7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack : Jamary Oliveira-Filho, MD, MS, PhD, Michael T Mullen, MD : Scott E Kasner, MD, Alejandro A Rabinstein, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 22, 2023. INTRODUCTION The management of patients with acute ischemic stroke involves several phases (see "Initial assessment and management of acute stroke"). The goals in the initial phase include: Ensuring medical stability Determining eligibility for thrombolytic therapy ( table 1) and/or mechanical thrombectomy ( algorithm 1) Determining the pathophysiologic basis of the stroke Timely restoration of blood flow using thrombolytic therapy is the most effective maneuver for salvaging ischemic brain tissue that is not already infarcted. Intravenous thrombolysis can be administered up to 4.5 hours after symptom onset, and mechanical thrombectomy can be administered up to 24 hours after symptom onset. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use" and "Mechanical thrombectomy for acute ischemic stroke".) In addition to reperfusion therapies for acute treatment, there are two major classes of antithrombotic drugs that can be used to prevent recurrent ischemic stroke: Antiplatelets Anticoagulants https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 1/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate This topic will review the use of antithrombotic treatments for patients in the first days after acute ischemic stroke onset. Chronic antiplatelet and anticoagulation therapies for secondary stroke prevention are discussed separately. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke" and "Stroke in patients with atrial fibrillation" and "Atrial fibrillation in adults: Use of oral anticoagulants".) TREATMENT ON PRESENTATION Evaluate for reperfusion therapy All patients with acute ischemic stroke should be evaluated to determine eligibility for reperfusion therapy with intravenous thrombolysis using recombinant tissue plasminogen activator (tPA; alteplase or tenecteplase) and/or mechanical thrombectomy ( algorithm 1). (See "Approach to reperfusion therapy for acute ischemic stroke".) Start antiplatelets as soon as possible Aspirin and other antithrombotic agents should not be given alone or in combination for the first 24 hours following treatment with intravenous thrombolysis. Otherwise, in the absence of contraindications (see 'Hemorrhagic transformation and systemic bleeding' below) or a known cardiac source that requires anticoagulation, antiplatelet therapy with aspirin alone or with dual antiplatelet therapy (DAPT) should be started as soon as possible after the diagnosis of transient ischemic attack (TIA) or ischemic stroke is confirmed, even before the evaluation for ischemic mechanism is complete ( algorithm 2 and algorithm 3) [1-3]. Note that oral antiplatelets (or any oral medications) should be administered only after a dysphagia screen to evaluate the safety of swallowing. (See "Complications of stroke: An overview", section on 'Dysphagia'.) Once the ischemic mechanism is determined, antithrombotic therapy can be modified as necessary. (See 'Treatment by ischemic mechanism' below.) Aspirin alone Indications for aspirin For patients with a TIA or acute ischemic stroke who do not have a known cardioembolic source at presentation, early aspirin monotherapy (162 to 325 mg daily) is indicated in the following clinical settings: 2 Low-risk TIA, as defined by an ABCD (for Age, Blood pressure, Clinical features, Duration of symptoms, and Diabetes) score <4 ( table 2). https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 2/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Ischemic stroke of moderate or greater severity, as defined by a National Institutes of Health Stroke Scale (NIHSS) score >5 ( table 3). For patients already on antiplatelet therapy with either aspirin or clopidogrel at the time of stroke onset, we continue their existing antiplatelet regimen when the NIHSS score is >5. Efficacy of aspirin In large randomized controlled trials, early (within 48 hours) initiation of aspirin was beneficial for the treatment of acute ischemic stroke, as shown in two major trials: The International Stroke Trial (IST) enrolled 19,435 patients with suspected acute ischemic stroke [4]. Patients allocated to aspirin (300 mg) within 48 hours of symptom onset experienced significant reductions in the 14-day recurrence of ischemic stroke (2.8 versus 3.9 percent) and in the combined outcome of nonfatal stroke or death (11.3 versus 12.4 percent). In the Chinese Acute Stroke Trial (CAST), 21,100 Chinese patients were randomized to 160 mg of aspirin daily or placebo, also within 48 hours of the onset of acute ischemic stroke [5]. Aspirin-allocated patients experienced a 14 percent relative risk reduction in mortality at four weeks (3.3 versus 3.9 percent). Subsequent studies of pooled data from trials of early aspirin use in acute ischemic stroke (mainly IST and CAST) have made the following additional observations: In a combined analysis of the IST and CAST trials, aspirin therapy in acute ischemic stroke led to a reduction of 11 nonfatal strokes or deaths per 1000 patients in the first few weeks but caused approximately two hemorrhagic strokes [6]. Thus, approximately nine nonfatal strokes or deaths were avoided for every 1000 treated patients. These effects were similar in the presence or absence of atrial fibrillation. Using the endpoint of death or residual impairment leaving the patient dependent, the combined data demonstrated a reduction of 13 per 1000 patients after several weeks to six months of follow-up. A 2022 systematic review of antiplatelet therapy for acute stroke included 11 trials involving over 42,000 participants, but the IST and CAST trials contributed nearly all of the data [7]. The reviewers concluded that starting aspirin (160 to 300 mg daily) within 48 hours of presumed ischemic stroke onset reduced the risk of early recurrent ischemic stroke without a major risk of early hemorrhagic complications and improved long-term outcomes. The number needed to treat to avoid death or dependency was 79. In an analysis of pooled individual patient data from IST and CAST, aspirin reduced the risk of recurrent ischemic stroke for patients with mild and moderate stroke-related neurologic deficits at baseline but not for those with severe deficits [8]. For patients with mild and https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 3/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate moderate deficits, the risk reduction was maximal by the third day after starting aspirin (two- to three-day hazard ratio [HR] 0.37, 95% CI 0.25-0.57). Short-term dual antiplatelet therapy (DAPT) Indications for DAPT For patients with a TIA or acute ischemic stroke who do not have a known cardioembolic source at presentation and who are able to swallow, short-term DAPT using aspirin plus clopidogrel is indicated in the following clinical settings: 2 High-risk TIA, defined as an ABCD score of 4. (See 'Efficacy of DAPT' below.) For patients on antiplatelet therapy with either aspirin or clopidogrel at the time of TIA onset, we switch to DAPT using aspirin plus clopidogrel for the first 21 days for high-risk 2 TIA (ie, an ABCD score of 4). For patients on other antiplatelet agents, the decision should be individualized based upon the underlying indication. Minor ischemic stroke, defined by an NIHSS score 5 ( table 3). (See 'Efficacy of DAPT' below.) Stroke due to intracranial large artery atherosclerosis, defined by ischemic stroke attributed to an intracranial large artery atherosclerotic stenosis of 70 to 99 percent. (See "Intracranial large artery atherosclerosis: Treatment and prognosis", section on 'Antiplatelet therapy'.) Regimen We use aspirin (160 to 325 mg loading dose, followed by 50 to 100 mg daily) plus clopidogrel (300 to 600 mg loading dose, followed by 75 mg daily) for short-term DAPT. An alternative is aspirin (300 to 325 mg on the first day followed by 75 to 100 mg daily) plus ticagrelor (180 mg loading dose followed by 90 mg twice daily). Duration The duration of DAPT is typically limited to 21 days for patients with high-risk TIA or minor ischemic stroke but may be extended to 90 days for patients with stroke due to intracranial large artery atherosclerotic stenosis of 70 to 99 percent. Thereafter, antiplatelet treatment with aspirin alone, clopidogrel alone, or aspirin-extended-release dipyridamole should be continued indefinitely. Benefit is short term In the longer term (beyond 90 days after stroke), DAPT using aspirin and clopidogrel is not recommended for stroke prevention. As an example, the MATCH trial, with over 7500 patients who were treated and followed for 18 months, found that the combined use of aspirin and clopidogrel did not offer greater benefit for stroke prevention than either agent alone but did substantially increase the risk of bleeding https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 4/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate complications [9]. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Aspirin plus clopidogrel'.) Efficacy of DAPT High-risk TIA and minor ischemic stroke There is high-quality evidence that early initiation and short-term use of DAPT for select patients with acute high-risk TIA or minor ischemic stroke reduce the risk of recurrent ischemic stroke, with a possible small increase in the risk of moderate or major bleeding and no apparent impact on mortality [3,10-15]. The broadly similar results from major randomized trials [16-18] and the findings of the network meta-analysis [19] discussed below suggest that DAPT with aspirin and clopidogrel or DAPT with aspirin and ticagrelor are both reasonable options for patients with high-risk TIA or minor stroke. We favor aspirin and clopidogrel as this combination will generally cost less. There is limited evidence from a subgroup analysis of the csps.com trial from Japan supporting treatment with DAPT using cilostazol in combination with aspirin or clopidogrel and started as early as eight days after stroke onset [20]. However, this study has important limitations, including post hoc design, unblinded treatment, homogeneous population studied, and early stopping of the trial. Higher-quality data are needed to determine the effectiveness of cilostazol in this setting, and for now we do not use cilostazol as a component of early DAPT. Some randomized trials have defined minor ischemic stroke as an NIHSS score 3, while others have used an NIHSS 5. UpToDate contributors to this topic generally define minor stroke by a NIHSS score of 5. However, the volume of infarcted tissue should be accounted for, since the risk of hemorrhagic transformation is likely related more closely to infarct size than to the NIHSS score. Some patients with an NIHSS score 5 may have a relatively large volume of infarcted tissue. In such cases, clinical judgment applies, and antiplatelet monotherapy may be preferred over DAPT. Meta-analysis A 2018 meta-analysis pooled data from three eligible trials and over 10,400 patients with acute high-risk TIA or acute minor ischemic stroke who were assigned to DAPT using aspirin and clopidogrel or to aspirin alone started within 24 hours of symptom onset [13]. The two largest trials (POINT [16] and CHANCE [17]) in the meta- 2 analysis contributed 96 percent of the patients. High-risk TIA was defined as an ABCD score of 4 ( table 2). Minor stroke was defined as an NIHSS score of 3 ( table 3). At 90 days, DAPT reduced the risk of nonfatal recurrent stroke compared with aspirin alone (6.3 versus 4.4 percent; relative risk [RR] 0.70, 95% CI 0.61-0.80; absolute risk reduction [ARR] 1.9 percent), possibly increased the risk of moderate or severe extracranial bleeding (RR 1.71, 95% CI 0.92-3.20; absolute risk increase [ARI] 0.2 percent), but had no apparent effect https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 5/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate on mortality (RR 1.27, 95% CI 0.73-2.23). Importantly, most strokes occurred within the first 10 days of randomization; the stroke rates between the treatment groups diverged quickly in the first days of treatment, but there was little or no incremental benefit of DAPT beyond 10 to 20 days. A similar 2021 meta-analysis pooled data from four trials (including POINT [16], CHANCE [17], and THALES [18]) comparing early treatment with DAPT versus aspirin alone for patients (over 21,000) with acute ischemic stroke or TIA [21]. Compared with aspirin alone, the risk of recurrent stroke was reduced with DAPT (5.8 versus 7.7 percent; RR 0.76, 95% CI 0.68-0.83; ARR 1.9 percent), whereas the risk of major bleeding was increased with DAPT (0.7 versus 0.3 percent; RR 2.22, 95% CI 1.14-4.34; ARI 0.4 percent). In a 2022 network meta-analysis of short-term DAPT that included five randomized trials with over 22,000 patients, both clopidogrel plus aspirin and ticagrelor plus aspirin were better than aspirin alone for reducing the risk of recurrent stroke and death, while the risk was similar comparing clopidogrel plus aspirin versus ticagrelor plus aspirin (HR 0.94, 95% CI 0.78-1.13) [19]. POINT and CHANCE trials The international POINT trial randomly assigned 4881 adults within 12 hours of onset of minor ischemic stroke or high-risk TIA to either DAPT using clopidogrel (600 mg loading dose, then 75 mg daily for 90 days) plus aspirin or to placebo plus aspirin for 90 days [16]. The aspirin dose in both groups was 50 to 325 mg daily. At 90 days, the composite outcome of major ischemic events (ischemic stroke, myocardial infarction, or death from an ischemic vascular event) was reduced for the clopidogrel-plus- aspirin group compared with the placebo-plus-aspirin group (5.0 versus 6.5 percent; ARR 1.5 percent; HR 0.75, 95% CI 0.59-0.95), as was the outcome of ischemic or hemorrhagic stroke (4.8 versus 6.4 percent; HR 0.74, 95% CI 0.58-0.94). However, the rate of major hemorrhage was increased for the clopidogrel-plus-aspirin group (0.9 versus 0.4 percent; HR 2.32, 95% CI 1.10-4.87). The CHANCE trial randomly assigned 5170 Chinese patients within 24 hours of onset of high-risk TIA or minor ischemic stroke to DAPT using either clopidogrel and aspirin (clopidogrel 300 mg loading dose, then 75 mg daily for 90 days, plus aspirin 75 mg daily for the first 21 days) or placebo and aspirin (75 mg daily for 90 days) [17]. Over one-half of the subjects in CHANCE had intracranial atherosclerosis. At 90 days, there was a significant reduction in all stroke for the clopidogrel-plus-aspirin group compared with the placebo plus aspirin group (8.2 versus 11.7 percent; ARR 3.5 percent; HR 0.68, 95% CI 0.57-0.81). The rate of hemorrhagic stroke was low in both treatment groups (0.3 percent in each). https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 6/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate The results of the CHANCE and POINT trials are not generalizable to all patients with TIA or acute ischemic stroke. Both trials excluded patients with isolated sensory symptoms, isolated visual changes, or isolated dizziness or vertigo. The POINT trial also excluded patients who were candidates for intravenous thrombolysis, endovascular interventions, and carotid endarterectomy. The Chinese population included in the CHANCE trial has higher rates of large artery intracranial atherosclerotic disease and lower rates of vascular risk factor control relative to other populations (see "Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Epidemiology'). Thus, it is uncertain how to apply the results of these trials to other populations, particularly patients with low-risk TIA, and those with moderate or severe acute ischemic stroke, who may be at higher risk for hemorrhagic transformation with DAPT. THALES trial The THALES trial, published in 2020, was not included in the meta-analysis cited above but provides additional data on the use of DAPT in patients with TIA and minor stroke. THALES randomly assigned 11,016 patients with mild to moderate noncardioembolic stroke (defined by an NIHSS score of 5) or high-risk TIA (defined by an 2 ABCD score of 6 or 7) to DAPT with ticagrelor and aspirin or to placebo and aspirin for 30 days [18]. Ticagrelor was given as a 180 mg loading dose followed by 90 mg twice daily; aspirin was given as 300 to 325 mg on the first day followed by 75 to 100 mg daily. The composite outcome of stroke or death within 30 days was lower for the ticagrelor-plus- aspirin group compared with the placebo-plus-aspirin group (5.5 versus 6.6 percent; ARR 1.1 percent; HR 0.83, 95% CI 0.71-0.96). There were 3314 patients in the THALES trial with an NIHSS score of 4 or 5; these patients would have been excluded from CHANCE and POINT because of their NIHSS score. In subgroup analysis, the benefit of DAPT was similar for patients with an NIHSS score of 4 or 5 and those with lower NIHSS score and/or TIA [22]. Severe bleeding was uncommon but was more frequent for the ticagrelor-plus-aspirin group (0.5 versus 0.1 percent; HR 3.99, 95% CI 1.74-9.14). Disability was similar between the two groups. Based on the results of the THALES trial, the US Food and Drug Administration (FDA) approved ticagrelor in combination with aspirin for the short-term treatment of acute minor ischemic stroke or high-risk TIA [23]. The THALES trial results are comparable to the POINT and CHANCE trials in supporting the role of DAPT for minor noncardioembolic stroke or high-risk TIA. Importantly, THALES supports the use of DAPT in subjects with minor stroke and an NIHSS score 5; DAPT using aspirin and clopidogrel was not studied in patients with an NIHSS score of 4 or 5 as they were not included in the POINT and CHANCE trials. https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 7/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate CYP2C19 variants and clopidogrel metabolism Genetic variation in clopidogrel metabolism due to loss-of-function CYP2C19 variants may affect the efficacy of clopidogrel, but evidence is conflicting. In a subgroup analysis of 2933 subjects in CHANCE who had genotyping for CYP2C19 genetic variants, the CYP2C19 *2 or *3 loss-of-function alleles were present in 59 percent [24]. Combined treatment with clopidogrel plus aspirin significantly reduced the risk of new stroke in noncarriers of the CYP2C19 loss-of-function alleles (6.7 percent, versus 12.4 percent for aspirin alone; HR 0.51, 95% CI 0.35-0.75) but not in carriers of the *2 or *3 loss-of-function alleles (9.4 versus 10.8 percent; HR 0.93, 95% CI 0.69-1.26). The CHANCE-2 trial enrolled 6412 Chinese patients with CYP2C19 loss-of-function alleles and acute minor ischemic stroke or high-risk TIA and randomly assigned them to DAPT for 21 days with either ticagrelor plus aspirin, or clopidogrel plus aspirin [25]. At 90 days, recurrent stroke was reduced in the ticagrelor group (6 versus 7.6 percent; HR 0.77, 95% CI 0.64-0.94). However, in a substudy of the POINT trial with 932 patients genotyped for CYP2C19 alleles, the rate of stroke or major ischemic events was similar for noncarriers and carriers of CYP2C19 loss-of-function alleles [26]. Confidence in this result is limited since the number of patients with CYP2C19 loss-of-function alleles (n = 326) in the POINT substudy was much lower than the cohort evaluated in CHANCE-2, and the event numbers in each group were very low. Notably, the POINT trial used a clopidogrel loading dose of 600 mg, compared with a 300 mg loading dose used in both CHANCE and CHANCE-2. It is possible that a higher clopidogrel loading dose may overcome some of the metabolic differences in patients with and without loss-of-function CYP2C19 variants. The possible relationship of loss-of-function CYP2C19 alleles and clinical outcomes for patients taking clopidogrel is discussed in greater detail separately. (See "Clopidogrel resistance and clopidogrel treatment failure", section on 'Loss of function gene carriers and outcomes'.) Intracranial large artery atherosclerosis It is possible (but not established) that treatment with DAPT (aspirin and clopidogrel) for 90 days in patients who had recently symptomatic intracranial large artery atherosclerosis with severe stenosis (70 to 99 percent) may have contributed to the relatively low rate of combined stroke and death that was observed in the aggressive medical treatment arm of the SAMMPRIS trial [27,28]. (See "Intracranial large artery atherosclerosis: Treatment and prognosis", section on 'Stenting'.) Other antiplatelets We typically do not use other antiplatelets as monotherapy in the setting of acute ischemic stroke, but exceptions may be made in select clinical scenarios, such as when https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 8/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate an allergy to aspirin or clopidogrel is present. Ticagrelor Few randomized trials have tested aspirin directly against other antiplatelet agents for the treatment of ischemic stroke or TIA in the acute period. In the SOCRATES trial of over 13,000 subjects with acute ischemic stroke or TIA, ticagrelor monotherapy was not significantly better than aspirin monotherapy (both started within 24 hours of symptom onset) for the 90-day composite endpoint of stroke, myocardial infarction, or death [29]. However, in a prespecified exploratory analysis, ticagrelor was superior to aspirin in the subgroup of patients who had stroke of possible atherosclerotic origin, which was defined by the presence of ipsilateral atherosclerotic stenosis of an extracranial or intracranial artery (including <50 percent stenosis) or mobile thrombus or thick plaque ( 4 mm) in the aortic arch [30]. These data suggest that patients with atherosclerotic stroke may benefit from antiplatelet therapy other than aspirin. However, the optimal definition of "atherosclerotic" stroke and the optimal treatment strategy are uncertain. Clopidogrel Clopidogrel has not been well studied as monotherapy in trials that start treatment in the first 24 to 48 hours of acute ischemic stroke. However, clopidogrel is a first-line antiplatelet agent for the secondary prevention of ischemic stroke, as demonstrated in trials that started treatment one week or more after the onset of ischemic stroke. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Clopidogrel'.) The short-term use of clopidogrel in combination with aspirin for acute ischemic stroke is discussed below. Cilostazol Cilostazol monotherapy is a reasonable option for long-term secondary ischemic stroke prevention in East Asian populations, and for all populations if other agents are not available or tolerated. This is reviewed separately. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Cilostazol'.) Limited role of early anticoagulation In agreement with the national guidelines [1,31], we recommend not using full-dose parenteral anticoagulation (eg, intravenous heparin) for treatment of unselected patients with acute ischemic stroke because of minimal efficacy and an increased risk of bleeding complications. Instead, we recommend early antiplatelet therapy for most patients with acute ischemic stroke or TIA. (See 'Treatment on presentation' above and 'Treatment by ischemic mechanism' below.) Patients already on anticoagulation For most patients on anticoagulation at the time of acute ischemic stroke onset, anticoagulation should be stopped, at least for the short term, https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 9/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate while determining eligibility for acute reperfusion therapies. However, there is no consensus regarding continuation or temporary stopping of anticoagulation at the time of acute ischemic stroke onset in patients using anticoagulation, and evidence related to this question is limited to observational studies [32]. For patients with uncomplicated minor stroke and an appropriate indication, long-term oral anticoagulation can be restarted when the patient is stable, such as at hospital discharge or 24 to 48 hours after stroke onset, depending upon the agent chosen and individual patient factors. Subtherapeutic anticoagulation intensity may be implicated in patients with atrial fibrillation and should be managed accordingly (see 'Anticoagulant failure' below). For patients with large acute infarction, we start aspirin in the interim if there are no significant bleeding complications; oral anticoagulation can be resumed according to indication (and aspirin stopped) after one to two weeks if the patient is stable. (See 'Atrial fibrillation' below and 'Timing of long-term anticoagulation' below and 'Contraindications' below.) A similar approach, stated by European guidelines, suggests anticoagulation can be started or resumed immediately for patients with a TIA and started or resumed at 3 days after onset for patients with minor ischemic stroke and persisting mild neurologic deficit [33]. For patients with ischemic stroke and a moderate neurologic deficit, anticoagulation can be started or resumed at six to eight days, and for those with a severe neurologic deficit, at 12 to 14 days; in both cases, repeat brain imaging should be obtained to exclude significant hemorrhagic transformation within 24 hours prior to starting or resuming anticoagulation. Indications to start or continue anticoagulation TIA For patients with a clear indication for anticoagulation (eg, atrial fibrillation, venous thromboembolism, mechanical heart valve) at onset of TIA, we recommend starting or continuing anticoagulation rather than antiplatelet therapy. In patients who are subtherapeutically or not anticoagulated at presentation, bridging anticoagulation with heparin, low molecular weight heparin, or a direct oral anticoagulant (DOAC) should be considered. In patients who are therapeutically anticoagulated at presentation, management should be individualized based on the underlying mechanism of the TIA. In some instances, such as when the TIA is more likely due to atherosclerosis than to cardioembolism, it may be reasonable to add antiplatelet therapy. Triple therapy (ie, anticoagulation plus DAPT) is associated with a high risk of hemorrhage and should be avoided. (See 'Anticoagulant failure' below.) Acute ischemic stroke Although benefit is unproven, we suggest early parenteral anticoagulation rather than aspirin only for select patients with acute cardioembolic https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 10/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate ischemic stroke or TIA due to intracardiac thrombus in the left ventricle or thrombus associated with mechanical or native heart valves who are at high short-term risk for recurrent stroke. While many specialists believe it has no role at all in the early acute phase of ischemic stroke, some experts have used early anticoagulation for other ischemic stroke subtypes, including cardioembolic stroke due to atrial fibrillation and stroke due to large artery stenoses or arterial dissection. However, a review of the literature does not support the routine use of anticoagulation in these subgroups [31]. Patients with mechanical heart valves or intracardiac thrombus were either not included or were underrepresented in trials of acute antithrombotic therapy for stroke. In the only trial of intravenous unfractionated heparin in hyperacute stroke, a single center in Italy randomly assigned 418 patients with nonlacunar hemispheric infarction (of cardioembolic, atherothrombotic, or unknown/undetermined origin) to receive either intravenous heparin or saline within three hours of stroke onset [34]. Treatment continued for five days. A favorable outcome at 90 days, the primary endpoint, was significantly more frequent in patients assigned to heparin compared with those assigned to saline (39 versus 29 percent). Heparin use was associated with an increased risk of intracranial and extracranial bleeding but no increase in mortality. A majority of patients enrolled in the trial were eligible for intravenous thrombolysis, but none received it since intravenous thrombolysis had not been approved in Italy at the time. No or uncertain role No benefit for acute stroke due to atrial fibrillation Early treatment with heparin for patients who have an acute cardioembolic stroke does not reduce the risk of recurrent ischemic stroke but is associated with an increased risk of symptomatic intracranial hemorrhage, as discussed below. (See 'Atrial fibrillation' below.) No benefit for progressing stroke Heparin was once widely used to treat patients who continued to have neurologic deterioration in the first hours or days after ischemic stroke (ie, progressing stroke, also referred to as stroke in evolution). The TOAST trial did not find an improvement in outcomes with danaparoid treatment in such patients [35], nor did a nonrandomized study of heparin therapy [36]. These findings do not support a role for heparin in halting neurologic worsening after stroke. No benefit for unselected patients The largest randomized controlled trial (IST) studied two doses of subcutaneous heparin in 19,435 patients with undefined ischemic stroke and found no significant benefit with heparin [4]. A systematic review updated in 2021 https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 11/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate examined the effect of anticoagulant therapy versus control in the early treatment of patients with acute ischemic stroke [37]. This review included 28 trials involving 24,025 subjects; approximately 80 percent of the subjects were from the IST trial. There was considerable variation in the quality of the trials. The anticoagulants tested were standard unfractionated heparin, low molecular weight heparins, heparinoids, oral anticoagulants, and thrombin inhibitors. The following were the major findings [37]: Anticoagulant therapy did not reduce the risk of death from all causes (odds ratio [OR] 0.99, 95% CI 0.90-1.09). Anticoagulants did not reduce the risk of being dead or dependent at the end of follow- up (OR 0.98, 95% CI 0.92-1.03). Anticoagulants reduced the odds of recurrent ischemic stroke (OR 0.75, 95% CI 0.65-0.88) but increased the risk of symptomatic intracranial hemorrhage (OR 2.99, 95% CI 2.24-3.99). Uncertain benefit for large vessel atherosclerotic disease Clinical trials have not adequately evaluated adjusted intravenous anticoagulation in patients with selected stroke subtypes. With this caveat in mind, there are conflicting data regarding the benefit of intravenous unfractionated heparin or low molecular weight heparin in the subgroup of patients with large vessel atherosclerotic disease. Note that these trials included many patients with minor ischemic stroke who would now be treated with short-term DAPT, but the comparator at the time was aspirin monotherapy. The TOAST trial evaluated the efficacy of the low molecular weight heparinoid danaparoid administered as an intravenous bolus within 24 hours of symptom onset and continued for seven days in 1281 patients with acute ischemic stroke [35]. Compared with placebo, danaparoid was associated with no improvement in overall outcome at three months (75 versus 74 percent rates of favorable outcome). However, subgroup analysis suggested a higher rate of favorable outcomes in patients treated with danaparoid who had a large artery atherosclerotic stroke (68 versus 55 percent with placebo). The FISS-tris trial evaluated the low molecular weight heparin nadroparin (3800 anti- factor Xa international units, 0.4 mL subcutaneously twice daily) versus aspirin (160 mg once daily) started within 48 hours of acute ischemic stroke onset and continued for 10 days [38]. The main study population was 353 patients with confirmed large artery occlusive disease, consisting of 300 with intracranial, 11 with extracranial, and 42 with both intracranial and extracranial disease. The mean time to treatment was nearly 30 hours. There was no significant difference between treatment with nadroparin or https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 12/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate aspirin for the proportion of patients with good outcome at six months, defined by a table 4) score of 85 (73 versus 69 percent). However, there was a Barthel Index ( significant benefit to low molecular weight heparin in a prespecified secondary outcome measure, good outcome defined by a modified Rankin Scale ( table 5) score of 0 to 1 (54 versus 44 percent; OR 1.55, 95% CI 1.02-2.35). Contraindications Anticoagulation in the setting of acute stroke may only be considered after a brain imaging study has excluded hemorrhage and estimated the size of the infarct. Early anticoagulation should be avoided when potential contraindications to anticoagulation are present, such as a large infarction (based upon clinical syndrome or brain imaging findings); severe uncontrolled, persistent hypertension (eg, systolic blood pressure 185 or diastolic blood pressure 110 mmHg); symptomatic hemorrhagic infarction; or other bleeding conditions. Although there is no standard definition, many stroke experts consider "large" infarcts to be those that involve more than one-third of the middle cerebral artery territory or more than one- half of the posterior cerebral artery territory based upon neuroimaging with computed tomography (CT) or magnetic resonance imaging (MRI). Infarct size can also be clinically defined, but this process can underestimate the true infarct volume when so-called "silent" areas of association cortex are involved. Clinical estimation of infarct size may be improved by using validated scales that have been correlated with infarct volume and clinical outcome, such as the NIHSS ( table 3). As an example, one study found that an NIHSS score >15 was associated with a median infarct volume 3 of 55.8 cm and worse outcome than NIHSS scores of 1 to 7 (median infarct volume of 7.9 cm ) 3 3 or 8 to 15 (median infarct volume of 31.4 cm ) [39]. Thus, patients with an NIHSS score >15 generally have a large infarct. However, it should be recognized that part of the clinical deficit in the early hours of an acute stroke may be attributed to the penumbra, where the brain is ischemic but not infarcted. Additionally, NIHSS cutoffs may not apply equally well in both hemispheres. It is possible to have a relatively large infarct in the right hemisphere with a low NIHSS [40]. TREATMENT BY ISCHEMIC MECHANISM Once the evaluation for transient ischemic attack (TIA) or ischemic stroke is complete, antithrombotic therapy can be modified as necessary according to the ischemic mechanism ( algorithm 4 and algorithm 5). Cardioembolic source https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 13/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Atrial fibrillation While parenteral anticoagulation (eg, intravenous heparin) is generally not recommended for treating ischemic stroke in the acute period, oral anticoagulation with warfarin or a direct oral anticoagulant (DOAC) is recommended for secondary stroke prevention in patients with atrial fibrillation and other high-risk sources of cardiogenic embolism. (See "Stroke in patients with atrial fibrillation" and "Atrial fibrillation in adults: Use of oral anticoagulants".) The timing of oral anticoagulation initiation for such patients is mainly dependent on the size of the acute infarct and the presence of factors such as symptomatic hemorrhagic transformation and/or poorly controlled hypertension. Oral anticoagulation can be started immediately for patients with TIA due to atrial fibrillation and soon after onset for medically stable patients with a small- or moderate-sized infarct and no bleeding complications. For patients with large infarctions, symptomatic hemorrhagic transformation, or poorly controlled hypertension, withholding oral anticoagulation for one to two weeks is generally recommended [41]. (See 'Timing of long-term anticoagulation' below.) Although once widely practiced, early treatment with heparin for patients with atrial fibrillation who have an acute cardioembolic stroke causes more harm than good. A 2007 meta-analysis examined seven randomized controlled trials involving 4624 patients and compared heparin or low molecular weight heparins started within 48 hours for acute cardioembolic stroke with other treatments (aspirin or placebo) [42]. The following observations were reported: Parenteral anticoagulants led to a nonsignificant reduction in recurrent ischemic stroke within 7 to 14 days (3.0 versus 4.9 percent; OR 0.68, 95% CI 0.44-1.06) Parenteral anticoagulants led to an increase in symptomatic intracranial hemorrhage (2.5 versus 0.7 percent; OR 2.89, 95% CI 1.19-7.01)