High-risk Transient Ischemic Attack Research Articles

Review of the Ticagrelor Trials Evidence Base.

Ticagrelor is a platelet P2Y12 receptor inhibitor approved for use in patients with acute coronary syndromes, coronary artery disease, and low-moderate risk acute ischemic stroke or high-risk transient ischemic attack. Clinical trials have evaluated the efficacy and safety of ticagrelor on ischemic and bleeding outcomes for different indications and with varying treatment approaches. As a result, there is a large body of clinical evidence demonstrating different degrees of net clinical benefit compared with other platelet inhibitor drugs based on indication, patient characteristics, clinical presentation, treatment duration, and other factors. We provide a review of the major trials of ticagrelor in the context of other randomized trials of clopidogrel and prasugrel to organize the volume of available information, elevate corroborating and conflicting data, and identify potential gaps as areas for further exploration of optimal antiplatelet treatment.

Comparison of Dual Antiplatelet Therapies for Minor, Nondisabling, Acute Ischemic Stroke: A Bayesian Network Meta-Analysis.

Dual antiplatelet therapy (DAPT) appears to be an effective treatment option for minor (nondisabling) acute ischemic stroke. This conclusion is based on trials that include both transient ischemic attack (TIA) and minor stroke; however, these 2 conditions may differ. To compare DAPT regimens specifically for minor stroke. PubMed was searched for randomized clinical trials published up to November 4, 2023. Search terms strategy included TIA, transient ischemic attack, minor stroke, or moderate stroke, with the filter randomized controlled trial. Unpublished data on minor stroke were sourced from authors and/or institutions. Trials testing DAPT within the first 24 hours of a minor stroke (defined as a National Institutes of Health Stroke Scale score ≤5) were included by consensus. Of 1508 studies screened, 6 (0.3%) initially met inclusion criteria and were reviewed. The study was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by multiple observers. Bayesian fixed-effect network meta-analysis was conducted. Secondary analysis performed for high-risk TIA alone. Treatments were ranked using a probability measure called surface under the cumulative rank curve (SUCRA). The primary outcome was subsequent ischemic stroke at 90 days. Secondary outcomes included major hemorrhage, mortality, and hemorrhagic stroke. The number needed to treat (NNT) and number needed to harm (NNH) were obtained. Five trials were included that described 28 148 patients, of whom 22 203 (78.9%) had a minor stroke. Of these, 13 995 (63.0%) were in DAPT groups and 8208 (37.0%) in aspirin (acetylsalicylic acid) groups. Aspirin and ticagrelor had a 94% probability of being the superior treatment for minor stroke (SUCRA, 0.94) for the primary outcome. Both aspirin and ticagrelor (NNT, 40; 95% CI, 31-64) and aspirin and clopidogrel (NNT, 58; 95% CI, 39-136) were superior to aspirin alone in the prevention of recurrent ischemic stroke at 90 days. Both treatments had higher rates of major hemorrhage than aspirin alone (NNH for aspirin and ticagrelor, 284; 95% CI, 108-1715 vs NNH for aspirin and clopidogrel, 330; 95% CI, 118-3430), but neither had increased risk of hemorrhagic stroke or death. For high-risk TIA, ticagrelor and aspirin had a 60% probability (SUCRA, 0.60) and clopidogrel and aspirin had a 40% probability (SUCRA 0.40) of being a superior treatment; neither was optimum, but both were superior to aspirin alone for the primary outcome. These findings suggest that DAPT with aspirin and ticagrelor has higher probability of being the superior treatment among patients with minor stroke when presence of CYP2C19 loss-of-function alleles has not been excluded. For patients with TIA, the superiority of aspirin and ticagrelor vs aspirin and clopidogrel was not demonstrated.

Safety and Efficacy of Dual Antiplatelet Therapy in Patients with Minor Ischemic Stroke or High-risk Transient Ischemic Attack After Intravenous Thrombolysis (P8-5.029)

Safety and Efficacy of Dual Antiplatelet Therapy in Patients with Minor Ischemic Stroke or High-risk Transient Ischemic Attack After Intravenous Thrombolysis (P8-5.029)

Cost-Effectiveness of Increased Use of Dual Antiplatelet Therapy After High-Risk Transient Ischemic Attack or Minor Stroke.

Rates of dual antiplatelet therapy (DAPT) after high-risk transient ischemic attack or minor ischemic stroke (TIAMIS) are suboptimal. We performed a cost-effectiveness analysis to characterize the parameters of a quality improvement (QI) intervention designed to increase DAPT use after TIAMIS. We constructed a decision tree model that compared current national rates of DAPT use after TIAMIS with rates after implementing a theoretical QI intervention designed to increase appropriate DAPT use. The base case assumed that a QI intervention increased the rate of DAPT use to 65% from 45%. Costs (payer and societal) and outcomes (stroke, myocardial infarction, major bleed, or death) were modeled using a lifetime horizon. An incremental cost-effectiveness ratio <$100 000 per quality-adjusted life year was considered cost-effective. Deterministic and probabilistic sensitivity analyses were performed. From the payer perspective, a QI intervention was associated with $9657 in lifetime cost savings and 0.18 more quality-adjusted life years compared with current national treatment rates. A QI intervention was cost-effective in 73% of probabilistic sensitivity analysis iterations. Results were similar from the societal perspective. The maximum acceptable, initial, 1-time payer cost of a QI intervention was $28 032 per patient. A QI intervention that increased DAPT use to at least 51% was cost-effective in the base case. Increasing DAPT use after TIAMIS with a QI intervention is cost-effective over a wide range of costs and proportion of patients with TIAMIS treated with DAPT after implementation of a QI intervention. Our results support the development of future interventions focused on increasing DAPT use after TIAMIS.

Stroke and high-risk TIA outcomes with reduction of treatment duration when treatment initiated in emergency rooms (SHORTER-study).

Following transient ischemic attack (TIA) and minor stroke, the risk of recurrent stroke can be significantly reduced with short-duration dual antiplatelet therapy (DAPT). We wish to investigate whether 10 days of DAPT is as effective as 21 days' treatment. This is an open-label, randomized, parallel-group study comparing whether 10 days of DAPT treatment (ASA + clopidogrel) is non-inferior to 21 days of DAPT in patients with acute ischemic stroke (AIS) or high-risk TIA. In both groups, DAPT is started within 24 hours of symptom onset. This study is being conducted in approximately 15 study sites in the Kingdom of Saudi Arabia. The planned sample size is 1932. Non-inferiority of 10 days compared to 21 days of DAPT in the prevention of the composite endpoint of stroke and death at 90 days in AIS/TIA patients. The primary safety outcome is major intra-cranial and systemic hemorrhage. Enrolment started in the second quarter of 2023, and the completion of the study is expected in the fourth quarter of 2025. The trial is expected to show that 10 days of DAPT is non-inferior for the prevention of early recurrence of vascular events in patients with high-risk TIAs and minor strokes.

LDL-C Levels and Bleeding Risk in Patients Taking DAPT After Minor Ischemic Stroke or TIA

Evidence on the bleeding risk associated with low-density lipoprotein cholesterol (LDL-C) levels in patients receiving dual antiplatelet therapy (DAPT) remains sparse. To investigate the association of LDL-C levels with bleeding risk in patients with minor ischemic stroke (MIS) or high-risk transient ischemic attack (HRTIA) receiving DAPT. This cohort study was an analysis of pooled data from 2 randomized, double-blind, placebo-controlled clinical trials in China of patients with MIS or HRTIA who were receiving DAPT: the CHANCE (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) trial enrolled patients at 114 sites from October 2009 to July 2012, and the CHANCE-2 enrolled patients at 202 centers from September 2019 to March 2021. Both sets of patients were followed up for 90 days. Data analysis was performed from August 2022 to May 2023. Baseline LDL-C levels and receipt of ticagrelor-aspirin and clopidogrel-aspirin DAPT. The primary outcome was any bleeding, and the secondary outcome was severe or moderate bleeding within 3 months after randomization. The association of LDL-C levels and all outcomes was assessed by using the Cox proportional hazard model. Hazard ratios (HRs) with 95% CIs were calculated on univariable (unadjusted) Cox regression models. Adjusted HRs (aHRs) and their 95% CIs were calculated on multivariable Cox regression models. In total, 8996 patients with acute MIS or HRTIA who were receiving DAPT were included in the 2 trials, of whom 1066 without serum specimens and 490 patients with missing baseline LDL-C value were excluded. Finally, 7440 patients with DAPT (4486 in the clopidogrel-aspirin group and 2954 in the ticagrelor-aspirin group) were included in this study. The median (IQR) age was 64.32 (56.56-71.30) years, and 2479 patients (33.32%) were women. A total of 270 (3.63%) bleeding events were reported at 3 months, and LDL-C less than 70 mg/dL was associated with an increased risk of both any bleeding (aHR, 1.48; 95% CI, 1.03-2.12), and severe or moderate bleeding (aHR, 2.78; 95% CI, 1.18-6.53). The risk of any bleeding was increased at lower LDL-C levels in the ticagrelor-aspirin group (aHR, 1.71; 95% CI, 1.08-2.72). However, an increased risk of any bleeding was not observed in the clopidogrel-aspirin group (aHR, 1.30; 95% CI, 0.73-2.30). There was no significant association between LDL-C levels and the risk of severe or moderate bleeding in either the ticagrelor-aspirin or clopidogrel-aspirin group. These findings suggest that low LDL-C levels are associated with an increased bleeding risk within 3 months among patients with MIS or HRTIA receiving DAPT, especially those taking ticagrelor-aspirin. Weighing the risks and benefits is crucial when simultaneously considering the selection of LDL-C target strategies and DAPT regimens among these patients.

Clopidogrel with indobufen or aspirin in minor ischemic stroke or high-risk transient ischemic attack: a randomized controlled clinical study

BackgroundIschemic stroke and transient ischemic attack (TIA) are the most prevalent cerebrovascular diseases. The conventional antiplatelet drugs are associated with an inherent bleeding risk, while indobufen is a new antiplatelet drug and has the similar mechanism of antiplatelet aggregation as aspirin with more safety profile. However, there have been no studies evaluating the combination therapy of indobufen and clopidogrel for antiplatelet therapy in cerebrovascular diseases.ObjectiveThe CARMIA study aims to investigate the effectiveness and safety of a new dual antiplatelet therapy consisting of indobufen and clopidogrel comparing with the conventional dual antiplatelet therapy consisting of aspirin and clopidogrel in patients with minor ischemic stroke or high-risk TIA.MethodsAn open-label randomized controlled clinical trial was conducted at a clinical center. We randomly assigned patients who had experienced a minor stroke or transient ischemic attack (TIA) within 72 h of onset, or within 1 month if they had intracranial stenosis (IS), to receive either indobufen 100 mg twice daily or aspirin 100 mg once daily for 21 days. For patients with IS, the treatment duration was extended to 3 months. All patients received a loading dose of 300 mg clopidogrel orally on the first day, followed by 75 mg once daily from the second day to 1 year. We collected prospective data using paper-based case report forms, and followed up on enrolled patients was conducted to assess the incidence of recurrent ischemic stroke or TIA, mRS score, NIHSS (National Institutes of Health Stroke Scale) score, and any bleeding events occurring within 3 month after onset.ResultsWe enrolled 202 patients diagnosed with ischemic stroke or transient ischemic attack. After applying the criteria, 182 patients were eligible for data analysis. Endpoint events (recurrence of ischemic stroke/TIA, myocardial infarction, or death) were observed in 6 patients (6.5%) receiving aspirin and clopidogrel, including 4 (4.3%) with stroke recurrence, 1 (1.1%) with TIA recurrence, and 1 (1%) with death. In contrast, no endpoint events were reported in the indobufen and clopidogrel group (P = 0.029). The group of patients receiving indobufen and clopidogrel exhibited significantly lower modified Rankin Scale (mRS) score. (scores range from 0 to 6, with higher scores indicating more severe disability) compared to the aspirin and clopidogrel group (common odds ratio 3.629, 95% CI 1.874–7.036, P < 0.0001). Although the improvement rate of NIHSS score in the indobufen and clopidogrel group was higher than that in the aspirin and clopidogrel group, the difference was not statistically significant (P > 0.05). Bleeding events were observed in 8 patients (8.6%) receiving aspirin and clopidogrel, including 4 (4.3%) with skin bleeding, 2 (2.2%) with gingival bleeding, 1 (1.1%) with gastrointestinal bleeding, and 1 (1.1%) with urinary system bleeding. On the other hand, only 1 patient (1.1%) in the indobufen and clopidogrel group experienced skin bleeding (P = 0.035).ConclusionThe combination of indobufen and clopidogrel has shown non-inferior and potentially superior effectiveness and safety compared to aspirin combined with clopidogrel in patients with minor ischemic stroke and high-risk TIA in the CARMIA study (registered under chictr.org.cn with registration number ChiCTR2100043087 in 01/02/2021).

Abstract TMP64: Time-Trends and Determinants of Dual Antiplatelet Therapy Prescription After Acute Moderate-to-Severe Non-Cardioembolic Ischemic Stroke

Introduction: Short-term dual antiplatelet therapy (DAPT) lowers the risk of early stroke recurrence after mild non-cardioembolic ischemic stroke (NCIS) and high-risk transient ischemic attack. However, DAPT benefit in moderate-to-severe NCIS is unknown. We sought to investigate time-trends and determinants of DAPT prescription after moderate-to-severe NCIS in the Florida Stroke Registry (FSR). Methods: Within 168 FSR-participating hospitals, between January 2010 and September 2022, we analyzed NCIS patients with NIHSS score &gt;3, without other indication(s) for DAPT (e.g., carotid stenting) or systemic anticoagulation, hemorrhagic complications, and whom received at least one antiplatelet agent upon discharge. Using single antiplatelet therapy (SAPT) as comparison, we assessed DAPT determinants through logistic regression models adjusted for demographics, hospital characteristics, clinical presentation, vascular risk factors and stroke subtype. Results: Out of 283,264 ischemic stroke patients during the study period, 53,282 had moderate-to-severe NCIS (mean age 68 +/-14 years, 50% women, median presenting NIHSS score 7 [interquartile range 6]). DAPT was prescribed in 15,107 (28.4%) and SAPT in 38,175 (71.6%). DAPT prescription increased from 24.2% in 2010 to 44.8% in 2022 (Figure 1). Independent determinants of DAPT prescription are shown in Table 1. Conclusion: DAPT prescription after moderate-to-severe NCIS is common now, and has nearly doubled over the past decade. Major DAPT determinants were premorbid SAPT and large-artery atherosclerosis. Further research may determine DAPT efficacy and safety in this population.

Abstract WP150: Correlation Between CYP2C19 Genotype and Platelet Reactivity Units in Patients Receiving Clopidogrel After Acute Ischemic Stroke

Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard of care for secondary prevention in non-cardioembolic minor acute ischemic stroke (AIS) and high-risk transient ischemic attack (TIA). However, clopidogrel is a prodrug metabolized to its active form by the CYP2C19 enzyme and therefore has decreased efficacy in patients with at least one loss-of-function (LOF) allele in the CYP2C19 gene that encodes the enzyme. The use of ticagrelor over clopidogrel for DAPT improves outcomes in CYP2C19 LOF carriers; however, CYP2C19 genotyping is not currently standard practice in the cerebrovascular population. P2Y12 assays that measure P2Y12 receptor-mediated platelet aggregation in platelet reactivity units (PRUs) are more widely accessible, but it is unclear if this assay correlates with CYP2C19 genotype in this population. Therefore, we aimed to investigate the correlation between CYP2C19 genotype and PRUs to evaluate PRUs as a potential surrogate biomarker for identifying suboptimal clopidogrel response. We hypothesized that PRUs would be increased in CYP2C19 LOF carriers compared to non-carriers due to the reduced bioactivation of clopidogrel in patients with decreased CYP2C19 enzymatic function. This prospective, observational study enrolled patients &gt; 18 years of age presenting with minor AIS or high-risk TIA and discharged from University of Virginia Health on DAPT for secondary stroke prevention. A whole blood sample for P2Y12 assay and CYP2C19 genotyping was obtained at least 12 hours after a 300 milligram clopidogrel loading dose. The primary outcome was the correlation between PRUs and CYP2C19 LOF allele carrier status. Of 35 patients genotyped, 27 (77%) subjects self-reported European ancestry, 7 (20%) African ancestry, and 1 (3%) Asian ancestry. Six participants (17%) were found to be LOF carriers. LOF carriers had significantly increased PRUs compared to non-carriers (mean difference +103.7; 95% CI +30.71 to +176.1; p&lt;0.01), indicating diminished pharmacodynamic response to clopidogrel. This suggests that measurement of PRUs via an accessible and established P2Y12 assay may be a viable surrogate biomarker for identifying suboptimal clopidogrel response in the cerebrovascular population.

Dual Antiplatelet Therapy for the Acute Management and Long-term Secondary Prevention of Ischemic Stroke and Transient Ischemic Attack, An Updated Review.

To improve the efficacy over antiplatelet monotherapy, dual antiplatelet therapy (DAPT) has been increasingly adopted in the management of non-cardioembolic stroke. For minor ischemic stroke and high-risk transient ischemic attack, the aspirin-clopidogrel combination is now recommended for acute short-term treatment, whereas aspirin-ticagrelor combination may be considered in selected patients, especially those with resistance to clopidogrel. For long-term stroke prevention, aspirin-dipyridamole combination has been used as an alternative to antiplatelet monotherapy, and aspirin or clopidogrel combined with cilostazole may be prescribed for added protection in high-risk patients. In this paper, we review the development of DAPT from a historical perspective and describe the findings from major clinical trials published up until the end of 2023. Using the 2021 American Heart Association guideline for secondary stroke prevention as a basis for our recommendations, we further discuss areas of controversy and more recent developments to provide an updated review for clinicians to consider in their daily practice.

Efficacy and safety of dual antiplatelet therapy in the elderly for stroke prevention: a subgroup analysis of the CHANCE-2 trial

ObjectivesEvidence of the optimal antiplatelet therapy for elderly patients who had a stroke is limited, especially those elder than 80 years. This study aimed to explore the efficacy and safety...

Baseline Stroke Risk and Efficacy of Dual-Antiplatelet Therapy: A Post Hoc Analysis of the POINT Trial.

High-risk transient ischemic attacks and minor ischemic strokes are followed by a variable risk of ischemic stroke. We aimed to determine how baseline stroke risk modified the efficacy of clopidogrel-aspirin (referred to here as dual-antiplatelet therapy [DAPT]) for transient ischemic attack and minor ischemic stroke. We performed an unplanned secondary analysis of the POINT trial (Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke). We first evaluated the associations of the CHA2DS2-VASc and stroke prognosis instrument II (SPI-II) scores with the risk of incident ischemic stroke and major hemorrhage (intracranial hemorrhage or major systemic hemorrhage). We then tested for heterogeneity of the relative and absolute treatment effect of DAPT relative to aspirin across low- and high-risk patient subgroups. A total of 4841 trial participants were included in this analysis, with 2400 participants assigned to treatment with short-term DAPT and 2430 participants to treatment with aspirin and placebo. The dichotomized SPI-II score, but not the CHA2DS2-VASc score (P=0.18), was associated with the risk of incident ischemic stroke. A high-risk SPI-II score (>3) was associated with greater risk of incident ischemic stroke (hazard ratio of incident ischemic stroke relative to low-risk SPI-II score of 1.84 [95% CI, 1.44-2.35]; P<0.001) and numerically greater risk of major hemorrhage though not meeting statistical significance (hazard ratio, 1.80 [95% CI, 0.90-3.57]; P=0.10). The relative risk reduction with DAPT was similar across SPI-II strata (Pinteraction=0.31). The absolute risk reduction for ischemic stroke with DAPT compared with aspirin was nearly 4-fold higher (2.80% versus 0.76%; number needed to treat, 31 versus 131) in the high-risk SPI-II stratum relative to the low-risk stratum. The absolute risk increase for major hemorrhage with DAPT compared with aspirin was 3-fold higher (0.84% versus 0.30%; number needed to harm, 119 versus 331) in the high-risk SPI-II stratum relative to the low-risk stratum. Stratification by baseline stroke risk identifies a patient subgroup that derives greater absolute benefit from treatment with DAPT. URL: https://www.clinicaltrials.gov; Unique identifier: NCT00991029.

Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke

BackgroundDual antiplatelet treatment has been shown to lower the risk of recurrent stroke as compared with aspirin alone when treatment is initiated early (≤24 hours) after an acute mild stroke. The effect of clopidogrel plus aspirin as compared with aspirin alone administered within 72 hours after the onset of acute cerebral ischemia from atherosclerosis has not been well studied.MethodsIn 222 hospitals in China, we conducted a double-blind, randomized, placebo-controlled, two-by-two factorial trial involving patients with mild ischemic stroke or high-risk transient ischemic attack (TIA) of presumed atherosclerotic cause who had not undergone thrombolysis or thrombectomy. Patients were randomly assigned, in a 1:1 ratio, within 72 hours after symptom onset to receive clopidogrel (300 mg on day 1 and 75 mg daily on days 2 to 90) plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 21) or matching clopidogrel placebo plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 90). There was no interaction between this component of the factorial trial design and a second part that compared immediate with delayed statin treatment (not reported here). The primary efficacy outcome was new stroke, and the primary safety outcome was moderate-to-severe bleeding — both assessed within 90 days.ResultsA total of 6100 patients were enrolled, with 3050 assigned to each trial group. TIA was the qualifying event for enrollment in 13.1% of the patients. A total of 12.8% of the patients were assigned to a treatment group no more than 24 hours after stroke onset, and 87.2% were assigned after 24 hours and no more than 72 hours after stroke onset. A new stroke occurred in 222 patients (7.3%) in the clopidogrel–aspirin group and in 279 (9.2%) in the aspirin group (hazard ratio, 0.79; 95% confidence interval [CI], 0.66 to 0.94; P=0.008). Moderate-to-severe bleeding occurred in 27 patients (0.9%) in the clopidogrel–aspirin group and in 13 (0.4%) in the aspirin group (hazard ratio, 2.08; 95% CI, 1.07 to 4.04; P=0.03).ConclusionsAmong patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, combined clopidogrel–aspirin therapy initiated within 72 hours after stroke onset led to a lower risk of new stroke at 90 days than aspirin therapy alone but was associated with a low but higher risk of moderate-to-severe bleeding. (Funded by the National Natural Science Foundation of China and others; INSPIRES ClinicalTrials.gov number, NCT03635749.)

Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial

People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA). AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19). Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator. Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA. Bristol Myers Squibb and Janssen Research & Development.

Effects of remnant cholesterol on the efficacy of genotype-guided dual antiplatelet in CYP2C19 loss-of -function carriers with minor stroke or transient ischaemic attack: a post-hoc analysis of the CHANCE-2 trial

The atherogenicity of remnant cholesterol (RC), a contributor to residual risk of cardiovascular events, has been underlined by recent guidelines. We aimed to evaluate the relationship between RC levels and the efficacy and safety of genotype-guided dual antiplatelet therapy in the CHANCE-2 trial. This post-hoc study used data from the CHANCE-2 trial, which was a randomised, double-blind, placebo-controlled trial of 6412 patients (aged >40 years) enrolled from 202 hospitals in China, between Sept 23, 2019, and March 22, 2021, who carried CYP2C19 loss-of-function alleles and had either an acute minor stroke or high-risk transient ischaemic attack (TIA), and could start treatment within 24h of symptom onset. Participants received either (1:1) ticagrelor plus aspirin (control) or clopidogrel plus aspirin (intervention) and the effect of reducing the 3-month risk of any new stroke was assessed (ischemic or haemorrhagic, primary outcome). From the CHANCE-2 study population, we enrolled 5890 patients with complete data on RC. The cutoff point of RC for distinguishing patients with greater benefit from ticagrelor-aspirin versus clopidogrel-aspirin was determined with subpopulation treatment effect pattern plot. The primary efficacy and safety outcome was recurrent stroke and severe or moderate bleeding within 90 days, respectively. CHANCE-2 is registered with ClinicalTrials.gov, NCT04078737. The cutoff to define elevated RC was 0.91mmol/L. Ticagrelor-aspirin versus clopidogrel-aspirin was associated with a reduced risk of recurrent stroke in patients with non-elevated RC levels (122 [5.3%] versus 179 [7.8%]; hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.54-0.85), but this benefit was absent in those with elevated RC levels (58 [8.4%] versus 48 [7.3%]; HR, 1.10; 95% CI, 0.73-1.65; P-interaction=0.03). When analyzed as a continuous variable, the benefit of ticagrelor-aspirin on recurrent stroke decreased as RC levels increased. The rates of severe or moderate bleeding between treatment groups were similar across RC categories (0.3% versus 0.3%, P-interaction=0.95). Our post-hoc findings suggest that RC could be a potential biomarker to discriminate patients who received more benefits from ticagrelor-aspirin versus clopidogrel-aspirin therapy in CYP2C19 loss-of-function carriers with minor stroke or TIA. These findings need to be validated in an independent study. The National Key Research and Development Program of China, Beijing Natural Science Foundation Haidian original innovation joint fund, Fund for Young Talents of Beijing Medical Management Center, the high-level public health talents, Training Fund for Open Projects at Clinical Institutes and Departments of Capital Medical University; and Salubris.

No association between SARS-CoV-2 vaccination and ischaemic stroke or high-risk transient ischaemic attack

BackgroundInitiation of SARS-CoV-2 (Severe acute respiratory syndrome coronavirus type 2) vaccinations aroused scepticism within the general-public about risks including stroke. Our aim was to explore temporal associations between vaccination and cerebrovascular events through an analysis of a prospective large-scale cohort of consecutive stroke and high-risk TIA (transitory ischaemic attack) patients. MethodsWe prospectively recruited a cohort of consecutive ischaemic stroke and high-risk TIA (ABCD2-Score ≥ 4) patients treated at the Innsbruck University Hospital (STROKE-CARD Registry Study, NCT04582825) from December 2020 until February 2022. SARS-CoV-2 vaccination status and the time of administration was ascertained by electronic health-data. A Cox model with vaccination status as time-dependent co-variable was employed to examine its association with ischaemic events. ResultsData on 572 participants were available with 355 (62.1%) vaccinated against SARS-CoV-2 before suffering cerebral ischaemia. In our cohort, no temporal association between vaccination and cerebrovascular event was detected (HR 1.06 [0.85–1.34; p = 0.60]) and this also applies to TIA (HR [0.82 0.37–1.85; p = 0.64]) or minor stroke (HR 1.18 [0.89–1.56; p = 0.26]) and subgroups defined by sex and age. Neither vector-based (HR 1.11 [0.79–1.56; p = 0.55]) nor mRNA-based (HR 1.06 [0.84–1.34; p = 0.61]) vaccinations were associated with the occurrence of cerebral ischaemia. ConclusionAmong patients with stroke or high-risk TIA, SARS-CoV-2 vaccination was not associated with cerebral ischaemia.

Ticagrelor plus aspirin vs clopidogrel plus aspirin in mild non-cardioembolic ischemic stroke: A protocol of a randomized, controlled, active comparator arm, outcome assessor blind, feasibility study

Background &amp; Objectives: The risk of recurrence after a transient ischemic attack (TIA) or minor stroke is high especially within three months after first event. The aim of study is assessing the efficacy of ticagrelor plus aspirin in reduction of mild non-cardioembolic ischemic stroke or high risk TIA recurrence during first 3 months. Methods: This is a randomized, controlled, active comparator arm, outcome assessor blind, parallel group, feasibility study design on 90 patients with diagnosis of non-cardioembolic minor ischemic stroke or high risk TIA admitted in Bou-Ali Sina Hospital, Sari, Iran. After meeting all inclusion and exclusion criteria, patients will be randomized to ticagrelor 90 mg BID plus aspirin (ASA) 80 mg daily or clopidogrel 75 mg daily plus ASA 80 mg daily (1:1 ratio) until 21 days and then ASA 80 mg daily. Participants will be visited at month one and three. Any adverse events, serious side effects and outcome events will be recorded. The primary outcome is defined as ischemic stroke recurrence. Conclusion: Ticagrelor plus ASA is expected to be effective for prevention of recurrence in mild non-cardioembolic stroke and high risk TIA. Trial Registration: ClinicalTrials.gov: NCT04738097

Asundexian: an oral small moleculefactor XIa inhibitor for the treatment of thrombotic disorders.

Oral anticoagulants, including warfarin and direct oral anticoagulants, are the standard of care for thrombosis prevention and treatment; however, concerns of bleeding often dictate treatment decisions. Inhibition of the intrinsic coagulation system via factor XIa may allow for selective inhibition of the coagulation cascade without significantly impacting hemostasis after injury. Asundexian is an oral small moleculefactor XIa inhibitor that, via this novel mechanism, may prove to be a safe and effective option compared with available anticoagulants. Early clinical data forasundexian was promising as a safer alternative to current therapiesand prompted further analysis incertainpatient populations atincreasedthrombotic risk. Currently, studies areongoing to evaluate thesafety and efficacy in stroke prevention in atrial fibrillation and in patients following an acute noncardioembolic ischemic stroke or high-risk transient ischemic attack.

Cost-effectiveness of ticagrelor plus aspirin versus aspirin in acute ischaemic stroke or transient ischaemic attack: an economic evaluation of the THALES trial

ObjectiveTHALES demonstrated that ticagrelor plus aspirin reduced the risk of stroke or death but increased bleeding versus aspirin during the 30 days following a mild-to-moderate acute non-cardioembolic ischaemic stroke (AIS)...

Determination of the Potential Clinical Benefits of Small Molecule Factor XIa Inhibitors in Arterial Thrombosis.

Anticoagulants are the mainstay for the prevention and treatment of thrombosis. However, bleeding complications remain a primary concern. Recent advances in understanding the contribution of activated factor XI (FXIa) in arterial thrombosis with a limited impact on hemostasis have led to the development of several FXIa-targeting modalities. Injectable agents including monoclonal antibodies and antisense oligonucleotides against FXIa have been primarily studied in venous thrombosis. The orally active small molecules that specifically inhibit the active site of FXIa are currently being investigated for their antithrombotic activity in both arteries and veins. This review focuses on a discussion of the potential clinical benefits of small molecule FXIa inhibitors, mainly asundexian and milvexian, in arterial thrombosis based on their pharmacological profiles and the compelling results of phase 2 clinical studies. The preclinical and epidemiological basis for the impact of FXIa in hemostasis and arterial thrombosis is also addressed. In recent clinical study results, asundexian appears to reduce ischemic events in patients with myocardial infarction and minor-to-moderate stroke, whereas milvexian possibly provides benefits in patients with minor stroke or high-risk transient ischemic attack (TIA). In addition, asundexian and milvexian had a minor impact on hemostasis even in combination with dual-antiplatelet therapy. Other orally active FXIa inhibitors also produce antithrombotic activity in vivo with low bleeding risk. Therefore, FXIa inhibitors might represent a new class of direct-acting oral anticoagulants (DOACs) for the treatment of thrombosis, although the explicit clinical positions of asundexian and milvexian in patients with ischemic stroke, high-risk TIA, and coronary artery disease require confirmation from the outcomes of ongoing phase 3 trials.