Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke.

BACKGROUND: Dual 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. METHODS: In 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. RESULTS: A 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). CONCLUSIONS: Among 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.).

Real-time pandemic surveillance using hospital admissions and mobility data.

Forecasting the burden of COVID-19 has been impeded by limitations in data, with case reporting biased by testing practices, death counts lagging far behind infections, and hospital census reflecting time-varying patient access, admission criteria, and demographics. Here, we show that hospital admissions coupled with mobility data can reliably predict severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission rates and healthcare demand. Using a forecasting model that has guided mitigation policies in Austin, TX, we estimate that the local reproduction number had an initial 7-d average of 5.8 (95% credible interval [CrI]: 3.6 to 7.9) and reached a low of 0.65 (95% CrI: 0.52 to 0.77) after the summer 2020 surge. Estimated case detection rates ranged from 17.2% (95% CrI: 11.8 to 22.1%) at the outset to a high of 70% (95% CrI: 64 to 80%) in January 2021, and infection prevalence remained above 0.1% between April 2020 and March 1, 2021, peaking at 0.8% (0.7-0.9%) in early January 2021. As precautionary behaviors increased safety in public spaces, the relationship between mobility and transmission weakened. We estimate that mobility-associated transmission was 62% (95% CrI: 52 to 68%) lower in February 2021 compared to March 2020. In a retrospective comparison, the 95% CrIs of our 1, 2, and 3 wk ahead forecasts contained 93.6%, 89.9%, and 87.7% of reported data, respectively. Developed by a task force including scientists, public health officials, policy makers, and hospital executives, this model can reliably project COVID-19 healthcare needs in US cities.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Stratification by baseline stroke risk identifies a patient subgroup that derives greater absolute benefit from treatment with DAPT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00991029.

Dual Antiplatelet Therapy After Embolic Stroke of Undetermined Source: A Subgroup Analysis of the CHANCE-2 Trial.

BACKGROUND: The atherosclerotic sources of embolism are a significant contributor to embolic stroke of undetermined source (ESUS). However, there is limited evidence for the efficacy of intensive dual antiplatelet therapy for ESUS. We conducted an investigation to determine whether gene-directed dual antiplatelet therapy could reduce the risk of recurrent stroke in patients with ESUS. METHODS: CHANCE-2 (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events-II) was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial that objectively compared ticagrelor plus aspirin and clopidogrel plus aspirin in patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles in China. All study participants were classified into ESUS and non-ESUS groups for the prespecified exploratory analysis. Cox proportional hazards models were used to assess the interaction of the state of ESUS with the effects of dual antiplatelet therapy with ticagrelor-aspirin versus clopidogrel-aspirin, adjusting for sociodemographic and clinical factors. RESULTS: The subgroup analysis comprised 5796 participants (90.4% of the total 6412 participants) in the CHANCE-2 trial, with a median age of 64.9 years (range, 57.0-71.4 years), of whom 1964 (33.9%) were female. These participants underwent diffusion-weighted imaging as part of the study protocol. After systematic evaluation, 15.2% of patients (881/5796) were deemed to have ESUS. The incidence of stroke recurrence in patients with ESUS was found to be 5.6% in the ticagrelor-aspirin group and 9.2% in the clopidogrel-aspirin group (hazard ratio, 0.57 [95% CI, 0.33-0.99]; P=0.04). In patients without ESUS, the respective incidence rates were 5.6% and 7.5% (hazard ratio, 0.72 [95% CI, 0.58-0.90]; P<0.01). The P value was 0.56 for the treatment × ESUS status interaction effect. CONCLUSIONS: In this prespecified exploratory analysis, ticagrelor with aspirin was superior to clopidogrel with aspirin for preventing stroke at 90 days in patients with acute ischemic stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles and were classified as ESUS. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04078737.

Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA.

BACKGROUND: Comparisons between ticagrelor and clopidogrel for the secondary prevention of stroke in CYP2C19 loss-of-function carriers have not been extensively performed. METHODS: We conducted a randomized, double-blind, placebo-controlled trial at 202 centers in China involving patients with a minor ischemic stroke or transient ischemic attack (TIA) who carried CYP2C19 loss-of-function alleles. Patients were assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive ticagrelor (180 mg on day 1 followed by 90 mg twice daily on days 2 through 90) and placebo clopidogrel or to receive clopidogrel (300 mg on day 1 followed by 75 mg once daily on days 2 through 90) and placebo ticagrelor; both groups received aspirin for 21 days. The primary efficacy outcome was new stroke, and the primary safety outcome was severe or moderate bleeding, both within 90 days. RESULTS: A total of 11,255 patients were screened and 6412 patients were enrolled, with 3205 assigned to the ticagrelor group and 3207 to the clopidogrel group. The median age of the patients was 64.8 years, and 33.8% were women; 98.0% belonged to the Han Chinese ethnic group. Stroke occurred within 90 days in 191 patients (6.0%) in the ticagrelor group and 243 patients (7.6%) in the clopidogrel group (hazard ratio, 0.77; 95% confidence interval, 0.64 to 0.94; P = 0.008). Secondary outcomes were generally in the same direction as the primary outcome. Severe or moderate bleeding occurred in 9 patients (0.3%) in the ticagrelor group and in 11 patients (0.3%) in the clopidogrel group; any bleeding occurred in 170 patients (5.3%) and 80 patients (2.5%), respectively. CONCLUSIONS: Among Chinese patients with minor ischemic stroke or TIA who were carriers of CYP2C19 loss-of-function alleles, the risk of stroke at 90 days was modestly lower with ticagrelor than with clopidogrel. The risk of severe or moderate bleeding did not differ between the two treatment groups, but ticagrelor was associated with more total bleeding events than clopidogrel. (Funded by the Ministry of Science and Technology of the People's Republic of China and others; CHANCE-2 ClinicalTrials.gov number, NCT04078737.).

Genotype-Guided Dual Antiplatelet Use for Transient Ischemic Attack and Minor Stroke by Imaging Status: Subgroup Analysis of the CHANCE-2 Trial.

OBJECTIVE: This study was performed to investigate whether ticagrelor/aspirin versus clopidogrel/aspirin can further reduce the residual risk of stroke recurrence in patients with positive diffusion-weighted imaging (DWI) in the High-Risk Patients with Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial. METHODS: Patients with DWI data in the CHANCE-2 trial were included and divided into those with and without acute infarction according to their DWI findings. The primary efficacy outcome and safety outcome were stroke recurrence and moderate to severe bleeding within 3 months of follow-up, respectively. RESULTS: Of the 6,412 patients enrolled in the CHANCE-2 trial, 5,796 (90.4%) patients with DWI data were included in the subgroup analysis. A total of 4,369 patients (75.4%) had an acute infarction on DWI. Patients with positive DWI had higher risk of recurrent stroke (8.1%) than those without infarction (2.2%) within 3-month follow-up. Compared with clopidogrel/aspirin, ticagrelor/aspirin was associated with lower risk of stroke in patients with positive DWI (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.52-0.80, p < 0.001) than in those negative DWI (HR = 1.22, 95% CI = 0.55-2.72, p = 0.63), with a significant interaction association (p for interaction = 0.049). The risk of moderate to severe bleeding was similar between ticagrelor/aspirin and clopidogrel/aspirin treatment in the different groups. INTERPRETATION: Our study demonstrates that imaging evaluation should be emphasized before targeting the best candidates for genotype-guided dual antiplatelet therapy in future clinical research and practice. ANN NEUROL 2023;93:783-792.

Diagnosis, Workup, Risk Reduction of Transient Ischemic Attack in the Emergency Department Setting: A Scientific Statement From the American Heart Association.

At least 240 000 individuals experience a transient ischemic attack each year in the United States. Transient ischemic attack is a strong predictor of subsequent stroke. The 90-day stroke risk after transient ischemic attack can be as high as 17.8%, with almost half occurring within 2 days of the index event. Diagnosing transient ischemic attack can also be challenging given the transitory nature of symptoms, often reassuring neurological examination at the time of evaluation, and lack of confirmatory testing. Limited resources, such as imaging availability and access to specialists, can further exacerbate this challenge. This scientific statement focuses on the correct clinical diagnosis, risk assessment, and management decisions of patients with suspected transient ischemic attack. Identification of high-risk patients can be achieved through use of comprehensive protocols incorporating acute phase imaging of both the brain and cerebral vasculature, thoughtful use of risk stratification scales, and ancillary testing with the ultimate goal of determining who can be safely discharged home from the emergency department versus admitted to the hospital. We discuss various methods for rapid yet comprehensive evaluations, keeping resource-limited sites in mind. In addition, we discuss strategies for secondary prevention of future cerebrovascular events using maximal medical therapy and patient education.

Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA.

BACKGROUND: Trials have evaluated the use of clopidogrel and aspirin to prevent stroke after an ischemic stroke or transient ischemic attack (TIA). In a previous trial, ticagrelor was not better than aspirin in preventing vascular events or death after stroke or TIA. The effect of the combination of ticagrelor and aspirin on prevention of stroke has not been well studied. METHODS: We conducted a randomized, placebo-controlled, double-blind trial involving patients who had had a mild-to-moderate acute noncardioembolic ischemic stroke, with a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less (range, 0 to 42, with higher scores indicating more severe stroke), or TIA and who were not undergoing thrombolysis or thrombectomy. The patients were assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive a 30-day regimen of either ticagrelor (180-mg loading dose followed by 90 mg twice daily) plus aspirin (300 to 325 mg on the first day followed by 75 to 100 mg daily) or matching placebo plus aspirin. The primary outcome was a composite of stroke or death within 30 days. Secondary outcomes were first subsequent ischemic stroke and the incidence of disability within 30 days. The primary safety outcome was severe bleeding. RESULTS: A total of 11,016 patients underwent randomization (5523 in the ticagrelor-aspirin group and 5493 in the aspirin group). A primary-outcome event occurred in 303 patients (5.5%) in the ticagrelor-aspirin group and in 362 patients (6.6%) in the aspirin group (hazard ratio, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P = 0.02). Ischemic stroke occurred in 276 patients (5.0%) in the ticagrelor-aspirin group and in 345 patients (6.3%) in the aspirin group (hazard ratio, 0.79; 95% CI, 0.68 to 0.93; P = 0.004). The incidence of disability did not differ significantly between the two groups. Severe bleeding occurred in 28 patients (0.5%) in the ticagrelor-aspirin group and in 7 patients (0.1%) in the aspirin group (P = 0.001). CONCLUSIONS: Among patients with a mild-to-moderate acute noncardioembolic ischemic stroke (NIHSS score ≤5) or TIA who were not undergoing intravenous or endovascular thrombolysis, the risk of the composite of stroke or death within 30 days was lower with ticagrelor-aspirin than with aspirin alone, but the incidence of disability did not differ significantly between the two groups. Severe bleeding was more frequent with ticagrelor. (Funded by AstraZeneca; THALES ClinicalTrial.gov number, NCT03354429.).

Bleeding Risk of Dual Antiplatelet Therapy after Minor Stroke or Transient Ischemic Attack.

OBJECTIVE: This study was undertaken to identify the risk of bleeding events and potential risk factors within 90 days in patients who carried CYP2C19 loss-of-function alleles and received dual antiplatelet therapy after minor stroke or transient ischemic attack. METHODS: A total of 6,412 patients were enrolled from the CHANCE-2 (Clopidogrel with Aspirin in High-Risk Patients with Acute Non-disabling Cerebrovascular Events II) trial. The main outcome was any bleeding within 90 days defined by the criteria from GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries). RESULTS: A total of 250 (3.9%) bleeding events were reported, which occurred mainly within the 21 days of dual antiplatelet therapy (200 cases, 3.1%). Minor bleeding of the skin bruises, epistaxis, and gum bleeding were most frequent. Multivariate analysis showed that treatment with ticagrelor-aspirin compared with clopidogrel-aspirin was associated with increased bleeding (hazard ratio [HR] = 2.21, 95% confidence interval [CI] = 1.68-2.89, p < 0.001). Current smoking was associated with a lower risk of bleeding (HR = 0.70, 95% CI = 0.52-0.95, p = 0.02). Additionally, ticagrelor-aspirin compared with clopidogrel-aspirin was associated with higher risk of bleeding in patients aged <65 years (HR = 2.87, 95% CI = 1.95-4.22) and those without diabetes mellitus (HR = 2.65, 95% CI = 1.88-3.73; p for interaction = 0.04 and 0.03, respectively). INTERPRETATION: Bleeding events mostly occurred within the 21-day dual antiplatelet therapy stage and were generally mild. The risk of bleeding was greater in nonsmoking patients, and was associated with treatment with ticagrelor-aspirin compared with clopidogrel-aspirin, particularly in patients aged <65 years and nondiabetic patients. ANN NEUROL 2022;91:380-388.

Ticagrelor-Aspirin Versus Clopidogrel-Aspirin Among CYP2C19 Loss-of-Function Carriers With Minor Stroke or Transient Ischemic Attack in Relation to Renal Function: A Post Hoc Analysis of the CHANCE-2 Trial.

BACKGROUND: Evidence on the risk-benefit ratio of dual antiplatelet therapies among patients with stroke and impaired renal function is limited and inconsistent. OBJECTIVE: To investigate the effect of renal function on the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin treatment. DESIGN: Post hoc analysis of a multicenter, randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT04078737). SETTING: 202 centers in China. PATIENTS: CYP2C19 loss-of-function allele carriers with minor stroke or transient ischemic attack. INTERVENTION: Ticagrelor-aspirin and clopidogrel-aspirin. MEASUREMENTS: Renal function was evaluated by estimated glomerular filtration rate (eGFR) levels. The primary efficacy and safety outcomes were recurrent stroke and severe or moderate bleeding within 90 days, respectively. RESULTS: Among 6378 patients, 4050 (63.5%) had normal (eGFR ≥90 mL/min/1.73 m2), 2010 (31.5%) had mildly decreased (eGFR 60 to 89 mL/min/1.73 m2), and 318 (5.0%) had moderately to severely decreased (eGFR <60 mL/min/1.73 m2) renal function. The corresponding differences in recurrent stroke between ticagrelor-aspirin and clopidogrel-aspirin for normal, mildly decreased, and moderately to severely decreased renal function was -2.8 percentage points (95% CI, -4.4 to -1.3 percentage points) (hazard ratio [HR], 0.63 [CI, 0.49 to 0.81]), -0.2 percentage point (CI, -2.4 to 2.0 percentage points) (HR, 0.98 [CI, 0.69 to 1.39]), and 3.7 percentage points (CI, -2.3 to 10.1 percentage points) (HR, 1.31 [CI, 0.48 to 3.55]), respectively. Rates of severe or moderate bleeding did not substantially differ by treatment assignments across eGFR categories. LIMITATION: Renal function was only evaluated by using eGFR, and the proportion of patients with severely decreased renal function was low. CONCLUSION: Patients with normal, rather than impaired, renal function received greater benefit from ticagrelor-aspirin versus clopidogrel-aspirin. PRIMARY FUNDING SOURCE: Ministry of Science and Technology of the People's Republic of China.

Effect of Hypertension on Efficacy and Safety of Ticagrelor-Aspirin Versus Clopidogrel-Aspirin in Minor Stroke or Transient Ischemic Attack.

BACKGROUND: Hypertension is a risk factor of poor stroke outcomes and associated with antiplatelet resistance. This study aimed to explore the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in patients with different hypertension status, using randomized trial data from the CHANCE-2 trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events-II). METHODS: A total of 6412 patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles were enrolled and randomized to either ticagrelor-aspirin or clopidogrel-aspirin group. Hypertension status were classified into no, newly diagnosed, and previously diagnosed hypertension according to medical history, blood pressure, and antihypertensive medications during hospitalization. The primary efficacy and safety outcomes were stroke recurrence and moderate to severe bleeding risk within 90-day follow-up. RESULTS: Ticagrelor-aspirin was associated with reduced risk of new stroke in patients without hypertension (32 [4.8%] versus 60 [7.2%]; hazard ratio, 0.55 [95% CI, 0.35-0.86]), but not in those with a newly diagnosed hypertension (20 [5.3%] versus 36 [9.1%]; hazard ratio 0.59 [95% CI, 0.33-1.07]), or those with a previously diagnosed hypertension (139 [7.0%] versus 147 [7.4%]; hazard ratio, 0.93 [95% CI, 0.74-1.18]) compared with clopidogrel-aspirin (P=0.04 for interaction). The risk of bleeding for ticagrelor-aspirin was not associated with hypertension status (0.1% versus 0.4%; 0.3% versus 0.5%, 0.4% versus 0.3%, P=0.50 for interaction). All the efficacy and safety outcomes between treatments did not differ by blood pressure levels on admission. CONCLUSIONS: In the CHANCE-2 trial, patients without hypertension received a significantly greater benefit from ticagrelor- aspirin than those with previous hypertension after minor stroke or transient ischemic attack, and a similar benefit trend was observed in those with newly diagnosed hypertension. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04078737.

P2Y12 Inhibitors Plus Aspirin Versus Aspirin Alone in Patients With Minor Stroke or High-Risk Transient Ischemic Attack.

BACKGROUND AND PURPOSE: We performed a systemic review and meta-analysis to elucidate the effectiveness and safety of dual antiplatelet (DAPT) therapy with P2Y12 inhibitors (clopidogrel/ticagrelor) and aspirin versus aspirin monotherapy in patients with mild ischemic stroke or high-risk transient ischemic attack. METHODS: Following Preferred Reported Items for Systematic Review and Meta-Analysis standards for meta-analyses, Medline, Embase, Cochrane Central Register of Controlled Trials, and the Cochrane Library were searched for randomized controlled trials that included patients with a diagnosis of an acute mild ischemic stroke or high-risk transient ischemic attack, intervention of DAPT therapy with clopidogrel/ticagrelor and aspirin versus aspirin alone from January 2012 to July 2020. The outcomes included subsequent stroke, all-cause mortality, cardiovascular death, hemorrhage (mild, moderate, or severe), and myocardial infarction. A DerSimonian-Laird random-effects model was used to estimate pooled risk ratio (RR) and corresponding 95% CI in R package meta. We assessed the heterogeneity of data across studies with use of the Cochran Q statistic and I2 test. RESULTS: Four eligible trials involving 21 493 participants were included in the meta-analysis. DAPT therapy started within 24 hours of symptom onset reduced the risk of stroke recurrence by 24% (RR, 0.76 [95% CI, 0.68-0.83], I2=0%) but was not associated with a change in all-cause mortality (RR, 1.30 [95% CI, 0.90-1.89], I2=0%), cardiovascular death (RR, 1.34 [95% CI, 0.56-3.17], I2=0%), mild bleeding (RR, 1.25 [95% CI, 0.37-4.29], I2=94%), or myocardial infarction (RR, 1.45 [95% CI, 0.62-3.39], I2=0%). However, DAPT was associated with an increased risk of severe or moderate bleeding (RR, 2.17 [95% CI, 1.16-4.08], I2=41%); further sensitivity tests found that the association was limited to trials with DAPT treatment duration over 21 days (RR, 2.86 [95% CI, 1.75-4.67], I2=0%) or ticagrelor (RR, 2.17 [95% CI, 1.16-4.08], I2=37%) but not within 21 days or clopidogrel. CONCLUSIONS: In patients with noncardioembolic mild stroke or high-risk transient ischemic attack, DAPT with aspirin and clopidogrel/ticagrelor is more effective than aspirin alone for recurrent stroke prevention with a small absolute increase in the risk of severe or moderate bleeding.

Antiplatelet Use and Ischemic Stroke Risk in Minor Stroke or Transient Ischemic Attack: A Post Hoc Analysis of the POINT Trial.

BACKGROUND AND PURPOSE: Dual antiplatelet therapy has been shown to reduce the risk of recurrent stroke in patients with minor stroke or transient ischemic attack. However, whether the effect of dual antiplatelet therapy is modified by pretreatment antiplatelet status is unclear. METHODS: This is a post hoc analysis of the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke). Patients were divided into 2 groups based on pretreatment antiplatelet use. The primary outcome was ischemic stroke within 90 days of randomization. RESULTS: We included 4881 patients of whom 41% belonged to the no pretreatment antiplatelet. Ischemic stroke occurred in 6% and 5% in the antiplatelet pretreatment and no antiplatelet pretreatment, respectively. Antiplatelet pretreatment was not associated with the risk of ischemic stroke (adjusted hazard ratio, 1.05 [95% CI, 0.81-137]) or risk of major hemorrhage (hazard ratio, 1.10 [95% CI, 0.55-2.21]; P=0.794). The effect of dual antiplatelet therapy on recurrent ischemic stroke risk was not different in patients who were on antiplatelet before randomization (adjusted hazard ratio, 0.69 [95% CI, 0.50-0.94]) as opposed to those who were not (adjusted hazard ratio, 0.75 [95% CI, 0.50-1.12]), P for interaction = 0.685. CONCLUSIONS: In patients with minor stroke and high-risk transient ischemic attack, dual antiplatelet therapy reduces the risk of ischemic stroke regardless of premorbid antiplatelet use.

Ischemic Benefit and Hemorrhage Risk of Ticagrelor-Aspirin Versus Aspirin in Patients With Acute Ischemic Stroke or Transient Ischemic Attack.

Background and Purpose: In patients with acute mild-moderate ischemic stroke or high-risk transient ischemic attack, the THALES trial (Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and Aspirin for Prevention of Stroke and Death) demonstrated that when added to aspirin, ticagrelor reduced stroke or death but increased risk of severe hemorrhage compared with placebo. The primary efficacy outcome of THALES included hemorrhagic stroke and death, events also counted in the primary safety outcome. We sought to disentangle risk and benefit, assess their relative impact, and attempt to identify subgroups with disproportionate risk or benefit. Methods: In a randomized, placebo-controlled, double-blind trial of patients with mild-to-moderate acute noncardioembolic ischemic stroke or high-risk transient ischemic attack, patients were randomized within 24 hours after symptom onset to a 30-day regimen of either ticagrelor plus aspirin or matching placebo plus aspirin. For the present analyses, we defined the efficacy outcome, major ischemic events, as the composite of ischemic stroke or nonhemorrhagic death, and defined the safety outcome, major hemorrhage, as intracranial hemorrhage or hemorrhagic death. Net clinical impact was defined as the combination of these 2 end points. Results: In 11 016 patients (5523 ticagrelor-aspirin and 5493 aspirin), a major ischemic event occurred in 294 patients (5.3%) in the ticagrelor-aspirin group and in 359 patients (6.5%) in the aspirin group (absolute risk reduction 1.19% [95% CI, 0.31%­2.07%]). Major hemorrhage occurred in 22 patients (0.4%) in the ticagrelor-aspirin group and 6 patients (0.1%) in the aspirin group (absolute risk increase 0.29% [95% CI, 0.10%­0.48%]). Net clinical impact favored ticagrelor-aspirin (absolute risk reduction 0.97% [95% CI, 0.08%­1.87%]). Findings were similar when different thresholds for disability were applied and over a range of predefined subgroups. Conclusions: In patients with mild-moderate ischemic stroke or high-risk transient ischemic attack, ischemic benefits of 30-day treatment with ticagrelor-aspirin outweigh risks of hemorrhage. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354429.

Carotid Stenosis and Recurrent Ischemic Stroke: A Post-Hoc Analysis of the POINT Trial.

BACKGROUND AND PURPOSE: Randomized trials demonstrated the benefit of dual antiplatelet therapy in patients with minor ischemic stroke or high-risk transient ischemic attack. We sought to determine whether the presence of carotid stenosis was associated with increased risk of ischemic stroke and whether the addition of clopidogrel to aspirin was associated with more benefit in patients with versus without carotid stenosis. METHODS: This is a post-hoc analysis of the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) that randomized patients with minor ischemic stroke or high-risk transient ischemic attack within 12 hours from last known normal to receive either clopidogrel plus aspirin or aspirin alone. The primary predictor was the presence of ≥50% stenosis in either cervical internal carotid artery. The primary outcome was ischemic stroke. We built Cox regression models to determine the association between carotid stenosis and ischemic stroke and whether the effect of clopidogrel was modified by ≥50% carotid stenosis. RESULTS: Among 4881 patients enrolled POINT, 3941 patients met the inclusion criteria. In adjusted models, ≥50% carotid stenosis was associated with ischemic stroke risk (hazard ratio, 2.45 [95% CI, 1.68-3.57], P<0.001). The effect of clopidogrel (versus placebo) on ischemic stroke risk was not significantly different in patients with <50% carotid stenosis (adjusted hazard ratio, 0.68 [95% CI, 0.50-0.93], P=0.014) versus those with ≥50% carotid stenosis (adjusted hazard ratio, 0.88 [95% CI, 0.45-1.72], P=0.703), P value for interaction=0.573. CONCLUSIONS: The presence of carotid stenosis was associated with increased risk of ischemic stroke during follow-up. The effect of added clopidogrel was not significantly different in patients with versus without carotid stenosis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354429.

Cilostazol for Secondary Stroke Prevention: History, Evidence, Limitations, and Possibilities.

Cilostazol is a PDE3 (phosphodiesterase III) inhibitor with a long track record of safety that is Food and Drug Administration and European Medicines Agency approved for the treatment of claudication in patients with peripheral arterial disease. In addition, cilostazol has been approved for secondary stroke prevention in several Asian countries based on trials that have demonstrated a reduction in stroke recurrence among patients with noncardioembolic stroke. The onset of benefit appears after 60 to 90 days of treatment, which is consistent with cilostazol's pleiotropic effects on platelet aggregation, vascular remodeling, blood flow, and plasma lipids. Cilostazol appears safe and does not increase the risk of major bleeding when given alone or in combination with aspirin or clopidogrel. Adverse effects such as headache, gastrointestinal symptoms, and palpitations, however, contributed to a 6% increase in drug discontinuation among patients randomized to cilostazol in a large secondary stroke prevention trial (CSPS.com [Cilostazol Stroke Prevention Study for Antiplatelet Combination]). Due to limitations of prior trials, such as open-label design, premature trial termination, large loss to follow-up, lack of functional or cognitive outcome data, and exclusive enrollment in Asia, the existing trials have not led to a change in clinical practice or guidelines in Western countries. These limitations could be addressed by a double-blind placebo-controlled randomized trial conducted in a broader population. If positive, it would increase the evidence in support of long-term treatment with cilostazol for secondary prevention in the millions of patients worldwide who have experienced a noncardioembolic ischemic stroke.

Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA.

BACKGROUND: Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population. METHODS: In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days. RESULTS: A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P=0.02). CONCLUSIONS: In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029 .).

Time Course for Benefit and Risk of Clopidogrel and Aspirin After Acute Transient Ischemic Attack and Minor Ischemic Stroke.

BACKGROUND: In patients with acute minor ischemic stroke or high-risk transient ischemic attack enrolled in the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke [POINT] Trial), the combination of clopidogrel and aspirin for 90 days reduced major ischemic events but increased major hemorrhage in comparison to aspirin alone. METHODS: In a secondary analysis of POINT (N=4881), we assessed the time course for benefit and risk from the combination of clopidogrel and aspirin. The primary efficacy outcome was a composite of ischemic stroke, myocardial infarction, or ischemic vascular death. The primary safety outcome was major hemorrhage. Risks and benefits were estimated for delayed times of treatment initiation using left-truncated models. RESULTS: Through 90 days, the rate of major ischemic events was initially high then decreased markedly, whereas the rate of major hemorrhage remained low but relatively constant throughout. With the use of a model-based approach, the optimal change point for major ischemic events was 21 days (0-21 days hazard ratio 0.65 for clopidogrel-aspirin versus aspirin; 95% CI, 0.50-0.85; P=0.0015, in comparison to 22-90 days hazard ratio, 1.38; 95% CI, 0.81-2.35; P=0.24). Models showed benefits of clopidogrel-aspirin for treatment delayed as long as 3 days after symptom onset. CONCLUSIONS: The benefit of clopidogrel-aspirin occurs predominantly within the first 21 days, and outweighs the low, but ongoing risk of major hemorrhage. When considered with the results of the CHANCE trial (Clopidogrel in High-Risk Patients With Non-disabling Cerebrovascular Events), a similar trial treating with clopidogrel-aspirin for 21 days and showing no increase in major hemorrhage, these results suggest that limiting clopidogrel-aspirin use to 21 days may maximize benefit and reduce risk after high-risk transient ischemic attack or minor ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

Disability After Minor Stroke and Transient Ischemic Attack in the POINT Trial.

Background and Purpose- While combination aspirin and clopidogrel reduces recurrent stroke compared with aspirin alone in patients with transient ischemic attack (TIA) or minor stroke, the effect on disability is uncertain. Methods- The POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) randomized patients with TIA or minor stroke (National Institutes of Health Stroke Scale score ≤3) within 12 hours of onset to dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel versus aspirin alone. The primary outcome measure was a composite of stroke, myocardial infarction, or vascular death. We performed a post hoc exploratory analysis to examine the effect of treatment on overall disability (defined as modified Rankin Scale score >1) at 90 days, as well as disability ascribed by the local investigator to index or recurrent stroke. We also evaluated predictors of disability. Results- At 90 days, 188 of 1964 (9.6%) of patients enrolled with TIA and 471 of 2586 (18.2%) of those enrolled with stroke were disabled. Overall disability was similar between patients assigned DAPT versus aspirin alone (14.7% versus 14.3%; odds ratio, 0.97 [95% CI, 0.82-1.14]; P=0.69). However, there were numerically fewer patients with disability in conjunction with a primary outcome event in the DAPT arm (3.0% versus 4.0%; odds ratio, 0.73 [95% CI, 0.53-1.01]; P=0.06) and significantly fewer patients in the DAPT arm with disability attributed by the investigators to either the index event or recurrent stroke (5.9% versus 7.4%; odds ratio, 0.78 [95% CI, 0.62-0.99]; P=0.04). Notably, disability attributed to the index event accounted for the majority of this difference (4.5% versus 6.0%; odds ratio, 0.74 [95% CI, 0.57-0.96]; P=0.02). In multivariate analysis, age, subsequent ischemic stroke, serious adverse events, and major bleeding were significantly associated with disability in TIA; for those with stroke, female sex, hypertension, or diabetes mellitus, National Institutes of Health Stroke Scale score, recurrent ischemic stroke, subsequent myocardial infarction, and serious adverse events were associated with disability. Conclusions- In addition to reducing recurrent stroke in patients with acute minor stroke and TIA, DAPT might reduce stroke-related disability. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

Ticagrelor Added to Aspirin in Acute Nonsevere Ischemic Stroke or Transient Ischemic Attack of Atherosclerotic Origin.

BACKGROUND AND PURPOSE: Among patients with a transient ischemic attack or minor ischemic strokes, those with ipsilateral atherosclerotic stenosis of cervicocranial vasculature have the highest risk of recurrent vascular events. METHODS: In the double-blind THALES (The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death) trial, we randomized patients with a noncardioembolic, nonsevere ischemic stroke, or high-risk transient ischemic attack to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2-30) or placebo added to aspirin (300-325 mg on day 1 followed by 75-100 mg daily for days 2-30) within 24 hours of symptom onset. The present paper reports a prespecified analysis in patients with and without ipsilateral, potentially causal atherosclerotic stenosis ≥30% of cervicocranial vasculature. The primary end point was time to the occurrence of stroke or death within 30 days. RESULTS: Of 11 016 randomized patients, 2351 (21.3%) patients had an ipsilateral atherosclerotic stenosis. After 30 days, a primary end point occurred in 92/1136 (8.1%) patients with ipsilateral stenosis randomized to ticagrelor and in 132/1215 (10.9%) randomized to placebo (hazard ratio 0.73 [95% CI, 0.56-0.96], P=0.023) resulting in a number needed to treat of 34 (95% CI, 19-171). In patients without ipsilateral stenosis, the corresponding event rate was 211/4387 (4.8%) and 230/4278 (5.4%), respectively (hazard ratio, 0.89 [95% CI, 0.74-1.08]; P=0.23, Pinteraction=0.245). Severe bleeding occurred in 4 (0.4%) and 3 (0.2%) patients with ipsilateral atherosclerotic stenosis on ticagrelor and on placebo, respectively (P=NS), and in 24 (0.5%) and 4 (0.1%), respectively, in 8665 patients without ipsilateral stenosis (hazard ratio=5.87 [95% CI, 2.04-16.9], P=0.001). CONCLUSIONS: In this exploratory analysis comparing ticagrelor added to aspirin to aspirin alone, we found no treatment by ipsilateral atherosclerosis stenosis subgroup interaction but did identify a higher absolute risk and a greater absolute risk reduction of stroke or death at 30 days in patients with ipsilateral atherosclerosis stenosis than in those without. In this easily identified population, ticagrelor added to aspirin provided a clinically meaningful benefit with a number needed to treat of 34 (95% CI, 19-171). Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03354429.