Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

Characterization of Postoperative Infection Risk in Cardiac Surgery Patients With Delayed Sternal Closure

Objectives: To compare the incidence of postoperative infection in cardiac surgery patients who had delayed sternal closure (DSC) with those who had primary sternal closure (PSC) and evaluate the effectiveness of antibiotic prophylaxis in DSC patients. Design: Retrospective, observational cohort study with propensity score matching. Setting: Single academic medical center. Participants: Cardiothoracic surgery patients, excluding transplantation patients, from a single academic medical center who had DSC or PSC between November 2015 and November 2018. Interventions: None. Measurements and Main Results: Of 2,685 patients who had cardiac surgery with cardiopulmonary bypass, 99 had DSC. Fifty-nine DSC patients met study inclusion criteria, and the final propensity score matched cohort included 57 patients with DSC and 57 patients with PSC. Propensity score matching reduced bias but was unable to balance all covariates. The most common indication for DSC was coagulopathy in 32 of the 57 patients. All patients in the PSC group received routine antibiotic prophylaxis for 48 hours after surgery. Patients in the DSC group received prolonged broadened prophylaxis until 48 hours after sternal closure. Despite prolonged broadened antibiotic prophylaxis, the DSC group had a higher rate of postoperative infection (31.6% v 3.5%; p \u3c 0.005), mainly pneumonia (19.3% v 1.8%; p \u3c 0.005), in the first 30 days after surgery. There was no difference in the incidence of sepsis (5.3% v 0%; p = 0.24), superficial skin and soft tissue infection (1.8% v 1.8%; p = 1), or mediastinitis/deep tissue infection (5.3% v 0%; p = 0.24) in patients with DSC. Seventy-seven percent of causative organisms for infection were Gram-negative bacteria in the matched cohort. Conclusion: The incidence of postoperative infection, particularly pneumonia, is high in cardiothoracic surgery patients with DSC, even with prolonged broadened antibiotic prophylaxis, but the rate of mediastinitis/deep tissue infection did not appear to be greater with DSC. Additional research is needed into optimal antibiotic prophylaxis in this high-risk group of patients

Platelet Transfusion and In-Hospital Mortality in Veno-Arterial Extracorporeal Membrane Oxygenation Patients

Thrombocytopenia is common during extracorporeal membrane oxygenation (ECMO), and platelets are sometimes transfused to meet arbitrary goals. We performed a retrospective cohort study of veno-arterial (VA) ECMO patients from a single academic medical center and explored the relationship between platelet transfusion and in-hospital mortality using multivariable logistic regression. One hundred eighty-eight VA ECMO patients were included in the study. Ninety-one patients (48.4%) were transfused platelets during ECMO. Patients who received platelet transfusion had more coronary artery disease, lower platelet counts at cannulation, higher predicted mortality, lower nadir platelet counts, more ECMO days, and more red blood cell (RBC) and plasma transfusion. Mortality was 19.6% for patients who received no platelets, 40.8% for patients who received 1-3 platelets, and 78.6% for patients who received 4 or more platelets ( P \u3c 0.001). After controlling for confounding variables including baseline severity of illness, central cannulation, postcardiotomy status, RBC and plasma transfusion, major bleeding, and total ECMO days, transfusion of 4 or more platelets remained associated with in-hospital mortality; OR = 4.68 (95% CI = 1.18-27.28), P = 0.03. Our findings highlight the need for randomized controlled trials that compare different platelet transfusion triggers, so that providers can better understand when platelet transfusion is indicated in VA ECMO patients

Von Willebrand Factor Concentrate Administration for Acquired Von Willebrand Syndrome- Related Bleeding During Adult Extracorporeal Membrane Oxygenation

Objective: To review the use of Von Willebrand Factor (VWF) concentrate for treatment of acquired Von Willebrand syndrome (VWS)-related bleeding in adult extracorporeal membrane oxygenation (ECMO) patients and determine if it was associated with improved VWF laboratory parameters. Design: Retrospective observational cohort study. Setting: Tertiary care academic medical center. Participants: Adult ECMO patients who received VWF concentrate for treatment of acquired VWS- related bleeding. Interventions: None, observational study. Measurements and Main Results: Ten adult ECMO patients received VWF concentrate for treatment of bleeding with evidence of acquired VWS over a 15-month period. Six patients were on veno-arterial ECMO and 4 were on veno-venous ECMO. The most common site of bleeding was airway or tracheal bleeding. The mean dose of VWF concentrate was 41 IU/kg. Mean VWF antigen was 263 ± 93 IU/dL before treatment and 394 ± 54 after treatment. Mean ristocetin cofactor activity was 127 ± 47 IU/dL before treatment and 240 ± 33 after treatment. The mean VWF ristocetin cofactor activity antigen ratio increased from 0.52 ± 0.14 before treatment to 0.62 ± 0.04 after treatment. Four of 10 patients had complete resolution of their bleeding within 24 hours, and 6 of 10 had complete resolution of their bleeding within 2- to- 4 days. There were 3 patients who had thrombotic events potentially related to VWF concentrate administration. No patient had an arterial thrombosis, stroke, or myocardial infarction. Conclusions: VWF concentrate administration increases VWF function in adult ECMO patients, but also may be associated with increased thrombotic risk. Larger studies are needed to determine VWF concentrate\u27s safety, efficacy, and optimal dosing in adult ECMO patients

Precannulation International Normalized Ratio is Independently Associated With Mortality in Veno-Arterial Extracorporeal Membrane Oxygenation

Objectives: To explore whether precannulation international normalized ratio (INR) is associated with in-hospital mortality in venoarterial extracorporeal membrane oxygenation (VA-ECMO) patients. Design: A retrospective, observational cohort study. Setting: A quaternary care academic medical center. Participants: Patients with cardiogenic shock on VA-ECMO for \u3e24 hours. Interventions: None, observational study. Measurements and Main Results: A total of 188 patients who were on VA-ECMO were included over three years. Patients were stratified into three groups based on their pre-ECMO INR: INR \u3c1.5, INR 1.5 to 1.8, and INR \u3e1.8. For all patients, demographics, comorbidities, and ECMO details were recorded. The study\u27s primary outcome was in-hospital mortality and secondary outcomes included major bleeding, minor bleeding, allogeneic transfusion, ischemic stroke, intracranial hemorrhage, acute renal failure, acute liver failure, gastrointestinal bleeding, intensive care unit and hospital lengths of stay. A multivariate logistic regression was used to determine whether precannulation INR was associated independently with in-hospital mortality. In-hospital mortality differed significantly by INR group (51.6% INR \u3e1.8 v 42.3% INR 1.5-1.8 v 24.3% INR \u3c1.5; p = 0.004). In a multivariate logistic regression model, precannulation INR \u3e1.8 was associated independently with an increased odds of mortality (odds ratio, 2.48; 95% confidence interval, 1.05-6.04) after controlling for sex, Survival after VA- ECMO score, and ECMO indication. An INR within 1.5 to 1.8 did not confer an increased mortality risk. Conclusions: An INR \u3e1.8 before VA-ECMO cannulation is associated independently with in-hospital mortality. Precannulation INR should be considered by clinicians so that ECMO resources can be better allocated and risks of organ failure and intracranial hemorrhage can be better understood