Long-Term Outcomes After Reversible Cerebral Vasoconstriction Syndrome.

Background and Purpose- We aimed to further investigate the long-term outcomes after reversible cerebral vasoconstriction syndrome (RCVS). Methods- A longitudinal follow-up study was conducted in 173 RCVS patients. Results- Of the 172 patients who completed a mean follow-up of 9.2±3.3 years, 10 had a recurrent RCVS that was benign in all. Independent predictors of relapse were having a history of migraine and having exercise as a trigger for thunderclap headache during initial RCVS. After new delivery, the rate of postpartum RCVS was 9%. Conclusions- Overall, long-term outcome after RCVS is excellent.

Labbé vein thrombosis.

PURPOSE: Evaluate the prevalence of Labbé vein thrombosis (LVT) and its liability for the lesions observed in the case of associated ipsilateral transverse sinus thrombosis (TST). METHODS: MRI findings of 58 consecutive patients (≥ 18 years) with acute LVT and TST (group 1) were compared with those of 149 patients with acute TST-no LVT (group 2) observed during the same period. RESULTS: The prevalence of LVT was 15.2%. Group 1: TST extended to sigmoid sinus in 94.8%, resulting in complete sinuses occlusion. Any lesion was observed in 81% within LV territory: swelling (n = 5, 8.6%), edema (n = 9; 15.5%), non-hemorrhagic Infarct (n = 1; 1.7%), multiple temporal lobe hemorrhages (n = 31; 53.5%), temporal lobe hematoma (n = 13; 22.4%), and pericerebral hemorrhages (n = 28; 50%). The hemorrhagic lesions were not related to dominant TST or to extensive venous thrombosis. There was a prevalence of left TST- LVT (n = 32; 55.2%) and a higher prevalence of hemorrhagic lesions in this subset (59.4%). Risk factors were also associated (p = 0.03). Group 2: the TST resulted in an occlusion of the TS: (i) complete (n = 16; 10.7%); (ii) incomplete (n = 97; 82.8%); and (iii) segmental, involving the TS before (n = 32; 21.5%) or after (n = 10; 6.7%) LV ending within the TS. No parenchymal/pericerebral lesions were associated. CONCLUSION: This study shows a strong association between the following: (i) the extent of thrombosis in the TS and the presence of LVT (p < 0.0001), (ii) the concomitance of LVT-TST and the presence of lesions in the LV territory and at the temporo-frontal convexity, (iii) risk factors and group 1 (p = 0.03).

The Intracranial-B2LEED3S Score and the Risk of Intracranial Hemorrhage in Ischemic Stroke Patients Under Antiplatelet Treatment.

BACKGROUND: Chronic antiplatelet therapy in the post-acute phase of non-cardioembolic ischemic stroke is limited by the risk of intracranial hemorrhage (ICH) complications. METHODS: We developed an ICH risk score based on the PERFORM trial cohort (n = 19,100), which included patients with a non-cardioembolic ischemic stroke or transient ischemic attack, and externally validated this score in one contemporary trial of very similar size and inclusion criteria, the PRoFESS trial (n = 20,332 patients). Outcome was ICH over 2 years. A Cox proportional-hazard regression analysis identified risk factors. Discrimination was quantified with c-statistics and calibration was assessed by comparing predicted and observed ICH risk in PERFORM and PRoFESS. RESULTS: ICH occurred within 2 years in 263 (1.4%) patients in PERFORM trial and in 246 (1.2%) patients in PRoFESS trial. A 13-point score based on 9 items (Intracranial-B2LEED3S score - low body mass index, blood pressure, lacune, elderly, Asian ethnicity, coronary artery or cerebrovascular disease history, dual antithrombotic agent or oral anticoagulant, gender) was derived from the PERFORM trial. In PERFORM, the observed 2-year ICH risk varied from 0.75% in low-risk (score ≤2) to 2.44% in high-risk patients (score ≥5) with an acceptable calibration but a low discrimination both in PERFORM (c-statistic 0.64, 95% CI 0.61-0.68) and on external validation in PRoFESS (0.58, 95% CI 0.55-0.62). CONCLUSION: The Intracranial-B2LEED3S score helps identify patients who are at a high risk of bleeding. However, other variables need to be identified to improve the score (e.g., microbleeds) (Clinical Trial Registration Information ISRCTN66157730). URL: http://www.isrctn.com/ISRCTN66157730?totalResults=5&pageSize=10&page=1&searchType=basic-search&offset=3&q=&filters=conditionCategory%3ACirculatory+System%2CrecruitmentCountry%3ATaiwan%2CrecruitmentCountry%3AAustria&sort=.

Specificities of Ischemic Stroke Risk Factors in Arab-Speaking Countries.

BACKGROUND: Stroke is largely preventable, and therefore, a better understanding of risk factors is an essential step in reducing the population stroke rate and resulting disease burden in Arab countries. SUMMARY: We performed 2 separate analyses in 2 similar populations of patients with noncardioembolic ischemic stroke. This first involved 3,635 patients in the Outcomes in Patients with TIA and Cerebrovascular disease (OPTIC) registry (followed for 2 years), with baseline collection of the usual risk factors and 5 socioeconomic variables (unemployment status, residence in rural area, living in fully serviced accommodation, no health-insurance coverage, and low educational level). The second involved patients in the PERFORM trial (n = 19,100 followed up for 2 years), with baseline collection of the usual risk factors and 1 socioeconomic variable (low educational level). The primary outcome was a composite of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death. Stroke risk factors were more prevalent in patients in Arab countries. The incidence of major cardiovascular events (MACE; age- and gender-adjusted) was higher in Arab countries (OPTIC, 18.5 vs. 13.3%; PERFORM, 18.4 vs. 9.7%; both p ≤ 0.0001). These results remained significant after adjustment on risk factors and were attenuated in OPTIC after further adjustment on socioeconomic variables (hazard ratio 1.24; 95% CI 0.98-1.55; p = 0.07). Key Messages: Patients with ischemic stroke living in Arab countries had a lower mean socioeconomic status, a much higher prevalence of diabetes mellitus, and a higher rate of MACE compared with patients from non-Arab countries. This finding is partly explained by a higher prevalence of risk factors and also by a high prevalence of poverty and low educational level.

Clinical Outcome of Anticoagulant Treatment in Head or Neck Infection-Associated Cerebral Venous Thrombosis.

BACKGROUND AND PURPOSE: Local infections of the head or neck are a cause of cerebral venous thrombosis. Treatment of infectious cerebral venous thrombosis with heparin is controversial. We examined whether this treatment was associated with intracranial hemorrhagic complications and poor clinical outcome. METHODS: We retrieved data from a prospective cohort study of 624 cerebral venous thrombosis patients. We compared patients with and without an infection of the head or neck and anticoagulated versus not anticoagulated. We examined death or dependency and new intracerebral hemorrhages. RESULTS: Six hundred four of 624 patients were eligible for the study. Fifty-seven patients had an infection of the head or neck (9.4%). Comparing data between infection and noninfection patients, the frequency of therapeutic doses of heparin was similar in both groups (82.5% versus 83.7%). New intracerebral hemorrhages were more common in patients with an infection (12.3% versus 5.3%; P=0.04), but death or dependency did not differ between patients with and without an infection (15.8% versus 13.7%). In patients with an infection of the head or neck, there was no significant difference in the frequency of new intracerebral hemorrhages and poor outcome between patients who did or did not receive therapeutic doses of heparin. CONCLUSIONS: New intracerebral hemorrhages were more frequent in patients with an infection. The use of therapeutic doses of heparin did not seem to influence the risk of new intracranial hemorrhages or poor clinical outcome, but the number of patients who did not receive anticoagulation was too small to draw firm conclusions about safety of heparin in adults with cerebral venous thrombosis and an infection of the head or neck.

Paracetamol, Ibuprofen, and Recurrent Major Cardiovascular and Major Bleeding Events in 19 120 Patients With Recent Ischemic Stroke.

BACKGROUND AND PURPOSE: The presumed safety of paracetamol in high-cardiovascular risk patients has been questioned. We determined whether paracetamol or ibuprofen use is associated with major cardiovascular events (MACE) or major bleeding in 19 120 patients with recent ischemic stroke or transient ischemic attack of mainly atherothrombotic origin included in the Prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) trial. METHODS: We performed 2 nested case-control analysis (2153 cases with MACE during trial follow-up and 4306 controls matched on Essen stroke risk score; 809 cases with major bleeding matched with 1616 controls) and a separate time-varying analysis. RESULTS: 12.3% were prescribed paracetamol and 2.5% ibuprofen. Median duration of treatment was 14 (interquartile range 5-145) days for paracetamol and 9 (5-30) days for ibuprofen. Paracetamol, but not ibuprofen, was associated with increased risk of MACE (odds ratio 1.21, 95% confidence interval [CI] 1.04-1.42) or a major bleeding (odds ratio 1.60, 95% CI 1.26-2.03), with no impact of daily dose and duration of paracetamol treatment. Time-varying analysis found an increased risk of MACE with both paracetamol (hazard ratio 1.22, 95% CI 1.05-1.43) and ibuprofen (hazard ratio 1.47, 95% CI 1.06-2.03) and of major bleeding with paracetamol (hazard ratio 1.95, 95% CI 1.45-2.62). CONCLUSIONS: There was a weak and inconsistent signal for association between paracetamol or ibuprofen and MACE or major bleeding, which may be related to either a genuine but modest effect of these drugs or to residual confounding. CLINICAL TRIAL REGISTRATION: http://www.isrctn.com. Unique identifier: ISRCTN66157730.

The Link Between Migraine, Reversible Cerebral Vasoconstriction Syndrome and Cervical Artery Dissection.

Headache is the common thread of migraine, reversible cerebral vasoconstriction syndrome (RCVS) and cervical artery dissection (CeAD), three medical conditions that otherwise appear to be very different. However, epidemiological, clinical and genetic data suggest that these conditions share common and complex features and are, at least partly, linked. The purpose of this manuscript is to review existing evidence for an association between migraine, RCVS and CeAD and discuss the potential underlying mechanisms.

Radiological findings in cerebral venous thrombosis presenting as subarachnoid hemorrhage: a series of 22 cases.

INTRODUCTION: The main objectives of the present study are to assess the incidence of cerebral venous thrombosis (CVT) presenting as isolated subarachnoid hemorrhage (SAH) and to determine the occurrence of cortical venous thrombosis (CoVT). METHODS: Among 332 patients with CVT, investigated with the same CT and MR standardized protocol, 33 (10 %) presented with SAH, associated in 11 cases with hemorrhagic infarct or intracerebral hemorrhage. This study is based on 22 cases of CVT presenting as SAH in the absence of hemorrhagic brain lesion. Diagnosis of sinus thrombosis was established on T2* and magnetic resonance venography and that of CoVT on T2* sequence. Diagnostic of SAH was based on fluid-attenuated inversion recovery (FLAIR) sequence. RESULTS: CVT involved lateral sinus in 18 patients, superior sagittal sinus in 16, and straight sinus in 1. Cortical veins were involved in all patients, in continuity with dural sinus thrombosis when present. SAH was circumscribed to few sulci in all cases and mainly localized at the convexity (21 cases). CoVT implied different areas on the same side in four patients and was bilateral in seven. There was no perimesencephalic or basal cisterns hemorrhage. Cortical swelling was present in 12 cases, associated with localized edema. All patients except one had a favorable outcome. CONCLUSION: This report shows that the incidence of CVT presenting as isolated SAH is evaluated to 6.4 % and that SAH is, in all cases, in the vicinity of CoVT and when dural thrombosis is present in continuity with it.

Cerebral venous thrombosis in the absence of headache.

BACKGROUND AND PURPOSE: Although headache is the most common symptom in cerebral venous thrombosis, 5% to 30% of patients do not report headache at baseline. Characteristics of these patients have not been investigated. METHODS: In post hoc analysis of the International Study on Cerebral Vein and Dural Sinus Thrombosis study, patients who might not have been able to report headache (aphasia, stupor, coma, or mental status disorder) were excluded. RESULTS: Three hundred eighty-two of the original 624 patients (61%) were included, of whom 38 (10%) did not report headache at baseline. Patients without headache were older (mean age, 45 versus 37; P=0.001) and less often female (63% versus 77%; P=0.06). Paresis (42% versus 27%; P=0.05) and seizures (58% versus 32%; P=0.001) were more common in patients without headache, whereas papilledema was less common (8% versus 35%; P=0.001). Isolated cortical vein thrombosis (16% versus 2%; P=0.001), brain parenchymal lesions (66% versus 46%; P=0.02), and malignancies (18% versus 6%; P=0.009) were more common among patients without headache. Outcome at last follow-up was worse in patients without headache (modified Rankin Scale, 0-1; 76% versus 89%; P=0.04; mortality, 13% versus 5%; P=0.05), but after adjustment for prognostic variables, headache was not an independent predictor of outcome. CONCLUSIONS: Patients with cerebral venous thrombosis but without headache are a heterogeneous subgroup, in which older patients, men, and some associated conditions are over-represented. Patients without headache had a worse clinical outcome, but after adjustment for imbalances, headache was not an independent predictor of outcome.

Prognostic factors and treatment effect in the CHIMES study.

BACKGROUND: Stroke trials often analyze patients with heterogeneous prognoses using a single definition of outcome, which may not be applicable to all subgroups. We aimed to evaluate the treatment effects of MCL601 among patients stratified by prognosis in the Chinese Medicine Neuroaid Efficacy on Stroke Recovery (CHIMES) study. METHODS: Analyses were performed using data from the CHIMES study, an international, randomized, placebo-controlled, double-blind trial comparing MLC601 with placebo in patients with ischemic stroke of intermediate severity in the preceding 72 hours. All subjects with baseline data and the modified Rankin Scale (mRS) score at 3 months were included. RESULTS: Data from 1006 subjects were analyzed. The predictive variables for mRS score greater than 1 at month 3 were age older than 60 years (P < .001), baseline National Institutes of Health Stroke Scale score 10-14 (P < .001), stroke onset to initiation of study treatment of more than 48 hours (P < .001), and female sex (P = .026). A higher number of predictors was associated with poorer mRS score at month 3 for both placebo (P < .001) and treatment (P < .001) groups. The odds ratio (OR) for achieving a good outcome increased with the number of predictors and reached statistical significance in favor of MLC601 among patients with 2 to 4 predictors combined (unadjusted OR = 1.44, 95% confidence interval, 1.02-2.03; adjusted OR = 1.60, 95% confidence interval, 1.10-2.34). CONCLUSIONS: Age, sex, baseline National Institutes of Health Stroke Scale score, and time to first dose are predictors of functional outcome in the CHIMES study. Stratification by prognosis showed that patients with 2 or more predictors of poorer outcome have better treatment effect with MLC601 than patients with single or no prognostic factor. These results have implications on designing future stroke trials.

Degree of blood pressure reduction and recurrent stroke: the PROGRESS trial.

OBJECTIVE: There is ongoing controversy regarding a 'J-curve' phenomenon such that low and high blood pressure (BP) levels are associated with increased risks of recurrent stroke. We aimed to determine whether large treatment-related BP reductions are associated with increased risks of recurrent stroke. DESIGN: Data are from the PROGRESS trial, where 6105 patients with cerebrovascular disease were randomly assigned to either active treatment (perindopril ± indapamide) or placebo(s). There were no BP criteria for entry. BP was measured at every visit, and participant groups defined by reduction in systolic BP (SBP) from baseline were used for the analyses. Outcome was recurrent stroke. RESULTS: During a mean follow-up of 3.9 years, 727 recurrent strokes were observed. There were clear associations between the magnitude of SBP reduction and the risk of recurrent stroke. After adjustment for cardiovascular risk factors and randomised treatment, annual incidence was 2.08%, 2.10%, 2.31% and 2.96% for participant groups defined by SBP reductions of ≥ 20, 10-19, 0-9 and <0 mm Hg, respectively (p=0.0006 for trend). CONCLUSIONS: The present analysis provided no evidence of an increase in recurrent stroke associated with larger reductions in SBP produced by treatment among patients with cerebrovascular disease.

Cerebral venous thrombosis causing posterior fossa lesions: description of a case series and assessment of safety of anticoagulation.

BACKGROUND: Isolated posterior fossa parenchymal lesions associated with cerebral venous thrombosis (CVT) are rare. Posterior fossa lesions are an independent predictor of death in CVT. We aim to describe the characteristics and outcome of patients with CVT and isolated posterior fossa lesions and assess the safety of anticoagulation in patients with posterior fossa lesions associated with CVT. METHODS: We retrieved data from all patients with posterior fossa parenchymal lesions in the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) cohort related to clinical features, therapy and outcome. Fisher's exact test was used to evaluate associations. To assess the safety of anticoagulation in CVT patients with posterior fossa lesions we considered all patients with a lesion in this topography, either isolated or with concomitant supratentorial lesions, and compared the rate of new intracranial haemorrhages on repeated imaging with the remaining cohort. RESULTS: Out of 624 patients, 12 had isolated posterior fossa lesions and 14 had posterior fossa lesion with accompanying supratentorial lesions. The lateral sinus was most frequently occluded (n = 11). Involvement of the superior sagittal sinus was significantly less frequent compared to the remaining patients of the cohort (p = 0.013). None of the patients with isolated posterior fossa lesion died but 3 remained dependent on follow-up. Poor outcome (modified Rankin Scale ≥3) was more frequent in patients with any posterior fossa lesion, even when on anticoagulation (29.2% vs. 11.9%; OR 3.04; 95% CI 1.2-7.6; p = 0.018). Of the 24 anticoagulated patients with a posterior fossa lesion, 3 (12.5%) had new haemorrhages on repeated imaging, compared with 30 out of 495 anticoagulated patients (6.1%) without posterior fossa lesions (p = 0.19). CONCLUSIONS: We describe the largest series of CVT patients with associated posterior fossa lesions. When compared to anticoagulated CVT patients without posterior fossa lesions, CVT patients with posterior fossa lesions on full anticoagulation did not have a significant increase in the rate of new intracranial haemorrhages.

[Not Available]. / INTRODUCTION.

Despite a decrease in stroke mortality, the global burden of stroke is increasing worldwide, hence the importance of improving prevention, acute treatment and rehabilitation. Nume- rous randomized clinical trials have been performed in the acute treatment of the three main varieties of stroke, namely acute cerebral ischemia, intracerebral hemorrhage and suba- rachnoid hemorrhage. They have all shown that " time is brain ". Stroke, however, is only the tip of the iceberg: MRI studies have shown the frequency of silent ischemic and hemorrhagic lesions contributing to cognitive impairment and eventually to dementia. This again underlines the needfor effective prevention strategies to reduce the incidence of stroke.

Effects of MLC601 on early vascular events in patients after stroke: the CHIMES study.

BACKGROUND AND PURPOSE: Early vascular events are an important cause of morbidity and mortality in the first 3 months after a stroke. We aimed to investigate the effects of MLC601 on the occurrence of early vascular events within 3 months of stroke onset. METHODS: Post hoc analysis was performed on data from subjects included in the CHInese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study, a randomized, placebo-controlled, double-blinded trial that compared MLC601 with placebo in 1099 subjects with ischemic stroke of intermediate severity in the preceding 72 hours. Early vascular events were defined as a composite of recurrent stroke, acute coronary syndrome, and vascular death occurring within 3 months of stroke onset. RESULTS: The frequency of early vascular events during the 3-month follow-up was significantly less in the MLC601 group than in the placebo group (16 [2.9%] versus 31 events [5.6%]; risk difference=-2.7%; 95% confidence interval, -5.1% to -0.4%; P=0.025) without an increase in nonvascular deaths. Kaplan-Meier survival analysis showed a difference in the risk of vascular outcomes between the 2 groups as early as the first month after stroke (Log-rank P=0.024; hazard ratio, 0.51; 95% confidence interval, 0.28-0.93). CONCLUSIONS: Treatment with MLC601 was associated with reduced early vascular events among subjects in the CHIMES study. The mechanisms for this effect require further study. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00554723.

Differences and similarities between spontaneous dissections of the internal carotid artery and the vertebral artery.

BACKGROUND AND PURPOSE: To compare potential risk factors, clinical symptoms, diagnostic delay, and 3-month outcome between spontaneous internal carotid artery dissection (sICAD) and spontaneous vertebral artery dissection (sVAD). METHODS: We compared patients with sICAD (n=668) and sVAD (n=302) treated in 3 university hospitals. RESULTS: Patients with sICAD were older (46.3 ± 9.6 versus 42.0 ± 10.2 years; P<0.001), more often men (62.7% versus 53.0%; P=0.004), and presented more frequently with tinnitus (10.9% versus 3.4%; P<0.001) and more severe ischemic strokes (median National Institutes of Health Stroke Scale, 10 ± 7.1 versus 5 ± 5.9; P<0.001). Patients with sVAD had more often bilateral dissections (15.2% versus 7.6%; P<0.001) and were more often smokers (36.0% versus 28.7%; P=0.007). Thunderclap headache (9.2% versus 3.6%; P=0.001) and neck pain were more common (65.8% versus 33.5%; P<0.001) in sVAD. Subarachnoid hemorrhage (6.0% versus 0.6%; P<0.001) and ischemic stroke (69.5% versus 52.2%; P<0.001) were more frequent in sVAD. After multivariate analysis, sex difference lost its significance (P=0.21), and all other variables remained significant. Time to diagnosis was similar in sICAD and sVAD and improved between 2001 and 2012 compared with the previous 10-year period (8.0 ± 10.5 days versus 10.7 ± 13.2 days; P=0.004). In sVAD, favorable outcome 3 months after ischemic stroke (modified Rankin Scale, 0-2: 88.8% versus 58.4%; P<0.001), recurrent transient ischemic attack (4.8% versus 1.1%; P=0.001), and recurrent ischemic stroke (2.8% versus 0.7%; P=0.02) within 3 months were more frequent. CONCLUSIONS: sICAD and sVAD patients differ in many aspects. Future studies should perform separate analyses of these 2 entities.

Chinese medicine neuroaid efficacy on stroke recovery: a double-blind, placebo-controlled, randomized study.

BACKGROUND AND PURPOSE: Previous clinical studies suggested benefit for poststroke recovery when MLC601 was administered between 2 weeks and 6 months of stroke onset. The Chinese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study tested the hypothesis that MLC601 is superior to placebo in acute, moderately severe ischemic stroke within a 72-hour time window. METHODS: This multicenter, double-blind, placebo-controlled trial randomized 1100 patients with a National Institutes of Health Stroke Scale score 6 to 14, within 72 hours of onset, to trial medications for 3 months. The primary outcome was a shift in the modified Rankin Scale. Secondary outcomes were modified Rankin Scale dichotomy, National Institutes of Health Stroke Scale improvement, difference in National Institutes of Health Stroke Scale total and motor scores, Barthel index, and mini-mental state examination. Planned subgroup analyses were performed according to age, sex, time to first dose, baseline National Institutes of Health Stroke Scale, presence of cortical signs, and antiplatelet use. RESULTS: The modified Rankin Scale shift analysis-adjusted odds ratio was 1.09 (95% confidence interval, 0.86-1.32). Statistical difference was not detected between the treatment groups for any of the secondary outcomes. Subgroup analyses showed no statistical heterogeneity for the primary outcome; however, a trend toward benefit in the subgroup receiving treatment beyond 48 hours from stroke onset was noted. Serious and nonserious adverse events rates were similar between the 2 groups. CONCLUSIONS: MLC601 is statistically no better than placebo in improving outcomes at 3 months when used among patients with acute ischemic stroke of intermediate severity. Longer treatment duration and follow-up of participants with treatment initiated after 48 hours may be considered in future studies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00554723.

[Platelets, atherothrombosis, antiplatelet drugs and cerebral ischemia]. / Plaquettes, athérothrombose, antiplaquettaires et ischémie cérébrale.

Platelets play a much more important role in myocardial ischemia than in cerebral ischemia, because atherothrombosis - the underlying cause of the vast majority of myocardial infarcts - is responsible for only 25-30% of cerebral infarcts. Aspirin is the only effective antiplatelet drug for primary prevention of ischemic events, especially those affecting the heart. For secondary prevention of cerebral infarction, clopidogrel and the combination of aspirin with extended-release dipyridamole are both marginally better than aspirin alone, but aspirin remains the gold standard worldwide because of its remarkable cost/benefit/tolerability ratio. The clopidogrel-aspirin combination is to be avoided because of the risk of hemorrhage, particularly in the brain and gastrointestinal tract. Revascularization strategies and the choice of antiplatelet drugs for the acute phase of myocardial and cerebral ischemia are very different, consisting of endovascular treatment and aggressive platelet inhibition for coronary infarcts, versus intravenous thrombolysis and / or aspirin for cerebral infarcts. None of the new antiplatelet drugs used in acute coronary syndromes has so far been studied in acute cerebral ischemia.

The EffecTs of Amlodipine and other Blood PREssure Lowering Agents on Microvascular FuncTion in Small Vessel Diseases (TREAT-SVDs) trial: Study protocol for a randomised crossover trial.

Background: Hypertension is the leading modifiable risk factor for cerebral small vessel diseases (SVDs). Yet, it is unknown whether antihypertensive drug classes differentially affect microvascular function in SVDs. Aims: To test whether amlodipine has a beneficial effect on microvascular function when compared to either losartan or atenolol, and whether losartan has a beneficial effect when compared to atenolol in patients with symptomatic SVDs. Design: TREAT-SVDs is an investigator-led, prospective, open-label, randomised crossover trial with blinded endpoint assessment (PROBE design) conducted at five study sites across Europe. Patients aged 18 years or older with symptomatic SVD who have an indication for antihypertensive treatment and are suffering from either sporadic SVD and a history of lacunar stroke or vascular cognitive impairment (group A) or CADASIL (group B) are randomly allocated 1:1:1 to one of three sequences of antihypertensive treatment. Patients stop their regular antihypertensive medication for a 2-week run-in period followed by 4-week periods of monotherapy with amlodipine, losartan and atenolol in random order as open-label medication in standard dose. Outcomes: The primary outcome measure is cerebrovascular reactivity (CVR) as determined by blood oxygen level dependent brain MRI signal response to hypercapnic challenge with change in CVR in normal appearing white matter as primary endpoint. Secondary outcome measures are mean systolic blood pressure (BP) and BP variability (BPv). Discussion: TREAT-SVDs will provide insights into the effects of different antihypertensive drugs on CVR, BP, and BPv in patients with symptomatic sporadic and hereditary SVDs. Funding: European Union's Horizon 2020 programme. Trial registration: NCT03082014.

Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial.

BACKGROUND: Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease. METHODS: We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated. FINDINGS: Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years [SD 9·9]) and 26 with CADASIL (53·1 years [7·0]) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10-4%/mm Hg [SE 20·1; 95% CI -37·6 to 41·2] for amlodipine; 16·7 × 10-4%/mm Hg [20·0; -22·3 to 55·8] for losartan; -7·1 × 10-4%/mm Hg [19·6; -45·5 to 31·1] for atenolol; poverall=0·39) but did differ in patients with CADASIL (15·7 × 10-4%/mm Hg [SE 27·5; 95% CI -38·3 to 69·7] for amlodipine; 19·4 × 10-4%/mm Hg [27·9; -35·3 to 74·2] for losartan; -23·9 × 10-4%/mm Hg [27·5; -77·7 to 30·0] for atenolol; poverall=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (-39·6 × 10-4%/mm Hg [95% CI -72·5 to -6·6; p=0·019) and with losartan compared with atenolol (-43·3 × 10-4%/mm Hg [-74·3 to -12·3]; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake. INTERPRETATION: 4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research. FUNDING: EU Horizon 2020 programme.

Effects of blood pressure lowering on intracranial and extracranial bleeding in patients on antithrombotic therapy: the PROGRESS trial.

BACKGROUND AND PURPOSE: Observational studies demonstrate strong associations between blood pressure and bleeding complications of antithrombotic therapy. The objective was to determine whether blood pressure lowering reduces risks of bleeding in patients on antithrombotic therapy. METHODS: This is a subsidiary analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, a randomized, placebo-controlled trial. A total of 6105 patients with cerebrovascular disease were randomly assigned to either active treatment (perindopril ± indapamide) or placebo(s). The outcomes were intracranial and extracranial bleeding. RESULTS: There were 4876 (80%) patients on antithrombotic therapy at baseline. Over a mean follow-up of 3.9 years, 119 intracranial and 123 extracranial bleeding events were observed. Among patients with and without antithrombotic therapy, active treatment lowered blood pressure by 8.9/4.0 and 9.3/3.8 mm Hg and reduced the risks of intracranial bleeding by 46% (95% CI, 7%-69%) and 70% (39%-85%), respectively. However, active treatment did not reduce the risks of extracranial bleeding significantly in either group. Among patients on antithrombotic therapy, the lowest risk of intracranial bleeding was observed in participants with the lowest follow-up systolic blood pressure levels (median, 113 mm Hg). CONCLUSIONS: Blood pressure lowering provides protection against intracranial bleeding among patients with cerebrovascular disease including those receiving antithrombotic therapy.