P2Y12 Inhibitors and Mortality in Patients Hospitalized With Intracerebral Hemorrhage

Chen Jin; Ying Song; Brian Mac Grory; Jie-Lena Sun; Brooke Alhanti; Gregg C Fonarow; Lee H Schwamm; Kevin N Sheth; Eric E Smith; Steven R Messé; Jeffrey L Saver; Deepak L Bhatt; Ying Xian

doi:10.1001/jamanetworkopen.2026.22239

. 2026 Jul 9;9(7):e2622239. doi: 10.1001/jamanetworkopen.2026.22239

P2Y12 Inhibitors and Mortality in Patients Hospitalized With Intracerebral Hemorrhage

Chen Jin ^1,^✉, Ying Song ¹, Brian Mac Grory ^2,³, Jie-Lena Sun ², Brooke Alhanti ², Gregg C Fonarow ⁴, Lee H Schwamm ⁵, Kevin N Sheth ⁵, Eric E Smith ⁶, Steven R Messé ⁷, Jeffrey L Saver ⁸, Deepak L Bhatt ⁹, Ying Xian ^10,¹¹

¹Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

²Department of Neurology, Duke University School of Medicine, Durham, North Carolina

³Duke Clinical Research Institute, Durham, North Carolina

⁴Department of Medicine, Ahmanson-UCLA (University of California, Los Angeles) Cardiomyopathy Center, UCLA

⁵Department of Neurology, Yale University School of Medicine, New Haven, Connecticut

⁶Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada

⁷Department of Neurology, University of Pennsylvania, Philadelphia

⁸Department of Neurology, UCLA, Los Angeles, California

⁹Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, New York

¹⁰Department of Neurology, University of Texas Southwestern Medical Center, Dallas

¹¹Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas

Accepted for Publication: May 5, 2026.

Published: July 9, 2026. doi:10.1001/jamanetworkopen.2026.22239

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License, which does not permit alteration or commercial use, including those for text and data mining, AI training, and similar technologies. © 2026 Jin C et al. JAMA Network Open.

^✉

Corresponding Author: Chen Jin, MD, MSc, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (fwgxb@126.com).

Author Contributions: Ms Sun had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Jin and Song contributed equally.

Concept and design: Jin, Song, Mac Grory, Fonarow, Schwamm, Sheth, Smith, Saver, Bhatt, Xian.

Acquisition, analysis, or interpretation of data: Jin, Song, Mac Grory, Sun, Alhanti, Fonarow, Smith, Messé, Saver, Bhatt, Xian.

Drafting of the manuscript: Jin, Song, Saver, Xian.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Mac Grory, Sun, Alhanti.

Supervision: Mac Grory, Alhanti, Fonarow, Schwamm, Sheth, Xian.

Conflict of Interest Disclosures: Dr Fonarow reported receiving personal fees from Abbott, AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Johnson & Johnson, Medtronic, Merck, Novartis, and Pfizer and being an Associate Editor of JAMA Cardiology outside the submitted work. Dr Schwamm reported receiving personal fees from Medtronic and in-kind research payment for manuscript preparation from Genentech outside the submitted work. Dr Sheth reported receiving grants from the National Institutes of Health (NIH), American Heart Association, and Hyperfine; receiving personal fees from Bexorg, Astrocyte, Merck, Diamedica, and BrainQ; and owning a patent for Alva issued outside the submitted work. Dr Messé reported receiving personal fees from Bristol-Myers Squibb and Novartis during the conduct of the study. Dr Saver reported receiving personal fees from Abbott, Aeromics, Bayer, Biogen, Boehringer Ingelheim, BrainQ, BrainsGate, CSL Behring, Medtronic USA, Roche, Stream Medical, Johnson & Johnson, MIVI Neuroscience, and Occlutech and owning stocks in MindRhythm, Neuronics Medical, and Rapid Medical during the conduct of the study. Dr Bhatt reported receiving personal fees for advisory board membership from Angiowave, Antlia Bioscience, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, E-Star Biotech, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, NirvaMed, Novo Nordisk, Repair Biotechnologies, Stasys, SandboxAQ (stock options), Tourmaline Bio, and Viatris; receiving personal fees for board of directors service from American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); receiving personal fees for consulting from Alnylam, Altimmune, Broadview Ventures, Corcept Therapeutics, Corsera, GlaxoSmithKline, Hims, Sanofi, SERB, SFJ, Summa Therapeutics, and Worldwide Clinical Trials; receiving personal fees for data monitoring committees from Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research, Boston Scientific, Cleveland Clinic, Contego Medical, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Novartis, and Population Health Research Institute; receiving honoraria from Rutgers University, American College of Cardiology, Arnold & Porter, Baim Institute for Clinical Research, Belvoir Publications, Canadian Medical and Surgical Knowledge Translation Research Group, CSL Behring, Duke Clinical Research Institute, Engage Health Media, HMP Global, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME, Philips, Population Health Research Institute, WebMD, Wiley, Clinical Cardiology (Deputy Editor, unpaid), Progress in Cardiovascular Diseases (Deputy Editor, unpaid), and Added Health (Editorial Board; stock options); being named on a patent for sotagliflozin (received no income from this patent); receiving research funding from Abbott, Acesion Pharma, Afimmune, Alnylam, Amarin, Amgen, AstraZeneca, Atricure, Bayer, Boehringer Ingelheim, Boston Scientific, CellProthera, Cereno Scientific, Chiesi, Cleerly, CSL Behring, Faraday Pharmaceuticals, Fractyl, Idorsia, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, MiRUS, Moderna, Novartis, Novo Nordisk, Pfizer, PhaseBio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, and 89Bio; receiving royalties from Elsevier (Editor, Braunwald’s Heart Disease); and being a site co-investigator for Cleerly outside the submitted work. Dr Xian reported receiving grants from the National Institute on Aging during the conduct of the study. No other disclosures were reported.

Data Sharing Statement: See Supplement 2.

Additional Information: The Get With The Guidelines–Stroke program is funded by the American Heart Association and sponsored in part by Novartis, Novo Nordisk, AstraZeneca, Bayer, and HCA Healthcare.

^✉

Corresponding author.

PMCID: PMC13352121 PMID: 42424082

This cohort study examines the association of P2Y purinergic receptor 12 (P2Y12) inhibitor antiplatelet use with stroke severity and in-hospital outcomes among patients with spontaneous intracerebral hemorrhage who used the antiplatelet therapy 7 days before hospitalization.

Key Points

Question

What is the association between prior P2Y purinergic receptor 12 (P2Y12) inhibitor antiplatelet use, stroke severity, and in-hospital outcomes among patients with spontaneous intracerebral hemorrhage (ICH)?

Findings

In this cohort study of 252 691 patients with ICH not associated with anticoagulation, use of P2Y12 inhibitors before ICH was associated with more severe strokes, in-hospital death, and worse functional outcomes compared with aspirin monotherapy or no antiplatelet use.

Meaning

Among patients with spontaneous ICH in this study, prior use of P2Y12 inhibitor monotherapy or in combination with aspirin was not uncommon and was associated with more severe strokes and worse clinical outcomes.

Abstract

Importance

Although P2Y purinergic receptor 12 (P2Y12) inhibitors are commonly used in patients with atherosclerotic cardiovascular disease, there are limited data on intracerebral hemorrhage (ICH) associated with use of P2Y12 inhibitors.

Objective

To compare stroke severity, in-hospital mortality, and functional outcomes in ICH among patients receiving P2Y12 inhibitor monotherapy, dual antiplatelet therapy (DAPT) with P2Y12 inhibitor plus aspirin, aspirin monotherapy, or no antiplatelet therapy prior to ICH.

Design, Setting, and Participants

This cohort study obtained data from the nationwide Get With The Guidelines–Stroke registry, which contains data from participating hospitals. Participants were patients hospitalized with spontaneous ICH between January 2013 to December 2021. The analysis was completed in January 2025.

Exposures

Antiplatelet therapy before ICH, defined as any use within 7 days prior to hospital arrival.

Main Outcomes and Measures

The primary outcomes were severe stroke at presentation and in-hospital mortality. Severity was assessed using the National Institutes of Health Stroke Scale (NIHSS; range: 0-42, with higher scores indicating greater severity), with a score of 21 or higher indicating severe stroke. Secondary outcomes included in-hospital mortality or discharge to hospice, discharge to home, independent ambulation, and modified Rankin Scale (mRS) score at discharge. An mRS score of 0 to 2 at discharge indicated functional independence.

Results

Of the 252 691 patients included (median [IQR] age, 67 [56-78] years; 134 684 males [53.3%]), 6355 (2.5%) were receiving P2Y12 inhibitor monotherapy, 10 607 (4.2%) were receiving DAPT, 63 299 (25.0%) were receiving aspirin monotherapy, and 172 430 (68.2%) were receiving no antiplatelet agents prior to ICH. Patients taking P2Y12 inhibitors were older and had higher prevalence of cardiovascular risk factors. Overall, 1701 patients (26.8%) receiving P2Y12 monotherapy and 2688 patients (25.3%) receiving DAPT experienced severe ICH (NIHSS score ≥21) compared with 12 952 patients (20.5%) who used aspirin monotherapy and 39 970 (23.2%) patients who received no antiplatelet (P < .001). In-hospital mortality rates were highest in patients using DAPT (24.0%), followed by patients receiving P2Y12 inhibitor monotherapy (23.8%), no antiplatelet (16.8%), and aspirin monotherapy (16.5%) (P < .001). After risk adjustment, patients with prior use of P2Y12 inhibitors were more likely to present with severe stroke (P2Y12 inhibitor monotherapy: adjusted odds ratio [AOR], 1.43 [95% CI, 1.34-1.52]; P < .001; DAPT: AOR, 1.40 [95% CI, 1.33-1.47]; P < .001) and more likely to die in the hospital (P2Y12 inhibitor monotherapy: AOR, 1.55 [95% CI, 1.46-1.66]; P < .001; DAPT: AOR, 1.61 [95% CI, 1.53-1.71]; P < .001) compared with those using aspirin monotherapy. Furthermore, these patients were less likely to be discharged to home, be able to ambulate independently, or have functional independence at discharge. In contrast, there were no statistically significant differences in in-hospital outcomes between aspirin monotherapy and no antiplatelet therapy groups.

Conclusions and Relevance

In this registry-based cohort study of patients with ICH not associated with anticoagulation, P2Y12 inhibitors, either as monotherapy or in combination with aspirin, were associated with more severe stroke, in-hospital death, worse clinical outcomes, and reduced functional recovery compared with aspirin monotherapy or no antiplatelet therapy.

Introduction

P2Y purinergic receptor 12 (P2Y12) inhibitors, including clopidogrel, prasugrel, and ticagrelor, play a critical role in the management of coronary artery disease, cerebrovascular disease, and peripheral artery disease.^{1,2,3,4,5,6,7,8,9,10,11,12,13,14} Despite the favorable risk-benefit profile in preventing ischemic events relative to bleeding complications, intracerebral hemorrhage (ICH) remains the most serious complication associated with P2Y12 inhibitors.¹⁵ Previous research examining ICH in patients receiving P2Y12 inhibitor therapy was either limited in size and scope or primarily focused on anticoagulant-associated rather than antiplatelet-associated ICHs.^{16,17,18,19,20,21} Given the widespread adoption of P2Y12 inhibitors in clinical practice, coupled with the substantial challenges in achieving hemostasis when bleeding occurs,^22,23,24 there is an urgent need to better understand the clinical characteristics and outcomes in patients who experience ICH while receiving P2Y12 inhibitors.

Leveraging data from the American Heart Association/American Stroke Association (AHA/ASA) Get With The Guidelines–Stroke (GWTG-Stroke) registry, we examined clinical characteristics and outcomes among patients who developed ICH while receiving various antiplatelet regimens. We aimed to compare stroke severity, in-hospital mortality, and functional outcomes in ICH among patients receiving P2Y12 inhibitor monotherapy, dual antiplatelet therapy (DAPT) with P2Y12 inhibitor plus aspirin, aspirin monotherapy, or no antiplatelet therapy prior to ICH. We hypothesized that P2Y12 inhibitors are associated with greater stroke severity and worse in-hospital outcomes in patients presenting with nonanticoagulant-associated spontaneous ICH.

Methods

Data Source

The GWTG-Stroke is a national stroke registry and quality improvement initiative sponsored by the AHA/ASA. Standardized data collection includes patient demographic characteristics, medical history, prestroke medication use including antiplatelet therapy, diagnostic evaluations, brain imaging findings, in-hospital treatment, and clinical outcomes.²⁵ A previous validation study demonstrated a high degree of accuracy and concordance between registry data entries and source documentation through medical record review.²⁶ Participating hospitals in the GWTG-Stroke program receive either institutional human research approval for enrollment without individual patient consent, in accordance with 45 CFR §46, or waivers of authorization and exemption from subsequent review by their respective institutional review board. The GWTG-Stroke data are collected for clinical care and quality improvement. Data-sharing agreements require an application process for other researchers to access the data. IQVIA Inc serves as the data collection and coordination center for the program, whereas the Duke Clinical Research Institute serves as the data analysis center and has an agreement to analyze the deidentified data for research purposes. The Duke University Institutional Review Board approved this cohort study and waived informed patient consent in accordance with 45 CFR §46.104. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Study Population

The study inclusion and exclusion are detailed in the Figure. Briefly, we identified all patients presenting with nonanticoagulation-associated spontaneous ICH from the GWTG-Stroke registry between January 2013 to December 2021. We excluded patients with indications for oral anticoagulant (medical history of atrial fibrillation [16.2%] or prior anticoagulant use); with use of antiplatelet agents other than aspirin, clopidogrel, prasugrel, or ticagrelor; with in-hospital stroke; who were transferred to another hospital; who left against medical advice; or with missing National Institutes of Health Stroke Scale (NIHSS) score at admission. Baseline characteristics of patients included and those excluded due to missing NIHSS score are shown in eTable 1 in Supplement 1.

Flowchart of cohort selection and antiplatelet therapy groups in I C H registry. Light gray flowchart with dark text and thin gray arrows. Upper center box: 510528 adults with I C H identified in the G W T G Stroke registry from January 2013 to December 2021. A vertical connector descends to a large right side exclusion box labeled 257837 Excluded, followed by stacked exclusion reasons and counts: 82951 Atrial fibrillation; 28449 Taking anticoagulants prior to I C H; 18395 Taking antiplatelet other than aspirin, clopidogrel, prasugrel, or ticagrelor prior to I C H; 4348 In hospital stroke; 14379 Transferred out, or left against medical advice; 109315 Missing N I H S S score. From the top box, a central downward arrow continues to a middle box: 252691 Included in final study population, from 1977 hospitals. From this middle box, four separate downward arrows branch to four bottom boxes arranged left to right. Far left bottom box: 6355 were receiving P 2 Y 12 inhibitor monotherapy, with subcounts 6237 Clopidogrel, 39 Prasugrel, 79 Ticagrelor. Left center bottom box: 10607 were receiving dual antiplatelet therapy, with subcounts 10061 Clopidogrel, 150 Prasugrel and aspirin, 396 Ticagrelor and aspirin. Right center bottom box: 63299 were receiving aspirin monotherapy. Far right bottom box: 172430 were not receiving antiplatelet therapy. No axes, scales, legends, or panel labels present. — GWTG-Stroke, Get With The Guidelines–Stroke; ICH indicates intracerebral hemorrhage; NIHSS, National Institutes of Health Stroke Scale; P2Y12, P2Y purinergic receptor 12.

Exposure

Prior antiplatelet therapy was documented as part of routine care and was defined as any use within 7 days prior to hospital arrival. We stratified antiplatelet therapy into 4 mutually exclusive categories: (1) P2Y12 inhibitor monotherapy (clopidogrel, prasugrel, or ticagrelor), (2) DAPT consisting of a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) plus aspirin, (3) aspirin monotherapy, and (4) no antiplatelet therapy. For the purpose of this study, phosphodiesterase inhibitors, such as dipyridamole or nonsteroidal anti-inflammatory drugs other than aspirin, were excluded.

Outcome Measures

The primary outcomes were presenting stroke severity and in-hospital mortality. Stroke severity was measured by NIHSS (score range: 0-42, with higher scores indicating greater stroke severity), which has demonstrated comparable prognostic utility to traditional ICH severity measures.²⁷ We defined severe stroke as an initial NIHSS score of 21 or higher.^20,28 Although the ICH score is a validated grading scale for stroke severity, we did not report ICH score due to a high proportion of missing data (63.0%).

Secondary outcomes included a composite end point of in-hospital mortality or discharge to hospice, discharge to home, independent ambulation among previously ambulatory patients prior to ICH, and modified Rankin Scale (mRS) score at discharge. The mRS is a validated measure of functional outcome in patients after a stroke and has a score range of 0 to 6, with higher scores indicating greater functional impairment and a score of 6 indicating death.²⁹ We defined functional independence as an mRS score of 0 to 2 at discharge.

Statistical Analysis

Medians with IQRs, means with SDs, and frequencies with percentages were presented to describe the distributions of continuous and categorical variables. We compared baseline characteristics across antiplatelet therapy groups using Pearson χ² test for categorical variables and Kruskal-Wallis test for continuous variables. We performed multivariable logistic regression models to investigate the associations between prior antiplatelet therapy (exposure) and each outcome. The prior antiplatelet therapy was included as an independent variable in the model, with aspirin monotherapy or no antiplatelet therapy as the reference.

The stroke severity model (co–primary outcome) was adjusted for baseline demographic and pre-ICH clinical variables previously established in the GWTG-Stroke analyses.^20,21 Because stroke severity was measured at presentation and not affected by in-hospital treatment, it adjusted for baseline demographic and pre-ICH clinical variables only, without any hospital characteristics. These covariates included age, sex, self-reported race and ethnicity (documented in electronic health records by admission or medical staff, usually during hospital registration), insurance status, arrival mode, medical history, preadmission medications (eg, antihypertensive agents, cholesterol-lowering drugs, diabetes medication), and systolic blood pressure. Race and ethnicity were included in the analysis because prior study demonstrated racial or ethnic differences in process of care and outcomes among patients hospitalized with ICH.³⁰ Racial and ethnic categories included Asian, Hispanic, non-Hispanic Black, non-Hispanic White, and other (American Indian or Alaska Native, Native Hawaiian or Pacific Islander, or unknown).

Models of co–primary outcome of in-hospital mortality and all secondary outcomes were adjusted for patient characteristics along with hospital characteristics, including teaching status, stroke center designation status, bed size, annual ICH volume, and geographic region. Given that a greater stroke severity may represent a consequence of hematoma expansion attributable to antiplatelet therapy, we did not include NIHSS score from the primary analysis, as it may lie on the causal pathway as an intermediate variable rather than a confounder.³¹ Instead, we incorporated NIHSS scores along with other covariates in an exploratory analysis to estimate the association of P2Y12 inhibitors with outcomes after accounting for baseline stroke severity. Because patients treated at the same hospital may share common clinical practices, treatment protocols, and case mix, ignoring this clustering can lead to underestimated SEs and inflated type I errors. We therefore fit logistic regression models using generalized estimating equations with compound symmetry covariance structures to account for clustering of patients within hospitals.

There were no substantial missing covariate data (eg, >5%) except for insurance status and systolic blood pressure. All missing covariates were imputed with multiple imputation approach, according to Rubin rules, before entering into the model. There were no missing data in outcome measures, except for ambulatory status and mRS score at discharge. These 2 outcomes were not imputed and were reported among complete cases.

We also performed exploratory analyses of stroke severity and clinical outcomes stratified by specific P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor monotherapy, or in combination with aspirin). Due to the relatively small number of patients receiving prasugrel or ticagrelor, these analyses were exploratory in nature and were performed without risk adjustment.

All statistical analyses were performed using SAS version 9.4 (SAS Institute). All P values were 2-sided, with P < .05 considered statistically significant. The analysis was completed in January 2025.

Results

Baseline Characteristics

After exclusions, the final study population consisted of 252 691 patients with spontaneous ICH from 1977 US hospitals (Figure). Among patients with ICH who had no medical history of atrial fibrillation or anticoagulant use (median [IQR] age, 67 [56-78] years; 118 007 females [46.7%], 134 684 males [53.3%]), 6355 (2.5%) were receiving P2Y12 inhibitor monotherapy (clopidogrel: 6237 [98.1%], prasugrel: 39 [0.6%], ticagrelor: 79 [1.2%]), 10 607 (4.2%) were receiving DAPT (clopidogrel: 10 061 [94.9%], prasugrel: 150 [1.4%], ticagrelor: 396 [3.7%]), 63 299 (25.0%) were receiving aspirin monotherapy, and 172 430 (68.2%) were not receiving any antiplatelet therapy prior to ICH (Table 1).

Table 1. Baseline Characteristics by Antiplatelet Agent.

Characteristics	Patients, No. (%)				P value^a
Characteristics	P2Y12 inhibitor monotherapy (n = 6355)	Dual antiplatelet therapy (n = 10 607)	Aspirin monotherapy (n = 63 299)	No antiplatelet therapy (n = 172 430)	P value^a
Patient characteristics
Age, median (IQR), y	75 (66-83)	72 (64-80)	73 (64-82)	63 (53-75)	<.001
Sex
Female	3199 (50.3)	4274 (40.3)	29 588 (46.7)	81 000 (47.0)	<.001
Male	3156 (49.7)	6333 (59.7)	33 711 (53.3)	91 430 (53.0)	<.001
Race and ethnicity^b
Asian	342 (5.4)	403 (3.8)	2929 (4.6)	10 540 (6.1)	<.001
Hispanic	634 (10.0)	908 (8.6)	5268 (8.3)	21 506 (12.5)
Non-Hispanic Black	974 (15.3)	1605 (15.1)	10 995 (17.4)	37 301 (21.6)
Non-Hispanic White	4081 (64.2)	7143 (67.4)	41 118 (65.0)	91 893 (53.3)
Other^c	323 (5.1)	544 (5.1)	2975 (4.7)	11 136 (6.5)
Insurance
Private	1722 (29.2)	2900 (30.6)	18 330 (32.1)	48 577 (35.2)	<.001
Medicare	3533 (59.8)	5610 (59.3)	32 335 (56.6)	59 286 (43.0)
Medicaid	554 (9.4)	808 (8.5)	4945 (8.7)	18 375 (13.3)
Self-pay	96 (1.6)	146 (1.5)	1536 (2.7)	11738 (8.5)
Mode of arrival
EMS arrival	3354 (53.0)	5161 (48.9)	30 549 (48.5)	82 108 (47.8)	<.001
Transfer-in	1980 (31.3)	3740 (35.4)	21 268 (33.7)	60 781 (35.4)	<.001
Arrived off hours^d	3611 (56.8)	6086 (57.4)	35 905 (56.7)	100 958 (58.6)	<.001
Onset to arrival time, h					<.001
Median (IQR)	3.1 (1.2-8.1)	3.4 (1.3-8.3)	3.6 (1.3-9.0)	3.3 (1.1-8.7)	<.001
Mean (SD)	6.7 (11.1)	6.8 (10.8)	7.4 (12.3)	7.5 (13.1)	<.001
Medical history
Previous stroke or TIA	3632 (57.2)	5225 (49.3)	18 640 (29.4)	27 837 (16.1)	<.001
CAD or prior MI	2449 (38.5)	6095 (57.5)	13 942 (22.0)	9904 (5.7)	<.001
Carotid stenosis	391 (6.2)	910 (8.6)	1485 (2.3)	899 (0.5)	<.001
Diabetes	2661 (41.9)	4792 (45.2)	21 761 (34.4)	34 036 (19.7)	<.001
PVD	432 (6.8)	1011 (9.5)	1977 (3.1)	1698 (1.0)	<.001
Hypertension	5516 (86.8)	9180 (86.5)	52 954 (83.7)	117 385 (68.1)	<.001
Smoker	774 (12.2)	1580 (14.9)	7657 (12.1)	2712 (16.0)	<.001
Dyslipidemia	3681 (57.9)	6836 (64.4)	32 943 (52.0)	41 818 (24.3)	<.001
Heart failure	474 (7.5)	1129 (10.6)	4394 (6.9)	4643 (2.7)	<.001
Medication prior to admission
Antihypertensive	4391 (69.1)	7700 (72.6)	40 652 (64.2)	60 374 (35.0)	<.001
Cholesterol reducer	4469 (70.3)	8463 (79.8)	36 495 (57.7)	32 799 (19.0)	<.001
Diabetes medication	1842 (29.0)	3407 (32.1)	14 680 (23.2)	17 664 (10.2)	<.001
NIHSS score at presentation^e
Median (IQR)	9 (3-21)	8 (2-21)	7 (2-18)	9 (2-20)	<.001
Mean (SD)	12.7 (11.3)	12.2 (11.4)	11.0 (10.5)	11.8 (10.8)	<.001
0-4	2206 (34.7)	3876 (36.5)	24 839 (39.2)	62 756 (36.4)	<.001
5-15	1788 (28.1)	3030 (28.6)	19 158 (30.3)	51 174 (29.7)
16-20	660 (10.4)	1012 (9.5)	6350 (10.0)	18 530 (10.7)
21-42	1701 (26.8)	2688 (25.3)	12 952 (20.5)	39 970 (23.2)
Vital signs and laboratory values, median (IQR)^f
Heart rate, bpm	79 (69-91)	78 (68-90)	79 (69-91)	83 (72-95)	<.001
SBP, mm Hg	162 (142-188)	161 (140-186)	163 (144-188)	163 (141-191)	<.001
DBP, mm Hg	85 (73-98)	84 (72-98)	86 (74-100)	91 (77-108)	<.001
Serum creatinine, mg/dL	1.0 (0.8-1.3)	1.0 (0.8-1.4)	0.9 (0.8-1.2)	0.9 (0.7-1.2)	<.001
INR, mg/dL	1.0 (1.0-1.1)	1.0 (1.0-1.1)	1.0 (1.0-1.1)	1.0 (1.0-1.1)	<.001
Blood glucose, mg/dL	137 (110-182)	139 (111-186)	130 (107-168)	126 (106-161)	<.001
LDL cholesterol, mg/dL	79 (60-103)	75 (57-100)	86 (65-112)	99 (76-125)	<.001
Hospital characteristics
Teaching hospital	5144 (81.8)	8814 (83.9)	53 212 (84.8)	145 612 (85.5)	<.001
Stroke center
Comprehensive stroke center	2248 (35.4)	4155 (39.2)	24 713 (39.0)	68 676 (39.8)	<.001
Primary stroke center	3121 (49.1)	4857 (45.8)	29 329 (46.3)	79 477 (46.1)
Nonstroke center	986 (15.5)	1595 (15.0)	9257 (14.6)	24 277 (14.1)
Bed size, median (IQR)	432 (294-659)	458 (317-685)	456 (303-681)	462 (317-692)	<.001
Annual ICH volume, median (IQR)	76 (40-131)	84 (44-138)	82 (43-137)	86 (47-142)	<.001
Region
Northeast	1221 (19.2)	2305 (21.7)	13 753 (21.7)	32 372 (18.8)	<.001
Midwest	1151 (18.1)	2355 (22.2)	14 143 (22.3)	30 901 (17.9)
South	2756 (43.4)	4469 (42.1)	23 445 (37.0)	71 417 (41.4)
West	1227 (19.3)	1478 (13.9)	11 958 (18.9)	37 740 (21.9)
Rural hospital	117 (1.8)	224 (2.1)	1137 (1.8)	2368 (1.4)	<.001

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Abbreviations: bpm, beats per minute; CAD, coronary artery disease; DBP, diastolic blood pressure; EMS, emergency medical services; ICH, intracerebral hemorrhage; INR, international normalized ratio; LDL, low-density lipoprotein; MI, myocardial infarction; NIHSS, National Institutes of Health Stroke Scale; P2Y12, P2Y purinergic receptor 12; PVD, peripheral vascular disease; SBP, systolic blood pressure; TIA, transient ischemic attack.

SI conversion factor: To convert glucose to millimoles per liter, multiply by 0.0555; LDL cholesterol to millimoles per liter, multiply by 0.0259; serum creatinine to micromoles per liter, multiply by 88.4.

^{^a}

Calculated using Pearson χ² test for categorical variables and Kruskal-Wallis test for continuous variables.

^{^b}

Race and ethnicity were self-reported.

^{^c}

Other included American Indian or Alaska Native, Native Hawaiian or Pacific Islander, or unknown.

^{^d}

Arrival at the hospital on weekdays from 6:00 pm to 7:00 am, weekends, or holidays.

^{^e}

NIHSS score range: 0 to 42, with higher scores indicating greater stroke severity.

^{^f}

First value on admission.

Baseline characteristics by antiplatelet regimens are shown in Table 1. Patients receiving P2Y12 inhibitors (monotherapy and DAPT) compared with patients receiving aspirin monotherapy and patients receiving no antiplatelet therapy were generally older and had a higher prevalence of cardiovascular risk factors, including previous stroke or transient ischemic attack (TIA) (57.2% and 49.3% vs 29.4% and 16.1%; P < .001), coronary artery disease (38.5% and 57.5% vs 22.0% and 5.7%; P < .001), carotid stenosis (6.2% and 8.6% vs 2.3% and 0.5%; P < .001), diabetes (41.9% and 45.2% vs 34.4% and 19.7%; P < .001), peripheral vascular disease (6.8% and 9.5% vs 3.1% and 1.0%; P < .001), hypertension (86.8% and 86.5% vs 83.7% and 68.1%; P < .001), dyslipidemia (57.9% and 64.4% vs 52.0% and 24.3%; P < .001), and heart failure (7.5% and 10.6% vs 6.9% and 2.7%; P < .001). Similarly, patients treated with aspirin monotherapy were older and had a greater burden of cardiovascular risk factors than patients without treatment, suggesting a gradient of cardiovascular risk across groups that mirrors the clinical indications underlying antiplatelet prescribing decisions.

Stroke Severity and Prior Antiplatelet Therapy

The median (IQR) admission NIHSS scores were 9 (3-21) for the P2Y12 inhibitor monotherapy, 8 (2-21) for DAPT, 7 (2-18) for aspirin monotherapy, and 9 (2-20) for no antiplatelet therapy groups (P < .001). A total of 1701 patients (26.8%) receiving P2Y12 monotherapy and 2688 patients (25.3%) receiving DAPT experienced severe stroke (NIHSS score ≥21) compared with patients who used aspirin monotherapy or those with no antiplatelet therapy (12 952 [20.5%] or 39 970 [23.2%]) (P < .001). After risk adjustment, P2Y12 inhibitor monotherapy (AOR, 1.43; 95% CI, 1.34-1.52; P < .001), DAPT (AOR, 1.40; 95% CI, 1.33-1.47; P < .001), and no antiplatelet therapy (AOR, 1.07; 95% CI, 1.05-1.10; P < .001) were associated with increased odds of severe stroke compared with aspirin monotherapy (Table 2).

Table 2. Stroke Severity and Clinical Outcomes by Antiplatelet Agent.

Stroke severity and clinical outcomes measures	Event rate, No./total No. (%)	Aspirin monotherapy as the reference, OR (95% CI)		No antiplatelet as the reference, OR (95% CI)
Stroke severity and clinical outcomes measures	Event rate, No./total No. (%)	Unadjusted	Adjusted^a	Unadjusted	Adjusted^a
Severe stroke (NIHSS score: ≥21) ^b
P2Y12 inhibitor monotherapy	1701/6355 (26.8)	1.42 (1.34-1.51)	1.43 (1.34-1.52)	1.21 (1.14-1.28)	1.33 (1.25-1.41)
DAPT	2688/10 607 (25.3)	1.32 (1.26-1.38)	1.40 (1.33-1.47)	1.13 (1.08-1.18)	1.30 (1.24-1.37)
Aspirin monotherapy	12 952/63 299 (20.5)	1 [Reference]	1 [Reference]	0.85 (0.83-0.87)	0.93 (0.91-0.96)
No antiplatelet therapy	39 970/172 430 (23.2)	1.17 (1.15-1.20)	1.07 (1.05-1.10)	1 [Reference]	1 [Reference]
In-hospital mortality
P2Y12 inhibitor monotherapy	1511/6355 (23.8)	1.55 (1.46-1.65)	1.55 (1.46-1.66)	1.54 (1.45-1.64)	1.56 (1.46-1.67)
DAPT	2547/10 607 (24.0)	1.60 (1.52-1.68)	1.61 (1.53-1.71)	1.58 (1.51-1.66)	1.62 (1.53-1.71)
Aspirin monotherapy	10 416/63 299 (16.5)	1 [Reference]	1 [Reference]	0.99 (0.96-1.02)	1.00 (0.97-1.04)
No antiplatelet therapy	29 039/172 430 (16.8)	1.01 (0.98-1.04)	1.00 (0.97-1.03)	1 [Reference]	1 [Reference]
In-hospital mortality or discharge to hospice
P2Y12 inhibitor monotherapy	2240/6355 (35.2)	1.51 (1.43-1.59)	1.42 (1.34-1.51)	1.71 (1.62-1.80)	1.40 (1.32-1.49)
DAPT	3534/10 607 (33.3)	1.40 (1.34-1.46)	1.43 (1.36-1.50)	1.58 (1.51-1.65)	1.41 (1.34-1.48)
Aspirin monotherapy	16 430/63 299 (26.0)	1 [Reference]	1 [Reference]	1.13 (1.11-1.16)	0.98 (0.96-1.01)
No antiplatelet therapy	41 076/172 430 (23.8)	0.88 (0.86-0.90)	1.02 (0.99-1.04)	1 [Reference]	1 [Reference]
Discharge to home
P2Y12 inhibitor monotherapy	1467/6355 (23.1)	0.82 (0.77-0.86)	0.90 (0.84-0.96)	0.67 (0.63-0.71)	0.91 (0.86-0.98)
DAPT	2594/10 607 (24.5)	0.90 (0.86-0.94)	0.89 (0.85-0.94)	0.74 (0.71-0.77)	0.91 (0.86-0.96)
Aspirin monotherapy	16 918/63 299 (26.7)	1 [Reference]	1 [Reference]	0.82 (0.80-0.84)	1.02 (0.99-1.04)
No antiplatelet therapy	53 580/172 430 (31.1)	1.22 (1.19-1.24)	0.98 (0.96-1.01)	1 [Reference]	1 [Reference]
Independent ambulation at discharge^c
P2Y12 inhibitor monotherapy	978/3580 (27.3)	0.78 (0.73-0.84)	0.85 (0.78-0.92)	0.70 (0.65-0.75)	0.87 (0.80-0.94)
DAPT	1889/6262 (30.2)	0.89 (0.84-0.95)	0.90 (0.84-0.96)	0.80 (0.75-0.84)	0.92 (0.86-0.98)
Aspirin monotherapy	12 873/39 351 (32.7)	1 [Reference]	1 [Reference]	0.89 (0.87-0.91)	1.03 (1.00-1.05)
No antiplatelet therapy	38 340/108 787 (35.2)	1.12 (1.09-1.15)	0.98 (0.95-1.00)	1 [Reference]	1 [Reference]
mRS score 0-2 at discharge^d
P2Y12 inhibitor monotherapy	622/4732 (13.1)	0.72 (0.66-0.79)	0.85 (0.77-0.94)	0.59 (0.54-0.65)	0.87 (0.79-0.97)
DAPT	1173/7871 (14.9)	0.83 (0.77-0.89)	0.85 (0.79-0.92)	0.68 (0.63-0.73)	0.88 (0.81-0.94)
Aspirin monotherapy	7858/44 769 (17.6)	1 [Reference]	1 [Reference]	0.82 (0.79-0.85)	1.03 (0.99-1.06)
No antiplatelet therapy	24 649/120 723 (20.4)	1.22 (1.18-1.26)	0.97 (0.94-1.01)	1 [Reference]	1 [Reference]

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Abbreviations: DAPT, dual antiplatelet therapy; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; P2Y12, P2Y purinergic receptor 12.

^{^a}

Stroke severity was adjusted for the following patient characteristics: age, sex, race and ethnicity, insurance, arrival mode, medical history, antihypertensive, cholesterol reducer, diabetes medication prior to admission, and systolic blood pressure. Clinical outcomes were adjusted for both patient characteristics and the following hospital characteristics: teaching status, stroke center status, bed size, annual intracerebral hemorrhage (ICH) volume, and region.

^{^b}

NIHSS score range: 0 to 42, with higher scores indicating greater stroke severity.

^{^c}

Among 163 408 patients who were able to ambulate independently prior to ICH. Data were missing for 5428 patients (3.3%). This outcome was not imputed and was reported among 157 980 complete cases.

^{^d}

Data were missing for 74 596 patients (29.5%). This outcome was not imputed and was reported among 178 095 complete cases. mRS score ranges from 0 to 6, with a higher score indicating worse functional outcome and 6 indicating death. Patients with mRS score of 0 to 2 were classified as having functional independence.

In-Hospital Outcomes and Prior Antiplatelet Therapy

The unadjusted in-hospital mortality was highest with DAPT (24.0% [2547 of 10 607]), followed by P2Y12 inhibitor monotherapy (23.8% [1511 of 6355]), no antiplatelet therapy (16.8% [29 039 of 172 430]), and aspirin monotherapy (16.5% [10 416 of 63 299]; P < .001) (Table 2). After risk adjustment, both P2Y12 inhibitor monotherapy (AOR, 1.55; 95% CI, 1.46-1.66; P < .001) and DAPT (AOR, 1.61; 95% CI, 1.53-1.71; P < .001) were associated with increased odds of in-hospital mortality compared with aspirin monotherapy. Similarly, both P2Y12 inhibitor monotherapy (35.2% [2240 of 6355]; AOR, 1.42; 95% CI, 1.34-1.51; P < .001) and DAPT (33.3% [3534 of 10 607]; AOR, 1.43; 95% CI, 1.36-1.50; P < .001) were associated with greater odds of composite end point of death or discharge to hospice compared with aspirin monotherapy (26.0% [16 430 of 63 299]). In contrast, there were no statistically significant differences in in-hospital outcomes between aspirin monotherapy and no antiplatelet therapy.

Among patients with ICH associated with P2Y12 inhibitor monotherapy or DAPT, 23.1% (1467 of 6355) or 24.5% (2594 of 10607) were discharged to home, 27.3% (978 of 3580) or 30.2% (1889 of 6262) maintained independent ambulation, and 13.1% (622 of 4732) or 14.9% (1173 of 7871) achieved functional independence (mRS score 0-2) at discharge. After risk adjustment, P2Y12 inhibitor–associated ICHs were associated with lower odds of home discharge, independent ambulation, and functional independence at discharge compared with aspirin monotherapy. The observed associations persisted after further adjustment for NIHSS score (eTable 2 in Supplement 1). However, the magnitudes were attenuated after NIHSS score adjustment, suggesting that initial stroke severity may act as a partial mediator of the association between P2Y12 inhibitor use and outcome.

Type of Prior P2Y12 Inhibitors (Exploratory Analysis)

Baseline characteristics are shown in eTable 3 in Supplement 1. Stroke severity and clinical outcomes stratified by specific P2Y12 inhibitors are provided in Table 3. The median (IQR) NIHSS score was highest among patients receiving prasugrel monotherapy (13 [3-18]), followed by ticagrelor monotherapy (11 [3-22]), clopidogrel monotherapy (9 [3-22]), DAPT with prasugrel plus aspirin (9 [1-22]), clopidogrel plus aspirin (8 [2-21]), and ticagrelor plus aspirin (6 [2-19]). Unadjusted in-hospital mortality was highest with prasugrel monotherapy (35.9% [14 of 39]; 95% CI, 20.8%-51.0%), followed by DAPT with prasugrel plus aspirin (30.0% [45 of 150]; 95% CI, 22.7%-37.3%), ticagrelor monotherapy (25.3% [20 of 79]; 95% CI, 15.7%-34.9%), clopidogrel plus aspirin (24.0% [2419 of 10 061]; 95% CI, 23.2%-24.9%), clopidogrel monotherapy (23.7% [1477 of 6237]; 95% CI, 22.6%-24.7%), and ticagrelor plus aspirin (21.0% [83 of 396]; 95% CI, 17.0%-25.0%) (P < .001).

Table 3. Stroke Severity and Clinical Outcomes by Type of P2Y12 Inhibitors.

Outcome	Patients, No./total No. (%)
Outcome	Clopidogrel monotherapy (n = 6237)	Prasugrel monotherapy (n = 39)	Ticagrelor monotherapy (n = 79)	Clopidogrel plus aspirin (n = 10 061)	Prasugrel plus aspirin (n = 150)	Ticagrelor plus aspirin (n = 396)
NIHSS score at presentation, No. (%)^a
Median (IQR)	9 (3-22)	13 (3-18)	11 (3-22)	8 (2-21)	9 (1-22)	6 (2-19)
Mean (SD)	12.7 (11.4)	12.6 (9.8)	13.4 (11.6)	12.2 (11.3)	12.6 (12.1)	11.3 (11.5)
0-4	2166 (34.7)	10 (25.6)	30 (38.0)	3643 (36.2)	61 (40.7)	172 (43.4)
5-15	1757 (28.2)	15 (38.5)	16 (20.3)	2901 (28.8)	30 (20.0)	99 (25.0)
16-20	644 (10.3)	6 (15.4)	10 (12.7)	959 (9.5)	17 (11.3)	36 (9.1)
21-42	1670 (26.8)	8 (20.5)	23 (29.1)	2558 (25.4)	42 (28.0)	89 (22.5)
In-hospital mortality	1477/6237 (23.7)	14/39 (35.9)	20/79 (25.3)	2419/10 061 (24.0)	45/150 (30.0)	83/396 (21.0)
In-hospital mortality or discharge to hospice	2198/6237 (35.2)	17/39 (43.6)	25/79 (31.6)	3371/10 061 (33.5)	51/150 (34.0)	112/396 (28.3)
Discharge to home	1440/6237 (23.1)	5/39 (12.8)	22/79 (27.8)	2429/10 061 (24.1)	43/150 (28.7)	122/396 (30.8)
Independent ambulation at discharge^b	960/3508 (27.4)	5/22 (22.7)	13/50 (26.0)	1762/5898 (29.9)	30/97 (30.9)	97/267 (36.3)
mRS score 0-2 at discharge^c	609/4641 (13.1)	1/29 (3.4)	12/62 (19.4)	1090/7453 (14.6)	21/113 (18.6)	62/304 (20.4)

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Abbreviations: mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; P2Y12, P2Y purinergic receptor 12.

^{^a}

NIHSS score range: 0 to 42, with higher scores indicating greater stroke severity.

^{^b}

Among 10 158 patients who were able to ambulate independently prior to intracerebral hemorrhage. Data were missing for 316 patients (3.1%).

^{^c}

Data were missing for 4360 patients (25.7%). mRS score ranges from 0 to 6, with a higher score indicating worse functional outcome and 6 indicating death. Patients with mRS score of 0 to 2 were classified as having functional independence.

Discussion

In this analysis of 252 691 nonanticoagulant-associated spontaneous ICH hospitalizations, we found that approximately 1 in 15 patients were taking P2Y12 inhibitors, either alone or in combination with aspirin, prior to their hemorrhagic event. Our findings demonstrate that patients receiving P2Y12 inhibitor monotherapy or DAPT experienced significantly higher odds of severe stroke, increased mortality, and worse functional outcomes compared with those receiving aspirin monotherapy or no antiplatelet therapy. Despite advances in ICH management, the clinical outcomes remain poor, with 1 in 4 patients experiencing in-hospital death and 1 in 3 patients either dying or requiring hospice care at discharge. These findings underscore the critical need to develop management strategies for this clinically challenging patient population.

Antiplatelet therapy is the cornerstone for the prevention and treatment of atherosclerotic cardiovascular disease.^1,2,3,4,5 In particular, the combination of a P2Y12 inhibitor and aspirin has emerged as the standard therapeutic approach for multiple conditions, including acute coronary syndrome, percutaneous coronary intervention, carotid artery stenting, recent minor ischemic stroke, and high-risk TIA. In addition, P2Y12 inhibitor monotherapy is often used as an alternative to aspirin for primary and secondary prevention of cardiovascular disease. While P2Y12 inhibitors have proven effective in reducing thrombotic events, a major limitation of these agents when combined with aspirin is the increased bleeding risk, including the potentially devastating complication of ICH.¹⁵

The Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial and 2 meta-analyses demonstrated a lower risk of intracranial hemorrhage associated with P2Y12 inhibitor monotherapy compared with aspirin monotherapy.^9,10,11 In contrast, DAPT with clopidogrel plus aspirin was shown to increase intracranial hemorrhage risk by 42% compared with aspirin alone in a patient-level meta-analysis of 6 randomized clinical trials of cardiovascular or cerebrovascular disease.³² Similarly, the risk of intracranial hemorrhage is higher with ticagrelor plus aspirin than with aspirin monotherapy.^33,34,35,36 While the absolute risk remains low—as demonstrated in the THEMIS-PCI trial, where extended DAPT showed a 0.2% to 0.3% annual incidence of intracranial hemorrhage—the global impact could be substantial given the widespread adoption of P2Y12 inhibitor in clinical practice.^15,35

Previous studies have examined the association between antiplatelet therapy and ICH outcomes.^{16,17,18,19,20,21,37} However, due to the small number of P2Y12 inhibitor–associated ICHs, these studies did not differentiate between specific antiplatelet agents, instead broadly categorizing them as single vs dual therapy or aspirin vs nonaspirin antiplatelet therapy. In our analysis of nonanticoagulation-associated hemorrhage, P2Y12 inhibitor–associated ICHs were not uncommon, representing 1 in every 15 nontraumatic ICH cases. Overall, patients receiving antiplatelet therapy had higher cardiovascular risk profiles, characterized by advanced age and increased comorbidity burden compared with patients with spontaneous ICH without antecedent antiplatelet use. Although the differences in baseline characteristics between P2Y12 inhibitor and aspirin monotherapy groups were less pronounced, both P2Y12 inhibitor monotherapy and DAPT were independently associated with increased odds of severe stroke (40%-43% increase) and in-hospital mortality (55%-61% increase) compared with aspirin monotherapy.

The differential outcomes observed across antiplatelet regimens may be explained by their distinct pharmacological mechanisms. Aspirin inhibits the cyclooxygenase pathway, whereas P2Y12 inhibitors specifically block adenosine diphosphate–induced platelet aggregation.³⁸ The combination of aspirin and P2Y12 inhibitors in DAPT may produce synergistic effects on platelet inhibition, potentially contributing to an increased risk of ICH expansion and subsequent adverse outcomes when bleeding occurs.³⁷ As emerging evidence suggests that shorter durations of DAPT decrease bleeding risk in acute coronary syndrome, minor stroke, and high-risk TIA, further studies are needed to evaluate the implications of limiting DAPT duration in settings where evidence remains uncertain.^12,13,39

We observed minimal differences in stroke severity and outcomes between patients receiving DAPT and patients receiving P2Y12 inhibitor monotherapy. Although DAPT provides more potent platelet inhibition, these findings may reflect differences in underlying cardiovascular risk profiles between the groups. Patients receiving DAPT had a higher prevalence of coronary artery disease (57.5% vs 38.5%) but lower prevalence of previous stroke or TIA (49.3% vs 57.2%) compared with those receiving P2Y12 inhibitor monotherapy. These differences likely correspond to variation in treatment indications and duration of therapy prior to ICH (eg, shorter-course DAPT following minor stroke or TIA or after drug-eluting stent vs long-term P2Y12 inhibitor monotherapy). Future studies with imaging end points and longitudinal treatment exposure data are needed to elucidate the association between P2Y12 inhibitor monotherapy and DAPT with ICH severity and outcomes.

The paradoxical finding of increased stroke severity in patients not receiving antiplatelet therapy compared with those receiving aspirin monotherapy is likely multifactorial. Patients not receiving treatment were generally young and had fewer cardiovascular comorbidities, suggesting potential differences in cerebral reserve, vascular pathology (eg, structural lesions such as arteriovenous or cavernous malformations), and hemorrhage location distribution compared with older patients with chronic cerebrovascular disease being treated with aspirin monotherapy. However, due to lack of neuroimaging data, including hematoma volume, location, and presence of hematoma expansion, these interpretations should be considered hypothesis-generating and warrant further investigation.

In addition, a 3-group comparison highlights a clinically meaningful gradient across antiplatelet exposures and ICH. Despite higher NIHSS scores among antiplatelet-naive patients vs patients receiving aspirin monotherapy, in-hospital mortality was similar between these groups and was substantially lower than among patients receiving P2Y12 inhibitors. This divergence between initial severity and outcomes supports the relatively safe profile of aspirin in the ICH context and contrasts with the worse outcomes observed with P2Y12 inhibitors. These distinct clinical profiles and outcome patterns observed across therapy categories may help explain previously conflicting results from studies that grouped all antiplatelet agents into a single exposure category, where some investigations suggested worse outcomes while others found no statistically significant differences.¹⁸

While many patients may be treated with antiplatelet therapy appropriately for their underlying conditions, the management of P2Y12-associated ICH presents substantial challenges due to the lack of definitive treatment options.⁴⁰ The current guidelines warn against platelet transfusions in patients with ICH taking aspirin if no procedure is being performed, based on evidence from the PATCH trial.²⁴ The antiplatelet effects of P2Y12 inhibitors cannot be reversed with platelet transfusion.^23,41 As of today, no reversal agents for P2Y12 inhibitors are commercially available. Unlike clopidogrel and prasugrel, ticagrelor binds to P2Y12 receptors reversibly. A specific reversal agent, bentracimab, is currently undergoing late-stage clinical investigation.^42,43 Our exploratory analyses suggest differential stroke severity and outcomes by each type of P2Y12 inhibitors. While these findings are not conclusive given the relatively small number of patients receiving prasugrel or ticagrelor and the differences in baseline characteristics across subgroups that limit direct comparisons, these data can be used as a historical control and may inform the design of future clinical trials evaluating the safety and effectiveness of reversal agents for P2Y12 inhibitors. In addition, we excluded patients with indications for oral anticoagulant because anticoagulant-associated ICH differs from antiplatelet-associated ICH in pathophysiologic processes, hematoma characteristics, management, and outcomes. The proportion of patients with atrial fibrillation in our cohort (16.2%) is comparable to that reported in prior ICH registries (eg, 15.9% in the GWTG-Stroke cohort; 10.8% in the Ontario cohort), supporting the representativeness of our study population.^20,44 Future studies are needed to evaluate the role of prior antithrombotic therapy in patients with atrial fibrillation and ICH.

Limitations

Our study has limitations. First, the observational nature of this analysis introduces the potential for residual confounding despite risk adjustment. Second, the GWTG-Stroke registry lacks detailed neuroimaging data. Information on hematoma volume, location, the presence of hematoma expansion, interventricular hemorrhage, and spot signs could provide more direct insight into the association of P2Y12 inhibitors with ICH severity, and outcomes. Nevertheless, our findings still provide valuable clinical insights regarding the clinical characteristics and outcomes of P2Y12 inhibitor–associated ICH, particularly given the low incidence risk of ICH on an individual level. For instance, in the THEMIS trial, it took more than 3 years to identify 70 intracranial hemorrhages in a cohort of 9652 patients receiving DAPT.³⁴

Third, our definition of prior antiplatelet therapy included any administration within 7 days preceding ICH without capturing specific timing of the last intake. While some patients may have discontinued antiplatelet therapy, potentially affecting stroke severity and outcomes, such discontinuation would more likely present as ischemic rather than hemorrhagic events. Fourth, clopidogrel was used by the large majority of patients receiving P2Y12 inhibitor monotherapy or DAPT. Given the small number of patients treated with prasugrel or ticagrelor in our study, the findings stratified by P2Y12 inhibitor type should be interpreted as hypothesis-generating rather than confirmatory. Fifth, the exclusion of patients with missing NIHSS score may introduce selection bias and reduce generalizability. We compared baseline characteristics between included patients and those who were excluded due to missing NIHSS score and observed modest differences between groups. However, it is unlikely that clinicians would differentially document NIHSS score based on preadmission antiplatelet therapy status. Therefore, although some selection bias cannot be excluded, substantial bias related to antiplatelet exposure is unlikely.

Sixth, information on withdrawal of care decisions, which can affect observed mortality, is not available in the GWTG-Stroke registry. Therefore, residual confounding may remain. Seventh, the registry contains only inpatient data and does not capture postdischarge outcomes, such as 90-day or 1-year mRS scores.⁴⁵ Future studies incorporating longitudinal follow-up are needed to better characterize long-term functional outcomes after ICH. Eighth, our data are derived from hospitals participating in the GWTG-Stroke program, with more than 85% of patients receiving care at teaching, primary, or comprehensive stroke centers. While this approach may limit generalizability, the registry captures 76.6% of incident stroke hospitalizations in the US.^46,47

Conclusions

In this registry-based cohort study of patients with ICH not associated with anticoagulation, prior use of P2Y12 inhibitors, either as monotherapy or combined with aspirin, was associated with severe strokes, worse clinical outcomes (including increased in-hospital mortality), and reduced functional recovery compared with patients receiving aspirin monotherapy or no antiplatelet therapy. These findings underscore the urgent need for further investigation to establish optimal management strategies for P2Y12 inhibitor–associated ICH.

Supplement 1.

eTable 1. Baseline Characteristics of Patients Included and Excluded Due to NIHSS Missing

eTable 2. Clinical Outcomes by Antiplatelet Agent: Sensitivity Analysis With Further Adjustment for NIHSS

eTable 3. Baseline Characteristics by Type of P2Y₁₂ Inhibitors

jamanetwopen-e2622239-s001.pdf^{(296.8KB, pdf)}

Supplement 2.

Data Sharing Statement

jamanetwopen-e2622239-s002.pdf^{(15.2KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eTable 1. Baseline Characteristics of Patients Included and Excluded Due to NIHSS Missing

eTable 2. Clinical Outcomes by Antiplatelet Agent: Sensitivity Analysis With Further Adjustment for NIHSS

eTable 3. Baseline Characteristics by Type of P2Y₁₂ Inhibitors

jamanetwopen-e2622239-s001.pdf^{(296.8KB, pdf)}

Supplement 2.

Data Sharing Statement

jamanetwopen-e2622239-s002.pdf^{(15.2KB, pdf)}

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[zoi260622r20] 20.Inohara T, Xian Y, Liang L, et al. Association of intracerebral hemorrhage among patients taking non-vitamin K antagonist vs vitamin K antagonist oral anticoagulants with in-hospital mortality. JAMA. 2018;319(5):463-473. doi: 10.1001/jama.2017.21917 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi260622r21] 21.Xian Y, Zhang S, Inohara T, et al. Clinical characteristics and outcomes associated with oral anticoagulant use among patients hospitalized with intracerebral hemorrhage. JAMA Netw Open. 2021;4(2):e2037438. doi: 10.1001/jamanetworkopen.2020.37438 [DOI] [PMC free article] [PubMed] [Google Scholar]

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[zoi260622r37] 37.Morotti A, Nawabi J, Li Q, et al. Characteristics of intracerebral hemorrhage associated with dual antiplatelet treatment. J Neurol. 2025;272(9):601. doi: 10.1007/s00415-025-13339-y [DOI] [PubMed] [Google Scholar]

[zoi260622r38] 38.Verheugt FWA, Ten Berg JM, Storey RF, Cuisset T, Granger CB. Antithrombotics: from aspirin to DOACs in coronary artery disease and atrial fibrillation. J Am Coll Cardiol. 2019;74(5):699-711. doi: 10.1016/j.jacc.2019.02.080 [DOI] [PubMed] [Google Scholar]

[zoi260622r39] 39.Tarantini G, Honton B, Paradies V, et al. ; TARGET-FIRST Investigators . Early discontinuation of aspirin after PCI in low-risk acute myocardial infarction. N Engl J Med. 2025;393(21):2083-2094. doi: 10.1056/NEJMoa2508808 [DOI] [PubMed] [Google Scholar]

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[zoi260622r41] 41.Teng R, Carlson GF, Nylander S, Andersson TLG. Effects of autologous platelet transfusion on platelet inhibition in ticagrelor-treated and clopidogrel-treated subjects. J Thromb Haemost. 2016;14(12):2342-2352. doi: 10.1111/jth.13511 [DOI] [PubMed] [Google Scholar]

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PERMALINK

P2Y12 Inhibitors and Mortality in Patients Hospitalized With Intracerebral Hemorrhage

Chen Jin, MD, MSc

Ying Song, MD

Brian Mac Grory, MD

Jie-Lena Sun, MS

Brooke Alhanti, PhD

Gregg C Fonarow, MD

Lee H Schwamm, MD

Kevin N Sheth, MD

Eric E Smith, MD, MPH

Steven R Messé, MD

Jeffrey L Saver, MD

Deepak L Bhatt, MD, MPH, MBA

Ying Xian, MD, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Exposures

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Data Source

Study Population

Figure. Flowchart of the Study Population.

Exposure

Outcome Measures

Statistical Analysis

Results

Baseline Characteristics

Table 1. Baseline Characteristics by Antiplatelet Agent.

Stroke Severity and Prior Antiplatelet Therapy

Table 2. Stroke Severity and Clinical Outcomes by Antiplatelet Agent.

In-Hospital Outcomes and Prior Antiplatelet Therapy

Type of Prior P2Y12 Inhibitors (Exploratory Analysis)

Table 3. Stroke Severity and Clinical Outcomes by Type of P2Y12 Inhibitors.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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