Safety and efficacy of intensive vs. guideline antiplatelet therapy in high-risk patients with recent ischemic stroke or transient ischemic attack: rationale and design of the Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) trial (ISRCTN47823388)

RATIONALE: The risk of recurrence following a stroke or transient ischemic attack is high, especially immediately after the event. HYPOTHESIS: Because two antiplatelet agents are superior to one in patients with non-cardioembolic events, more intensive treatment might be even more effective. SAMPLE SIZE ESTIMATES: The sample size of 4100 patients will allow a shift to less recurrence, and less severe recurrence, to be detected (odds ratio 0·68) with 90% power at 5% significance. METHODS AND DESIGN: Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (ISRCTN47823388) is comparing the safety and efficacy of intensive (combined aspirin, clopidogrel, and dipyridamole) vs. guideline antiplatelet therapy, both given for one-month. This international collaborative parallel-group prospective randomized open-label blinded-end-point phase III trial plans to recruit 4100 patients with acute ischemic stroke or transient ischemic attack. Randomization and data collection are performed over a secure Internet site with real-time data validation and concealment of allocation. Outcomes, serious adverse events, and neuroimaging are adjudicated centrally with blinding to treatment allocation. STUDY OUTCOME: The primary outcome is stroke recurrence and its severity ('ordinal recurrence' based on modified Rankin Scale) at 90 days, with masked assessment centrally by telephone. Secondary outcomes include vascular events, functional measures (disability, mood, cognition, quality of life), and safety (bleeding, death, serious adverse events). DISCUSSION: The trial has recruited more than 50% of its target sample size (latest number: 2399) and is running in 104 sites in 4 countries. One-third of patients presented with a transient ischemic attack

Remote assessment of platelet function in patients with acute stroke or transient ischaemic attack

Background: Antiplatelets reduce recurrence after cerebral ischaemia. The international TARDIS trial assessed the safety and efficacy of intensive (combined aspirin, dipyridamole and clopidogrel) versus guideline (aspirin and dipyridamole, or clopidogrel alone) antiplatelet agents given for one month in patients with acute stroke or TIA. The aim of this substudy was to assess the effect of antiplatelet agents taken at baseline on platelet function reactivity and activation. Methods: In a substudy, platelet function, assessed by remotely measured surface expression of P-selectin (CD62P, Platelet Solutions Ltd), was assessed at baseline in patients who were and were not taking antiplatelet agents at the time of randomisation. Data are Median Fluorescence values (MF). Results: The aspirin P-selectin test demonstrated that platelet expression was lower in 485 patients taking aspirin than in 171 patients taking no aspirin: mean 209 (SD 188) vs. 552 (431), difference 343 (95% confidence intervals, CI 295.3, 390.7) (2p<0.001). Aspirin did not suppress P-selectin levels below 500 units in 22 (4.5%) patients. The clopidogrel P-selectin test showed that platelet reactivity was lower in 96 patients taking clopidogrel than in 586 patients taking no clopidogrel: 653 (297) vs. 969 (315), difference 316.1 (95% CI 248.6, 383.6) (2p<0.001). However, clopidogrel did not suppress P selectin level below 860 units in 24 (24.7%) patients. Conclusions: Aspirin and clopidogrel each suppress stimulated platelet P-selectin although one quarter of patients on clopidogrel have high on-treatment platelet reactivity. Platelet function testing, assessed as platelet P-selectin expression, may be performed remotely in the context of a large multicentre trial

Zwischen Abschottung und Ambitionen: Arbeiten Deutschland und Frankreich in der europäischen Flüchtlingskrise zusammen?

Mehr als eine Million Menschen versuchten 2015 die Flucht über das Mittelmeer in die Europäische Union. Seit sich Deutschland im Sommer 2015 für die Aufnahme der Geflüchteten stark machte, ist die europäische Dimension der Flüchtlingskrise grell beleuchtet. "Flüchtlingskrise" steht dabei verkürzt für eine tiefe Krise der Asylpolitik in vielen europäischen Ländern sowie die nicht existierende europapolitische Lösung in dieser Frage. Zudem bedeutet dies: Krise der Einreisebedingungen, Krise der Umverteilung innerhalb der EU und Krise der Aufnahmebedingungen in den Mitgliedstaaten. Obwohl Deutschland und Frankreich seit etwas mehr als einem Jahrzehnt in Erklärungen auch die gemeinsame Verantwortung im Bereich der Asyl- und Einwanderungspolitik nennen, ziehen beide Partner nicht an einem Strang. Deutschen Ambitionen, innerhalb der EU weitere Umverteilung von Geflüchteten zu beschließen, erteilte Frankreich eine Absage. Fehlende Investitionen in das Asylverfahren, in die Unterbringung und Integration von Asylbewerbern seit Beginn des neuen Jahrtausends führten in Frankreich eine Asylkrise herbei. Auch eine Reform des Asylrechts konnte keine Verbesserung bringen, zumal die Reform just zu dem Zeitpunkt erfolgte, als 2015 Geflüchtete so zahlreich die EU-Außengrenzen überschritten. Die 2017 anstehenden französischen Wahlen geben keinen Anlass zur Hoffnung auf mutige Schritte in der Migrationspolitik. Die französische Regierung müsste verstehen und zugleich der Bevölkerung begreiflich machen, dass eine stärkere europäische Solidarität auch auf nationaler Ebene vorteilhaft sein kann

Baseline characteristics of the 3,096 patients recruited into the 'Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke' (TARDIS) trial

Background: The risk of recurrence following ischaemic stroke (IS) or transient ischaemic attack (TIA) is highest immediately after the event. Antiplatelet agents are effective in reducing the risk of recurrence and two agents are superior to one in the early phase after ictus. Design: The Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) trial was an international multicentre prospective randomised open-label blinded-endpoint trial that assessed the safety and efficacy of short-term intensive antiplatelet therapy with three agents (combined aspirin, clopidogrel and dipyridamole) as compared with guideline treatment in acute IS or TIA. The primary outcome was stroke recurrence and its severity, measured using the modified Rankin Scale at 90 days. Secondary outcomes included recurrent vascular events, functional measures (cognition, disability, mood, quality of life) and safety (bleeding, death, serious adverse events). Data are number (%) or mean (standard deviation, SD). Results: Recruitment ran from April 2009 to March 2016. 3,096 patients were recruited from 106 sites in 4 countries (Denmark 1.6%, Georgia 2.7%, New Zealand 0.2%, UK 95.4%). Randomisation characteristics included: age 69.0 (10.1) years; male 1945 (62.8%); time onset to randomisation 29.4 (11.9) hours; stroke severity (National Institutes for Health Stroke Scale) 2.8 (3.6); blood pressure 143.5 (18.2)/79.5 (11.4) mmHg; IS 2143 (69.2%), TIA 953 (30.8%). Conclusion: TARDIS was a large trial of intensive/triple antiplatelet therapy in acute IS and TIA, and included participants from four predominantly Caucasian countries who were representative of patients in many western stroke services

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Background: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. Methods: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. Findings: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001). Interpretation: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice

Clinical utility of remote platelet function measurement using P-selectin: assessment of aspirin, clopidogrel, and prasugrel and bleeding disorders

Vascular diseases such as myocardial infarction and ischemic stroke are associated with increased platelet function whilst the risk of recurrence is reduced by antiplatelet agents such as aspirin, clopidogrel, and prasugrel. However, some patients exhibit high platelet reactivity, especially with clopidogrel. Existing platelet function tests may not be ideal in that they can be expensive, are often time consuming, and measurements must be made near to the patient and within a few hours of blood collection. Platelet activation leads to translocation of P-selectin from alpha-granules to the cell surface. Following activation with arachidonic acid (which is blocked by aspirin) or adenosine diphosphate (inhibited by clopidogrel) and fixation, samples may be stored or posted to a laboratory performing flow cytometric quantification of platelet P-selectin expression. Acute myocardial infarction and ischemic stroke are associated with high platelet reactivity on clopidogrel in 6–58% of patients when assessed with P-selectin expression, and high reactivity was associated with an increased risk of recurrence after myocardial infarction. Use of P-selectin expression tests may also be of relevance to surgical and veterinary practice and the diagnosis of mild bleeding disorders. The present review explores this topic in further detail

Characteristics and outcomes of patients with or without a bleeding event: results from the triple antiplatelets for reducing dependency in ischaemic stroke (TARDIS) trial

Background: Several studies showed that hyperglycaemia is associated with poorer prognosis in intracerebral haemorrhage. We explored the characteristics and outcomes of patients with hyperglycaemia in the Tranexamic acid in IntraCerebral Haemorrhage-2 (TICH-2) trial. Methods: Of the 2325 patients recruited, 2028 with available baseline glucose levels were included for analysis. Baseline characteristics, radiological and clinical outcomes were compared between patients with admission glucose levels of <7.8 and ≥7.8 mmol/L (hyperglycaemia). Results: 545 (26.9%) patients had hyperglycaemia and did not differ from normoglycaemic patients in age (69.3 years vs 68.7 years) and sex (female: 246, 45.1% vs 641, 43.2%). Hyperglycaemic patients were more likely to be diabetic (187, 34.3% vs 94, 6.3%), have worse NIHSS (13.8 ± 7.7 vs 12.1 ± 7.1), larger baseline haematoma (30.2 ± 31.5 mL vs 21.2 ± 24.3 mL) and perihaematomal oedema volumes (15.8 ± 18.1 mL vs 11.7 ± 14.1 mL). There were no significant differences in haematoma expansion and increase in oedema volume between the two groups (table). Hyperglycaemia did not increase the risk of death or worse modified Rankin Scale at day 90 after adjusting for covariates including baseline haematoma volume. Discussion: Hyperglycaemia was associated with larger haematomas and more severe stroke on admission but did not result in worse outcomes after accounting for baseline haematoma volume

France and Migration Between Logistification and Ethical Minimalism

The article analizes French migration policies in historical perspective, arguing that the country progressively adopted a discursive and legal framework that implements a managerial dimension of migration policies which can be described as logistification and resonates with developments in other European countries and the European Unio