Timing of Antithrombotic Therapy Among Patients With Hemorrhagic Transformation After an Ischemic Stroke

Abstract

Background

Evidence to guide the optimal timing of antiplatelet and oral anticoagulants (OACs) therapy after hemorrhagic infarction (HI) versus parenchymal hematoma (PH) is limited and inconsistent, leading to substantial variation in practice. This study's goal was to study the practice pattern and compare clinical outcomes associated with early‐versus‐delayed initiation of antiplatelet/OACs after hemorrhagic transformation (HT).

Methods

This multicenter, retrospective, cross‐sectional study included patients with acute ischemic stroke and HT. Patients with an HI or PH were categorized by HT to antithrombotic initiation time, and their outcomes—30‐day HT exacerbation, composite outcomes of recurrent stroke/systemic emboli, 90‐day vascular death, and functional outcomes—were compared.

Results

Of 748 patients, 496 received antiplatelets, and 252 received OACs after HT. The median HT‐to‐antiplatelet time was significantly shorter after HI than PH (1 [interquartile range, 0–2] versus 3 [interquartile range, 1–5] days; P<0.001). There were no statistically significant differences in HT exacerbation and composite outcomes (30‐day), as well as vascular death and unfavorable functional outcomes (90‐day), between patients who received same‐day, early (HI, <1 day; PH, <3 days), or late (HI, >1 day; PH, >3 days) antiplatelets after either HI or PH. Among patients on OACs, those with HI had shorter median HT‐to‐OAC time than PH (7 [interquartile range, 2–15] versus 15 [interquartile range, 7–32] days; P<0.001). Although HT exacerbation rates (30‐day) were comparable between early (HI, <7 days; PH, <15 days) and late (HI, >7 days; PH, >15 days) OAC initiation after either HI or PH, late initiation after PH was accompanied by higher rates of composite outcomes (30‐day) than early initiation (20.7% versus 3%; P=0.044). Regression models adjusted for demographics, National Institutes of Health Stroke Scale, and stroke severity showed no statistically significant association between early initiation of antiplatelets or OACs with HT exacerbation risk.

Conclusions

Our study found no statistically significant difference in HT exacerbation between early and late initiation of antiplatelets or OACs among patients with HI/PH, while prolonged delay among patients with PH were accompanied by increased systemic thromboembolic events. Although these findings offer preliminary clinical insight, prospective studies are needed.

Nonstandard Abbreviations and Acronyms

AIS

acute ischemic stroke

ECASS

European Cooperative Acute Stroke Study

ELAN

Early Versus Late Initiation of Direct Oral Anticoagulants in Post–Ischemic Stroke Patients With Atrial Fibrillation

HT

hemorrhagic transformation

IS

ischemic stroke

IVT

intravenous thrombolysis

mRS

Modified Rankin Scale

MT

mechanical thrombectomy

NIHSS

National Institutes of Health Stroke Scale

OAC

oral anticoagulant

PH

parenchymal hematoma

TIMING

Timing of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation

Clinical Perspective.

What Is New?

• In this multicenter cross‐sectional study, we examined the timing of antithrombotic initiation or resumption—both antiplatelets and oral anticoagulants—after hemorrhagic transformation among patients with acute ischemic stroke and its association with clinical outcomes.

What Are the Clinical Implications?

• Although clinicians tended to delay oral anticoagulant initiation more than antiplatelets after either type of hemorrhagic transformation and were more conservative after parenchymal hematoma than hemorrhagic infarction, no statistically significant difference in hemorrhagic transformation exacerbation risk was observed between early and late initiation groups for both antiplatelets and oral anticoagulants, whereas delayed oral anticoagulant initiation was accompanied by a higher frequency of thromboembolic events in certain subgroups.

Clinicians have been cautious about using antithrombotics for acute ischemic stroke (AIS) following hemorrhagic transformation (HT) due to concerns that these treatments might exacerbate the hemorrhage and worsen patient outcomes. ¹ , ² Recent studies have shown that the presence of HT often results in delays in initiating or resuming antithrombotic therapy, with delays ranging from 1 day to 2 weeks. ² , ³ , ⁴

Several observational studies and 1 post hoc analysis have suggested that initiating or resuming antithrombotics, primarily oral anticoagulants (OACs), after HT is safe and can reduce ischemic recurrence (Table S1). ¹ , ² , ³ , ⁴ , ⁵ , ⁶ However, evaluating the impact of post‐HT antithrombotic therapy on patient outcomes has been challenging due to limitations in the existing studies, including small sample sizes, ² , ³ , ⁴ , ⁶ inclusion of only patients with atrial fibrillation (AF), ² , ⁶ single‐center designs, ⁴ a focus on OACs, ² , ⁴ , ⁶ or a lack of exploration of timing among patients with similar HT types. ² , ³ , ⁴

As a result, there is no clear consensus on the optimal timing for resuming antithrombotic therapy after HT. This uncertainty is clinically significant, as clinicians often delay antithrombotic initiation when HT is detected on early poststroke neuroimaging. To address this gap, this collaborative multicenter study aims to investigate whether the time from HT to the initiation or resumption of antithrombotic therapy—both anticoagulants and antiplatelets—is associated with 30‐day outcomes, including HT exacerbation, recurrent AIS, and systemic embolism, as well as 90‐day vascular death. Additionally, the study will examine the relationship between the timing of antithrombotic resumption and functional outcomes at 90 days, as measured by the modified Rankin Scale (mRS). We primarily hypothesized that early initiation of antithrombotic therapy following HT is not associated with an increased risk of HT exacerbation.

Methods

Study Design

This is a multicenter, retrospective observational study that uses prospectively collected data from 9 health care centers across several countries. The participating centers include 2 health centers in Pennsylvania, 1 health center in Arizona, 1 health center in Nebraska, 1 health center in West Virginia, 1 health center in Greece, 2 health centers in Iran, and 1 health center in Turkey.

This was an investigator‐initiated study conducted under a prespecified protocol developed by investigators at Pennsylvania State University, which served as the central coordinating center. A standardized data collection form and unified data framework were developed at the coordinating center and distributed to all participating institutions to ensure consistency in variable definitions and data structure. Data were collected independently at each site in accordance with the common protocol.

The institutional review board at each participating institution approved the study. Researchers at each institution were responsible for verifying and deidentifying the data locally before secure transfer. Only deidentified individual patient data from each center were shared with the coordinating center, where pooled data management and statistical analyses were performed by investigators at Pennsylvania State University. The requirement for informed consent was waived due to the retrospective nature of the study and the use of deidentified data.

The data that support the findings of this study are available from the corresponding author upon reasonable request. The results are reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. ⁷

Study Population

This study included consecutive adult patients with acute AIS who experienced HT following the index stroke and were subsequently started on antiplatelets or OACs from 2019 to 2024. Patients were excluded during data collection if they met any of the following criteria: (1) malignant infarction involving more than two thirds of the middle cerebral artery territories, (2) hemorrhagic tendencies (defined as a baseline platelet count <100 000/mm³ or an international normalized ratio ≥1.7), (3) presence of any condition requiring surgery within 90 days, (4) life expectancy of <6 months at the time of AIS, (5) endocarditis, (6) cerebral amyloid angiopathy, and (7) cerebral vasculitis. Furthermore, after the data collection process, the data set was cleaned on the basis of the following exclusion criteria: (1) absence of follow‐up or missing outcome data, (2) long or indeterminate interval between admission and HT occurrence, (3) missing HT to antithrombotic timing data, and (4) unknown HT subtype (Figure 1).

Figure 1. Flow diagram of patients included in the study.

In the OAC group, 189 (75%) individuals also received antiplatelets for treatment. APLT indicates antiplatelet; HI, hemorrhagic infarction; OAC, oral anticoagulant; and PH, parenchymal hematoma.

The final study population (n=748) was divided into 2 treatment groups: antiplatelet and oral anticoagulant (OAC). The antiplatelet group included patients who only received post‐HT antiplatelets and had available HT‐to‐antiplatelet time data (n=496). The OAC group comprised patients who received post‐HT OACs, with or without post‐HT antiplatelet, and had available HT‐to‐OAC time data (n=252). Patients were further categorized within each group on the basis of the HT type, and the data were analyzed accordingly.

Study Measures and Outcomes

The study measures included demographics such as age, sex, race, ethnicity, and body mass index; comorbidities including hypertension, type 2 diabetes, hyperlipidemia, AF or atrial flutter, hypercoagulable conditions, ischemic or hemorrhagic stroke, myocardial infarction, mechanical valve, systemic embolism, and Alzheimer or vascular dementia; lifestyle factors such as tobacco and alcohol use; and medication use, specifically antiplatelet or OAC use before the index event. Additional measures included prestroke functional status using the mRS, clinical indicators like stroke severity from imaging, National Institutes of Health Stroke Scale (NIHSS) score on admission, and admission‐to‐HT interval. Reperfusion treatments such as intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) were analyzed, along with symptom onset‐to‐treatment times. Post‐HT treatments were evaluated, including pre‐ and post‐HT antiplatelet and OAC use and the time from HT to initiation or resumption of these therapies. The imaging‐based severity of the stroke was determined by separate investigators in each center. Lesions were categorized on the basis of their size (small‐size lesion, <1.5 cm; large‐size lesion, ≥1.5 cm) and vascular territory (partial middle cerebral artery or posterior cerebral artery, complete middle cerebral artery or posterior cerebral artery, cerebellum or brain stem, and multiple vascular territories).

The study's primary objective was to assess whether the time from HT to the initiation of antithrombotic therapy was associated with clinical outcomes across various HT categories. For this purpose, patients in the antiplatelet treatment group with a specific type of HT were categorized into 3 groups based on HT‐to‐antiplatelet timing: same‐day, early, and late initiation of antiplatelet. Same‐day initiation was defined as no delay (0 days) between HT and antiplatelet initiation. In contrast, the distinction between early and late initiation was based on the median time from HT to antiplatelet initiation. Similarly, the median time from HT to OAC initiation was used to classify patients in the OAC treatment group into early and late initiation groups. Same‐day and early initiation groups were merged for patients in the OAC treatment group due to the limited number of cases. Clinical outcomes were then compared across HT‐to‐antithrombotic timing groups for patients with the same HT type.

Outcome measures included (1) a composite of recurrent AIS and systemic embolism within 30 days, (2) HT exacerbation within 30 days, (3) vascular death within 90 days, and (4) mRS score at 90 days. HT exacerbation was defined as the emergence of new neurological symptoms or worsening of preexisting symptoms due to HT progression, confirmed by either enlargement of the original HT or newly developed HT within the infarcted area on visual analysis. Vascular death was defined as death caused by vascular diseases, including sudden cardiac death, heart failure, myocardial infarction, stroke, systemic embolism, and extracranial bleeding. Additionally, the 90‐day mRS score was compared among different patient groups to evaluate functional outcomes. A 90‐day mRS score <3 is considered a favorable functional outcome. ⁸

Imaging Analysis

Brain magnetic resonance imaging or computed tomography scans were used to diagnose and classify acute or recurrent ischemic stroke (IS), as well as to confirm and classify HT and HT exacerbation. The ECASS (European Cooperative Acute Stroke Study) radiographic criteria were used to classify patients on the basis of their HT type, including hemorrhagic infarction (HI)‐1, HI‐2, parenchymal hematoma (PH)‐1, and PH‐2. ⁹ The definition of each HT type is presented in Table S2. When multiple types of HT coexisted, the predominant type was reported.

The exacerbation of HT refers to the growth or enlargement of the initial HT or the appearance of new HT beyond the original boundaries, as observed on the imaging obtained due to any decline in neurological status. Therefore, only symptomatic HT exacerbation was considered. The investigator teams of neurologists and radiologists at each participating center conducted and verified these imaging analyses.

Statistical Analysis

All analyses were conducted separately for the antiplatelet and OAC groups and were further stratified by HT type. The Kolmogorov–Smirnov test was used to assess the normality of data distribution. Results were presented as the median and interquartile range (IQR) for continuous variables and frequency (percentage) for categorical variables. The Mann–Whitney U test was used to compare quantitative variables between 2 groups, while the Kruskal–Wallis test was used for comparisons between >2 groups. Categorical variables were analyzed using the χ² test or Fisher's exact test as appropriate.

Data with missing outcome measures were excluded from each outcome analysis, and a complete‐case analysis approach was adopted. Kaplan–Meier curves were used to visualize differences in the time to each outcome event across HT‐to‐antithrombotic timing groups, and differences in cumulative event rates were compared using the log‐rank test. Multivariable logistic regression models, adjusted for available confounding factors, including age, sex, race, ethnicity, admission NIHSS score, and imaging‐based stroke severity, were used to explore the association between HT‐to‐antithrombotic time and clinical outcomes. Adjusted odds ratios with 95% CIs were reported among patients with HI and PH.

To assess the robustness of our primary findings, several sensitivity analyses were conducted. First, outcomes were examined in patients who received both antiplatelets and OACs after HT. Second, we evaluated whether baseline stroke severity, as measured by NIHSS score on admission, influenced post‐HT antithrombotic initiation patterns and outcomes. For this purpose, 2 approaches were adopted. In the first, patients with HI and high NIHSS on admission were selected, and the study objectives were explored exclusively within this subgroup. In the second approach, patients with HI were initially grouped by timing of antithrombotic initiation and subsequently matched using propensity scores based on admission NIHSS score to balance stroke severity across timing groups. The “nearest‐neighbor” propensity score matching was applied in a 1‐to‐1 manner based on NIHSS score at admission, without replacement. ¹⁰ In all sensitivity analyses, patients were stratified by HT type, and outcomes were compared according to HT‐to‐antithrombotic timing, using the same methods as in the primary analyses.

Data analysis was performed using IBM SPSS Statistics for Windows version 27.0 (IBM Corporation, Groupon, NY), and figures were generated using Prism version 10.3.1 (GraphPad Software, La Jolla, CA). All P values were 2‐sided, with P<0.05 considered statistically significant.

Results

Patient Characteristics

The study included a total of 1022 consecutive patients with AIS and HT from 9 health care centers across 4 countries: the United States, Greece, Iran, and Turkey. After data compilation and processing, 274 patients were excluded from the analysis due to missing exposure or outcome data (Figure 1). Ultimately, data from 748 patients were included in the final analysis. The general characteristics of the included and excluded patients are compared in Table S3. A summary of variables with missing data is provided in Table S4.

The general characteristics of patients in each treatment group are presented in Table 1 (further details in Table S5). The median time from admission to HT was 1 (IQR: 0–1) day in both study groups. The distribution of admission‐to‐HT days is presented in Figure S1. Of 496 patients in the antiplatelet treatment group, 346 (69.8%) had HI, and 150 (30.2%) had PH. There were no significant differences between patients with HI and PH in terms of age, sex, body mass index, ethnicity, and comorbidities. Larger lesions (>1.5 cm) with complete middle or posterior cerebral artery occlusion were more common among patients with PH (40.3% versus 15.0%; P<0.001). Although patients with PH were more likely to have received IVT or MT, the time to therapy did not differ significantly from that of patients with HI.

Table 1.

General Characteristics of the Patients With HI and PH in Each Study Group

Characteristics	Antiplatelet group			OAC group
	HI (n=346)	PH (n=150)	P value (HI vs PH)	HI (n=187)	PH (n=65)	P value (HI vs PH)
Age, y, median (IQR)	68 (58–77)	68.5 (58–77)	0.680	72 (62–82)	65 (59–78)	0.041
Sex, n (%)
Male	212 (61.3)	78 (52)	0.054	92 (49.2)	38 (58.5)	0.198
Female	134 (38.7)	72 (48)		95 (50.8)	27 (41.5)
Body mass index, kg/m2, median (IQR)	28.7 (24.8–32.9)	28.7 (25–33.5)	0.982	28.6 (24.4–32.4)	27.6 (25–30.9)	0.649
Race, n (%)
White	282 (82)	123 (82)	0.076	163 (87.6)	55 (85.9)	0.199*
Black	22 (6.4)	14 (9.3)		10 (5.4)	4 (6.3)
Asian	13 (3.8)	9 (6)		6 (3.2)	5 (7.8)
Others†	27 (7.8)	4 (2.7)		7 (3.8)	0 (0)
Ethnicity, n (%)
Hispanic	19 (5.5)	6 (4)	0.478	8 (4.3)	3 (4.6)	1.000*
Non‐Hispanic	325 (94.5)	144 (96)		178 (95.7)	62 (95.4)
Past medical history, n (%)
Hypertension	267 (77.2)	108 (72)	0.218	149 (79.7)	49 (75.4)	0.467
Type 2 diabetes	126 (36.4)	47 (31.3)	0.275	62 (33.2)	15 (23.1)	0.129
Hyperlipidemia	187 (54)	93 (62)	0.101	100 (53.5)	39 (60)	0.362
Atrial fibrillation or flutter	52 (15)	30 (20)	0.171	103 (55.1)	34 (52.3)	0.699
Thromboembolic risk condition‡	72 (21.1)	39 (26)	0.146	103 (55.1)	29 (44.6)	0.230
Ischemic stroke	58 (16.8)	22 (14.7)	0.560	40 (21.4)	12 (18.5)	0.615
Hemorrhagic stroke	1 (0.3)	2 (1.3)	0.217*	2 (1.1)	1 (1.5)	1.000*
Myocardial infarction	76 (22)	30 (20)	0.624	41 (21.9)	16 (24.6)	0.655
Mechanical valve	4 (1.2)	4 (2.7)	0.252	8 (4.3)	5 (7.7)	0.329*
Systemic embolism	27 (7.8)	11 (7.4)	0.872	33 (17.6)	8 (12.3)	0.435
Alzheimer or vascular dementia	11 (3.2)	4 (2.7)	1.000	7 (3.7)	5 (7.7)	0.195*
Habitual history, n (%)
Ever tobacco use	142 (41)	47 (31.3)	0.041	50 (26.7)	24 (36.9)	0.120
Regular alcohol drinking	59 (17.1)	13 (8.7)	0.015	26 (13.9)	11 (17.2)	0.522
Prestroke drug history, n (%)
Antiplatelets
No	219 (63.5)	94 (62.7)	0.966	120 (64.2)	43 (66.2)	0.678
Single antiplatelet	105 (30.4)	46 (30.7)		56 (29.9)	20 (30.8)
Dual antiplatelet	21 (6.1)	10 (6.7)		11 (5.9)	2 (3.1)
Anticoagulants
No	328 (94.8)	133 (88.7)	<0.001*	112 (59.9)	45 (69.2)	0.155
Vitamin K antagonistss	4 (1.2)	12 (8)		24 (12.8)	10 (15.4)
Novel OACs	14 (4)	5 (3.3)		51 (27.3)	10 (15.4)
Prestroke mRS, median, n (%)	0 (0–1)	0 (0–1)	0.780	0 (0–1)	0 (0–1)	0.105
Imaging‐based stroke severity, n (%)
Small‐size lesion (≤1.5 cm)	74 (21.4)	30 (20.1)	0.001	39 (21.2)	7 (10.8)	0.081*
Large‐size lesion (≥1.5 cm) involving branches of middle cerebral or posterior cerebral artery	156 (45.1)	45 (30.2)		87 (47.3)	27 (41.5)
Large‐size lesion (≥1.5 cm) with complete middle cerebral or posterior cerebral artery involvement	52 (15)	60 (40.3)		29 (15.8)	19 (29.2)
Large‐size lesion (≥1.5 cm) involving the cerebellum or brain stem	24 (6.9)	1 (0.7)		4 (2.2)	1 (1.5)
Multiple vascular territories	40 (11.6)	13 (8.7)		25 (13.6)	11 (16.9)
Admission characteristics, median (IQR)
NIHSS score on admission	12 (4–20)	15.5 (8–20)	0.015	13 (5–20)	13 (8–18)	0.910
Admission to HT time, d	1 (0–1)	1 (1–1)	0.251	1 (0–1)	1 (1–1)	0.926
Acute post‐HT thrombolysis, n (%)
None	168 (48.6)	39 (26)	0.001	88 (47.1)	21 (32.3)	0.001*
IVT	32 (9.2)	17 (11.3)		8 (4.3)	11 (16.9)
MT	82 (23.7)	39 (26)		63 (33.7)	16 (24.6)
Both IVT and MT	64 (18.5)	55 (36.7)		28 (15)	17 (26.2)
Symptom to IVT, min, median (IQR)	137.5 (95–170)	132 (100–169)	0.779	130 (103–195)	163.5 (87.5–234.5)	0.664
Symptom to MT, min, median (IQR)	293 (221–615)	264.5 (201–350)	0.075	265.5 (188.5–401.5)	278 (170–326)	0.667
Acute pre‐HT antithrombotic, n (%)
Antiplatelet
No	192 (55.5)	110 (73.3)	0.001	125 (66.8)	52 (80)	0.046
Yes	154 (44.5)	40 (26.7)		62 (33.2)	13 (20)
Anticoagulation
No	340 (98.3)	148 (98.7)	…	169 (90.4)	58 (90.6)	0.953
Yes	6 (1.7)	2 (1.3)		18 (9.6)	6 (9.4)
Acute post‐HT antithrombotic, n (%)
Antiplatelet
No	0 (0)	0 (0)	…	42 (22.5)	21 (32.3)	0.114
Yes	346 (100)	150 (100)		145 (77.5)	44 (67.7)
Anticoagulation
No	345 (100)	149 (100)	…	0 (0)	0 (0)	…
Yes	0 (0)	0 (0)		187 (100)	65 (100)
Post‐HT antithrombotic time, median (IQR)
HT‐to‐antiplatelet time, d	1 (0–2)	3 (1–5)	<0.001	1 (0–2)	4.5 (1–6)	<0.001
HT‐to‐OAC time, d				7 (2–15)	15 (7–32)	<0.001
Post‐HT Antithrombotic delay, n (%)
0 d	140 (40.5)	28 (18.7)	…	18 (9.6)	4 (6.2)	…
1–median d	86 (24.9)	66 (44)		85 (45.5)	32 (49.2)
>Median d	120 (34.7)	56 (37.3)		84 (44.9)	29 (44.6)

All P values for continuous variables were calculated using the Mann–Whitney U test. Patients with HI include both patients with HI‐1 and HI‐2 and patients with PH include both patients with PH‐1 and PH‐2.

HI indicates hemorrhagic infarction; HT, hemorrhagic transformation; IQR, interquartile range; IVT, intravenous thrombolysis; mRS, modified Rankin Scale; MT, mechanical thrombectomy; NIHSS, National Institutes of Health Stroke Scale; OAC, oral anticoagulant; and PH, parenchymal hemorrhage.

^*All P values for categorical variables were calculated using the χ² test, except for ones calculated with Fischer's exact test.

^† The other race category includes, but is not limited to, American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, and multiracial individuals.

^‡ Thromboembolic risk conditions, such as atrial fibrillation/flutter, a mechanical heart valve, or hypercoagulable states are conditions that increase the risk of thromboembolic events and may require anticoagulation.

Of 252 patients in the OAC treatment group, 187 (74.2%) had HI, while 65 patients (25.8%) had PH. Patients with PH were significantly younger than those with HI (65 versus 72 years; P=0.041). However, no differences were observed between the groups in terms of sex, body mass index, ethnicity, comorbidities, imaging‐based stroke severity, or admission NIHSS scores. IVT or MT was more associated with PH (P=0.001). Of 252 patients in this group, 132 (52.4%) had a history of conditions associated with increased thromboembolic risk before the index IS. Of these, 95 patients (37.7%) had an existing indication for OAC therapy at the time of the index IS. Cardiac sources of embolism accounted for the majority, including AF/atrial flutter alone in 73 patients (76.8%) and both AF/atrial flutter with a mechanical heart valve in 8 patients (8.4%); 14 patients (14.7%) had other indications, including hypercoagulable states. The remaining 120 patients (47.6%) had no known prior history of thromboembolic risk conditions and were not on OAC therapy at the time of the index IS. In total, 157 patients (62.3%), 37 with a prior history of thromboembolic risk conditions and 120 without, were not on anticoagulation before the index AIS.

In the OAC treatment group, 22.5% of those with HI and 32.3% of those with PH also received antiplatelet following HT, with no statistically significant difference (P=0.114). Among the 189 patients who received both post‐HT antithrombotics, antiplatelet was initiated before OAC in 85.6% of cases, concurrently with OAC in 10.2%, and after OAC initiation in 4.3%. The distribution of time intervals between antiplatelet and OAC initiation after HT is shown in Figure S2.

Time Intervals Between HT and Antithrombotics

Following HT, patients with HI were started on antiplatelet therapy significantly earlier than those with PH (median, 1 [IQR, 0–2] day versus 3 [IQR, 1–5] days; P<0.001). While the median HT‐to‐antiplatelet time was 1 day for patients with HI‐1 (IQR, 0–2) or HI‐2 (IQR, 0–4), it was 2 days (IQR, 1–5) among patients with PH‐1 and 3 (IQR, 1–5) days among those with PH‐2. Moreover, same‐day initiation of antiplatelet after HT was more common in patients with HI than those with PH (40.5% versus 18.7%; Table 1).

The HT‐to‐OAC initiation time was also shorter for patients with HI compared with PH (median, 7 [IQR, 2–15] days versus 15 [IQR, 7–32] days; P<0.001). The median HT‐to‐OAC time differed by 2 days between patients with HI‐1 and HI‐2 (6 [IQR, 2–14.5] days versus 8 [IQR, 3–20] days) and between those with PH‐1 and PH‐2 (14 [IQR, 7–32] days versus 16 [IQR, 3.5–35] days). Patients with HI were more likely to continue post‐HT OAC therapy without interruption than those with PH (9.6% versus 6.2%; Table 1).

Figure 2 illustrates the time intervals between HI or PH and the initiation of antithrombotic therapy. Patients with HI experienced significantly shorter times from HT to either antiplatelet and OAC initiation compared with those with PH (P<0.001 and P=0.007, respectively).

Figure 2. Time intervals from HI or PH and the initiation of antithrombotics.

A, HT‐to‐antiplatelet time intervals. Compared with patients with PH, the HT‐to‐antiplatelet time was significantly shorter among those with HI (P<0.001). B, HT‐to‐OAC time intervals. Compared with those with PH, the HT‐to‐OAC time was significantly shorter among those with HI (P=0.007). APLT indicates antiplatelet; HI, hemorrhagic infarction; HT, hemorrhagic transformation; OAC, oral anticoagulant; and PH, parenchymal hematoma.

Patient Outcome in the Antiplatelet Treatment Group

Thirty‐Day Clinical Outcomes and 90‐Day Vascular Death

The rates of post‐HT 30‐day composite outcomes (AIS recurrence and systemic embolism), HT exacerbation, and 90‐day vascular death among patients who received post‐HT antiplatelets are presented in Figure 3 and Table S6. No statistically significant differences were observed in any of the outcome measures between same‐day, early (within 1 day after HI or within 3 days after PH), and late (after the first day following HI or after 3 days from PH) initiation groups for patients with the same type of HT, either HI or PH.

Figure 3. Rates of 30‐d composite outcomes, HT exacerbation, and 90‐day vascular death by HT‐to‐antiplatelet (on the left side) and HT‐to‐OAC (on the right side) timing among patients with HI or PH.

In the antiplatelet treatment group, the median HT‐to‐antiplatelet time is 1 day for patients with HI and 3 days for patients with PH. In the OAC treatment group, the median HT‐to‐OAC time is 7 for patients with HI and 15 for those with PH. Error bars show 95% CIs. The only statistically significant P value is mentioned. APLT indicates antiplatelet; HI, hemorrhagic infarction; HT, hemorrhagic transformation; OAC, oral anticoagulant; and PH, parenchymal hematoma.

Time to Clinical Outcomes and Vascular Death

Kaplan–Meier curves in Figure 4 illustrate the time intervals from HT to different outcomes, stratified by HT type and HT‐to‐antiplatelet timing (further details in Figure S3). Based on log‐rank tests, no statistically significant differences were observed in any of the clinical outcomes or vascular death between same‐day, early, and late initiation groups.

Figure 4. Kaplan–Meier curves demonstrating time intervals to clinical outcomes by HT‐to‐antithrombotic time and HT type.

A, Time intervals to composite outcome by HI‐to‐antiplatelet time. B, Time intervals to HT exacerbation by HI‐to‐antiplatelet time. C, Time intervals to vascular death by HI‐to‐antiplatelet time. D, Time intervals to composite outcome by PH‐to‐antiplatelet time. E, Time intervals to HT exacerbation by PH‐to‐antiplatelet time. F, Time intervals to vascular death by PH‐to‐antiplatelet time. G, Time intervals to composite outcome by HI‐to‐OAC time. H, Time intervals to HT exacerbation by HI‐to‐OAC time. I, Time intervals to vascular death by HI‐to‐OAC time. J, Time intervals to composite outcome by PH‐to‐OAC time. K, Time intervals to HT exacerbation by PH‐to‐OAC time. L, Time intervals to vascular death by PH‐to‐OAC time. APLT indicates antiplatelet; HI, hemorrhagic infarction; HT, hemorrhagic transformation; OAC, oral anticoagulant; and PH, parenchymal hematoma.

Ninety‐Day Functional Outcomes

The distribution of 90‐day mRS scores among patients in the antiplatelet group is presented in Figure 5 and Table S6. Among patients with HI, the same‐day group had the highest rate of favorable 90‐day mRS scores (<3); however, the observed differences were not statistically significant (P=0.054). Among those with PH, the highest rates of 90‐day favorable mRS were found in the early treatment group; however, the differences were not statistically significant (P=0.144). In addition, patients with PH‐2 who were initiated on antiplatelets within 3 days of HT were significantly more likely to have favorable functional outcomes within 90 days compared with those in the late treatment group (59.3% versus 22.2%; P=0.014).

Figure 5. Ninety‐day mRS of patients with HI or PH by HT‐to‐antiplatelet (green bars) and HT‐to‐OAC (blue bars) time.

None of the observed differences on rates of favorable mRS (<3) were statistically significant. APLT indicates antiplatelet; HI, hemorrhagic infarction; HT, hemorrhagic transformation; mRS, modified Rankin Scale; OAC, oral anticoagulant; and PH, parenchymal hematoma.

Patient Outcomes in the OAC Treatment Group

Thirty‐Day Clinical Outcomes and 90‐Day Vascular Death

The rates of post‐HT 30‐day composite outcomes (AIS recurrence and systemic embolism), HT exacerbation, and 90‐day vascular death among patients who received post‐HT OAC are demonstrated in Figure 3 and Table S7. The only statistically significant finding is the higher rates of 30‐day composite outcomes among patients with PH who received OAC therapy after a delay of >15 days (20.7% versus 3% for those receiving OAC within 0–15 days; P=0.044). In the 0‐ to 15‐day delay group, the composite outcome included only 1 case of recurrent IS, whereas in the >15‐day delay group, 2 patients experienced recurrent IS, 2 had systemic embolism, and 2 others had both recurrent IS and systemic embolism. Notably, the only composite outcome in the 0‐ to 15‐day delay group occurred before the initiation of OAC, whereas 5 of 6 composite outcomes in the >15‐day delay group occurred after the initiation of OAC (Table S5).

Time to Clinical Outcomes and Vascular Death

Kaplan–Meier curves in Figure 4 illustrate the time intervals from HT to different outcomes, stratified by HT type and HT‐to‐OAC timing (further details in Figure S4). Compared with patients with PH who received early OACs (<15 days), those receiving late OACs (>15 days) experienced shorter times to composite outcomes within 30 days (P=0.033).

Ninety‐Day Functional Outcomes

The distribution of 90‐day mRS across different HT groups of patients who received post‐HT OACs is presented in Figure 5 and Table S7. Although the same‐day/early initiation group showed higher rates of favorable functional outcomes (mRS score <3) in both HT types, the differences were not statistically significant (P=0.141 for HI and P=0.087 for PH).

Association Between Early Antithrombotic Initiation After HT and HT Exacerbation

To further evaluate the association between early initiation of antithrombotics after HT and risk of HT exacerbation, multivariable logistic regression models were used. Models were adjusted for all available potential confounding factors, including age, sex, race, ethnicity, admission NIHSS score, and imaging‐based index stroke severity (Table 2). Initiation of antiplatelets within the first day after HI or within 1 to 3 days after PH did not show a statistically significant association with increased risk of HT exacerbation compared with their late initiation (adjusted odds ratio, 0.65 [95% CI, 0.15–2.81]; P=0.561 for HI; adjusted odds ratio, 0.72 [95% CI, 0.21–2.46]; P=0.603 for PH); and initiation of OACs within 15 days after PH did not show a statistically significant association with increased risk of HT exacerbation compared with their late initiation (adjusted odds ratio, 0.44 [95% CI, 0.04–5.5]; P=0.527); Notably, none of the odds ratios were statistically significant, and we observed wide CIs in all analyses.

Table 2.

Multivariable Regression Analyses Evaluating the Association Between HT‐to‐Antithrombotic Timing and HT Exacerbation in Patients With HI and PH

Treatment group	HT type	Time from HT to antithrombotic	Odds ratio	Lower 95% CI	Upper 95% CI	P value
Antiplatelet	HI	>1 d	Reference	Reference	Reference	Reference
		<1 d	0.65	0.15	2.81	0.561
	PH	>3 d	Ref	Ref	Ref	Ref
		<3 d	0.72	0.21	2.46	0.603
OAC	HI	>7 d	Reference	Reference	Reference	Reference
		<7 d	1.59	0.17	15.1	0.686
	PH	>15 d	Reference	Reference	Reference	Reference
		<15 d	0.44	0.04	5.5	0.527

Odds ratios are adjusted for all potential confounders, including age, sex, race, ethnicity, admission National Institutes of Health Stroke Scale score, and imaging‐based index stroke severity.

HI, hemorrhagic infarction; HT, hemorrhagic transformation; OAC, oral anticoagulant; and PH, parenchymal hematoma.

Sensitivity Analysis

Outcome of Patients Who Received Both Antiplatelets and OACs After HT

In a sensitivity analysis, we examined the outcomes of patients who received both post‐HT antiplatelet and OAC therapy. Patients were stratified into HI and PH groups, and outcome measures were compared between groups on the basis of HT‐to‐antithrombotic timing. Patients with HI had a median HT‐to‐antiplatelet time of 1 day and a median HT‐to‐OAC time of 7 days. Among patients with PH, the median HT‐to‐antiplatelet and HT‐to‐OAC times were 3 days and 15 days, respectively (Tables S8 and S9).

Among patients with HI, the rates of 30‐day composite outcomes, 30‐day HT exacerbation, and 90‐day vascular death did not vary significantly on the basis of HT‐to‐antiplatelet or HT‐to‐OAC timing. However, patients with early initiation of antiplatelets (35.5%) had lower rates of 90‐day unfavorable functional outcomes compared with those with same‐day (64.9%) or late (60%) antiplatelet initiation (P=0.038). This finding contrasts with our primary analysis, which did not show a significant difference in the 90‐day rates of unfavorable functional outcomes by HT‐to‐antiplatelet timing.

Among patients with PH, the rates of 30‐day HT exacerbation, as well as 90‐day vascular death and unfavorable functional outcomes, did not differ significantly on the basis of HT‐to‐antiplatelet and HT‐to‐OAC timing. However, while 20% of patients with late OAC initiation experienced adverse composite outcomes within 30 days after HT, no such events were observed in those with same‐day or early initiation of OACs.

Outcome of Patients With High NIHSS Score on Admission

Although our analysis did not show a significant association between the timing of post‐HT antiplatelets or OACs and the outcome of patients with HI, a significant difference was observed in their admission NIHSS scores on the basis of the timing of antithrombotic initiation (Tables S6 and S7). More specifically, patients with HI who received same‐day antiplatelets after HT had a lower median admission NIHSS score compared with those who received antiplatelets either early (7.5 [IQR, 2.5–16] versus 13 [IQR, 5–20]; P=0.005) or late (7.5 [IQR, 2.5–16] versus 16 [IQR, 9–22]; P<0.001). Similarly, patients with HI initiated on OACs within 7 days after HT had lower admission NIHSS scores than those who received OACs beyond 7 days after HT (11 [IQR, 4–17] versus 15 [IQR, 7–23]; P=0.045). These differences imply an admission NIHSS score–derived practice pattern for starting antithrombotics after HT.

To assess whether the unincreased risk of HT exacerbation following early antithrombotic initiation also applies to patients with HI with high admission NIHSS scores, we conducted a sensitivity analysis restricted to this subgroup. Patients were stratified into low and high NIHSS score groups based on the median NIHSS score among those with HI, which equaled 12. Among patients with a high NIHSS score (>12), there was no statistically significant difference in 30‐day HT exacerbation rates between those who received same‐day (3/48 [6.2%]), early (2/39 [5.1%]), or late antiplatelet (5/75 [6.7%]; P=1.000). Similarly, 30‐day HT exacerbation rates did not significantly differ between patients with high NIHSS scores initiated on OACs within 7 days after HT (2/40 [5%]) versus those who received OACs after 7 days (5/48 [10.4%]; P=0.448).

In a secondary analysis, patients with HI were first grouped on the basis of the timing of antithrombotic initiation following HT. These groups were then matched on the basis of admission NIHSS scores using propensity score matching. Consistent with prior analyses, there was no statistically significant difference in 30‐day HT exacerbation rates between patients who received same‐day antiplatelets (3/131 [2.3%]) and those with any delay in antiplatelet initiation (2/131 [1.5%]; P=1.000). Similarly, patients who received same‐day or early OACs (2/86 [2.3%]) did not show a significantly higher risk of 30‐day HT exacerbation compared with those initiated on late OACs (5/63 [7.4%]; P=0.242). There was no statistically significant association between on‐admission NIHSS score and HT‐to‐antithrombotic timing among patients with PH, so no further sensitivity analysis was warranted.

Discussion

In this multicenter cross‐sectional study, we explored the timing of antithrombotic initiation or resumption (antiplatelets and OACs) following HT among patients with AIS and its association with clinical outcomes. Our findings indicate that clinicians were more cautious with OACs than antiplatelets, reflected by the longer HT‐to‐OAC timing and the lower rates of same‐day OAC initiation (8.7% for OACs versus 33.9% for antiplatelets). In addition, antithrombotic therapy was more delayed in patients with PH compared with those with HI, with median HT‐to‐antiplatelet times of 3 days versus 1 day and HT‐to‐OAC times of 15 versus 7 days, respectively. Our analyses did not show a statistically significant difference between early (including both same‐day and early) and late initiation of antiplatelets or OACs with regard to HT exacerbation. Besides, even after controlling regression models for key factors typically considered in timing of antithrombotics following HT, including NIHSS score, imaging findings, and HT type, no statistically significant association was observed. This conclusion is also supported by sensitivity analyses among patients with high NIHSS scores. However, further research is warranted to confirm these findings, as our results were accompanied by wide CIs, and residual confounding could not be excluded.

Among patients with HI, despite considerable variations in the timing of antiplatelets or OACs after HT, no statistically significant difference was found between early or late initiation with regard to HT exacerbation or composite outcomes, respectively. To further validate these findings, additional studies, particularly well‐designed longitudinal investigations, are required to more rigorously evaluate the safety of early antiplatelet initiation after HT. Despite the cross‐sectional design of the current study and the insufficient statistical power to define a definitive optimal timing for antiplatelet initiation after HT, it provides an informative framework for future research by providing preliminary early therapeutic windows, leveraging a comprehensive, multicenter data set of patients with HT.

Similarly, early initiation of antiplatelets in patients with PH was not associated with a statistically significant increase in the risk of HT exacerbation. Among patients undergoing OAC therapy after PH, there was no statistically significant difference in HT exacerbation after early or late initiation of OACs, and higher rates of thromboembolic events were observed in patients with an extended delay beyond 15 days. However, results from the PH subgroup, particularly those receiving OACs, should be interpreted with caution due to the limited sample size, considerable risk of false‐positive/negative findings due to multiple hypothesis testing across varying subgroups, and the possibility of residual confounding. Therefore, further research is warranted.

Our findings align with prior literature suggesting the safety of antiplatelets after HT. ³ , ¹¹ , ¹² For example, our analyses suggest that early initiation of antiplatelets within 24 hours following HI may not increase the risk of HT exacerbation and might be safe. Similarly, Zhong et al ¹³ showed that using antiplatelets within 24 hours after IVT‐induced HI is not associated with HT exacerbation. Their study also associated early antiplatelet initiation with better 90‐day functional outcomes and lower early neurological deterioration. Consistently, in our cohort, patients who received antiplatelets within 3 days after PH did not show an increased risk of HT exacerbation. Moreover, early antiplatelet use after PH was associated with improved functional outcomes, particularly in patients with PH‐2.

The randomized TIMING (Timing of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation) ¹⁴ and ELAN (Early Versus Late Initiation of Direct Oral Anticoagulants in Post–Ischemic Stroke Patients With Atrial Fibrillation) ¹⁵ trials have recently highlighted that early OAC therapy is not inferior to late OAC therapy in patients with AIS and AF, with no reported safety concerns. Additionally, multiple studies have demonstrated that OACs are safe after an HT in patients with AIS. ¹ , ² , ³ , ⁴ However, limited data on the safety of using OACs early after HT may lead clinicians to unnecessarily delay the resumption of OACs due to their concerns about hemorrhagic complications following OAC administration. ² , ³ , ⁴ Our analysis provides no evidence that delaying OACs following an HI or PH improves patients' outcomes. In contrast, our results suggest an increased risk of thromboembolic events in patients with PH when OAC initiation is delayed beyond 15 days. This risk difference between early and late OAC initiation was primarily driven by a higher incidence of systemic embolism rather than AIS recurrence: Four of 29 patients with PH with late OAC initiation experienced systemic emboli. Our findings align with a post hoc analysis of the ELAN trial, ⁶ which found no significant difference in the therapeutic impact or complication of OACs when administered early (within 2–7 days) versus late (within 3–14 days) after index AIS among patients with HI or PH. However, our study provides a more precise estimate of the optimal timing of OACs after HT, as we used the HT incidence as the reference point for calculating the time interval rather than the index AIS.

AIS management guidelines generally recommend initiating antiplatelets within 24 to 48 hours after symptom onset, ¹⁶ while the use of OACs is usually recommended to be individualized on the basis of the patient's risk of HT versus thromboembolic events. ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ The risk of HT is mainly determined on the basis of stroke severity and infarct size. ²⁵ This can explain the further delay in initiating antithrombotics among our patients with HI with higher admission NIHSS scores. However, such a difference was not observed in patients with PH. This finding is likely because PH is considered a more severe form of HT, and its presence in poststroke neuroimaging is considered an independent indication for further delaying OAC initiation. ²⁵ Notably, our sensitivity analysis suggested that early antithrombotic initiation after HI, even in patients with high admission NIHSS scores, may not be associated with an increased risk of HT exacerbation.

The study's main strengths were the use of a comprehensive multicenter data set and analysis of the outcome of patients in separate groups on the basis of HT type. However, the study findings should be interpreted in light of the following limitations:

1. The number of patients with PH, specifically those in the OAC treatment group, was limited; therefore, our findings on initiating OAC after PH should be interpreted cautiously.

2. We did not have access to detailed imaging protocols for each patient, and there was no uniform policy across centers on follow‐up imaging after HT, with repeat scans often at the attending physician's discretion. In addition, there was limited information on imaging rater qualifications and no measures were undertaken to ensure scoring validity or reproducibility.

3. Although our regression models were adjusted for major confounders, including age, sex, race, ethnicity, admission NIHSS score, and imaging‐based stroke severity, we did not have access to other potential confounding factors, such as post‐HT NIHSS score, dosing and types of antithrombotics, other hemorrhagic complications, physician judgment, level of comfort, or patient refusal, that may have influenced clinical decision making about antithrombotic initiation after HT. Additionally, the AIS lesion size was available only in a dichotomized format.

4. There was a statistically significant difference between included and excluded patients (Table S3) in several characteristics, such as age, imaging‐based stroke severity, NIHSS score on admission, and use of IVT/MT, which may limit the generalizability of the findings. Excluded patients were older, more likely to be White individuals, and had more comorbid conditions; therefore, the results should be interpreted accordingly.

5. Due to heterogeneity in data sources and study settings, the data collection process was not blinded across all participating centers, representing a potential source of bias.

Despite these limitations, our study contributes to improving the acute management of patients with AIS who experience HT and opens potential avenues for future research.

Conclusions

Our study found no statistically significant difference between early and late initiation of either antiplatelets or OACs with regard to HT exacerbation among patients with HI or PH, whereas prolonged delays in OACs among patients with PH were associated with an increased frequency of systemic thromboembolic events. These findings suggest that the overly cautious approach to prescribing antithrombotics after HT adopted in some clinical settings may need reconsideration, as in certain cases, further delays were associated with worse outcomes. While our data offer some evidence to inform clinical decision making, prospective studies are needed to validate these observations and address gaps in evidence for specific subgroups, such as those with large hemorrhage, severe stroke, treatment with IVT or MT, or prior antithrombotic use.

Sources of Funding

None.

Disclosures

None.

Supporting information

Tables S1–S9

Figures S1–S4

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