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

biv.mindfulness.data.figshare.xlsx

This is the data used for the manuscript "Cognitive control as a function of trait mindfulness" published in Journal of Cognitive Enhancement. <div><br></div><div>Please cite as: </div><div><br></div><div><div>Grundy, J.G., Krishnamoorthy, S., & Shedden, J. M. (2018, February 5). biv.mindfulness.data.figshare.xlsx. figshare. https://doi.org/10.6084/m9.figshare.5853750.v1</div></div><div><br></div

Effect of Ki-67-7 and curcumin on cell cycle phases.

<p>AY-27 cells were treated with Ki-67-7, curcumin or with both, as described earlier in legend to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048567#pone-0048567-g003" target="_blank">Figures 3A and 3B</a>. At the end of the incubation period, the cells were treated with PI and the distribution of cells in various cell cycle phases were determined by flow cytometry as described in Methods. Cells were scored as percentage distribution of cells in each of the cell cycle phases (G_o/G_1, S and G2/M). Bars indicate values which are the means ± S.E of three determinations.</p

Molecular targets of CusiRNA.

<p>The scheme displays the possible molecular targets of Ki-67-7 and curcumin when used in combination (CusiRNA). Arrowheads indicate the activation of indicated proteins; hammer heads indicate inhibition and the broken lines represent the possible role for putative intermediates. Further details are provided in the text.</p

Dose-dependent effects of curcumin on bladder cancer cell proliferation.

<p>T-24 (2a) and AY-27 (2b) cells were plated in 12-well plates (0.8×10⁵ cells/well) and cultured for 48 hr (40–50% confluence) as described in Methods. Following exposure to various concentrations of curcumin for 24 h, cells were washed with PBS and incubated for another 24 h in curcumin-free medium. Cells incubated with DMSO (0.1%) alone were treated as controls. DMSO alone had little impact on tumor cell growth (data not shown). Cell proliferation was assessed on the basis of cell viability, measured by MTT assay. Cell viability was expressed as percent of viability observed in DMSO-treated control cells. Values are from a representative (of two) (2a) or 3–8 (mean ± S.E) determinations (2b). ^*P<0.05, ^**P<0.01,^***P<0.005.</p

Effect of Ki-67-7 and curcumin on the regulatory proteins of cell cycle phases and apoptosis: Western blot analysis.

<p>Bladder cancer cells (T-24 and AY-27) were cultured and exposed to Ki-67-7 and curcumin as described above in legend to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048567#pone-0048567-g003" target="_blank">Figures 3A and 3B</a>. At the end of the treatment period, total protein was extracted and subjected to Western blotting using appropriate antibodies as described in Methods. For purposes of associating proteins with specific roles, they were grouped in separate categories, such as gene transcription (A), cell-cycle progression (B) and apoptosis (C). β-actin was used as the internal control. Since different proteins (e.g. Cyclin D1 and NF-κB) from the same membrane were identified in separate categories, the same β-actin blot is displayed on more than one occasion. Data presented are western blots from a single experiment, which is representative of 2–3 identical experiments.</p

Effect of various DsiRNA constructs on a) Ki-67 mRNA expression and b) cell proliferation in bladder cancer cells; c) Dose-response studies with Ki-67-7. a) Rat TCC cells (AY-27) were cultured in 12-well plates (∼0.8

<p>×<b>10⁵ cells/well) as described in Materials and Methods.</b> After 24 h, they were transfected with each of the siRNA constructs (Ki-67-2, Ki-67-7 and Ki-67-9) targeted against Ki-67 mRNA. After 48 h, RNA was extracted and the levels of mRNA were determined by quantitative PCR as described in Methods. Cells treated with the transfection reagent alone were used as the control. The rate of expression of Ki-67 mRNA was normalized to the expression of β-actin. Values represent data from one (of two) experiment using the average of triplicate determinations. b) AY-27 cells were cultured in 12-well (0.8×10⁵ cells/well) plates for 24 h and transfected with various siRNA constructs as described in Methods. Cell viability was determined 48 h after transfection by MTT assay. Cells treated with transfection reagent alone served as the control ( = 100%). Bars indicate values which are the means ± S.E of three determinations. (^*P<0.05). c) AY-27 cells were cultured in 12-well plates (0.8×10⁵ cells/well) as described in Methods. Forty eight hours after siRNA transfection, the effect of various concentrations of Ki-67-7 on cell viability was determined by MTT assay. Cells treated with transfection reagent alone served as the control. Cell viability values are expressed as percent control and are the means ± S.E of 3-8 determinations (^*P<0.05, ^***P<0.005).</p