In May 2019, the Guideline Oversight Committee of the KSS decided to update the Korean CPG for antithrombotic therapy in patients with AIS or TIA and appointed members of the writing group recommended by the CPG Committee of the KSS. To achieve consensus, the CPG Committee organized an expert panel consisting of 35 experts. The writing group prepared revised recommendations, and expert panel members reached a consensus after two Delphi rounds in May 2020. The Guideline Oversight Committee reviewed and approved drafts prepared by the writing group.

For the updated information on antithrombotic therapy in AIS or TIA, we searched and assessed the results of randomized controlled trials (RCTs), pooled analyses, and updated major international guidelines published between January 2009 and May 2020. Additionally, we reviewed relevant articles solicited by experts who participated in the current guideline update.

For each recommendation, the LOE and GOR were determined based on the US Agency for Healthcare Policy and Research (currently the Agency for Healthcare Research and Quality) criteria (Table 1) [15]. We used this grading system to accord with recommendations of other subjects in the Korean CPGs for stroke.

The Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) trial compared triple antiplatelet therapy (aspirin, dipyridamole, and clopidogrel) and standard therapy (clopidogrel monotherapy or aspirin plus dipyridamole) in patients with acute non-cardioembolic ischemic stroke (presenting with limb weakness, dysphasia, or neuroimaging-positive hemianopia) or TIA (presenting with at least 10 minutes of limb weakness or isolated dysphasia) within 48 hours from symptom onset [9]. Patients from the United Kingdom (95%), Georgia, Denmark, and New Zealand were randomized to triple therapy (n=1,556) or standard treatment (n=1,540). During the trial, patients maintained their assigned treatment for the first 30 days and were treated according to local guidelines from day 31 to day 90. The TARDIS trial was terminated early after enrollment of 76% of the planned sample size because of a significant increase in major bleeding events and no signs of efficacy with triple therapy. Of the qualifying events, 72% were AISs. The median interval from onset to randomization was 29.3 hours, and 69% of patients were enrolled 24 hours after onset.

There was no difference in the primary efficacy outcome (incidence and severity of recurrent stroke or TIA at 90 days) between the triple and standard therapy groups (6% vs. 7%; adjusted common odds ratio [OR], 0.90; 95% CI, 0.67 to 1.20; P=0.47). However, triple therapy, compared to standard therapy, had significantly more bleeding events (20% vs. 9%) and was associated with a worse shift on the five-level ordinal bleeding severity scale (fatal, major, moderate, minor, and none) (adjusted common OR, 2.54; 95% CI, 2.05 to 3.16; P<0.0001). Intracranial bleeding occurred more frequently in the triple therapy group (1% vs. <1%; HR, 3.14; 95% CI, 1.14 to 8.61; P=0.026).

The Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial compared ticagrelor and aspirin in patients with acute minor ischemic stroke (NIHSS score ≤5) or high-risk TIA (ABCD₂ score ≥4) within 24 hours of symptom onset [10]. The ticagrelor group received a 180-mg loading dose followed by 90 mg twice daily for 90 days, and the aspirin group received a 300-mg loading dose followed by 100 mg once daily for 90 days. The trial enrolled 13,199 patients from 33 countries (66.5% white, 26.9% Asian, 1.8% black, and 2.1% other races). Of the enrolled patients, 36.5% were randomized within 12 hours of onset, and 73.2% had acute minor ischemic stroke.

Compared to aspirin, ticagrelor did not significantly reduce the primary endpoint of the composite of recurrent stroke, myocardial infarction, or death at 90 days (6.7% vs. 7.5%; HR, 0.89; 95% CI, 0.78 to 1.01; P=0.07). Of secondary efficacy outcomes, the ticagrelor group, compared to the aspirin group, had lower risks of ischemic stroke (5.8% vs. 6.7%; HR, 0.87; 95% CI, 0.76 to 1.00; P=0.046) and any stroke (5.9% vs. 6.8%; HR, 0.86; 95% CI, 0.75 to 0.99; P=0.03). However, the predefined statistical plan was a hierarchical testing sequence where the statistical significance for each secondary endpoint could be accepted if the primary endpoint achieved statistical significance. Therefore, the positive results for preventing ischemic stroke and any stroke should be considered exploratory. The ticagrelor and aspirin groups had a similar risk of major bleeding (0.5% vs. 0.6%; HR, 0.83; 95% CI, 0.52 to 1.34; P=0.45), but patients on ticagrelor were more likely than those on aspirin to experience dyspnea (6.2% vs. 1.4%).

The Acute Stroke or Transient Ischaemic Attack Treated with Ticagrelor and Acetylsalicylic acid for Prevention of Stroke and Death (THALES) trial was published after completing our consensus achievement for this guideline update; therefore, we have not reflected the results of the THALES trial in the updated recommendations. In brief, the THALES trial compared ticagrelor (180-mg loading dose followed by 90 mg twice daily) plus aspirin (300 to 325 mg on day 1 followed by 75 to 100 mg daily) versus aspirin monotherapy in 11,016 patients with acute minor ischemic stroke (NIHSS score ≤5) or high-risk TIA (ABCD₂ score ≥6 or relevant intracranial or extracranial stenosis ≥50%) within 24 hours of symptom onset [17]. At 30 days, the ticagrelor plus aspirin group compared to the aspirin monotherapy group had lower risks of the primary efficacy outcome of stroke or death (5.4% vs. 6.5%; HR, 0.83; 95% CI, 0.71 to 0.96; P=0.020) and ischemic stroke (5.0% vs. 6.3%; HR, 0.79; 95% CI, 0.68 to 0.93; P=0.004). However, the combination therapy group compared to the aspirin group had significantly more cases of severe bleeding (0.5% vs. 0.1%; HR, 3.99; 95% CI, 1.74 to 9.14; P=0.001) and intracranial hemorrhage (ICH) or fatal bleeding (0.4% vs. 0.1%; HR, 3.66; 95% CI, 1.48 to 9.02; P=0.005).

The previous recommendation to avoid antithrombotic therapy within the first 24 hours after intravenous thrombolysis (IVT) was based on expert consensus. No RCT has investigated the timing of antithrombotic initiation after IVT, and data from well-designed observational studies are scarce. A single-center observational study in Korea reported that the early administration of antithrombotics within 24 hours after reperfusion therapy was safe. In this study, of 712 patients treated with reperfusion therapy (34% IVT only, 34% IVT plus mechanical thrombectomy [MT], and 32% MT only), 456 (64%) patients received antithrombotic therapy within 24 hours after reperfusion therapy. Early initiation of antithrombotic therapy within 24 hours as compared to late initiation after 24 hours did not increase the risk of symptomatic HT (3.3% vs. 3.1%; adjusted OR, 0.85; 95% CI, 0.35 to 2.10). Any HT was even lower in the early initiation group (adjusted OR, 0.56; 95% CI, 0.35 to 0.89). The rate of 3-month favorable outcomes (modified Rankin Scale [mRS] score 0-1) was comparable between the early and late initiation groups (39.3% vs. 34.8%; OR, 1.09; 95% CI, 0.75 to 1.59). In the interaction analysis, the modality of reperfusion therapy (IVT, IVT plus MT, or MT) did not modify the associations between the initiation timing and symptomatic HT, any HT, or mRS outcome [18]. These findings were reflected in the 2019 American Heart Association/American Stroke Association stroke guidelines as follows: Section 3.9. Antiplatelet Treatment-Administration of aspirin is recommended in patients with AIS within 24 to 48 hours after onset. For patients treated with intravenous (IV) alteplase, aspirin administration is generally delayed until 24 hours later, but might be considered in the presence of concomitant conditions for which such treatment given in the absence of IV alteplase is known to provide substantial benefit or withholding such treatment is known to cause substantial risk (class of recommendation: I, LOE: A).

The Cilostazol in Acute Ischemic Stroke Treatment (CAIST) trial conducted in Korea was a randomized double-blind non-inferiority trial that compared cilostazol 200 mg/day and aspirin 300 mg/day in 458 patients with AIS (NIHSS ≤15) within 48 hours of symptom onset for 90 days [19]. The primary endpoint of 90-day mRS 0-2 was achieved in 76% of the cilostazol group and 75% of the aspirin group. Both intention-to-treat and per-protocol analyses showed non-inferiority of cilostazol to aspirin (one-sided 95% CI of the proportion difference, −6.15% to 7.22%; P=0.0004 [intention-to-treat analysis]; one-sided 95% CI, −9.82% to 4.51%; P=0.045 [per-protocol analysis]). Cardiovascular events (3% vs. 4%, P=0.41) and bleeding complications (11% vs. 13%, P=0.43) were comparable between the two groups. However, the trial had the shortcomings of a small sample size and wide non-inferiority margin.

An earlier RCT failed to demonstrate the safety and efficacy of IV abciximab in patients with AIS [20]. Accordingly, the previous Korean stroke guidelines did not recommend IV glycoprotein IIb/IIIa receptor antagonists for acute antithrombotic therapy [14]. In patients treated with MT, rescue therapy is often required for those with incomplete recanalization or re-occlusion due to in situ thrombosis. No RCT has demonstrated the benefit of parenteral glycoprotein IIb/IIIa receptor antagonists as rescue therapy during MT. A recent observational study suggested that tirofiban rescue therapy was safe in patients with unsuccessful recanalization after MT [21]. The rate of symptomatic ICH was 13.6% (21/154) in patients treated with tirofiban and 16.7% (80/478) in those who did not receive tirofiban (OR, 0.69; 95% CI, 0.36 to 1.31; P=0.26). The 90-day mortality rates in the two groups were 3.2% and 5.4% (OR, 0.66; 95% CI, 0.36 to 1.31; P=0.15). In the subgroup of patients with acute atherosclerotic large artery occlusion, tirofiban use was associated with lower mortality (11.3% vs. 23.4%, P=0.042).

Two recent Korean observational studies reported the safety and feasibility of IV or intra-arterial tirofiban in patients with acute atherosclerotic large artery occlusion who underwent MT. In one study of 118 patients with residual stenosis after MT, the tirofiban group (n=59) had a higher final successful recanalization rate (81.4% vs. 42.4%, P=0.016) and a numerically lower rate of major intracranial bleeding of parenchymal hematoma type 2 and/or thick subarachnoid hemorrhages (15.3% vs. 5.1%, P=0.068) than did the non-tirofiban group (n=59). The tirofiban group compared to the non-tirofiban group achieved a better 3-month functional outcome (mRS score 0-2, 52.5% vs. 32.2%, P=0.025) [22]. In another study, 98 patients who underwent thrombectomy followed by angioplasty, with or without stenting for the residual intracranial atherosclerotic stenosis, were divided into an IV tirofiban group (n=30) and control group (n=68). The rates of parenchymal hemorrhage (6.7% [n=2] vs. 5.9% [n=4], P=0.99), symptomatic hemorrhage (0% [n=0] vs. 2.9% [n=2], P=0.99), 90-day mortality (0% [n=0] vs. 4.4% [n=3], P=0.55), and 90-day mRS score of 0-2 (73.3% [n=22] vs. 57.4% [n=39], P=0.13) were not significantly different between the tirofiban and control groups. Early reocclusion occurred less frequently in the tirofiban group than in the control group (3.3% [n=1] vs. 25.0% [n=17], P=0.01) [23].

Long-term oral anticoagulation therapy with NOAC or warfarin is strongly recommended for secondary stroke prevention in patients with AF with prior ischemic stroke or TIA [11,13]. During the acute period after AF-related ischemic stroke, anticoagulation might reduce the risk of recurrent ischemic stroke, but potentially increases the risk of ICH.

Parenteral anticoagulation is not recommended because the benefit is offset by an increased risk of ICH [2,24-27]. For oral anticoagulation, no clinical trial has formally investigated warfarin treatment in patients with AIS, and the large NOAC trials excluded AF patients who had experienced stroke within 7 to 30 days [28-31]. Therefore, despite the clear benefit of long-term oral anticoagulation in AF patients with ischemic stroke or TIA, the optimal timing of initiating oral anticoagulation after acute cerebral ischemia is still uncertain. Recently, several observational studies and a small RCT have reported the safety and efficacy of early oral anticoagulation in AF patients with AIS or TIA [32-35]. However, the evidence level from these studies is insufficient, and the recommendation for early oral anticoagulation is not unified across guidelines. The European, Canadian, and Australian stroke guidelines do not provide specific recommendations for the timing of initiating oral anticoagulation after AIS [7,8,12]. The 2018 European Heart Rhythm Association provides specific recommendations for NOAC initiation according to stroke severity based on con­sensus of opinion [13]. The 2019 American Stroke Association Guidelines state that it is reasonable to initiate oral anticoagulation between 4 and 14 days after the onset of neurological symptoms (moderate strength of recommendation based on evidence from non-randomized studies) [6].