Presentation outside office hours does not negatively influence treatment times for reperfusion therapy for acute ischemic stroke.

BACKGROUND: Treatment outside office hours has been associated with increased workflow times for intravenous thrombolysis (IVT) in acute ischemic stroke (AIS). Limited data suggest that this "off-hours effect" also exists for endovascular treatment (EVT). We investigated this phenomenon in a well-organized acute stroke care region in the Netherlands. METHODS: Retrospective, observational cohort study of consecutive patients with AIS who received reperfusion therapy in the Greater Amsterdam Area, consisting of 14 primary stroke centers and 1 comprehensive stroke center (IVT: 2009-2015, EVT: 2014-2017). Office hours were defined as presentation during weekdays between 8 AM and 5 PM, excluding National Festive days. Primary outcome was door-to-treatment time (door-to-needle [DNT] for IVT, door-to-groin [DGT] for EVT). For DGT, we used the door time of the first hospital. Other outcomes were in-hospital mortality, modified Rankin Scale (mRS) score at 90 days and symptomatic intracranial hemorrhage (sICH). We performed multivariable linear and logistic regression analyses and used multiple imputation to account for missing values. RESULTS: In total, 59% (2450/4161) and 61% (239/395) of patients treated with IVT and EVT, respectively, presented outside office hours. Median DNT was minimally longer outside office hours (32 vs. 30 min, p = 0.024, adjusted difference 2.5 min, 95% CI 0.7-4.2). Presentation outside office hours was not associated with a longer DGT (median 130 min for both groups, adjusted difference 7.0 min, 95% CI - 4.2 to 18.1). Clinical outcome and sICH rate also did not differ. CONCLUSION: Presentation outside office hours did not lead to clinically relevant treatment delays for reperfusion therapy in patients with AIS.

Risk indicators for development of headache during dipyridamole treatment after cerebral ischaemia of arterial origin.

A considerable proportion of patients discontinue dipyridamole therapy because of headache. Risk indicators for the development of dipyridamole induced headache were identified by means of an exploratory analysis of data from the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) and the Second European Stroke Prevention Study (ESPS 2). In ESPRIT, dipyridamole induced headache was significantly associated with female sex, absence of hypertension and non-smoking (area under the receiver operator characteristic (ROC) curve 0.63 (95% CI 0.58 to 0.68)) and in ESPS 2 with female sex and absence of ischaemic lesions on imaging (area under the ROC curve 0.64 (95% CI 0.59 to 0.69)).

Dipyridamole plus aspirin versus aspirin alone in secondary prevention after TIA or stroke: a meta-analysis by risk.

OBJECTIVES: To study the effect of combination therapy with aspirin and dipyridamole (A+D) over aspirin alone (ASA) in secondary prevention after transient ischaemic attack (TIA) or minor stroke of presumed arterial origin and to perform subgroup analyses to identify patients that might benefit most from secondary prevention with A+D. DATA SOURCES: The previously published meta-analysis of individual patient data was updated with data from ESPRIT (n = 2,739); trials without data on the comparison of A+D versus ASA were excluded. REVIEW METHODS: A meta-analysis was performed using Cox regression, including several subgroup analyses and following baseline risk stratification. RESULTS: A total of 7612 patients (five trials) were included in the analyses, 3800 allocated to A+D and 3812 to ASA alone. The trial-adjusted hazard ratio (HR) for the composite event of vascular death, non-fatal myocardial infarction and non-fatal stroke was 0.82 (95% confidence interval (CI) 0.72 to 0.92). HRs did not differ in subgroup analyses based on age, sex, qualifying event, hypertension, diabetes, previous stroke, ischaemic heart disease, aspirin dose, type of vessel disease and dipyridamole formulation, nor across baseline risk strata as assessed with two different risk scores. A+D were also more effective than ASA alone in preventing recurrent stroke; HR 0.78 (95% CI 0.68 to 0.90). CONCLUSION: The combination of aspirin and dipyridamole is more effective than aspirin alone in patients with TIA or ischaemic stroke of presumed arterial origin in the secondary prevention of stroke and other vascular events. This superiority was found in all subgroups and was independent of baseline risk.

[No role for oral anticoagulants (target INR: 2.0-3.0) after transient ischaemic attack or cerebral infarction of arterial origin; the 'European/Australasian stroke prevention in reversible ischaemia trial' (ESPRIT)]. / Geen plaats voor orale antistollingsbehandeling (streef-INR: 2.0-3.0) na een 'transient ischaemic attack' ofeen herseninfarct van arteriële oorsprong; de 'European/Australasian stroke prevention in reversible ischaemia trial' (ESPRIT).

OBJECTIVE: The 'European/Australasian stroke prevention in reversible ischaemia trial' (ESPRIT) aimed to determine whether oral anticoagulation of moderate intensity (target international normalised ratio (INR): 2.0-3.0) is more effective than acetylsalicylic acid in preventing future vascular events in patients with transient ischaemic attack (TIA) or minor stroke of arterial origin. DESIGN: International, multicentre randomised clinical trial. METHOD: Patients were randomised within 6 months of TIA or minor stroke of arterial origin to oral anticoagulants (target INR: 2.0-3.0; n = 536) or acetylsalicylic acid (30-325 mg daily; n = 532). The primary endpoint was a composite of vascular death, non-fatal stroke, non-fatal myocardial infarction or major bleeding complications. In a post hoc analysis, the efficacy of anticoagulants was compared with that of the combination of acetylsalicylic acid and dipyridamole (200 mg twice daily), a third arm of ESPRIT. Treatment was unblinded, but auditing of endpoints was blinded. Data were analysed on an intent-to-treat basis. RESULTS: The comparison of anticoagulants and acetylsalicylic acid was stopped prematurely because the combination of acetylsalicylic acid and dipyridamole was found to be more effective than acetylsalicylic acid alone. The mean duration of follow-up was 4.6 years (SD: 2.2). The mean INR was 2.57 (SD: 0.86; nearly 70% of the time within target range). The primary endpoint occurred in 99 patients (19%) in the anticoagulation group and 98 patients (18%) in the acetylsalicylic acid group (hazard ratio: 1.02; 95% CI: 0.77-1.35). The hazard ratio was 0.73 (95% CI: 0.52-1.01) for ischaemic events and 2.56 (95% CI: 1.48-4.43) for major bleeding complications. The hazard ratio for the primary outcome event comparing anticoagulants with the combination of acetylsalicylic acid and dipyridamole was 1.31 (95% CI: 0.98-1.75). CONCLUSION: Oral anticoagulants (target INR: 2.0-3.0) were not more effective than acetylsalicylic acid in the secondary prevention of vascular events following TIA or minor stroke of arterial origin.

Medium intensity oral anticoagulants versus aspirin after cerebral ischaemia of arterial origin (ESPRIT): a randomised controlled trial.

BACKGROUND: Oral anticoagulants are better than aspirin for secondary prevention after myocardial infarction and after cerebral ischaemia in combination with non-rheumatic atrial fibrillation. The European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) aimed to determine whether oral anticoagulation with medium intensity is more effective than aspirin in preventing future vascular events in patients with transient ischaemic attack or minor stroke of presumed arterial origin. METHODS: In this international, multicentre trial, patients were randomly assigned within 6 months after a transient ischaemic attack or minor stroke of presumed arterial origin either anticoagulants (target INR range 2.0-3.0; n=536) or aspirin (30-325 mg daily; n=532). The primary outcome was the composite of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or major bleeding complication, whichever occurred first. In a post hoc analysis anticoagulants were compared with the combination of aspirin and dipyridamole (200 mg twice daily). Treatment was open, but auditing of outcome events was blinded. Primary analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN73824458) and with ClinicalTrials.gov (NCT00161070). FINDINGS: The anticoagulants versus aspirin comparison of ESPRIT was prematurely ended because ESPRIT reported previously that the combination of aspirin and dipyridamole was more effective than aspirin alone. Mean follow-up was 4.6 years (SD 2.2). The mean achieved INR was 2.57 (SD 0.86). A primary outcome event occurred in 99 (19%) patients on anticoagulants and in 98 (18%) patients on aspirin (hazard ratio [HR] 1.02, 95% CI 0.77-1.35). The HR for ischaemic events was 0.73 (0.52-1.01) and for major bleeding complications 2.56 (1.48-4.43). The HR for the primary outcome event comparing anticoagulants with the combination treatment of aspirin and dipyridamole was 1.31 (0.98-1.75). INTERPRETATION: Oral anticoagulants (target INR range 2.0-3.0) are not more effective than aspirin for secondary prevention after transient ischaemic attack or minor stroke of arterial origin. A possible protective effect against ischaemic events is offset by increased bleeding complications.

Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial.

BACKGROUND: Results of trials of aspirin and dipyridamole combined versus aspirin alone for the secondary prevention of vascular events after ischaemic stroke of presumed arterial origin are inconsistent. Our aim was to resolve this uncertainty. METHODS: We did a randomised controlled trial in which we assigned patients to aspirin (30-325 mg daily) with (n=1363) or without (n=1376) dipyridamole (200 mg twice daily) within 6 months of a transient ischaemic attack or minor stroke of presumed arterial origin. Our primary outcome event was the composite of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or major bleeding complication, whichever happened first. Treatment was open, but auditing of outcome events was blinded. Primary analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN73824458) and with (NCT00161070). FINDINGS: Mean follow-up was 3.5 years (SD 2.0). Median aspirin dose was 75 mg in both treatment groups (range 30-325); extended-release dipyridamole was used by 83% (n=1131) of patients on the combination regimen. Primary outcome events arose in 173 (13%) patients on aspirin and dipyridamole and in 216 (16%) on aspirin alone (hazard ratio 0.80, 95% CI 0.66-0.98; absolute risk reduction 1.0% per year, 95% CI 0.1-1.8). Addition of the ESPRIT data to the meta-analysis of previous trials resulted in an overall risk ratio for the composite of vascular death, stroke, or myocardial infarction of 0.82 (95% CI 0.74-0.91). Patients on aspirin and dipyridamole discontinued trial medication more often than those on aspirin alone (470 vs 184), mainly because of headache. INTERPRETATION: The ESPRIT results, combined with the results of previous trials, provide sufficient evidence to prefer the combination regimen of aspirin plus dipyridamole over aspirin alone as antithrombotic therapy after cerebral ischaemia of arterial origin.

Anticoagulants, aspirin and dipyridamole in the secondary prevention of cerebral ischaemia: which is the best for which patient?

In this paper, an overview is given of trials with oral anticoagulants and dipyridamole in the secondary prevention after transient ischaemic attack or minor stroke. In patients with atrial fibrillation, the secondary preventive treatment of first choice is oral anticoagulation with an aimed international normalised ratio between 2.0 and 3.0. In patients without a cardiac source of embolism, a combination therapy of low-dose aspirin and dipyridamole 200 mg twice daily is the treatment of choice. These treatment strategies do however not prevent all recurrent strokes or vascular complications, and research for more effective strategies is warranted.