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Comparative Study
. 2022 Feb 22;327(8):760-771.
doi: 10.1001/jama.2022.0948.

Association of Recent Use of Non-Vitamin K Antagonist Oral Anticoagulants With Intracranial Hemorrhage Among Patients With Acute Ischemic Stroke Treated With Alteplase

Wayneho Kam  1 , DaJuanicia N Holmes  2 , Adrian F Hernandez  2   3 , Jeffrey L Saver  4 , Gregg C Fonarow  5 , Eric E Smith  6 , Deepak L Bhatt  7 , Lee H Schwamm  8 , Mathew J Reeves  9 , Roland A Matsouaka  2   10 , Yosef M Khan  11 , Martin Unverdorben  12 , Mary C Birmingham  13 , Patrick D Lyden  14 , Andrew W Asimos  15 , Dorothea Altschul  16 , Timothy L Schoonover  17 , Mouhammad A Jumaa  18 , Jason T Nomura  19 , Muhammad Fareed K Suri  20 , S Arthur Moore  21 , Eugene F Lafranchise  22 , DaiWai Olson  23 , Eric D Peterson  24 , Ying Xian  23
Affiliations
Comparative Study

Association of Recent Use of Non-Vitamin K Antagonist Oral Anticoagulants With Intracranial Hemorrhage Among Patients With Acute Ischemic Stroke Treated With Alteplase

Wayneho Kam et al. JAMA. .

Abstract

Importance: Current guidelines recommend against use of intravenous alteplase in patients with acute ischemic stroke who are taking non-vitamin K antagonist oral anticoagulants (NOACs).

Objective: To evaluate the safety and functional outcomes of intravenous alteplase among patients who were taking NOACs prior to stroke and compare outcomes with patients who were not taking long-term anticoagulants.

Design, setting, and participants: A retrospective cohort study of 163 038 patients with acute ischemic stroke either taking NOACs or not taking anticoagulants prior to stroke and treated with intravenous alteplase within 4.5 hours of symptom onset at 1752 US hospitals participating in the Get With The Guidelines-Stroke program between April 2015 and March 2020, with complementary data from the Addressing Real-world Anticoagulant Management Issues in Stroke registry.

Exposures: Prestroke treatment with NOACs within 7 days prior to alteplase treatment.

Main outcomes and measures: The primary outcome was symptomatic intracranial hemorrhage occurring within 36 hours after intravenous alteplase administration. There were 4 secondary safety outcomes, including inpatient mortality, and 7 secondary functional outcomes assessed at hospital discharge, including the proportion of patients discharged home.

Results: Of 163 038 patients treated with intravenous alteplase (median age, 70 [IQR, 59 to 81] years; 49.1% women), 2207 (1.4%) were taking NOACs and 160 831 (98.6%) were not taking anticoagulants prior to their stroke. Patients taking NOACs were older (median age, 75 [IQR, 64 to 82] years vs 70 [IQR, 58 to 81] years for those not taking anticoagulants), had a higher prevalence of cardiovascular comorbidities, and experienced more severe strokes (median National Institutes of Health Stroke Scale score, 10 [IQR, 5 to 17] vs 7 [IQR, 4 to 14]) (all standardized differences >10). The unadjusted rate of symptomatic intracranial hemorrhage was 3.7% (95% CI, 2.9% to 4.5%) for patients taking NOACs vs 3.2% (95% CI, 3.1% to 3.3%) for patients not taking anticoagulants. After adjusting for baseline clinical factors, the risk of symptomatic intracranial hemorrhage was not significantly different between groups (adjusted odds ratio [OR], 0.88 [95% CI, 0.70 to 1.10]; adjusted risk difference [RD], -0.51% [95% CI, -1.36% to 0.34%]). There were no significant differences in the secondary safety outcomes, including inpatient mortality (6.3% for patients taking NOACs vs 4.9% for patients not taking anticoagulants; adjusted OR, 0.84 [95% CI, 0.69 to 1.01]; adjusted RD, -1.20% [95% CI, -2.39% to -0%]). Of the secondary functional outcomes, 4 of 7 showed significant differences in favor of the NOAC group after adjustment, including the proportion of patients discharged home (45.9% vs 53.6% for patients not taking anticoagulants; adjusted OR, 1.17 [95% CI, 1.06 to 1.29]; adjusted RD, 3.84% [95% CI, 1.46% to 6.22%]).

Conclusions and relevance: Among patients with acute ischemic stroke treated with intravenous alteplase, use of NOACs within the preceding 7 days, compared with no use of anticoagulants, was not associated with a significantly increased risk of intracranial hemorrhage.

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Conflict of interest statement

Conflict of Interest Disclosures: Ms Holmes reported having contracts with the American Heart Association to support the work on the analysis for this study. Dr Hernandez reported receiving grants from Pfizer, Bristol Myers Squibb, Janssen, Genentech, and Daiichi Sankyo and receiving personal fees from Bayer. Dr Saver reported serving as a consultant to Boehringer Ingelheim and receiving personal fees from Boehringer Ingelheim, Stryker, Medtronic, Rapid Medical, and Johnson & Johnson. Dr Fonarow reported serving as a consultant to AstraZeneca, Bayer, Janssen, Merck, and Novartis and receiving personal fees from AstraZeneca, Bayer, Janssen, and Novartis. Dr Bhatt reported receiving grants from Amarin, AstraZeneca, Bristol Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company, Pfizer, Forest Laboratories/AstraZeneca, Ischemix, Roche, Stasys, Amgen, Eli Lilly, Chiesi, Ironwood, Abbott, Regeneron, Idorsia, Synaptic, Fractyl, Afimmune, Ferring Pharmaceuticals, Lexicon, Contego Medical, MyoKardia/BMS, Owkin, HLS Therapeutics, Garmin, 89Bio, Faraday Pharmaceuticals, Javelin, and Reid Hoffman Foundation; receiving personal fees from Duke Clinical Research Institute, Mayo Clinic, Population Health Research Institute, Belvoir Publications, Slack Publications, WebMD, Elsevier, Cleveland Clinic, Mount Sinai School of Medicine, HMP Global, Harvard Clinical Research Institute (now Baim Institute for Clinical Research), the Journal of the American College of Cardiology, TobeSoft, Bayer, Medtelligence/ReachMD, CSL Behring, K2P, Canadian Medical and Surgical Knowledge Translation Research Group, MJH Life Sciences, Level Ex, Arnold and Porter Law Firm, Piper Sandler, Cowen and Company; receiving grants and other support from PLx Pharma, Cardax, Boston Scientific, PhaseBio, Novo Nordisk, Cereno Scientific, CellProthera, Janssen, Novo Nordisk, Novartis, and NirvaMed; receiving other support from FlowCo, CSI, Takeda, Medscape Cardiology, Regado Biosciences, Boston VA Research Institute, Clinical Cardiology, the US Department of Veterans Affairs, St Jude Medical (now Abbott), Biotronik, Merck, Svelte, and Philips; receiving personal fees, nonfinancial support, and other support from American College of Cardiology and Boehringer Ingelheim; receiving personal fees and nonfinancial support from the Society of Cardiovascular Patient Care; and receiving nonfinancial support from American Heart Association outside the submitted work. Dr Schwamm reported receiving personal fees from Genentech, Diffusion Pharma, and Penumbra; being a member of a steering committee (TIMELESS trial); being a member of data and safety monitoring boards for Diffusion Pharma (PHAST-TSC trial) and Penumbra (MIND trial); serving as a consultant to LifeImage; providing continuing medical education lectures of own content for PRIME Education and Boehringer Ingelheim; serving as a national primary investigator for the Stroke AF trial (funded by Medtronic) and as a site primary investigator for StrokeNet Network (National Institute of Neurological Disorders and Stroke); and serving as a consultant to the Massachusetts Department of Public Health. Dr Unverdorben reported being an employee of Daiichi Sankyo. Dr Birmingham reported being an employee of Janssen Scientific Affairs LLC. Dr Altschul reported receiving grants from the Valley Hospital Foundation and receiving personal fees from Siemens. Dr Jumaa reported receiving grants from Medtronic and Chiesi; serving as a consultant to Ocudyne and Microvention; and owning stock in AstraZeneca. Dr Nomura reported serving as a consultant to Philips Healthcare and receiving grants from Bristol Myers Squibb and Penumbra. Dr Olson reported receiving research support from NeurOptics Inc and the Texas State Legislature via the Lone Star Stroke Consortium and serving as Editor in Chief of the Journal of Neuroscience Nursing. Dr Peterson reported receiving grants from Genentech, Janssen, Bristol Myers Squibb, and Amgen and serving as a consultant to Pfizer, Novo Nordisk, and Boehringer Ingelham. Dr Xian reported receiving grants from Genentech, Janssen, Daiichi Sankyo, the American Heart Association, and the National Institute on Aging and receiving personal fees from Boehringer Ingelham. No other disclosures were reported.

Figures

Figure.
Figure.. Study Population in the Get With The Guidelines–Stroke (GWTG-Stroke) Registry
aPatients had taken non–vitamin K antagonist oral anticoagulants within 7 days before hospital arrival but the exact timing of the last dose was not captured in the GWTG-Stroke registry. bObtained from 47 patients in the Addressing Real-world Anticoagulant Management Issues in Stroke (ARAMIS) registry. The reported date and time that the patient last took their anticoagulant medication was used to generate the time epochs; however, if the exact date or time was not available, the response to the question “Did patient stop anticoagulant medication >2 days prior to stroke onset?” was alternatively used to define the time epochs of less than 48 hours and greater than 48 hours.
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