Cilostazol versus aspirin in ischemic stroke with cerebral microbleeds versus prior intracerebral hemorrhage

Background In PreventIon of CArdiovascular Events in Ischaemic Stroke Patients with High Risk of Cerebral HaemOrrhage (PICASSO), cilostazol versus aspirin was comparable for the end points of cerebral hemorrhage and major vascular events. However, underlying hemorrhage-prone lesions could modify the treatment effect. Aims We explored whether the safety and efficacy of cilostazol versus aspirin would differ between hemorrhage-prone lesions (multiple cerebral microbleeds vs. prior intracerebral hemorrhage). Methods In this post hoc analysis of PICASSO, we divided patients into the cerebral microbleeds and prior intracerebral hemorrhage subgroups. The primary safety end point was the first occurrence of cerebral hemorrhage. The primary efficacy end point was the composite of stroke, myocardial infarction, or vascular death. Results Of 1512 patients, 903 (59.7%) had multiple cerebral microbleeds and 609 (40.3%) had prior intracerebral hemorrhage. The cerebral hemorrhage risk was lower with cilostazol versus aspirin (0.12%/year vs. 1.49%/year; hazard ratio, 0.08 [95% confidence interval 0.01–0.60]; p = 0.015) in the cerebral microbleeds subgroup, but was not different (1.26%/year vs. 0.79%/year; hazards ratio 1.60 [0.52–4.90]; p = 0.408) in the prior intracerebral hemorrhage subgroup. The interaction of treatment-by-subgroup was significant ( pinteraction = 0.011). For the composite of major vascular events, there was a trend toward a lower risk with cilostazol versus aspirin (3.56%/year vs. 5.53%/year; hazards ratio 0.64 [0.41–1.01]; p = 0.056) in the cerebral microbleeds subgroup, but was comparable (5.21%/year vs. 5.05%/year; hazards ratio 1.03 [0.63–1.67]; p = 0.913) in the prior intracerebral hemorrhage subgroup without a significant treatment-by-subgroup interaction ( pinteraction = 0.165). Conclusions Cilostazol versus aspirin might be a better option in ischemic stroke with multiple cerebral microbleeds, but confirmatory trials are needed. Clinical Trial Registration URL: http://www.clinicaltrials.gov . NCT01013532.

Download Full-text

Clinical significance of cerebral microbleeds on MRI: A comprehensive meta-analysis of risk of intracerebral hemorrhage, ischemic stroke, mortality, and dementia in cohort studies (v1)

International Journal of Stroke ◽

10.1177/1747493017751931 ◽

2018 ◽

Vol 13 (5) ◽

pp. 454-468 ◽

Cited By ~ 30

Author(s):

Andreas Charidimou ◽

Sara Shams ◽

Jose R Romero ◽

Jie Ding ◽

Roland Veltkamp ◽

...

Keyword(s):

Ischemic Stroke ◽

High Risk ◽

Intracerebral Hemorrhage ◽

Meta Analysis ◽

Population Based ◽

Cerebral Microbleeds ◽

Clinical Settings ◽

Memory Clinic ◽

Increased Risk ◽

Stroke Death

Background Cerebral microbleeds can confer a high risk of intracerebral hemorrhage, ischemic stroke, death and dementia, but estimated risks remain imprecise and often conflicting. We investigated the association between cerebral microbleeds presence and these outcomes in a large meta-analysis of all published cohorts including: ischemic stroke/TIA, memory clinic, “high risk” elderly populations, and healthy individuals in population-based studies. Methods Cohorts (with > 100 participants) that assessed cerebral microbleeds presence on MRI, with subsequent follow-up (≥3 months) were identified. The association between cerebral microbleeds and each of the outcomes (ischemic stroke, intracerebral hemorrhage, death, and dementia) was quantified using random effects models of (a) unadjusted crude odds ratios and (b) covariate-adjusted hazard rations. Results We identified 31 cohorts ( n = 20,368): 19 ischemic stroke/TIA ( n = 7672), 4 memory clinic ( n = 1957), 3 high risk elderly ( n = 1458) and 5 population-based cohorts ( n = 11,722). Cerebral microbleeds were associated with an increased risk of ischemic stroke (OR: 2.14; 95% CI: 1.58–2.89 and adj-HR: 2.09; 95% CI: 1.71–2.57), but the relative increase in future intracerebral hemorrhage risk was greater (OR: 4.65; 95% CI: 2.68–8.08 and adj-HR: 3.93; 95% CI: 2.71–5.69). Cerebral microbleeds were an independent predictor of all-cause mortality (adj-HR: 1.36; 95% CI: 1.24–1.48). In three population-based studies, cerebral microbleeds were independently associated with incident dementia (adj-HR: 1.35; 95% CI: 1.00–1.82). Results were overall consistent in analyses stratified by different populations, but with different degrees of heterogeneity. Conclusions Our meta-analysis shows that cerebral microbleeds predict an increased risk of stroke, death, and dementia and provides up-to-date effect sizes across different clinical settings. These pooled estimates can inform clinical decisions and trials, further supporting cerebral microbleeds role as biomarkers of underlying subclinical brain pathology in research and clinical settings.

Download Full-text

Elevated Pulse Pressure and Recurrent Hemorrhagic Stroke Risk in Stroke With Cerebral Microbleeds or Intracerebral Hemorrhage

Journal of the American Heart Association ◽

10.1161/jaha.121.022317 ◽

2021 ◽

Author(s):

Jong‐Ho Park ◽

Juneyoung Lee ◽

Sun U. Kwon ◽

Hyuk Sung Kwon ◽

Min Hwan Lee ◽

...

Keyword(s):

Blood Pressure ◽

Ischemic Stroke ◽

Intracerebral Hemorrhage ◽

Cardiovascular Events ◽

Operating Characteristic ◽

Hemorrhagic Stroke ◽

Stroke Risk ◽

Characteristic Curve ◽

Cerebral Microbleeds ◽

Major Adverse Cardiovascular Events

Background Which type of recurrent stroke is associated with pulse pressure (PP) remains uncertain in ischemic stroke with cerebral microbleeds or intracerebral hemorrhage. Methods and Results The (PICASSO) Prevention of Cardiovascular Events in Ischemic Stroke Patients With High Risk of Cerebral Hemorrhage database involving 1454 subjects was analyzed. Subjects were stratified into quartiles according to the distribution of mean PP (mm Hg) during follow‐up (mean, 1.9 years): <47 (first quartile), 48 to 53 (second quartile), 54 to 59 (third quartile), and ≥60 mm Hg (fourth quartile). The primary end point was hemorrhagic stroke, and the secondary end points were ischemic stroke, stroke of any type, and major adverse cardiovascular events. Adjusted time‐dependent area under the receiver operating characteristic curve analysis was performed to assess the prediction accuracy of mean PP. The mean frequency of visit for blood pressure checkup was 9.4±5.5 times. The stroke incidence rate per 100 person‐years was 3.14, 2.24, 5.52, and 6.22, respectively in increasing quartile of mean PP, and the rate of major adverse cardiovascular events was 3.82, 2.84, 6.37, and 7.14, respectively. In the presence of mean arterial pressure, hemorrhagic stroke risk was higher in the highest quartile (adjusted hazard ratio, 6.03; 95% CI, 1.04–34.99) versus the lowest quartile, which was evident at higher mean systolic blood pressure. Higher mean PP as a continuous variable was also a predictor of hemorrhagic stroke (1.09, 1.03−1.15). The time‐dependent area under the receiver operating characteristic curve for hemorrhagic stroke was 0.79. Conclusions Long‐term elevated PP with higher systolic blood pressure confers a greater risk of subsequent hemorrhagic stroke among stroke patients with cerebral microbleeds or intracerebral hemorrhage. Registration URL: https://www.clinicaltrials.gov ; Unique identifier, NCT01013532.

Download Full-text

Rivaroxaban for Prevention of Covert Brain Infarcts and Cognitive Decline

Stroke ◽

10.1161/strokeaha.120.029762 ◽

2020 ◽

Vol 51 (10) ◽

pp. 2901-2909

Author(s):

Mukul Sharma ◽

Robert G. Hart ◽

Eric E. Smith ◽

Jacqueline Bosch ◽

John W. Eikelboom ◽

...

Keyword(s):

Ischemic Stroke ◽

White Matter ◽

Magnetic Resonance ◽

Cognitive Decline ◽

Odds Ratio ◽

White Matter Hyperintensities ◽

Cerebral Microbleeds ◽

Cognitive Tests ◽

Brain Infarcts ◽

End Point

Background and Purpose: Covert brain infarcts are associated with cognitive decline. It is not known whether therapies that prevent symptomatic stroke prevent covert infarcts. COMPASS compared rivaroxaban with and without aspirin with aspirin for the prevention of stroke, myocardial infarction, and vascular death in participants with stable vascular disease and was terminated early because of benefits of rivaroxaban 2.5 mg twice daily plus aspirin over aspirin. We obtained serial magnetic resonance imagings and cognitive tests in a consenting subgroup of COMPASS patients to examine treatment effects on infarcts, cerebral microbleeds, and white matter hyperintensities. Methods: Baseline and follow-up magnetic resonance imagings were completed in 1445 participants with a mean (SD) interval of 2.0 (0.7) years. Whole-brain T1, T2 fluid-attenuated inversion recovery, T2* sequences were centrally interpreted by blinded, trained readers. Participants had serial measurements of cognition and function. The primary end point was the proportion of participants with incident covert infarcts. Secondary end points were the composite of clinical stroke and covert brain infarcts, cerebral microbleeds, and white matter hyperintensities. Results: At baseline, 493 (34.1%) participants had infarcts. Incident covert infarcts occurred in 55 (3.8%) participants. In the overall trial rivaroxaban plus aspirin reduced ischemic stroke by 49% (0.7% versus 1.4%; hazard ratio [95% CI], 0.51 [0.38–0.68]). In the magnetic resonance imaging substudy the effects of rivaroxaban+aspirin versus aspirin were: covert infarcts: 2.7% versus 3.5% (odds ratio [95% CI], 0.77 [0.37–1.60]); Covert infarcts or ischemic stroke: 2.9% versus 5.3% (odds ratio [95% CI], 0.53 [0.27–1.03]). Incident microbleeds occurred in 6.6% of participants and 65.7% of participants had an increase in white matter hyperintensities volume with no effect of treatment for either end point. There was no effect on cognitive tests. Conclusions: Covert infarcts were not significantly reduced by treatment with rivaroxaban and aspirin but estimates for the combination of ischemic stroke and covert infarcts were consistent with the effect on ischemic stroke in the overall trial. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01776424.

Download Full-text

Prospective, Multicenter, Single-Arm Study of Mechanical Thrombectomy Using Solitaire Flow Restoration in Acute Ischemic Stroke

Stroke ◽

10.1161/strokeaha.113.001232 ◽

2013 ◽

Vol 44 (10) ◽

pp. 2802-2807 ◽

Cited By ~ 190

Author(s):

Vitor M. Pereira ◽

Jan Gralla ◽

Antoni Davalos ◽

Alain Bonafé ◽

Carlos Castaño ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Mechanical Thrombectomy ◽

Hemorrhagic Transformation ◽

Anterior Circulation ◽

Unique Identifier ◽

Vessel Occlusion ◽

Clinical Trial Registration ◽

End Point ◽

Flow Restoration

Background and Purpose— Mechanical thrombectomy using stent retriever devices have been advocated to increase revascularization in intracranial vessel occlusion. We present the results of a large prospective study on the use of the Solitaire Flow Restoration in patients with acute ischemic stroke. Methods— Solitaire Flow Restoration Thrombectomy for Acute Revascularization was an international, multicenter, prospective, single-arm study of Solitaire Flow Restoration thrombectomy in patients with large vessel anterior circulation strokes treated within 8 hours of symptom onset. Strict criteria for site selection were applied. The primary end point was the revascularization rate (thrombolysis in cerebral infarction ≥2b) of the occluded vessel as determined by an independent core laboratory. The secondary end point was the rate of good functional outcome (defined as 90-day modified Rankin scale, 0–2). Results— A total of 202 patients were enrolled across 14 comprehensive stroke centers in Europe, Canada, and Australia. The median age was 72 years, 60% were female patients. The median National Institute of Health Stroke Scale was 17. Most proximal intracranial occlusion was the internal carotid artery in 18%, and the middle cerebral artery in 82%. Successful revascularization was achieved in 79.2% of patients. Device and procedure-related severe adverse events were found in 7.4%. Favorable neurological outcome was found in 57.9%. The mortality rate was 6.9%. Any intracranial hemorrhagic transformation was found in 18.8% of patients, 1.5% were symptomatic. Conclusions— In this single-arm study, treatment with the Solitaire Flow Restoration device in intracranial anterior circulation occlusions results in high rates of revascularization, low risk of clinically relevant procedural complications, and good clinical outcomes in combination with low mortality at 90 days. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01327989.

Download Full-text

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

Stroke ◽

10.1161/strokeaha.120.032239 ◽

2020 ◽

Vol 51 (12) ◽

pp. 3504-3513

Author(s):

Pierre Amarenco ◽

Hans Denison ◽

Scott R. Evans ◽

Anders Himmelmann ◽

Stefan James ◽

...

Keyword(s):

Ischemic Stroke ◽

Transient Ischemic Attack ◽

Absolute Risk ◽

Hazard Ratio ◽

Number Needed To Treat ◽

Severe Bleeding ◽

Vascular Events ◽

End Point ◽

Atherosclerotic Stenosis ◽

Ischemic Attack

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, P interaction =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.

Download Full-text

Early versus delayed stenting for intracranial atherosclerotic artery stenosis with ischemic stroke

Journal of NeuroInterventional Surgery ◽

10.1136/neurintsurg-2019-015035 ◽

2019 ◽

Vol 12 (3) ◽

pp. 274-278 ◽

Cited By ~ 3

Author(s):

Yong Zhang ◽

Yujie Sun ◽

Xin Li ◽

Tonghui Liu ◽

Peng Liu ◽

...

Keyword(s):

Ischemic Stroke ◽

Clinical Outcomes ◽

Stent Placement ◽

Artery Stenosis ◽

Vascular Events ◽

Clinical Trial Registration ◽

Atherosclerotic Stenosis ◽

Intracranial Artery Stenosis ◽

Group 5 ◽

Cerebral Vascular

ObjectiveTo evaluate the clinical outcomes of early stenting (≤14 days) or late stenting (>14 days) in patients who underwent intracranial stent placement.MethodsPatients with ischemic stroke caused by 70–99% intracranial atherosclerotic stenosis combined with poor collaterals were enrolled. The early stenting group, who underwent stenting within 14 days of last ischemic symptoms, were compared with the late stenting group who underwent stenting >14 days from last ischemic symptom. The patients were treated either with a balloon-mounted stent or a self-expanding stent as determined by the operators following a guideline. The baseline characteristics and clinical outcomes were evaluated and compared.ResultsOne hundred and fifteen stroke patients were recruited into the study. Four patients (4/41) in the early stenting group and two patients (2/74) in the late stenting group were diagnosed with a cerebral vascular event associated with stenting within 3 days (p=0.184). In the long-term follow-up, eight patients in the early stenting group had restenosis ≥50%, which was higher than patients in the late stenting group (8/41 vs 4/74, p=0.018). The total rates of any ischemic stroke, transient ischemic attack, hemorrhagic stroke, and death in the early stenting group were higher than in the late stenting group (9/41 vs 6/74, p=0.035). The recurrence rate of ischemic stroke in the early stenting group was higher than in the late stenting group (5/41 vs 2/74, p=0.041).ConclusionsStent placement in the setting of ischemic stroke caused by intracranial artery stenosis within 14 days may confer a higher risk of long-time cerebral vascular events and lead to a higher risk of restenosis.Clinical trial registrationNCT01968122.

Download Full-text

Incident Cerebral Microbleeds After Intracerebral Hemorrhage

Stroke ◽

10.1161/strokeaha.118.023746 ◽

2019 ◽

Vol 50 (8) ◽

pp. 2227-2230

Author(s):

Luke A Perry ◽

Mark Rodrigues ◽

Rustam Al-Shahi Salman ◽

Neshika Samarasekera

Keyword(s):

Ischemic Stroke ◽

Intracerebral Hemorrhage ◽

Meta Analysis ◽

Brain Magnetic Resonance Imaging ◽

Cerebral Microbleeds ◽

Resonance Imaging ◽

Ovid Medline ◽

Subgroup Analyses ◽

Prognostic Implications

Background and Purpose— The frequency and prognostic implications of incident cerebral microbleeds (CMB), defined as development of one or more new CMB, after intracerebral hemorrhage (ICH) is unclear. Therefore, we performed a systematic review and meta-analysis to investigate the frequency and prognostic implications of incident CMB after ICH. Methods— We searched Ovid Medline and Embase in May 2018 for longitudinal studies of adults who underwent brain magnetic resonance imaging at 2 or more times after ICH. We calculated the pooled proportion of adults with incident CMB and sought associations between incident CMB and clinical outcomes (death, recurrent ICH, or new ischemic stroke). We planned subgroup analyses to investigate clinical variables associated with incident CMB. Results— We identified 2354 publications, of which we included 4 cohort studies involving 349 patients. The pooled proportion of adults with at least one new CMB during a mean 27 months follow-up (SD 20 months) was ≈40% (95% CI, 30%–50%). In one study, as the number of incident CMB increased (0 versus 1–3 new CMB versus ≥4 new CMB) the risk of recurrent symptomatic lobar ICH increased (hazard ratio 3.0; 95% CI, 1.2–7.3). No study reported on outcomes of incident ischemic stroke or death. Conclusions— Incident CMB occurs in ≈40% of adults after ICH. The association of incident CMB with recurrent lobar ICH needs confirmation and their association with death and ischemic stroke investigation.

Download Full-text

Anticoagulants Resumption after Warfarin-Related Intracerebral Haemorrhage: The Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy)

Thrombosis and Haemostasis ◽

10.1055/s-0038-1627454 ◽

2018 ◽

Vol 118 (03) ◽

pp. 572-580 ◽

Cited By ~ 7

Author(s):

Loris Poli ◽

Mario Grassi ◽

Marialuisa Zedde ◽

Simona Marcheselli ◽

Giorgio Silvestrelli ◽

...

Keyword(s):

Ischemic Stroke ◽

Multicenter Study ◽

Intracerebral Haemorrhage ◽

Cerebral Hemorrhage ◽

Multivariable Analysis ◽

Recurrent Bleeding ◽

Term Outcome ◽

Long Term Outcome ◽

End Point ◽

All Cause Mortality

AbstractWhether to resume antithrombotic treatment after oral anticoagulant–related intracerebral haemorrhage (OAC-ICH) is debatable. In this study, we aimed at investigating long-term outcome associated with OAC resumption after warfarin-related ICH, in comparison with secondary prevention strategies with platelet inhibitors or antithrombotic discontinuation. Participants were patients who sustained an incident ICH during warfarin treatment (2002–2014) included in the Multicenter Study on Cerebral Hemorrhage in Italy. Primary end-point was a composite of ischemic stroke/systemic embolism (SE) and all-cause mortality. Secondary end-points were ischemic stroke/SE, all-cause mortality and major recurrent bleeding. We computed individual propensity score (PS) as the probability that a patient resumes OACs or other agents given his pre-treatment variables, and performed Cox multivariable analysis using Inverse Probability of Treatment Weighting (IPTW) procedure. A total of 244 patients qualified for the analysis. Unlike antiplatelet agents, OAC resumption was associated with a lower rate of the primary end-point (weighted hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.09–0.45), as well as of overall mortality (weighted HR, 0.17; 95% CI, 0.06–0.45) and ischemic stroke/SE (weighted HR, 0.19; 95% CI, 0.06–0.60) with no significant increase of major bleeding in comparison with patients receiving no antithrombotics. In the subgroup of patients with atrial fibrillation, OACs resumption was also associated with a reduction of the primary end-point (weighted HR, 0.22; 95% CI, 0.09–0.54), and the secondary end-point ischemic stroke/SE (weighted HR, 0.09; 95% CI, 0.02–0.40). In conclusion, in patients who have an ICH while receiving warfarin, resuming anticoagulation results in a favorable trade-off between bleeding susceptibility and thromboembolic risk.

Download Full-text

Glycemia in Spontaneous Intracerebral Hemorrhage: Clinical Implications

Romanian Neurosurgery ◽

10.2478/romneu-2014-0043 ◽

2014 ◽

Vol 21 (3) ◽

pp. 315-326

Author(s):

Hernando Alvis-Miranda ◽

Gabriel Alcala-Cerra ◽

Luis Rafael Moscote-Salazar

Keyword(s):

Ischemic Stroke ◽

Intracerebral Hemorrhage ◽

Intracranial Hemorrhage ◽

Neuronal Death ◽

Cerebral Hemorrhage ◽

Severe Disability ◽

Clinical Implications ◽

Secondary Injury ◽

Spontaneous Intracerebral Hemorrhage ◽

Mortality And Morbidity

Abstract Spontaneous cerebral hemorrhage or intracranial hemorrhage accounts for 10-15% of all strokes. Intracranial hemorrhage is much less common than ischemic stroke, but has higher mortality and morbidity, one of the leading causes of severe disability. Various alterations, among these the endocrine were identified when an intracerebral hemorrhage, these stress-mediated mechanisms exacerbate secondary injury. Deep knowledge of the injuries which are directly involved alterations of glucose, offers insight as cytotoxicity, neuronal death and metabolic dysregulations alter the prognosis of patients with spontaneous intracerebral hemorrhage.

Download Full-text