Early Ischemic Recurrence Research Articles

Prognosis of ischemic stroke patients with both aortic atheroma and cardioembolic sources

This study aimed to investigate the relationship between complex aortic plaque (CAP) and short-term as well as long-term outcomes following cardioembolic stroke. CAP is a known risk factor for occurrence and recurrence of ischemic stroke. However, the association of CAP on cardioembolic stroke remains unclear. This was retrospective study using prospective cohort of consecutive patients with cardioembolic stroke who underwent transesophageal echocardiography. The functional outcome was evaluated using the modified Rankin Scale score at 3 months, and long-term outcomes were assessed by recurrence of ischemic stroke and occurrence of major adverse cardiovascular events (MACE). Among 759 patients with cardioembolic stroke, 91 (12.0%) had CAP. Early ischemic stroke recurrence within 3 months was associated with CAP (p = 0.025), whereas CAP was not associated with functional outcome at 3 months (odd ratio 1.01, 95% confidence interval [CI] 0.57–1.84, p = 0.973). During a median follow-up of 3.02 years, CAP was significantly associated with ischemic stroke recurrence (hazard ratio = 2.68, 95% CI 1.48–4.88, p = 0.001) and MACE occurrence (hazard ratio = 1.61, 95% CI 1.03–2.51, p = 0.039). In conclusion, CAP was associated with early ischemic stroke recurrence and poor long-term outcomes in patients with cardioembolic stroke. It might be helpful to consider transesophageal echocardiography for patients with cardioembolic stroke to identify CAP.

Early ischemic recurrence in acute spontaneous cervical artery dissection

Background and PurposeEarly ischemic recurrence (EIR) following the diagnosis of acute spontaneous cervical artery dissection (CeAD) has been little investigated. We aimed to determine the prevalence and determinants on admission of EIR in a large single-center retrospective cohort study of patients with CeAD. MethodsEIR was defined as any ipsilateral clinical or radiological cerebral ischemia or intracranial artery occlusion, not present on admission and occurring within 2 weeks. CeAD location, degree of stenosis, circle of Willis support, presence of intraluminal thrombus, intracranial extension, and intracranial embolism were analyzed on initial imaging by 2 independent observers. Uni- and multivariate logistic regression was used to determine their association with EIR. ResultsTwo hundred thirty-three consecutive patients with 286 CeAD were included. EIR was observed in 21 patients (9%,95%CI=5–13%) with a median time from diagnosis of 1.5 days (range:0.1–14.0 days). No EIR was observed in CeAD without ischemic presentation or with less than 70% stenosis. In the remaining cases, poor circle of Willis (OR=8.5, CI95%=2.0–35.4, p = 0.003), CeAD extending to other intracranial arteries than just V4 (OR=6.8, CI95%=1.4–32.6, p = 0.017), cervical artery occlusion (OR=9.5, CI95%=1.2- 39.0, p = 0.031), and cervical intraluminal thrombus (OR=17.5, CI95%=3.0–101.7, p = 0.001) were independently associated with EIR. ConclusionsOur results suggests that EIR is more frequent than previously reported, and that its risk might be stratified on admission with a standard workup. In particular, the presence of a poor circle of Willis, intracranial extension (other than just V4), cervical occlusion, or cervical intraluminal thrombus are associated with high risk of EIR, for which specific management should be further evaluated.

Monitoring of direct oral anticoagulants plasma levels for secondary stroke prevention

BackgroundPatients with atrial fibrillation have a relevant risk for ischemic stroke despite the recommended use of direct oral anticoagulants (DOAC). The risk correlates with the functional DOAC plasma levels in clinical trials, but the value of their measurement in community use remains undetermined. ObjectivesWe aim to investigate the clinical implications and the prognostic value of DOAC plasma level measurement during steady state. MethodsIn this observational clinical cohort study among patients with ischemic stroke and atrial fibrillation, 397 individuals on oral anticoagulants for secondary stroke prevention were included between 2016 and 2020. The functional DOAC plasma levels were measured during steady state. Early stroke recurrence within 3 months was recorded as the main outcome parameter. ResultsThree hundred ninety‐seven patients (201 female, mean age 78 [±9] years, median CHA2DS2VASc‐Score 6 [interquartile range 5–7]) were included. Mean DOAC plasma trough level was 95.9 (±66.9) ng/ml. A high glomerular filtration rate (GFR) was an independent predictor of lower levels in a multivariate model (R coefficient: −0.174, P= .014). During follow‐up, 10 patients (3%) suffered from early ischemic stroke recurrence despite the use of DOAC, while 10 clinically relevant bleeding complications occurred (3%). Ischemic stroke recurrence was associated with numerical lower plasma levels for patients on apixaban and dabigatran after propensity score matching. ConclusionsMonitoring of DOAC plasma levels could help to identify patients with increased risk for stroke recurrence and should be considered for certain subgroups, including patients with high GFR.

Evaluation of Systolic Blood Pressure, Use of Aspirin and Clopidogrel, and Stroke Recurrence in the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke Trial

Elevated systolic blood pressure (SBP) after acute ischemic stroke and transient ischemic attack (TIA) is associated with future stroke risk. To explore the association of dual antiplatelet therapy (DAPT) with stroke recurrence among patients with acute ischemic stroke and TIA with or without elevated baseline SBP. This cohort study performed a post hoc subgroup analysis of the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial, which was a multicenter trial conducted from 2010 to 2018 at 269 sites in 10 countries in North America, Europe, Australia, and New Zealand. Patients enrolled in POINT with available blood pressure and outcome data were included in this cohort. Statistical analysis was performed from November 2020 to January 2021. Baseline SBP less than 140 mm Hg vs greater than or equal to 140 mm Hg and the interaction term of SBP (<140 mm Hg vs ≥140 mm Hg) × treatment group (aspirin vs DAPT). The primary outcome was ischemic stroke during 90 days of follow-up. The statistical analysis fit Cox proportional hazards models adjusted for patient age, race, premorbid hypertension, diabetes, and final diagnosis of the qualifying event (stroke vs TIA). Among 4781 patients in the cohort, the mean (SD) age was 64.6 (13.1) years; 2142 (44.8%) were male individuals, 3487 (72.9%) were White individuals, and 266 (5.6%) had a primary outcome of ischemic stroke during follow-up. There were 946 patients (19.8%) with baseline SBP less than 140 mm Hg and 3835 (80.2%) with SBP greater than or equal to 140 mm Hg. The interaction term (SBP × treatment) was significant (P for interaction = .03). In the subgroup of patients with SBP less than 140 mm Hg, the hazard ratio (HR) of DAPT vs aspirin alone for ischemic stroke was 0.36 (95% CI, 0.18-0.72; P = .004), whereas the HR in the subgroup with SBP greater than or equal to 140 mm Hg was 0.79 (95% CI, 0.60-1.02; P = .08). When evaluating the outcome of ischemic stroke within 7 days of randomization, the interaction term was significant (P for interaction = .02), and the HR for patients with DAPT with SBP less than 140 mm Hg was 0.19 (95% CI, 0.07-0.55; P = .002). In the POINT trial, patients with SBP less than 140 mm Hg at presentation received a greater benefit from 90 days of DAPT than those with higher baseline SBP, particularly for reduction of early ischemic stroke recurrence. Additional research is needed to replicate these findings and potentially test whether mild SBP reduction and DAPT within 12 hours of stroke onset lowers early risk of stroke recurrence.

Anticoagulation After Stroke in Patients With Atrial Fibrillation.

Background and Purpose- Bridging therapy with low-molecular-weight heparin reportedly leads to a worse outcome for acute cardioembolic stroke patients because of a higher incidence of intracerebral bleeding. However, this practice is common in clinical settings. This observational study aimed to compare (1) the clinical profiles of patients receiving and not receiving bridging therapy, (2) overall group outcomes, and (3) outcomes according to the type of anticoagulant prescribed. Methods- We analyzed data of patients from the prospective RAF and RAF-NOACs studies. The primary outcome was defined as the composite of ischemic stroke, transient ischemic attack, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding observed at 90 days after the acute stroke. Results- Of 1810 patients who initiated oral anticoagulant therapy, 371 (20%) underwent bridging therapy with full-dose low-molecular-weight heparin. Older age and the presence of leukoaraiosis were inversely correlated with the use of bridging therapy. Forty-two bridged patients (11.3%) reached the combined outcome versus 72 (5.0%) of the nonbridged patients (P=0.0001). At multivariable analysis, bridging therapy was associated with the composite end point (odds ratio, 2.3; 95% CI, 1.4-3.7; P<0.0001), as well as ischemic (odds ratio, 2.2; 95% CI, 1.3-3.9; P=0.005) and hemorrhagic (odds ratio, 2.4; 95% CI, 1.2-4.9; P=0.01) end points separately. Conclusions- Our findings suggest that patients receiving low-molecular-weight heparin have a higher risk of early ischemic recurrence and hemorrhagic transformation compared with nonbridged patients.

FLAIR vascular hyperintensities predict early ischemic recurrence in TIA.

To evaluate the relationship between fluid-attenuated inversion recovery (FLAIR) vascular hyperintensity (FVH) and early ischemic lesion recurrence (follow-up diffusion-weighted imaging [FU-DWI] [+]) in patients with lesion-negative TIA. We recruited consecutive patients with lesion-negative TIA within 24 hours of symptom onset, who underwent follow-up MRI during the acute period. FVH was defined as a focal or serpentine high signal intensity on FLAIR images. Other potential confounders were adjusted to evaluate the relationship between FVH and FU-DWI (+). Furthermore, to compare clinical outcomes between the FU-DWI (+) and FU-DWI (-) groups, we assessed 1-year recurrent ischemic stroke or TIA. Among 392 patients with lesion-negative TIA, 82 patients had FU-DWI (+) on the follow-up MRI. In the multivariate analysis, FVH remained an independent predictor of FU-DWI (+) (adjusted odds ratio [aOR] = 4.77, 95% confidence interval [CI] 2.45-9.29, p < 0.001). The time to initial MRI (aOR = 0.49, 95% CI = 0.33-0.70, p < 0.001) and intracranial atherosclerosis (aOR = 2.07, 95% CI = 1.10-3.92, p = 0.025) were also associated with FU-DWI (+), independent of FVH. In clinical outcomes, the FU-DWI (+) group showed more frequent 1-year recurrent ischemic stroke events than the FU-DWI (-) group (10.7% vs 3.1%, respectively, p = 0.007). FVH is associated with FU-DWI (+) in patients with lesion-negative TIA. As FU-DWI (+) frequently occurs during the acute period and has a subsequent worse outcome after discharge, additional radiologic or clinical markers for it are necessary.

Abstract 1: Early Recurrence in Paroxysmal Versus Sustained Atrial Fibrillation in Patients With Acute Ischemic Stroke

Background and purpose: To date, there have been no thorough investigations on the possible role of atrial fibrillation (AF) pattern in stroke recurrence during early-phase post stroke. We investigated for differences in ischemic outcome between patients with paroxysmal AF (PAF) and those with sustained AF (SAF), within 90 days from acute ischemic stroke (AIS). Methods: Patients from the RAF and RAF-DOAC study databases were categorized into 2 groups: PAF and SAF (persistent + permanent AF). Early recurrence was defined as the composite of ischemic stroke, transient ischemic attack and symptomatic systemic embolism within 90 days from AIS. Results: A total of 2,150 patients (1,155 females, 53.7%) were enrolled: 930 (43.3%) had PAF and 1220 (56.7%) SAF. Patients with SAF were on average older, were more likely to have: diabetes mellitus, hypertension, a history of stroke/TIA, congestive heart failure, atrial enlargement, pacemaker and a high NIHSS. During the 90-day follow-up, 107 recurrent ischemic events were recorded from index stroke. Multivariate analysis for predictive factors of early ischemic recurrence indicated that SAF was associated with a non-significant increase in ischemic events at 90 days, compared to PAF (HR 1.23; 95% CI 0.74-2.04; p = 0.418) (Figure). Conclusions: PAF and SAF patients with acute stroke resulted having similar risks of ischemic recurrence within 90 days from index event. Therein, these findings suggest that AF pattern should not influence decision making concerning the timing of anticoagulant administration after an acute stroke.

Stroke : Highlights of Selected Articles

<i>Stroke</i> : Highlights of Selected Articles

CYP2C19 Genotype and Early Ischemic Lesion Recurrence in Stroke Patients Treated with Clopidogrel

Early recurrent ischemic lesions detected on diffusion-weighted imaging (DWI) have been proposed as a surrogate marker for clinical recurrence. We hypothesized that cytochrome P450 2C19 (CYP2C19) genotype influences the incidence of early recurrence on DWI in acute stroke patients treated with clopidogrel. We enrolled 76 Korean patients with acute ischemic stroke due to large artery atherosclerosis who were treated with clopidogrel. Early ischemic lesion recurrence was defined as new lesions separate from the index lesion. We compared the rates of early ischemic lesion recurrence on DWI based on the CYP2C19 genotypes. Early recurrence on DWI was observed in 36 patients (47.4%). A total of 76 patients were classified into 3 phenotypic groups: extensive metabolizers (EMs; n = 27, 35.5%), intermediate metabolizers (IMs; n = 36, 47.4%), and poor metabolizers (PMs; n = 13, 17.1%). Early recurrence on DWI was more common in PMs (84.6%), followed by IMs (50.0%), and EMs (25.9%; P < .001). PMs had a significantly higher recurrence rate than EMs (P < .001). In multivariate analysis, CYP2C19 genotypes were independently associated with early DWI recurrence (for PMs: odds ratio, 19.3; 95% confidence interval, 3.15-117.56). CYP2C19 genotypes are significantly associated with early lesion recurrence in Korean acute stroke patients treated with clopidogrel.

Is Aortic Atherothrombotic Disease Detected Using Multidetector-Row CT Associated With an Increased Risk of Early Ischemic Lesion Recurrence After Acute Ischemic Stroke?

Multidetector-row CT (MDCT) is emerging as a new tool for diagnosing aortic atherothrombotic disease (AAD). We elucidated whether MDCT-detected AAD is associated with an increased risk of early ischemic lesion recurrence on diffusion-weighted MRI after ischemic stroke. A consecutive series of patients with acute ischemic stroke confirmed using diffusion-weighted MRI who were hospitalized within 48 hours after symptom onset and underwent MDCT were identified in a prospective stroke registry database. AAD on MDCT was defined as the presence of plaque formation that was noncalcified and ≥4 mm thick, ulcerative, or soft and thrombosed (vulnerable) in the proximal aortic arch. Ischemic lesion recurrence on diffusion-weighted MRI was defined as the occurrence of any new lesion separate from the index lesion on follow-up diffusion-weighted MRI performed within 14 days after symptom onset. A total of 138 patients was selected. MDCT detected AAD in 24 of 138 (17.4%); ≥4 mm thickness in 17 of 138 (12.3%); ulcerated plaque in 20 of 138 (14.5%); and vulnerable plaque in 16 of 138 (11.6%). With respect to diffusion-weighted MRI lesion recurrence, the crude ORs (95% CIs) were as follows: AAD, 3.56 (1.43-8.89); vulnerable plaque, 3.21 (1.11-9.30); ulcerated plaque, 3.37 (1.27-8.95); and ≥4 mm thickness of the noncalcified plaque, 4.23 (1.11-16.19). These results remained significant after adjustments for potential confounders were made. This study shows that AAD detected by MDCT increases the risk of early ischemic lesion recurrence after acute ischemic stroke, thus supporting the role of MDCT in diagnosing AAD and assessing its contribution to recurrence.

Early Recurrence of Ischemic Stroke in Japanese Patients: The Japan Standard Stroke Registry Study

Background: To determine the factors that contribute to early ischemic stroke recurrence in Japanese patients. Methods: A multicenter stroke registration study based on a computerized database from 54 Japanese institutes, involving 8,036 patients with brain infarction who were hospitalized within 48 h after symptom onset between January 2000 and March 2004. Results: Within 30 days after the initial stroke, 395 patients (4.9%) developed a recurrent stroke. Recurrence most frequently occurred in atherothrombotic patients (6.6%), followed by cardioembolic patients (6.2%). Overall, hypertension (OR 1.348, 95% CI 1.071–1.696) and atrial fibrillation (OR 1.503, 95% CI 1.177–1.918), but not diabetes mellitus, were independently predictive of early recurrence. In atherothrombotic patients, diabetes mellitus (OR 1.485, 95% CI 1.058–2.085) and atrial fibrillation (OR 1.998, 95% CI 1.231–3.244) were independently related to early recurrence. At hospital discharge, the modified Rankin Scale score was higher in patients who had an early recurrence (p < 0.0001). Conclusions: This study was based on a large number of Japanese patients and confirmed that hypertension and atrial fibrillation contribute to early ischemic stroke recurrence. In addition, analysis by stroke subtype showed that diabetes mellitus was independently related to early recurrence in atherothrombotic patients.

Time period required for transcranial Doppler monitoring of embolic signals to predict recurrent risk of embolic transient ischemic attack and stroke from arterial stenosis.

We aimed to investigate whether the time period of transcranial Doppler monitoring for embolic signals can be reduced without loss of clinical yield compared with routinely performed 1-hour monitoring. Investigations on the basis of a post hoc analysis of a previously published cohort of 86 patients (55 men, 31 women; mean age 60.6 years) with a nondisabling arterioembolic ischemic event in the anterior circulation within the last 30 days (mean 7.3) and an ipsilateral medium-grade or high-grade stenosis of the carotid or middle cerebral artery. Patients underwent 1-hour monitoring for embolic signals and were followed up prospectively for 6 weeks to evaluate the relationship between embolic signals and risk of an early ischemic recurrence. Risk was also calculated after fictitious reduction of the monitoring period from 60 minutes to 50, 40, 30, 20, and 10 minutes, respectively, and compared with the results obtained from the 1-hour period. The number of patients positive for embolic signals decreased with the decreasing monitoring period. By this, the odds ratio of embolic signals for an early ischemic recurrence "decreased" from 40 (derived from the 1-hour monitoring) to 10 when the monitoring lasted < or =30 minutes. The relationship between the rate of embolic signals per hour and risk of a recurrent stroke is described by an S-shaped curve. As a consequence, risk estimated from reduced monitoring periods can differ considerably from that derived from the 1-hour monitoring if the signal frequency lies within a medium range (eg, between 3 and 15 signals in 30 minutes). The time period of monitoring for embolic signals may be reduced without loss of clinical relevant information when signal frequency is low or already high during the reduced monitoring period, but it should be prolonged to maximally an hour at signal numbers within a medium range. However, our results need to be externally validated on an independent cohort of patients or confirmed by a prospective study before this modification can be recommended in general.

Recurrent cardiac ischemic events early after discontinuation of short-term heparin treatment in acute coronary syndromes: Results from the thrombolysis in myocardial infarction (TIMI) 11B and efficacy and safety of subcutaneous enoxaparin in Non–Q-Wave coronary events (ESSENCE) studies

ObjectivesThe aim of this study was to determine whether discontinuation of low-molecular-weight heparin (LMWH) treatment results in a clustering of cardiac ischemic events as previously observed after cessation of unfractionated heparin (UFH) in acute coronary syndrome (ACS) patients. BackgroundClinical trials in patients with ACS have shown early recurrent ischemic events after discontinuation of UFH treatment. We analyzed whether LMWH cessation also results in early ischemic recurrence events and if continuation of a fixed-dose LMWH prevents this complication. MethodsThe combined incidence of death, myocardial infarction, or urgent revascularization in the first seven days after discontinuation of UFH (n = 3,012), short-term enoxaparin 1 mg/kg subcutaneously twice a day (n = 2,011), and short-term enoxaparin followed by prolonged enoxaparin 60 mg subcutaneously twice a day (n = 1,075) was analyzed from the combined Thrombolysis In Myocardial Infarction (TIMI) 11B/Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events (ESSENCE) database in a per patient analysis. ResultsThe cessation of both UFH and short-term enoxaparin resulted in a similar clustering of recurrent ischemic events on the first day, with an incidence of the primary end point of 2.8% in both groups. Of all recurrent events in the first week after cessation, 40% occurred in the first 24 h. The continuation of a fixed-dose enoxaparin treatment prevented this early excess, with a first day incidence of 0.4% (p < 0.0001). The TIMI risk score characteristics predicted the incidence of early rebound ischemic events. ConclusionsThere is significant clustering of recurrent ischemic events within 24 h after cessation of both short-term UFH and enoxaparin treatment, and patients should be carefully monitored during that period. This early rebound may be prevented by continuation of a fixed dose of enoxaparin.

Early ischemic lesion recurrence within a week after acute ischemic stroke.

Previous observations suggested that multiple ischemic lesions on diffusion-weighted imaging (DWI) are common in acute stroke patients. We hypothesized that a source of these multiple lesions was the recurrence of ischemic lesions within a week after a clinically symptomatic stroke. We analyzed 99 acute ischemic stroke patients scanned within 6 hours of onset and at subsequent times within the first week. Ischemic lesion recurrence was defined as any new lesion separate from the index lesion. Recurrent lesions occurring outside initial perfusion deficit were termed 'distant lesion recurrence'. We estimated the hazard ratio (HR) of recurrence associated with clinical and imaging characteristics using log-rank test. Any lesion recurrence was found in 34%, with distant lesion recurrence in 15%, while clinical recurrence was evident in 2%. Initial multiple DWI lesions were associated with any lesion recurrence (HR, 2.83; 95% confidence interval [CI], 1.65-10.29; p = 0.002) and with distant lesion recurrence (HR, 5.99; 95% CI, 4.05-64.07; p < 0.0001). Large-artery atherosclerosis was the most frequent stroke subtype associated with any lesion recurrence (p = 0.026). These results may indicate a prolonged state of increased ischemic risk over the first week and suggest DWI as a possible surrogate measure for recurrent stroke.

Cerebral microembolism in acute spontaneous internal carotid artery dissection.

The rate and risk factors for early ischemic recurrence in patients with internal carotid artery dissection (ICAD) are largely unknown. Serial transcranial Doppler (TCD) monitoring of microembolic signals (MES) was performed in 28 consecutive patients with acute ICAD. MES were identified in 13 patients, and early ischemic recurrence occurred in 7. Six of 13 patients with MES and 1 of 15 without MES experienced early ischemic recurrence (p = 0.029). MES detection on serial TCD monitoring may be associated with an increased risk of early ischemic recurrence in patients with acute ICAD.

Microembolic signals and risk of early recurrence in patients with stroke or transient ischemic attack.

Asymptomatic microembolic signals (MES) can be demonstrated in patients with cerebral ischemia using transcranial Doppler (TCD) ultrasonographic monitoring of the middle cerebral artery. However, the clinical relevance of MES remains uncertain. The purpose of this study was to estimate the independent contribution of microembolism to the risk of early ischemic recurrence (EIR) in patients with stroke or transient ischemic attack (TIA) of presumed arterial origin. We studied the incidence of EIR in 73 consecutive patients with carotid stroke or TIA in whom TCD scanning of the symptomatic middle cerebral artery was performed within 7 days from the onset of symptoms. Patients with a potential cardiac source of embolism were excluded from the study. Eight patients had EIR during a mean+/-SD follow-up of 10+/-8 days. The incidence of EIR was 4.3 per 100 patient-days in patients with MES and only 0.5 per 100 patient-days in patients without MES. The presence of MES was a significant predictor of EIR after adjustment for the presence of carotid stenosis or aortic arch atheroma, antiplatelet therapy during follow-up, and other potential confounding variables (relative risk, 8.7; 95% confidence interval, 2 to 38.2; P=0.0015). Microembolism is a significant independent predictor of EIR in patients with stroke or TIA of presumed arterial origin.