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Background and Objectives: The goal of this work was to investigate the short-term time-course benefit and risk of ticagrelor with aspirin in acute mild-moderate ischemic stroke or high-risk TIA in The Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial., Methods: In an exploratory analysis of the THALES trial, we evaluated the cumulative incidence of irreversible efficacy and safety outcomes at different time points during the 30-day treatment period. The efficacy outcome was major ischemic events defined as a composite of ischemic stroke or nonhemorrhagic death. The safety outcome was major hemorrhage defined as a composite of intracranial hemorrhage and fatal bleedings. Net clinical impact was defined as the combination of these 2 endpoints., Results: This analysis included a total of 11,016 patients (5,523 in the ticagrelor-aspirin group, 5,493 in the aspirin group) with a mean age of 65 years, and 39% were women. The reduction of major ischemic events by ticagrelor occurred in the first week (4.1% vs 5.3%; absolute risk reduction 1.15%, 95% CI 0.36%-1.94%) and remained throughout the 30-day treatment period. An increase in major hemorrhage was seen during the first week and remained relatively constant in the following weeks (absolute risk increase ≈0.3%). Cumulative analysis showed that the net clinical impact favored ticagrelor-aspirin in the first week (absolute risk reduction 0.97%, 95% CI, 0.17%-1.77%) and remained constant throughout the 30 days., Discussion: In patients with mild-moderate ischemic stroke or high-risk TIA, the treatment effect of ticagrelor-aspirin was present from the first week. The ischemic benefit of ticagrelor-aspirin outweighs the risk of major hemorrhage throughout the treatment period, which may support the use of 30-day treatment with ticagrelor and aspirin in these patients., Classification of Evidence: This study provides Class II evidence that, for patients with mild-moderate ischemic stroke or high-risk TIA, the ischemic benefit of ticagrelor-aspirin outweighs the risk of major hemorrhage throughout the 30-day treatment period., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction: Data on the prognostic value of hypertensive response to exercise in cardiovascular disease are limited. The aim was to determine whether SBP reactions during exercise have any prognostic value in relation to the long-term risk of stroke and myocardial infarction (MI)., Patients and Methods: A representative cohort of men from Gothenburg, Sweden, born in 1913, who performed a maximum exercise test at age 54 years, (n = 604), was followed-up for a maximum of 44 years with regard to stroke and MI., Results: Among the 604 men, the mean resting and maximum SBP was 141.5 (SD 18.8) and 212.1 (SD 24.6) mmHg, respectively. For maximum SBP, the risk of stroke increased by 34% (hazard ratio 1.34, 95% confidence interval 1.11-1.61) per 1-SD increase, while no risk increase was observed for MI. The highest risk of stroke among blood pressure groups was observed among men with a resting SBP of at least 140 mmHg and a maximum SBP of at least 210 mmHg with an hazard ratio of 2.09 (95% confidence interval 1.29-3.40), compared with men with a resting SBP of less than 140 mmHg and a maximum SBP of less than 210 mmHg, independent of smoking, blood glucose, cholesterol and BMI., Conclusion: Among middle-aged men with high resting and maximum blood pressure during maximum exercise workload, an increased risk of stroke was observed but not for MI. Further studies with larger sample sizes are needed to investigate the underlying mechanisms of the increased risk of stroke among individuals with hypertensive response to exercise., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background/aims: Standard approaches to trial design and analyses can be inefficient and non-pragmatic. Failure to consider a range of outcomes impedes evidence-based interpretation and reduces power. Traditional approaches synthesizing information obtained from separate analysis of each outcome fail to incorporate associations between outcomes and recognize the cumulative nature of outcomes in individual patients, suffer from competing risk complexities during interpretation, and since efficacy and safety analyses are often conducted on different populations, generalizability is unclear. Pragmatic and efficient approaches to trial design and analyses are needed., Methods: Approaches providing a pragmatic assessment of benefits and harms of interventions, summarizing outcomes experienced by patients, and providing sample size efficiencies are described. Ordinal outcomes recognize finer gradations of patient responses. Desirability of outcome ranking is an ordinal outcome combining benefits and harms within patients. Analysis of desirability of outcome ranking can be based on rank-based methodologies including the desirability of outcome ranking probability, the win ratio, and the proportion in favor of treatment. Partial credit analyses, involving grading the levels of the desirability of outcome ranking outcome similar to an academic test, provides an alternative approach. The methodologies are demonstrated using the acute stroke or transient ischemic attack treated with aspirin or ticagrelor and patient outcomes study (SOCRATES; NCT01994720), a randomized clinical trial., Results: Two 5-level ordinal outcomes were developed for SOCRATES. The first was based on a modified Rankin scale. The odds ratio is 0.86 (95% confidence interval = 0.75, 0.99; p = 0.04) indicating that the odds of worse stroke categorization for a trial participant assigned to ticagrelor is 0.86 times that of a trial participant assigned to aspirin. The 5-level desirability of outcome ranking outcome incorporated and prioritized survival; the number of strokes, myocardial infarction, and major bleeding events; and whether a stroke event was disabling. The desirability of outcome ranking probability and win ratio are 0.504 (95% confidence interval = 0.499, 0.508; p = 0.10) and 1.11 (95% confidence interval = 0.98, 1.26; p = 0.10), respectively, implying that the probability of a more desirable result with ticagrelor is 50.4% and that a more desirable result occurs 1.11 times more frequently on ticagrelor versus aspirin., Conclusion: Ordinal outcomes can improve efficiency through required pre-specification, careful construction, and analyses. Greater pragmatism can be obtained by composing outcomes within patients. Desirability of outcome ranking provides a global assessment of the benefits and harms that more closely reflect the experience of patients. The desirability of outcome ranking probability, the proportion in favor of treatment, the win ratio, and partial credit can more optimally inform patient treatment, enhance the understanding of the totality of intervention effects on patients, and potentially provide efficiencies over standard analyses. The methods provide the infrastructure for incorporating patient values and estimating personalized effects.

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.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: Adjudication of endpoints is a standard procedure in cardiovascular clinical trials. However, several studies indicate that the benefit of adjudication in estimating treatment effect may be limited., Aims: This post hoc analysis of SOCRATES (NCT01994720) compared the treatment effects and investigated the agreement of clinical event assessment by site investigators and independent adjudicators., Methods: SOCRATES compared ticagrelor and aspirin in 13,199 patients with acute minor stroke or high-risk transient ischemic attack. The primary endpoint was stroke, myocardial infarction, or death. Stroke was the major component of the primary endpoint and a secondary endpoint. The endpoints were adjudicated by a blinded independent committee. We compared the treatment effect on the primary endpoint and stroke alone based on the investigators' and adjudicators' assessments, and investigated the agreement rate on the stroke endpoint and major hemorrhages., Results: The hazard ratios (95% confidence interval) for ticagrelor versus aspirin therapy for the primary endpoint were 0.89 (0.78-1.01) when calculated on adjudicator-assessed events and 0.88 (0.78-1.00) for investigator-assessed events. The hazard ratios (95% confidence intervals) for stroke were 0.86 (0.75-0.99) based on the adjudicators' diagnoses and 0.85 (0.75-0.97) based on the investigators' diagnoses. The overall agreement between adjudicator- and investigator-diagnosed stroke was 91%, and for major hemorrhages was 88%., Conclusions: In SOCRATES, there was no clinically meaningful difference in the estimated treatment effect, on either the primary endpoint or stroke, by using investigator- or adjudicator-assessed events. Double-blind treatment outcome studies with stroke endpoints may not benefit from adjudication., Trial Registration: ClinicalTrials.gov Identifier: NCT01994720.

Rationale: In patients with acute cerebral ischemia, the rate of stroke, myocardial infarction, or death during 90 days was reported to be non-significantly lower with ticagrelor compared with aspirin, with no increase in major hemorrhage. Dual antiplatelet therapy may be more effective in this setting., Aim: To investigate whether ticagrelor combined with aspirin are superior to aspirin alone in preventing stroke or death in patients with non-severe, non-cardioembolic ischemic stroke or high-risk transient ischemic attack., Design: The Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and Aspirin for Prevention of Stroke and Death (THALES) trial is a randomized, placebo-controlled, double-blind, event-driven study. Patients will be randomized within 24 h of onset of acute ischemic symptoms. THALES is expected to randomize 13,000 at ∼450 sites worldwide, to collect 764 primary outcome events. Study treatments are ticagrelor 180 mg loading dose on day 1, then 90 mg twice daily on days 2-30, or matching placebo. All patients will also receive open-label aspirin 300-325 mg on day 1, then 75-100 mg once daily on days 2-30., Study Outcomes: The primary efficacy outcome is time to the composite endpoint of stroke or death through 30-day follow-up. The primary safety outcome is time to first severe bleeding event., Discussion: The THALES trial will provide important information about the benefits and risks of dual antiplatelet therapy with ticagrelor and aspirin in patients with acute cerebral ischemia in a global setting (funding: AstraZeneca)., Clinical Trial Registration Url: http://www.clinicaltrials.gov . Unique identifier: NCT03354429.

Objective: To examine factors associated with disability following TIA and minor stroke, including poststroke complications such as stroke recurrence, major bleeding, and other adverse medical events., Methods: The SOCRATES trial randomized patients with TIA/minor stroke (NIH Stroke Scale [NIHSS] score ≤5) within 24 hours of onset. We performed a post hoc analysis of factors associated with disability (modified Rankin Scale [mRS] score >1). TIA and minor stroke were analyzed separately. Patients with premorbid mRS >0 were excluded., Results: At 90 days, 687/3,663 (19%) patients with stroke were disabled; for TIA, 122/2,384 (5%) were disabled. In multivariate analyses, age, diabetes, and NIHSS were associated with disability in the stroke cohort, and age with disability in the TIA cohort. Postrandomization events (recurrent stroke, myocardial infarction, major bleeding, serious adverse events) were strongly associated with disability in both cohorts (stroke cohort: odds ratio [OR] 5.6, 95% confidence interval [CI] 4.5-6.9; TIA cohort: OR 14.8, 95% CI 9.9-22.0). Of the TIA patients who ended up disabled, 65% experienced a postrandomization event; for stroke patients who ended up disabled, 39% had a postrandomization event. Disability increased linearly with NIHSS score ( p < 0.0001) and was greater in those with limb weakness ( p < 0.0001)., Conclusions: After TIA and minor stroke, subsequent stroke and medical complications are strongly associated with disability. In addition, even within a low range of baseline scores, the NIHSS is a powerful predictor of disability in minor stroke patients, with items scoring limb weakness particularly associated with subsequent disability., (© 2019 American Academy of Neurology.)

Background and Purpose- Recurrent ischemia risk is high in the acute period after cerebral ischemic events. Effects of antiplatelet agents may vary by time to loading dose (TLD). We explored the risk of recurrent events and safety and efficacy of ticagrelor versus aspirin in relation to TLD. Methods- We randomized 13 199 patients with noncardioembolic, nonsevere ischemic stroke, or high-risk transient ischemic attack to 90-day ticagrelor or aspirin treatment within 24 hours of symptom onset. For this analysis, 13 126 patients were categorized by TLD as <12 hours or ≥12 hours from start of index event. The primary end point was the composite of stroke, myocardial infarction, or death within 90 days. Major bleeding was the primary safety end point. Results- TLD was <12 hours in 4403 (33.5%) and ≥12 hours in 8723 (66.5%). The Kaplan-Meier% for the primary end point for all patients with TLD<12 hours was 7.5% versus 6.9% in TLD≥12 hours. Among patients with TLD<12 hours, the primary end point occurred in 147/2196 (6.8%) randomized to ticagrelor and in 184/2207 (8.3%) randomized to aspirin (hazard ratio, 0.79; 95% CI, 0.64-0.98; P=0.036). Among patients with TLD≥12 hours, the primary end point occurred in 6.7% patients randomized to ticagrelor versus 7.0% to aspirin (hazard ratio, 0.95; 95% CI, 0.81-1.12; P=0.55). There was no significant treatment-by-TLD interaction. Major bleeding rates were comparable on ticagrelor and aspirin, regardless of TLD. Conclusions- The event rate for the primary end point was higher in patients treated early (<12 hours) versus later (≥12 hours). In this exploratory analysis, a larger numerical difference in the primary end point was observed among patients on ticagrelor than on aspirin when TLD was <12 hours compared with ≥12 hours, although the interaction terms for treatment-by-TLD were not significant. For major bleeding, no relation to TLD was observed. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01994720.

Background and Purpose: SOCRATES (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes), comparing ticagrelor with aspirin in patients with acute cerebral ischemia, found a nonsignificant 11% relative risk reduction for stroke, myocardial infarction, or death ( P =0.07). Aspirin intake before randomization could enhance the effect of ticagrelor by conferring dual antiplatelet effect during a high-risk period for subsequent stroke. Therefore, we explored the efficacy and safety of ticagrelor versus aspirin in the patients who received any aspirin the week before randomization., Methods: A prespecified subgroup analysis in SOCRATES (n=13 199), randomizing patients with acute ischemic stroke (National Institutes of Health Stroke Scale score of ≤5) or transient ischemic attack (ABCD 2 score of ≥4) to 90-day treatment with ticagrelor or aspirin. Patients in the prior-aspirin group had received any aspirin within the week before randomization. Primary end point was time to stroke, myocardial infarction, or death. Safety end point was PLATO (Study of Platelet Inhibition and Patient Outcomes) major bleeding., Results: The 4232 patients in the prior-aspirin group were older, had more vascular risk factors, and vascular disease than the other patients. In the prior-aspirin group, the primary end point occurred in 138/2130 (6.5%) of patients on ticagrelor and in 177/2102 (8.3%) on aspirin (hazard ratio, 0.76; 95% confidence interval, 0.61-0.95; P =0.02); in patients with no prior-aspirin usage an event occurred in 304/4459 (6.9%) and 320/4508 (7.1%) on ticagrelor and aspirin, respectively (hazard ratio, 0.96; 95% confidence interval, 0.82-1.12; P =0.59). The treatment-by-prior-aspirin interaction was not statistically significant ( P =0.10). In the prior-aspirin group, major bleeding occurred in 0.7% and 0.4% of patients on ticagrelor and aspirin, respectively (hazard ratio, 1.58; 95% confidence interval, 0.68-3.65; P =0.28)., Conclusions: In this secondary analysis from SOCRATES, fewer primary end points occurred on ticagrelor treatment than on aspirin in patients receiving aspirin before randomization, but there was no significant treatment-by-prior-aspirin interaction. A new study will investigate the benefit-risk of combining ticagrelor and aspirin in patients with acute cerebral ischemia (URL: https://www.clinicaltrials.gov. Unique identifier: NCT03354429)., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01994720., (© 2018 American Heart Association, Inc.)

Aims: Despite the widespread use of percutaneous closure of patent foramen ovale (PFO) in patients after a cryptogenic stroke, little is known about its impact on health-related quality of life (HRQoL). The aim of this study was to assess HRQoL in these patients compared to PFO patients not considered candidates for percutaneous closure, and to a normal population., Methods and Results: A total of 402 patients with cryptogenic stroke or transient ischaemic attack (TIA) who had been referred to our center for PFO closure were invited to a long-term clinical follow-up (mean follow-up 5.5 years; range 3-13 years). HRQoL was assessed using the SF-36 Health Survey and data were compared with an age- and gender-matched reference group from the Swedish SF-36 normative database. Fifteen patients had died and 43 did not answer the SF-36. Of the remaining 344 patients, 208 had undergone PFO closure, and 136 had not. The closure group and reference group reported similar HRQoL levels. However, the non-closure group showed significantly lower HRQoL in role limitation - physical, vitality, general health, mental health (p < 0.05) and social functioning (p = 0.05) than the reference group and also had significantly lower scores than the closure group, correcting for age differences, on physical functioning, role limitation - physical, vitality and general health (p < 0.05)., Conclusions: Non-closure patients had lower HRQoL than their counterparts in the normal population and the closure group. Percutaneous PFO closure is associated with a favorable quality of life., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Purpose: Ticagrelor is an effective antiplatelet therapy among patients with atherosclerotic disease and, therefore, could be more effective than aspirin in preventing recurrent stroke and cardiovascular events among patients with embolic stroke of unknown source (ESUS), which includes patients with ipsilateral stenosis <50% and aortic arch atherosclerosis., Methods: We randomized 13 199 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 2-90) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2-90) within 24 hours of symptom onset. In all patients, investigators informed on the presence of ipsilateral stenosis ≥50%, small deep infarct <15 mm, and on cardiac source of embolism detected after enrollment or rare causes, which allowed to construct an ESUS category in all other patients with documented brain infarction. The primary end point was the time to the occurrence of stroke, myocardial infarction, or death within 90 days., Results: ESUS was identified in 4329 (32.8%) patients. There was no treatment-by-ESUS category interaction ( P =0.83). Hazard ratio in ESUS patients was 0.87 (95% confidence interval, 0.68-1.10; P =0.24). However, hazard ratio was 0.51 (95% confidence interval, 0.29-0.90; P =0.02) in ESUS patients with ipsilateral stenosis <50% or aortic arch atherosclerosis (n=961) and 0.98 (95% confidence interval, 0.76-1.27; P =0.89) in the remaining ESUS patients (n=3368; P for heterogeneity =0.04)., Conclusions: In this post hoc, exploratory analysis, we found no treatment-by-ESUS category interaction. ESUS subgroups have heterogeneous response to treatment (Funded by AstraZeneca)., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994720., (© 2017 American Heart Association, Inc.)

Background: Ticagrelor is an effective antiplatelet therapy for patients with coronary atherosclerotic disease and might be more effective than aspirin in preventing recurrent stroke and cardiovascular events in patients with acute cerebral ischaemia of atherosclerotic origin. Our aim was to test for a treatment-by-ipsilateral atherosclerotic stenosis interaction in a subgroup analysis of patients in the Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial., Methods: SOCRATES was a randomised, double-blind, controlled trial of ticagrelor versus aspirin in patients aged 40 years or older with a non-cardioembolic, non-severe acute ischaemic stroke, or high-risk transient ischaemic attack from 674 hospitals in 33 countries. We randomly allocated patients (1:1) to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2-90, given orally) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2-90, given orally) within 24 h of symptom onset. Investigators classified all patients into atherosclerotic and non-atherosclerotic groups for the prespecified, exploratory analysis reported in this study. The primary endpoint was the time to occurrence of stroke, myocardial infarction, or death within 90 days. Efficacy analysis was by intention to treat. The SOCRATES trial is registered with ClinicalTrials.gov, number NCT01994720., Findings: Between Jan 7, 2014, and Oct 29, 2015, we randomly allocated 13 199 patients (6589 [50%] to ticagrelor and 6610 [50%] to aspirin). Potentially symptomatic ipsilateral atherosclerotic stenosis was reported in 3081 (23%) of 13 199 patients. We found a treatment-by-atherosclerotic stenosis interaction (p=0·017). 103 (6·7%) of 1542 patients with ipsilateral stenosis in the ticagrelor group and 147 (9·6%) of 1539 patients with ipsilateral stenosis in the aspirin group had an occurrence of stroke, myocardial infarction, or death within 90 days (hazard ratio 0·68 [95% CI 0·53-0·88]; p=0·003). In 10 118 patients with no ipsilateral stenosis, 339 (6·7%) of 5047 patients in the ticagrelor group had an occurrence of stroke, myocardial infarction, or death within 90 days compared with 350 (6·9%) of 5071 in the aspirin group (0·97 [0·84-1·13]; p=0·72). There were no significant differences in the proportion of life-threatening bleeding or major or minor bleeding events in patients with ipsilateral stenosis in the ticagrelor group compared with the aspirin group., Interpretation: In this prespecified exploratory analysis, ticagrelor was superior to aspirin at preventing stroke, myocardial infarction, or death at 90 days in patients with acute ischaemic stroke or transient ischaemic attack when associated with ipsilateral atherosclerotic stenosis. An understanding of stroke mechanisms and causes is important to deliver safe and efficacious treatments for early stroke prevention., Funding: AstraZeneca., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aims: Observational studies favor percutaneous closure of patent foramen ovale (PFO) over medical therapy to reduce the risk of recurrent stroke, whereas randomized clinical trials have not shown significant differences. This study aims to compare long-term outcomes of PFO closure versus non-closure., Methods and Results: Patients with PFO and stroke considered for PFO closure were invited to a long-term clinical follow-up. Of the 314 patients, 151 (48%) were accepted for closure and 163 (52%) were not accepted (mean age 50 vs. 58 years). The cumulative incidence of all-cause mortality, stroke or transient ischemic attacks (TIAs) for closure vs. non-closure under a mean follow-up time of five years was 10.6% (16 events) vs. 12.9% (21 events), p=0.53. Six patients, 3.7% vs. 3.6%, died in each group, but no deaths were associated with PFO closure, recurrent stroke or TIA. The incidence of recurrent stroke or TIA for closure vs. non-closure was 6.6% (10 events) vs. 9.2% (15 events), p=0.63. The respective event rates for stroke were 3.9% (6 events) vs. 5.5% (9 events), p=0.50 and for TIA, 2.6% (4 events) vs. 3.7% (6 events), p=0.59., Conclusion: PFO closure was associated with a low risk of recurrent events; however, compared to the non-closure group, no significant differences could be demonstrated. Careful patient selection can avoid under- as well as over-treatment of PFO patients., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: C-reactive protein (CRP) is a determinant of stroke, but there are no prospective studies on CRP and first ischemic stroke divided into etiologic subtypes. Our primary aim was to study CRP as a determinant of ischemic stroke, classified according to Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria, and intracerebral hemorrhage (ICH) in a prospective study. A secondary aim was to study the relationship between the 1444C>T polymorphism, plasma levels of CRP and stroke., Methods: The study was a prospective population-based case-referent study nested within the Northern Sweden Cohorts. We defined 308 cases of ischemic stroke and 61 ICH. Two controls for each case were defined from the same cohort., Results: The OR for the highest (>3 mg/l) versus lowest group (<1 mg/l) of CRP was 2.58 (95% CI 1.74-3.84) for ischemic stroke and 1.63 (95% CI 0.67-3.93) for ICH. In a multivariate model including traditional risk factors, CRP remained associated with ischemic stroke (OR 2.06; 95% CI 1.29-3.29). Small-vessel disease was associated with CRP in the multivariate model (OR 3.88; 95% CI 1.10-13.7). The CRP 1444 (CC/CT vs. TT) polymorphism was associated with plasma levels of CRP but neither with ischemic stroke nor with ICH., Conclusions: This prospective population-based study shows that CRP is significantly associated with the risk of having a first ischemic stroke, especially for small-vessel disease. No significant associations were found between the CRP 1444C>T polymorphism and any stroke subtype.

Background and Purpose: C-reactive protein (CRP) has evolved as an inflammatory risk marker of cardiovascular disease. Several single-nucleotide polymorphisms at the CRP locus have been found to be associated with CRP levels. The aim of the present study was to investigate CRP levels and genetic variants in etiological subtypes of ischemic stroke., Methods: The Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) comprises 600 consecutive ischemic stroke cases (18 to 69 years) and 600 matched controls from western Sweden. Stroke subtypes were defined by the TOAST classification. Serum CRP levels were determined by a high-sensitivity immunometric assay., Results: CRP levels were significantly higher for all ischemic stroke subtypes compared with controls, both in the acute phase and at the 3-month follow-up. After adjustment for traditional risk factors, CRP at follow-up was related to higher odds ratios (ORs) of overall ischemic stroke (OR, 1.25; 95% CI, 1.09 to 1.43) and large-vessel disease (OR, 1.48; 95% CI, 1.09 to 2.00). The CRP -286C>T>A, 1059G>C, and 1444C>T single-nucleotide polymorphisms showed significant associations with CRP levels. However, neither CRP genotypes nor haplotypes showed an association to overall ischemic stroke., Conclusions: This is the first large study on CRP in different TOAST subtypes in a young ischemic stroke population. CRP levels differed between etiological subtypes of ischemic stroke both in the acute phase and at the 3-month follow-up. CRP at follow-up was associated with overall ischemic stroke and the large-vessel disease subtype. Genetic variants at the CRP locus were associated with CRP levels, but no association was detected for overall ischemic stroke.

Background and Purpose: The tissue-type plasminogen activator (tPA) -7351C>T and the plasminogen activator inhibitor type 1 (PAI-1) -675 4G>5G polymorphisms influence transcriptional activity. Both variants have been associated with myocardial infarction, with increased risk for the T and 4G allele, respectively. In this study we investigated the possible association between these polymorphisms, the respective plasma protein levels, and ischemic stroke., Methods: In the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), 600 patients with acute ischemic stroke aged 18 to 69 years and 600 matched community controls were recruited. Stroke subtype was determined using Trial of Org 10172 in Acute Treatment criteria., Results: There were no associations between individual genetic variants and ischemic stroke. The multivariate-adjusted odds ratio for overall ischemic stroke was 1.11 (95% CI 0.87 to 1.43) for tPA T allele carriers, and 0.84 (95% CI, 0.64 to 1.11) for subjects homozygous for the PAI-1 4G allele. When genotypes were combined, a protective effect for the tPA CC/PAI-1 4G4G genotype combination was observed (odds ratio 0.65, 95% CI 0.43 to 0.98; P<0.05). Plasma levels of tPA and PAI-1 antigen at follow-up were independently associated with overall ischemic stroke. tPA-antigen differed by stroke subtype and was highest among those with large-vessel disease and cardioembolic stroke., Conclusions: Neither the tPA -7351C>T nor the PAI-1 to 675 4G>5G polymorphism showed significant association with ischemic stroke. For the tPA CC/PAI-1 4G4G genotype combination, a protective effect was observed. Collectively, these results are consistent with a more complex role for tPA and PAI-1 in the brain as compared with the heart.

Purpose: Patent foramen ovale (PFO) has been implicated as a risk factor for cryptogenic ischemic stroke (CS). However, there is still a lack of widely accepted, undisputed indications for PFO closure. The present study describes the concept of the multidisciplinary PFO conference and a decision making process for closure versus no closure that was developed into a formalized clinical algorithm, and presents the results of implementing these, in terms of number and proportion of PFO closures as well as repeat referrals. Design: Five specialists in neurology, cardiology, internal medicine, thromboembolism, and echocardiography evaluated the clinical data of 311 patients at PFO conferences during 2006 to 2009. The main criteria for closure were patients with first-ever CS with PFO and atrial septal aneurysm, or patients with recurrent CS and PFO without atrial septal aneurysm. Results: A total of 143 patients (46%) were accepted for closure and 167 patients were rejected. Patients accepted for closure were younger (mean 50 years versus 58 years) (P , 0.001). The acceptance rate for PFO closure was similar throughout these years, with an average of 45%. Three of 167 patients (1.8%) initially rejected for PFO closure were re-referred due to recurrent stroke, and the PFO closure was subsequently performed. Conclusion: The acceptance rate of less than 50% in the present study underscores the complex relationship between CS and PFO. Whatever the criteria used for PFO closure, any unit caring for these patients needs to have a rigorous process to avoid overtreatment as well as undertreatment and to ensure that personal preferences and economic incentives do not steer the selection process. Our algorithm provides a stable acceptance rate and a low rate of repeat referrals. [ABSTRACT FROM AUTHOR]

Background and purpose: The ANNEXA‐4 trial measured hemostatic efficacy of andexanet alfa in patients with major bleeding taking factor Xa inhibitors. A proportion of this was traumatic and nontraumatic intracranial bleeding. Different measurements were applied in the trial including volumetrics to assess for intracranial bleeding depending on the compartment involved. We aimed to determine the most reliable way to measure intracranial hemorrhage (ICrH) volume by comparing individual brain compartment and total ICrH volume. Methods: Thirty patients were randomly selected from the ANNEXA‐4 database to assess measurement of ICrH volume by compartment and in total. Total and compartmental hemorrhage volumes were measured by five readers using Quantomo software. Each reader measured baseline hemorrhage volumes twice separated by 1 week. Twenty‐eight different ANNEXA‐4 subjects were also randomly selected to assess intra‐rater reliability of total ICrH volume measurement change at baseline and 12‐h follow up, performed by three readers twice to assess hemostatic efficacy categories used in ANNEXA‐4. Results: Compartmental minimal detectable change percentages (MDC%) ranged between 9.72 and 224.13, with the greatest measurement error occurring in patients with a subdural hemorrhage. Total ICrH volume measurements had the lowest MDC%, which ranged between 6.57 and 33.52 depending on the reader. Conclusion: Measurement of total ICrH volumes is more accurate than volume by compartment with less measurement error. Determination of hemostatic efficacy was consistent across readers, and within the same reader, as well as when compared to consensus read. Volumetric analysis of intracranial hemostatic efficacy is feasible and reliable when using total ICrH volumes. [ABSTRACT FROM AUTHOR]