Early time course of major bleeding on antiplatelet therapy after TIA or ischemic stroke

Objective: To study the early time course of major bleeding and its subtypes in patients with cerebral ischemia on dual and single antiplatelet therapy. Methods: We performed a post hoc analysis on individual patient data from 6 randomized clinical trials (Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events [CAPRIE], Second European Stroke Prevention Study [ESPS-2], Management of Atherothrombosis With Clopidogrel in High Risk Patients [MATCH], Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance [CHARISMA], European/Australasian Stroke Prevention in Reversible Ischaemia Trial [ESPRIT], and Prevention Regimen for Effectively Avoiding Second Strokes [PRoFESS]) including 45,195 patients with a TIA or noncardioembolic ischemic stroke. We studied incidence rates of bleeding per antiplatelet regimen stratified by time from randomization (≤30, 31–90, 91–180, 181–365, >365 days). We calculated incidence rates per trial and pooled estimates with random-effects meta-analysis. We performed Poisson regression to assess differences between time periods with adjustment for age and sex. Results: The incidence of major bleeding on aspirin plus clopidogrel and aspirin plus -dipyridamole was highest in the first 30 days, 5.8 and 4.9 per 100 person-years, respectively, and was significantly higher than at 31 to 90 days (rate ratio 1.98, 95% confidence interval 1.16–3.40 for aspirin plus clopidogrel; rate ratio 1.94, 95% confidence interval 1.24–3.03 for aspirin plus dipyridamole). Incidence rates on aspirin and clopidogrel monotherapy were 2.8 and 2.5 per 100 person-years, respectively, in the first 30 days, with no significant change over time. The time course was similar for gastrointestinal bleeds. There was no early excess of intracranial hemorrhage in patients on either dual or single antiplatelet therapy. Conclusion: Dual antiplatelet therapy is associated with high early risks of major and gastrointestinal bleeding that decline after the first month in trial cohorts

Revised guideline 'Brain metastases':More treatment options

The guideline on brain metastasis from the Netherlands Society of Neurology has been updated. Important changes have been made, particularly with regard to treatment of brain metastases. Treatment of patients with brain metastases is complex and requires a multidisciplinary approach to formulate an optimal, individualized treatment plan. Neurosurgical resection may also be considered in patients with multiple brain metastases and one dominant, symptomatic lesion, if the patient is in good clinical condition. Stereotactic radiosurgery is a treatment option for patients with a maximum of 10 brain metastases, depending on the size and number of metastases. The indication for whole brain radiotherapy is relatively limited. Doctors should be cautious with whole brain radiotherapy in patients with a Karnofsky Performance Status <70. In patients with small, asymptomatic brain metastases, targeted therapy or immune therapy may be considered without locoregional therapy

Balancing Benefits and Risks of Long-Term Antiplatelet Therapy in Noncardioembolic Transient Ischemic Attack or Stroke

Lifelong treatment with antiplatelet drugs is recommended following a transient ischemic attack or ischemic stroke. Bleeding complications may offset the benefit of antiplatelet drugs in patients at increased risk of bleeding and low risk of recurrent ischemic events. We aimed to investigate the net benefit of antiplatelet treatment according to an individuals’ bleeding risk. METHODS: We pooled individual patient data from 6 randomized clinical trials (CAPRIE [Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events], ESPS-2 [European Stroke Prevention Study-2], MATCH [Management of Atherothrombosis With Clopidogrel in High-Risk Patients], CHARISMA [Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance], ESPRIT [European/Australasian Stroke Prevention in Reversible Ischemia Trial], and PRoFESS [Prevention Regimen for Effectively Avoiding Second Strokes]) investigating antiplatelet therapy in the subacute or chronic phase after noncardioembolic transient ischemic attack or stroke. Patients were stratified into quintiles according to their predicted risk of major bleeding with the S(2)TOP-BLEED score. The annual risk of major bleeding and recurrent ischemic events was assessed per quintile for 4 scenarios: (1) aspirin monotherapy, (2) aspirin-clopidogrel versus aspirin or clopidogrel monotherapy, (3) aspirin-dipyridamole versus clopidogrel, and (4) aspirin versus clopidogrel. Net benefit was calculated for the second, third, and fourth scenario. RESULTS: Thirty seven thousand eighty-seven patients were included in the analyses. Both risk of major bleeding and recurrent ischemic events increased over quintiles of predicted bleeding risk, but risk of ischemic events was consistently higher (eg, from 0.7%/y (bottom quintile) to 3.2%/y (top quintile) for major bleeding on aspirin and from 2.5%/y to 10.2%/y for risk of ischemic events on aspirin). Treatment with aspirin-clopidogrel led to more major bleedings (0.9%–1.7% per year), than reduction in ischemic events (ranging from 0.4% to 0.9/1.0% per year) across all quintiles. There was no clear preference for either aspirin-dipyridamole or clopidogrel according to baseline bleeding risk. CONCLUSIONS: Among patients with a transient ischemic attack or ischemic stroke included in clinical trials of antiplatelet therapy, the risk of recurrent ischemic events and of major bleeding increase in parallel. Antiplatelet treatment cannot be individualized solely based on bleeding risk assessment

Development and internal validation of a prediction rule for post-stroke infection and post-stroke pneumonia in acute stroke patients

Introduction Patients with acute stroke are at high risk for infection. These infections are associated with unfavourable outcome after stroke. A prediction rule can identify the patients at the highest risk for strategies to prevent infection. We aim to develop a prediction rule for post-stroke pneumonia and other infections in patients with acute stroke. Patients and methods We used data from the Preventive Antibiotics in Stroke Study, a multicentre randomised trial comparing preventive ceftriaxone vs. standard stroke care in patients with acute stroke. Possible predictors for post-stroke pneumonia or infection were selected from the literature. Backward elimination logistic regression analysis was used to construct prediction rules for pneumonia or infection. Internal validation was performed and a risk chart was constructed. We adjusted for preventive antibiotic use. Results Pneumonia was diagnosed in 159 of the 2538 included patients, and infection in 348. Pneumonia was predicted by higher age, male sex, pre-stroke disability, medical history of chronic obstructive pulmonary disease, more severe stroke, dysphagia and intracerebral haemorrhage (rather than ischaemic stroke). Infections were predicted by higher age, male sex, history of diabetes, chronic obstructive pulmonary disease, more severe stroke, dysphagia, use of bladder catheter, preventive antibiotic use and intracerebral

RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.</p

Predicting major bleeding in patients with noncardioembolic stroke on antiplatelets

Objective: To develop and externally validate a prediction model for major bleeding in patients with a TIA or ischemic stroke on antiplatelet agents. Methods: We combined individual patient data from 6 randomized clinical trials (CAPRIE, ESPS-2, MATCH, CHARISMA, ESPRIT, and PRoFESS) investigating antiplatelet therapy after TIA or ischemic stroke. Cox regression analyses stratified by trial were performed to study the association between predictors and major bleeding. A risk prediction model was derived and validated in the PERFORM trial. Performance was assessed with the c statistic and calibration plots. Results: Major bleeding occurred in 1,530 of the 43,112 patients during 94,833 person-years of follow-up. The observed 3-year risk of major bleeding was 4.6% (95% confidence interval [CI] 4.4%–4.9%). Predictors were male sex, smoking, type of antiplatelet agents (aspirin-clopidogrel), outcome on modified Rankin Scale ≥3, prior stroke, high blood pressure, lower body mass index, elderly, Asian ethnicity, and diabetes (S2TOP-BLEED). The S2TOP-BLEED score had a c statistic of 0.63 (95% CI 0.60–0.64) and showed good calibration in the development data. Major bleeding risk ranged from 2% in patients aged 45–54 years without additional risk factors to more than 10% in patients aged 75–84 years with multiple risk factors. In external validation, the model had a c statistic of 0.61 (95% CI 0.59–0.63) and slightly underestimated major bleeding risk. Conclusions: The S2TOP-BLEED score can be used to estimate 3-year major bleeding risk in patients with a TIA or ischemic stroke who use antiplatelet agents, based on readily available characteristics. The discriminatory performance may be improved by identifying stronger predictors of major bleeding

Blood pressure, blood pressure variability and the risk of poststroke dementia

OBJECTIVE: High blood pressure and blood pressure variability are potential, modifiable risk factors of poststroke dementia. We aimed to investigate the association between achieved blood pressure, blood pressure variability and poststroke dementia. METHODS: We studied 17 064 patients with noncardioembolic ischemic stroke included in the Prevention Regimen for Effectively avoiding Second Strokes (PRoFESS) trial. We analysed the data as a single observational cohort. We studied mean achieved SBP and DBP and blood pressure variability defined as coefficient of variation (SD/mean∗100). The association between blood pressure and dementia was investigated with logistic regression analysis, correcting for sociodemographic factors and cardiovascular risk factors. RESULTS: During 39 818 person-years of follow-up, 817 patients were diagnosed with dementia (2.1 per 100 person-years). We found a significant nonlinear association between mean SBP and the risk of dementia, implying a U-shaped association between mean SBP and dementia. Mean SBP of 120-129 mmHg was associated with a significantly higher risk of dementia than 130-139 mmHg [odds ratio (OR) 1.28; 95% confidence interval (95% CI) 1.03-1.58]. There was no indication of a U-shaped association between mean DBP and dementia, and no significant association between mean DBP categories and dementia. Higher blood pressure variability was associated with an increased risk of dementia (OR 1.06 per point increase, 95% CI 1.02-1.04), independent of mean SBP. CONCLUSION: Among patients with a recent noncardioembolic ischemic stroke, there appears to be a U-shaped association between achieved SBP and dementia. High blood pressure variability is associated with an increased risk of poststroke dementia

Blood pressure variability and white matter hyperintensities after ischemic stroke

Background: High blood pressure variability (BPV) may be a risk factor for stroke and dementia in patients with ischemic stroke, but the underlying mechanism is unknown. We aimed to investigate whether high BPV is associated with presence and progression of white matter hyperintensities (WMH). Methods: We performed a post-hoc analysis on the MRI substudy of the PRoFESS trial, including 771 patients with ischemic stroke who underwent MRI at baseline and after a median of 2.1 years. WMH were rated with a semi-quantitative scale. Visit-to-visit BPV was expressed as the coefficient of variation (interval 3–6 months, median number of visits 7). The association of BPV with WMH burden and progression was assessed with linear and logistic regression analyses adjusted for confounders. Results: BPV was associated with burden of periventricular WMH (β 0.36 95%CI 0.19–0.53, per one SD increase in BPV) and subcortical (log-transformed) WMH (β 0.25, 95%CI 0.08–0.42). BPV was not associated with periventricular (OR 1.09, 95%CI 0.94–1.27) and subcortical WMH progression (OR 1.15, 95%CI 0.99–1.35). Associations were independent of mean BP. Conclusion: High visit-to-visit BPV was associated with both subcortical and periventricular WMH burden in patients with ischemic stroke, but not with WMH progression in this study

Yield of angiographic examinations in isolated intraventricular hemorrhage : A case series and systematic review of the literature

Background: It is unknown which patients with non-traumatic isolated intraventricular hemorrhage should undergo angiographic imaging to detect an underlying macrovascular cause and which modality has the highest yield. We studied yield of angiographic examinations in patients with isolated intraventricular hemorrhage. Methods: We reviewed medical records of patients with intraventricular hemorrhage admitted to the University Medical Center Utrecht between 2002 and 2012. We searched PubMed and Embase for studies on angiographic examinations in intraventricular hemorrhage until January 2014. We calculated yield of angiographic imaging and investigated influence of age, hypertension and anticoagulant use with meta-regression analysis. Results: We identified 39 patients of whom 30 underwent an angiographic study. CTA suggested a macrovascular abnormality in nine patients, which was confirmed by DSA in seven. In the literature, we found 16 studies describing 209 patients. Pooled analysis showed a yield of 58% for DSA (95% CI 48–68%; 147 patients). One small study described the yield of CTA or MRA (0%; 4 patients). Yield of angiographic imaging decreased with increasing age (−2.6%; −5.0 to −0.2 per year increase) but was not affected by history of hypertension (−8.3%; −80.8 to 64.2) or anticoagulant use (−47.1%; −110.3 to 16.1). Conclusion: The reported yield of DSA in isolated intraventricular hemorrhage is around 50% but varies considerably, probably due to differences in clinical judgment on the need for angiography performance. The yield is higher in younger patients but based on the available data, it is not possible to set age or other criteria for patients in whom DSA can be safely omitted