) | >0.99 |
| w/o revision | 26 (26.0) | 7 (13.5) | 17 (35.4) | 0.073 | 9 (40.9) | 1 (3.8) | 0.59 |
| w/ revision evacuation | 11 (11.0) | 7 (13.5) | 4 (8.3) | 8 (36.4) | 1 (3.8) | ||
| % improvement in preop deficit | 70 (70.0) | 43 (82.7) | 27 (56.3) | 0.008* | 14 (63.6) | 13 (50.0) | 0.51 |
Values are given as median [IQR] or number of patients (%) unless otherwise indicated.
p < 0.05.
Characterization of disposition for each patient cohort
| Variable | Total Cohort (n = 100) | Non-ATT Cohort (n = 52) | ATT Cohort (n = 48) | p Value | Nonreversal Cohort (n = 22) | Reversal Cohort (n = 26) | p Value |
|---|---|---|---|---|---|---|---|
| ICU LOS, days† | 4 [2, 6] | 3 [2, 6] | 4 [2.5, 6] | 0.79 | 5.5 [3, 8] | 3 [2, 5.5] | 0.014* |
| Hospital LOS, day† | 7 [5, 11] | 6 [4, 10] | 7 [5, 13] | 0.32 | 10 [7, 14] | 6 [4, 9] | 0.072 |
| Disposition location | |||||||
| Home | 47 (47.0) | 25 (48.1) | 22 (45.8) | 0.027* | 13 (59.1) | 9 (34.6) | 0.078 |
| Acute rehabilitation | 23 (23.0) | 17 (32.7) | 6 (12.5) | 3 (13.6) | 3 (11.5) | ||
| Skilled nursing facility | 12 (12.0) | 5 (9.6) | 7 (14.6) | 4 (18.2) | 3 (11.5) | ||
| Hospice/morgue | 18 (18.0) | 5 (9.6) | 13 (27.1) | 2 (9.1) | 11 (42.3) | ||
| 30-day readmission‡ | 16 (18.2) | 12 (24.5) | 4 (10.3) | 0.15 | 1 (4.8) | 3 (17.6) | 0.97 |
| 30-day mortality | 17 (17.0) | 6 (11.5) | 11 (22.9) | 0.21 | 1 (4.5) | 10 (38.5) | 0.015* |
Values are given as median [IQR] or number of patients (%) unless otherwise indicated.
p < 0.05.
Adjusted for in-hospital mortality.
Patients who died in the hospital (n = 12) were removed from consideration for this data point. The 30-day total mortality is 17 patients: 12 who died in the hospital and 5 who died after discharge.
35名患者术后complications, with the most common events including SDH reexpansion (n = 14), adjacent cerebral infarction (n = 12), and venous thromboembolism (n = 6). After ATT reversal, there was an 11.5% incidence of perioperative thromboembolism before ATT reinitiation, in which all but 1 patient died. Among these patients, reversal was administered for either warfarin or triple AP therapy, and the majority of patients had hematological indications for ATT. The median intensive care unit (ICU) length of stay (LOS) and hospital LOS for the entire cohort were 4 and 7 days, respectively. When adjusted for in-hospital mortality, patients receiving reversal agents had a significantly shorter ICU LOS (p = 0.014) and a trend toward decreased hospital LOS (p = 0.072). The 30-day readmission rate was 18.2% with a median interval of 7 days and a trend toward increased readmission for non-ATT patients, most commonly due to unrelated medical complaints or neurological symptoms with stable neuroimaging. Finally, the 30-day all-cause mortality rate was 17%, with all but 1 death related to SDH. ATT use trended toward increased mortality, while reversal agents demonstrated a significant association on initial chi-square analysis (p = 0.005).
Table 4shows outcomes stratified by ATT category, type, and indication. Aspirin users had a trend toward lower mortality (p = 0.079) and increased neurological improvement (p = 0.08) compared with those who received adenosine diphosphate (ADP) receptor inhibitors and multiple AP agent regimens. Warfarin users had significantly higher rates of reversal (p = 0.043) and a trend toward increased mortality (p = 0.078), with no differences in SDH reexpansion rate or neurological improvement, compared with those who received DOACs and heparins. Patients on multiple ATT agents of any type had higher rates of SDH revision evacuation (p = 0.0026) and less neurological improvement (p = 0.033). Cardiac indications for ATT were associated with lower mortality in comparison with noncardiac causes (p = 0.042), whereas hematological and neurological indications posed the greatest mortality rates and poorer neurological outcomes (p = 0.0046).
Characterization of antithrombotic medication use and its impact on primary and secondary outcomes by chi-square analysis
| Variable | Total ATT Cohort (n = 48) | Nonreversal Cohort (n = 22) | Reversal Cohort (n = 26) | p Value | Mortality | p Value | SDH Reexpansion | p Value | SDH Revision | p Value | Neurological Improvement | p Value |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ATT category | ||||||||||||
| APs only | 26 (54.2) | 12 (54.5) | 14 (53.8) | 0.90 | 6 (23.1) | 0.89 | 11 (42.3) | 0.49 | 3 (11.5) | 0.47 | 13 (50.0) | 0.63 |
| ACs only | 19 (39.6) | 9 (40.9) | 10 (38.5) | 4 (21.1) | 10 (52.6) | 1 (5.3) | 12 (63.2) | |||||
| Both APs & ACs | 3 (6.3) | 1 (4.5) | 2 (7.7) | 1 (33.3) | 0 (0) | 0 (0) | 2 (66.7) | |||||
| AP type | ||||||||||||
| ASA 81 mg only | 12 (25.0) | 7 (31.8) | 5 (19.2) | 0.40 | 2 (16.7) | 0.079 | 2 (16.7) | 0.12 | 0 (0) | — | 9 (75.0) | 0.08 |
| ASA 325 mg only | 5 (10.4) | 2 (9.1) | 3 (11.5) | 0 (0) | 2 (40.0) | 0 (0) | 2 (40.0) | |||||
| ADP receptor inhibitor | 6 (12.5) | 3 (13.6) | 3 (11.5) | 2 (33.3) | 2 (33.3) | 0 (0) | 3 (50.0) | |||||
| DAPT/triple AP therapy | 7 (14.6) | 1 (4.5) | 5 (19.2) | 3 (42.9) | 5 (71.4) | 3 (42.9) | 1 (14.3) | |||||
| AC type | ||||||||||||
| Warfarin | 10 (20.8) | 2 (9.1) | 8 (30.8) | 0.043* | 4 (40.0) | 0.078 | 4 (40.0) | 0.64 | 0 (0) | — | 6 (60.0) | 0.75 |
| DOAC | 10 (20.8) | 6 (27.3) | 4 (15.4) | 1 (10.0) | 4 (40.0) | 1 (10.0) | 6 (60.0) | |||||
| Heparin/LMWH | 2 (4.2) | 2 (9.1) | 0 (0) | 0 (0) | 2 (100) | 0 (0) | 2 (100) | |||||
| No. of ATT agents | ||||||||||||
| 1 | 39 (81.3) | 20 (90.9) | 19 (73.1) | 0.23 | 7 (17.9) | 0.088 | 16 (41.0) | 0.43 | 1 (2.6) | 0.0026* | 24 (61.5) | 0.033* |
| >1 | 9 (18.8) | 2 (9.1) | 7 (26.9) | 4 (44.4) | 5 (55.6) | 3 (33.3) | 2 (22.2) | |||||
| Reported reasons for ATT use | ||||||||||||
| Health maintenance/pain | 9 (18.8) | 4 (18.2) | 5 (19.2) | 0.46 | 1 (11.1) | 0.042* | 3 (33.3) | 0.41 | 0 (0) | — | 8 (88.9) | 0.0046* |
| Cardiac | 25 (52.1) | 13 (59.1) | 12 (46.2) | 3 (12.0) | 10 (40.0) | 0 (0) | 15 (60.0) | |||||
| Hematological | 8 (16.7) | 3 (13.7) | 5 (19.2) | 4 (50.0) | 5 (62.5) | 2 (25.0) | 3 (37.5) | |||||
| Neurological | 6 (12.5) | 1 (4.5) | 5 (19.2) | 3 (50.0) | 4 (66.7) | 2 (33.3) | 0 (0) |
ASA = aspirin; DAPT = dual AP therapy; LMWH = low-molecular-weight heparin.
Values are given as number of patients (%) unless otherwise indicated.
p < 0.05.
More than half of the patients resumed therapeutic ATT with a median time to reinitiation of 16 days (range 6–209 days) (Table 5). Medication resumption spanned all ATT types, with a trend toward increased reinitiation rates (p = 0.10) and decreased time to reinitiation (p = 0.0031) in AC patients compared with AP users. Aspirin users had the lowest reinitiation rates, although this was not statistically significant. Patients who received reversal therapy demonstrated a trend toward higher reinitiation rates than the nonreversed ATT cohort (p = 0.11). Patients with cardiac and/or hematological disorders were most likely to undergo ATT reinitiation (p = 0.11), in which cardiac pathology had the shortest time to reinitiation (p = 0.0054). Notably, coronary stent placement, valve replacement, high-risk atrial fibrillation, and congenital heart abnormalities were the most common reasons for resuming ATT therapy after SDH evacuation.
Characterization of antithrombotic medication reinitiation in surviving patients
| Variable | Reinitiation | p Value | Time to Reinitiation, days | p Value | SDH Reexpansion After Reinitiation | p Value | SDH Revision After Reinitiation | p Value |
|---|---|---|---|---|---|---|---|---|
| Total ATT cohort survivors (n = 37) | 22 (59.5) | — | 16 [10, 34] | — | 7 (31.8) | 0.071 | 1 (4.55) | 0.28 |
| By ATT category | ||||||||
| APs (n = 22) | 10 (45.5) | 0.10 | 17 [10, 30] | 0.0031* | 6 (60.0) | >0.99 | 0 (0) | — |
| ACs (n = 17) | 13 (76.5) | 15 [8, 46] | 8 (61.5) | 1 (7.69) | ||||
| By ATT type | ||||||||
| ASA 81 mg only (n = 9) | 4 (44.4) | 0.32 | 18 [10, 117.5] | — | 0 (0) | — | 0 (0) | — |
| ASA 325 mg only (n = 5) | 1 (20.0) | 17 [—] | 1 (100) | 0 (0) | ||||
| ADP receptor inhibitor only (n = 3) | 2 (66.7) | 8 [—] | 0 (0) | 0 (0) | ||||
| DAPT (n = 3) | 2 (66.7) | 18 [—] | 1 (50.0) | 1 (50.0) | ||||
| Warfarin (n = 6) | 5 (83.3) | 12.5 [8, 58] | 3 (60.0) | 0 (0) | ||||
| DOAC (n = 9) | 5 (55.6) | 26 [17.5, 66.5] | 1 (20.0) | 0 (0) | ||||
| Heparin/LMWH (n = 2) | 2 (100) | 6.5 [—] | 2 (100) | 0 (0) | ||||
| By ATT indication | ||||||||
| Health maintenance/chronic pain (n = 8) | 2 (25.0) | 0.11 | 12.5 [—] | 0.0054*† | 0 (0) | — | 0 (0) | — |
| Cardiac (n = 23) | 16 (69.6) | 14 [9, 30] | 6 (37.5) | 0 (0) | ||||
| Hematological (n = 4) | 3 (75.0) | 26 [—] | 1 (33.3) | 0 (0) | ||||
| Neurological (n = 3) | 1 (33.3) | Unknown | 1 (100) | 1 (100) | ||||
| ATT reversal cohort survivors (n = 17) | 13 (76.5) | 0.11 | 11 [8, 24] | 0.43 | 3 (23.1) | 0.93 | 1 (7.69) | — |
Values are given as median [IQR] or number of patients (%) unless otherwise indicated. Variables for which statistical analysis was not completed due to study power are indicated by a dash. Rates and median time to ATT reinitiation are calculated for each category, type, and indication for ATT as well as for patients who received reversal. It is important to note that patients may have had multiple indications for ATT. Rates of SDH reexpansion and surgical revision required after reinitiation are also calculated for each variable and compared either to the rates for those not restarted on ATT or to multiple variables within the same category.
p < 0.05.
Because of missing data, comparison was made between cardiac and noncardiac indications for ATT reinitiation timing.
No mortalities resulted from ATT reinitiation. Radiographic SDH expansion was observed in 31.8% of patients who resumed ATT compared with 46.7% of those who did not (p = 0.071). Of the 4 patients receiving ATT who required a revision evacuation, none resumed ATT before SDH expansion. Insufficient data prevented analysis of outcomes based on ATT reinitiation, ATT type, and SDH chronicity, yet it is important to note that no adverse events resulted in chronic SDH patients resuming aspirin.
Multivariate Logistic Regression for Primary and Secondary Outcomes
Next, binary multivariate logistic regression was used to predict the likelihood of the following outcomes based on ATT use, category (APs or ACs), and reversal: 1) mortality, 2) radiographic SDH reexpansion, 3) revision evacuation, and 4) improvement of preoperative neurological deficits at the time of discharge for survivors (Table 6).
Multivariate logistic regression on initial patient cohort for primary and secondary endpoints of interest
| Population Independent Variable | Primary Endpoint: Mortality | Secondary Endpoints | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Postop SDH Expansion | Need for Revision SDH Evacuation | Improved Postop Neurological Status | ||||||||||
| OR | 95% CI | p Value | OR | 95% CI | p Value | OR | 95% CI | p Value | OR | 95% CI | p Value | |
| Age | 0.98 | 0.94 to 1.02 | 0.34 | 0.99 | 0.96–1.02 | 0.44 | 1.01 | 0.97–1.06 | 0.62 | 0.98 | 0.94–1.02 | 0.35 |
| Sex (F = 0, M = 1) | 1.38 | 0.34 to 6.41 | 0.66 | 1.56 | 0.59–4.31 | 0.38 | 3.54 | 0.77–21.54 | 0.13 | 0.90 | 0.28–2.83 | 0.86 |
| SDH chronicity | 6.94 × 107 | 0 to ∞ | 0.99 | 1.78 | 0.65–5.17 | 0.27 | 2.10 | 0.38–16.8 | 0.42 | 0.40 | 0.10 - -1.35 | 0.15 |
| SDH thickness | 0.97 | 0.85 to 1.11 | 0.69 | 0.99 | 0.90–1.08 | 0.77 | 0.93 | 0.80–1.06 | 0.31 | 0.95 | 0.86–1.05 | 0.32 |
| Preop MLS | 1.17 | 1.006 to 1.39 | 0.055* | 1.08 | 0.97–1.20 | 0.17 | 1.16 | 1.00–1.36 | 0.056* | 0.98 | 0.87–1.11 | 0.79 |
| Postop change in SDH thickness | 0.97 | 0.85 to 1.12 | 0.70 | 1.01 | 0.92–1.12 | 0.79 | 0.94 | 0.82–1.08 | 0.36 | 1.13 | 1.02–1.28 | 0.03† |
| Postop change in MLS | 1.09 | 0.92 to 1.32 | 0.33 | 0.95 | 0.82–1.09 | 0.45 | 1.00 | 0.82–1.20 | 0.95 | 0.86 | 0.72–1.01 | 0.072* |
| Additional ICH types | 0.88 | 0.17 to 4.02 | 0.87 | 1.05 | 0.34–3.14 | 0.93 | 0.42 | 0.051–2.19 | 0.35 | 0.83 | 0.22–3.25 | 0.78 |
| Preop ATT | 3.63 | 0.092 to 17.06 | 0.078* | 2.08 | 0.83–5.41 | 0.12 | 0.26 | 0.045–1.21 | 0.10 | 0.28 | 0.087–0.81 | 0.023† |
| Preop ATT type: AC | 0.78 | 0.14 to 3.98 | 0.77 | 0.85 | 0.24–2.96 | 0.80 | 0.51 | 0.022–5.47 | 0.60 | 1.85 | 0.50–7.26 | 0.37 |
| Preop ATT type: AP | 1.93 | 0.37 to 12.2 | 0.45 | 0.73 | 0.20–2.62 | 0.63 | 1.47 | 0.13–34.2 | 0.77 | 0.64 | 0.16–2.43 | 0.51 |
| ATT reversal | 19.02 | 1.89 to 566.3 | 0.032† | 0.45 | 0.092–1.89 | 0.29 | 5.24 | 0.16–1769 | 0.41 | 0.67 | 0.17–2.61 | 0.56 |
Featured variables for each regression include preoperative ATT use and ATT reversal. Control variables included age, sex, preoperative GCS scores, preoperative MLS, preoperative SDH thickness, postoperative change in SDH thickness and MLS, and presence of additional ICH.
p < 0.1.
p < 0.05.
Mortality analysis revealed a statistically significant association with ATT reversal (OR 19.02, 95% CI 1.890–566.3; p = 0.032) and a strong trend toward significance with preoperative ATT and MLS when controlling for covariates. No variables were associated with SDH reexpansion or revision surgery; however, a strong trend was observed with preoperative ATT and MLS. Male patients appeared 3.5 times more likely to require revision surgery than female patients, although this was not statistically significant. ATT use was significantly associated with decreased postoperative neurological improvement (OR 0.278, 95% CI 0.087–0.812; p = 0.023), while acute SDH chronicity trended toward significance. Increased SDH evacuation contributed to increased neurological improvement (OR 1.13, 95% CI 1.02–1.28; p = 0.03), while greater changes in postoperative MLS showed a similar yet nonsignificant trend. ATT reversal did not contribute to differences in secondary outcomes.
Crossover Cohort: Analysis of ATT Interruption
Crossover analysis was performed for the same endpoints by considering patients with clinically significant ATT interruption prior to delayed SDH evacuation as non-ATT patients (n = 12). This subgroup experienced 1 mortality, no readmissions, 6 SDH reexpansions with 1 revision surgery, and varying degrees of postoperative neurological improvement. Chi-square analysis (not shown) revealed a near-significant decrease in mortality for non-ATT patients (p = 0.051) with loss of associations with poorer neurological outcomes (p = 0.056 vs 0.0039) and increased SDH reexpansion (p = 0.38 vs 0.015) and revision surgery (p = 0.26 vs 0.073) for ATT use.
To further assess the impact of ATT interruption as potentially noninferior to non-ATT use, multivariate logistic regression was repeated for the same endpoints (Table 7). Mortality analysis now revealed a significant association with preoperative ATT (OR 4.083, 95% CI 1.109–17.11; p = 0.04) and preoperative MLS (OR 1.179, 95% CI 1.011–1.412; p = 0.049). The previous association between ATT reversal and increased mortality was no longer observed. Upon crossover, ATT use demonstrated no impact on SDH expansion, while male sex and increased preoperative MLS continued their trends toward increased revision evacuation rates. Likewise, ATT use was no longer associated with worse neurological outcomes, while SDH chronicity and changes in SDH and MLS maintained their trends. ATT category again yielded no difference in primary or secondary outcomes upon crossover. Finally, age, sex, SDH chronicity and thickness, and the presence of additional ICH accounted for no differences in outcomes for either cohort analysis.
Multivariate logistic regression on crossover patient cohort for primary and secondary outcomes of interest
| Population Independent Variable | Primary Endpoint: Mortality | Secondary Endpoints | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Postop SDH Expansion | Need for Revision SDH Evacuation | Improved Postop Neurological Status | ||||||||||
| OR | 95% CI | p Value | OR | 95% CI | p Value | OR | 95% CI | p Value | OR | 95% CI | p Value | |
| Age | 0.98 | 0.94 to 1.03 | 0.39 | 0.99 | 0.97–1.02 | 0.64 | 1.00 | 0.96 to 1.05 | 0.92 | 0.97 | 0.93–1.01 | 0.13 |
| Sex (F = 0, M = 1) | 1.36 | 0.33 to 6.39 | 0.67 | 1.58 | 0.60–4.33 | 0.36 | 3.03 | 0.68 to 17.57 | 0.17 | 0.78 | 0.25–2.35 | 0.66 |
| SDH chronicity | 7.25 × 107 | 0 to ∞ | 0.99 | 1.87 | 0.68–5.40 | 0.23 | 2.08 | 0.40 to 15.90 | 0.42 | 0.38 | 0.097–1.29 | 0.14 |
| SDH thickness | 0.97 | 0.84 to 1.10 | 0.63 | 0.99 | 0.90–1.08 | 0.76 | 0.94 | 0.81 to 1.07 | 0.36 | 0.96 | 0.87–1.06 | 0.39 |
| Preop MLS | 1.18 | 1.01 to 1.41 | 0.049† | 1.08 | 0.97–1.20 | 0.17 | 1.15 | 0.99 to 1.35 | 0.067* | 0.98 | 0.87–1.11 | 0.74 |
| Postop change in SDH thickness | 0.98 | 0.85 to 1.12 | 0.72 | 1.00 | 0.92–1.11 | 0.89 | 0.95 | 0.84 to 1.10 | 0.47 | 1.14 | 1.03–1.29 | 0.019† |
| Postop change in MLS | 1.07 | 0.89 to 1.29 | 0.45 | 0.94 | 0.81–1.08 | 0.39 | 1.01 | 0.83 to 1.21 | 0.95 | 0.87 | 0.73–1.02 | 0.098* |
| Additional ICH types | 0.88 | 0.16 to 4.21 | 0.88 | 1.12 | 0.37–3.32 | 0.84 | 0.42 | 0.053 to 2.15 | 0.34 | 0.80 | 0.22–3.10 | 0.74 |
| Preop ATT | 4.08 | 1.11 to 17.11 | 0.040† | 1.47 | 0.58–3.72 | 0.41 | 0.40 | 0.070 to 1.70 | 0.25 | 0.56 | 0.21–1.51 | 0.25 |
| Preop ATT type: AC | 0.86 | 0.16 to 4.09 | 0.85 | 1.24 | 0.39–3.87 | 0.71 | 0.35 | 0.017 to 2.76 | 0.38 | 1.11 | 0.31–4.28 | 0.87 |
| Preop ATT type: AP | 1.80 | 0.36 to 9.51 | 0.48 | 1.08 | 0.32–3.62 | 0.90 | 0.70 | 0.092 to 4.55 | 0.71 | 0.35 | 0.092–1.24 | 0.11 |
| ATT reversal | 4.55 × 108 | 6.22 × 10-92年to 0 | 0.99 | 0.40 | 0.041–3.05 | 0.39 | 1.58 × 108 | 0 to ∞ | >0.99 | 0.25 | 0.019–2.61 | 0.23 |
Featured variables for each regression include preoperative ATT use and ATT reversal. Control variables included age, sex, preoperative GCS scores, preoperative MLS, preoperative SDH thickness, postoperative change in SDH thickness and MLS, and presence of additional ICH.
p < 0.1.
p < 0.05.
Discussion
Current multidisciplinary clinical practice guidelines support antithrombotic discontinuation and reversal in the setting of ICH, regardless of etiology and management.10,15,19However, discontinuation timing, reversal regimen, and recommended laboratory monitoring are nonstandardized, and the evidence to guide nonelective neurosurgical intervention is highly limited.10,18,20Furthermore, prospective trials evaluating individual reversal agent efficacy have limited generalizability due to rare inclusion of SDH patients or those undergoing cranial neurosurgery at all.10We present a retrospective comparative analysis of 100 operative SDH patients to evaluate the impact of ATT and reversal strategies on mortality, hematoma reexpansion, revision surgery, and neurological outcomes. Our findings provide valuable insights into the vast array of challenges complicating antithrombotic management in this high-risk patient population.
First, preoperative ATT of any type was significantly associated with increased 30-day mortality, particularly when considering patients with ATT interruption prior to surgery. Among ATT users, aspirin had the lowest mortality rate, while warfarin contributed to higher postoperative mortality, consistent with previous studies.8,21- - - - - -26We also observed that ATT indication affected mortality, with higher rates of postoperative death in patients with hematological and neurological comorbidities, an aspect that has not yet been extensively studied.
Regarding secondary outcomes, ATT patients were 3 times less likely to experience postoperative neurological improvement than non-ATT users, consistent with previous studies reporting an increased risk for poor neurological outcomes in these patients.10,15This finding suggests that ATT itself hinders neurological recovery following nonelective neurosurgical intervention, possibly through an immune-mediated process, underlying vasculopathy, or unidentified confounder.27当控制慢性,急性SDH的发展rated decreased neurological improvement in comparison with chronic SDH, as expected from other studies.28However, acute chronicity also did not increase mortality, SDH reexpansion, or revision rates in our cohort. ATT users also had a significant increase in postoperative SDH reexpansion rates of up to 40%, similar to other studies,29然而,没有增加修订手术的必要性. Although close neurological monitoring remains necessary, this trend highlights the fact that clinically meaningful SDH reexpansion to the effect of prompting revision surgery mandates consideration of other factors, such as preexisting cerebral atrophy, underlying cerebral vasculopathies, surgical technique, and extent of SDH evacuation.30,31When accounting for ATT type, SDH reexpansion was less common with aspirin users, whereas patients on multiple ATT agents were more likely to require revision surgery. In summary, ATT use alone portends poor outcomes, particularly with warfarin or multiple-agent regimens.
Interruptions in ATT administration merit careful consideration when analyzing postoperative neurosurgical outcomes. In our study, an ATT washout period was implemented for 12 patients, allowing for optimal preoperative drug clearance and crossover to the non-ATT cohort for secondary comparative analysis. Crossover ultimately strengthened the association of ATT use with increased mortality while weakening previous trends toward increased SDH reexpansion and revision. Although ATT interruption was protective against mortality, it did not necessarily prevent hematoma reexpansion or the need for revision evacuation, a finding that also correlates with previous studies.32,33While the CHEST guidelines comprehensively address cessation and reinitiation for each ATT subtype and stratify risk by ATT indication and procedure type, recommendations are based on low-quality evidence and pertain only to elective neurosurgery.18Moreover, ATT interruption is not practical in urgent settings.29,34Taken together, our data show that the deleterious effects of ATT extend beyond mortality, impact neurological recovery and disposition, and may persist beyond drug washout—important considerations when discussing management options with patients and their families. Finally, ATT was safely reinitiated in nearly 60% of surviving patients in our study with no apparent increased risk in mortality or SDH reexpansion regardless of SDH chronicity or reversal, a practice consistent with multiple studies specifically examining chronic SDH and/or aspirin use.35,36
Antithrombotic reversal for urgent neurosurgery is influenced by a number of factors, including preoperative neurological status, ICH burden, ATT type, the presence of abnormalities on hematological assays, and the availability of blood products or AC inhibitors. Many of these factors were significantly worse for reversal patients, likely because of treatment bias favoring high-risk patients. The evidence supporting current reversal strategies is incomplete and controversial, particularly for operative neurotrauma, yet no alternative management has emerged to date.10,37At our institution, and as recommended in the literature, ACs are more often reversed regardless of management plan, whereas AP reversal only occurs at the time of urgent intervention.9ATT reversal in the context of urgent neurosurgery with or without evidence of therapeutic response on hematological assays has been insufficiently evaluated.9In our study, we initially found that patients undergoing ATT reversal were 19 times more likely to die within 30 days after SDH evacuation, even when controlling for confounders such as neurological presentation, age, ATT category, SDH chronicity, and ICH burden. This finding conflicts with literature reporting decreased mortality and ICH progression with FFP reversal of warfarin.38,39Interestingly, after patient crossover, the impact of ATT reversal on mortality was no longer significant. This could be attributed to study power, newly introduced skew toward another covariate, and/or an unidentified confounder such as concomitant cortical injury. Furthermore, the use of reversal agents did not affect the likelihood of neurological improvement, hematoma reexpansion, or revision surgery. These findings contradict previous research suggesting that reversal of an international normalized ratio > 1.3 within 4 hours for ICH was associated with lower rates of hematoma enlargement; however, the study of Kuramatsu et al. examined only spontaneous ICH resulting from AC use rather than also considering neurotrauma.39总之,对病人进行紧急SDHevacuation while receiving ATT, the risk for mortality is high, and reversal did not decrease the risk of reexpansion or need for additional surgery, nor did it improve neurological outcomes.
The only benefit for ATT reversal in our study was a decrease in ICU LOS when adjusted for in-hospital mortality, a metric not yet reported in the literature. It is critical to remember that while the benefits of ATT reversal in neurosurgical patients are largely unproven or inconsistent, their use should not be considered concomitantly benign.10,15,16Our study demonstrated an 11.5% thromboembolism rate after administration of reversal products, a rate that exceeds those in previous reports, such as the 7.21% event rate following the use of a prothrombin-complex concentrate and FFP.40Furthermore, the current literature emphasizes thromboembolism in the setting of ATT withdrawal with a clear paucity of consideration for additional risks incurred by active reversal rather than passive cessation in neurosurgical intervention.41Although our data were insufficient for further statistical analysis, adverse events following reversal were most common in patients prescribed warfarin or multiple ATT medications, certainly contributing to the significantly increased mortality of this group.
最后,没有证据表明前operative ATT increased the difficulty of achieving intraoperative hemostasis, and ATT reversal did not contribute to a perceived improvement given the respective lack of differences between the two cohorts in reported operative duration, EBL, and surgical drain duration. In the setting of ATT use, neurosurgeons often intuitively anticipate hemostatic dysfunction due to incomplete platelet plug formation or consumptive coagulopathy during invasive maneuvers, leading to longer surgical times, increased blood loss, and/or prolonged external drainage to prevent SDH reaccumulation.42Given the trend toward decreased SDH evacuation in ATT users, such technical challenges may have been partially overcome by an emphasis on sufficient decompression rather than maximal evacuation. Likewise, ATT reversal may impart anticipation of normalized hemostatic function for the neurosurgeon;42however, decreased operative time, EBL, and drain duration were not evident in our cohort. Although subject to bias, these findings emphasize that ATT history alone cannot reliably predict intraoperative hemostatic dysfunction, nor does its urgent reversal truly mitigate or eliminate surgical risk.
Limitations
The study limitations pertain to its retrospective design and heterogeneous patient population. The ATT reversal cohort analysis was subject to selection bias given their propensity for greater illness severity and perceived risk. Missing variables limited the analysis, such as ATT responsiveness, concomitant cerebral vasculopathies, and tranexamic acid use, which has previously shown a reduction in mortality and serious adverse events in clinical trials.43The study power was insufficient for us to conduct regression analysis on individual ATT medications, surgical technique, SDH chronicity and laterality, reversal agent subtype, and history of prior intracranial injury or surgery. This study did not render comparisons to treatment with medical management or middle meningeal artery embolization alone, the latter of which may serve as a potential treatment strategy for a select subset of patients.44Additionally, patients receiving replacement blood products for non–medication-induced coagulopathy or platelet dysfunction were not separately analyzed given the low prevalence of these patients. Future investigation should focus on these knowledge gaps in addition to gaining an improved understanding of the timing for safe ATT resumption in high-risk neurosurgical patients.
Conclusions
The impact of ATT and reversal strategies for patients undergoing urgent SDH evacuation is highly complex. While antithrombotics alone increase mortality in these patients, introducing procedural delay for medication interruption is protective in neurologically stable patients. Reversal agents, primarily consisting of replacement blood products, do not improve outcomes other than decreasing the LOS. While we do not advocate withholding reversal therapy for patients requiring urgent SDH evacuation, a careful risk-benefit analysis must be undertaken, particularly given the significant thromboembolism risk. Multidisciplinary, collaborative efforts are needed to better delineate patient selection for ATT, improve resource allocation and drug monitoring, and optimize effective reversal strategies when needed.
Disclosures
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
Author Contributions
Conception and design: DD Dang, Mugge, Ziu. Acquisition of data: DD Dang, Mugge, Ramanathan. Analysis and interpretation of data: DD Dang, Mugge, Awan, Diekemper. Drafting the article: DD Dang, Mugge, Ramanathan, JV Dang, Awan, Diekemper. Critically revising the article: DD Dang, Mugge, Ramanathan, JV Dang, Awan, Teicher, Ziu. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: DD Dang. Statistical analysis: DD Dang, Diekemper. Administrative/technical/material support: DD Dang. Study supervision: Ziu.
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