Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial.

BACKGROUND: Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown. METHODS: OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO2 on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q. RESULTS: In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; P=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; P<0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; P=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; P=0.007), CVR-WMH (0.07, 0-0.14; P=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P=0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; P=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P=4.9×10-8; cilostazol-placebo, 0.06, 0.03-0.09; P=5.1×10-5). Both drugs increased headaches (P=1.1×10-4), while cilostazol increased moderate-severe diarrhea (P=0.013). CONCLUSIONS: Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease. REGISTRATION: URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332.

Early Versus Late Initiation of Direct Oral Anticoagulants After Ischemic Stroke in People With Atrial Fibrillation and Hemorrhagic Transformation: Prespecified Subanalysis of the Randomized Controlled ELAN Trial.

BACKGROUND: Whether hemorrhagic transformation (HT) modifies the treatment effect of early compared with late initiation of direct oral anticoagulation in people with ischemic stroke and atrial fibrillation is unknown. METHODS: This is a post hoc analysis of the ELAN trial (Early Versus Late Initiation of Direct Oral Anticoagulants in Post-Ischaemic Stroke Patients With Atrial Fibrillation). The primary outcome was a composite of recurrent ischemic stroke, symptomatic intracranial hemorrhage, major extracranial bleeding, systemic embolism, or vascular death within 30 days. Secondary outcomes were the individual components, 30- and 90-day functional outcome. We estimated outcomes based on HT, subclassified as hemorrhagic infarction (HI) or parenchymal hemorrhage (PH) on prerandomization imaging (core laboratory rating) using adjusted risk differences between treatment arms. RESULTS: Overall, 247 of 1970 participants (12.5%) had HT (114 HI 1, 77 HI 2, 34 PH 1, 22 PH 2). For the primary outcome, the estimated adjusted risk difference (early versus late) was -2.2% (95% CI, -7.8% to 3.5%) in people with HT (HI: -4.7% [95% CI, -10.8% to 1.4%]; PH: 6.1% [95% CI, -8.5% to 20.6%]) and -0.9% (95% CI, -2.6% to 0.8%) in people without HT. Numbers of symptomatic intracranial hemorrhage were identical in people with and without HT. With early treatment, the estimated adjusted risk difference for poor 90-day functional outcome (modified Rankin Scale score, 3-6) was 11.5% (95% CI, -0.8% to 23.8%) in participants with HT (HI: 7.4% [95% CI, -6.4% to 21.2%]; PH: 25.1% [95% CI, 0.2% to 50.0%]) and -2.6% (95% CI, -7.1% to 1.8%) in people without HT. CONCLUSIONS: We found no evidence of major treatment effect heterogeneity or safety concerns with early compared with late direct oral anticoagulation initiation in people with and without HT. However, early direct oral anticoagulation initiation may worsen functional outcomes in people with PH. REGISTRATION: URL: http://www.clinicaltrials.gov; Unique identifier: NCT03148457.

Incidence and Outcomes of Patients With Early Cardiac Complications After Intracerebral Hemorrhage: A Report From VISTA.

BACKGROUND: The incidence and outcomes of early cardiac complications in patients with intracerebral hemorrhage (ICH) are poorly understood. These cardiac complications may be part of the so-called stroke-heart syndrome in patients with ICH. We investigated this issue in an individual patient data pooled analysis from an international repository of clinical trial data. METHODS: We used the Virtual International Stroke Trials Archive to investigate the incidence of cardiac complications within 30 days post-ICH or acute ischemic stroke (AIS). These complications included acute coronary syndrome encompassing myocardial injury, heart failure/left ventricular dysfunction, atrial fibrillation/atrial flutter, other arrhythmia/ECG abnormalities, and cardiorespiratory arrest. We used propensity score matching to compare the incidence of patients with stroke-heart syndrome in patients with ICH with those following AIS. Factors associated with 90-day mortality were evaluated using multivariate logistic regression analysis in the ICH cohort. RESULTS: We pooled data from 8698 participants recruited in acute stroke trials (mean age, 68±12 years; 56% male), of whom 914 (11%) were patients with ICH. Among the patients with ICH, 123 (13%) had stroke-heart syndrome in patients with ICH. Following propensity score matching, a total of 1828 patients (914 for each of the cohorts) were analyzed. While the overall incidence of cardiac events tended to be lower in the ICH group compared with the AIS group (the cumulative incidence freedom from the event, 86.3% [95% CI, 84.1-88.6] versus 83.6% [95% CI, 81.2-86.0]; P=0.100), the incidences cardiac events other than atrial fibrillation/atrial flutter were comparable between the 2 matched groups. The incidence of atrial fibrillation/atrial flutter was significantly lower in the ICH group than in the AIS group (P<0.001). The multivariate-adjusted analysis found that stroke-heart syndrome in patients with ICH was associated with 90-day mortality (adjusted odds ratio, 1.12 [95% CI, 1.06-1.19]; P<0.001). CONCLUSIONS: Cardiac events are common and negatively affect prognosis in patients with ICH, just as seen in AIS.

Impact of European Stroke Organisation secondary prevention guideline for ischaemic stroke / transient ischaemic attack.

OBJECTIVES: We aimed to assess secondary prevention strategies after ischaemic stroke or transient ischaemic attack (TIA). MATERIALS AND METHODS: We investigated the impact of European Stroke Organisation (ESO) Guideline recommendations for secondary prevention on recurrent events among people with non-cardioembolic ischaemic stroke or TIA. We assessed the following interventions by survival analysis or modelling impacts from clinical trial data: two blood pressure (BP) drugs compared to one drug; LDL-cholesterol target <1.8 mmol/L; and pioglitazone therapy. Outcomes were mortality, major adverse cardiovascular events (MACE) and recurrent stroke or myocardial infarction (MI). RESULTS: We included 4,037 people admitted between 01/12/2015 to 31/12/2018: mean (SD) age 68.6 (12.9) years; 1984 (49.1 %) female and median (IQR) follow-up 2.2 (1.5-3.1) years. Prescription of two BP drugs was associated with reduced mortality in our sample of 2238 people with hypertension (HR 0.64, 95 %CI 0.51-0.81; P<0.001). We estimate an LDL-cholesterol target <1.8 mmol/L could reduce MACE incidence from 128 to 114 events (95 %CI 103-127) in our sample of 1024 people with LDL-cholesterol 1.8 mmol/L who were not already prescribed intensive lipid-lowering therapy over median (IQR) 2.2 (1.5-2.9) years follow-up (ARR 1.38 %, NNT 73). We estimate pioglitazone therapy could reduce incidence of recurrent stroke or MI from 192 to 169 events (95 %CI 156-185) in our sample of 1587 people with diabetes or insulin resistance over median (IQR) 2.4 (1.7-3.2) years follow-up (ARR 1.45 %, NNT 69). CONCLUSIONS: We estimate that implementing ESO guidelines in a Scottish population after ischaemic stroke or TIA would reduce mortality and recurrent cardiovascular events.

Pioglitazone and barriers to effective post-stroke comorbidity management in stroke survivors with diabetes.

OBJECTIVES: To explore the barriers preventing pioglitazone use in stroke survivors and primary and secondary stroke care services. METHODS: A qualitative grounded theory approached design was used to assess post-stroke diabetes treatments and to assess clinical applicability of pioglitazone as a preventive treatment to minimize its side effects (SEs) associated. Three focus groups were established with 48 participants from Scotland and Wales health board centers during January 2019 to July 2022. RESULTS: A qualitative grounded theory approached design was used to assess post-stroke diabetes treatments and to assess clinical applicability of pioglitazone as a preventive treatment to minimize its SEs associated. Three focus groups were established with 48 participants from Scotland and Wales health board centers during January 2019 to July 2022. CONCLUSION: These strategies might allow greater treatment adherence by stroke survivors and increased confidence of the health care professionals in their practice. The findings suggest that further research will be needed to facilitate wider usage of pioglitazone in treating people with stroke and health education is necessitate when using diabetes drugs post-stroke.

tVNS in Stroke: A Narrative Review on the Current State and the Future.

Ischemic stroke is a leading cause of disability and there is a paucity of therapeutic strategies that promote functional recovery after stroke. Transcutaneous vagus nerve stimulation (tVNS) has shown promising evidence as a tool to reduce infarct size in animal models of hyperacute stroke. In chronic stroke, tVNS paired with limb movements has been shown to enhance neurological recovery. In this review, we summarize the current evidence for tVNS in preclinical models and clinical trials in humans. We highlight the mechanistic pathways involved in the beneficial effects of tVNS. We critically evaluate the current gaps in knowledge and recommend the key areas of research required to translate tVNS into clinical practice in acute and chronic stroke.

Sex differences in outcome after carotid revascularization in symptomatic and asymptomatic carotid artery stenosis.

OBJECTIVE: Sex differences regarding the safety and efficacy of carotid revascularization in carotid artery stenosis have been addressed in several studies with conflicting results. Moreover, women are underrepresented in clinical trials, leading to limited conclusions regarding the safety and efficacy of acute stroke treatments. METHODS: A systematic review and meta-analysis was performed by literature search including four databases from January 1985 to December 2021. Sex differences in the efficacy and safety of revascularization procedures, including carotid endarterectomy (CEA) and carotid artery stenting (CAS), for symptomatic and asymptomatic carotid artery stenoses were analyzed. RESULTS: Regarding CEA in symptomatic carotid artery stenosis, the stroke risk in men (3.6%) and women (3.9%) based on 99,495 patients (30 studies) did not differ (P = .16). There was also no difference in the stroke risk by different time frames up to 10 years. Compared with men, women treated with CEA had a significantly higher stroke or death rate at 4 months (2 studies, 2565 patients; 7.2% vs 5.0%; odds ratio [OR], 1.49; 95% confidence interval [CI], 1.04-2.12; I2 = 0%; P = .03), and a significantly higher rate of restenosis (1 study, 615; 17.2% vs 6.7%; OR, 2.81; 95% CI, 1.66-4.75; P = .0001). For CAS in symptomatic artery stenosis, data showed a non-significant tendency toward higher peri-procedural stroke in women, whereas for asymptomatic carotid artery stenosis, data based on 332,344 patients showed that women (compared with men) after CEA had similar rates of stroke, stroke or death, and the composite outcome stroke/death/myocardial infarction. The rate of restenosis at 1 year was significantly higher in women compared with men (1 study, 372 patients; 10.8% vs 3.2%; OR, 3.71; 95% CI, 1.49-9.2; P = .005). Furthermore, CAS in asymptomatic patients was associated with low risk of a postprocedural stroke in both sexes, but a significantly higher risk of in-hospital myocardial infarction in women than men (8445 patients, 1.2% vs 0.6%; OR, 2.01; 95% CI, 1.23-3.28; I2 = 0%; P = .005). CONCLUSIONS: A few sex-differences in short-term outcomes after carotid revascularization for symptomatic and asymptomatic carotid artery stenosis were found, although there were no significant differences in the overall stroke. This indicates a need for larger multicenter prospective studies to evaluate these sex-specific differences. More women, including those aged over 80 years, need to be enrolled in randomized controlled trials, to better understand if sex differences exist and to tailor carotid revascularization accordingly.

Impact of genetic polymorphisms on the risk of epilepsy amongst patients with acute brain injury: A systematic review.

BACKGROUND AND PURPOSE: The genetics of late seizure or epilepsy secondary to traumatic brain injury (TBI) or stroke are poorly understood. We undertook a systematic review to test the association of single-nucleotide polymorphisms (SNPs) with the risk of post-traumatic epilepsy (PTE) and post-stroke epilepsy (PSE). METHODS: We followed methods from our prespecified protocol on PROSPERO to identify indexed articles for this systematic review. We collated the association statistics from the included articles to assess the association of SNPs with the risk of epilepsy amongst TBI or stroke patients. We assessed study quality using the Q-Genie tool. We report odds ratios (OR) and hazard ratios with 95% confidence intervals (CIs). RESULTS: The literature search yielded 420 articles. We included 16 studies in our systematic review, of which seven were of poor quality. We examined published data on 127 SNPs from 32 genes identified in PTE and PSE patients. Eleven SNPs were associated with a significantly increased risk of PTE. Three SNPs, TRMP6 rs2274924, ALDH2 rs671, and CD40 -1C/T, were significantly associated with an increased risk of PSE, while two, AT1R rs12721273 and rs55707609, were significantly associated with reduced risk. The meta-analysis for the association of the APOE ɛ4 with PTE was nonsignificant (OR 1.8, CI 0.6-5.6). CONCLUSIONS: The current evidence on the association of genetic polymorphisms in epilepsy secondary to TBI or stroke is of low quality and lacks validation. A collaborative effort to pool genetic data linked to epileptogenesis in stroke and TBI patients is warranted.

Preventing Recurrent Cardioembolic Stroke: Right Approach, Right Patient (PRECISE) Study Protocol.

Cardiac rhythm monitoring is performed to search for atrial fibrillation (AF) after ischaemic stroke or transient ischaemic attack (TIA). Prolonged cardiac rhythm monitoring increases AF detection but is challenging to implement in many healthcare settings and is not needed for all people after ischaemic stroke/TIA. We aimed to develop and validate a model that includes clinical, electrocardiogram (ECG), blood-based, and genetic biomarkers to identify people with a low probability of AF detection after ischaemic stroke or TIA. We will recruit 675 consenting participants who are aged over 18 years, who were admitted with ischaemic stroke or TIA in the 5 days prior, who are not known to have AF, and who would be suitable for anticoagulation if AF is found. We will collect baseline demographic and clinical data, a 12-lead ECG, and a venous blood sample for blood biomarkers (including midregional pro-atrial natriuretic peptide, MRproANP) and genetic data. We will perform up to 28 days of cardiac rhythm monitoring using an R-test or patch device to search for AF in all participants. The sample size of 675 participants is based on true sensitivity of 92.5%, null hypothesis sensitivity of 80%, 80% power, and 5% significance. The primary outcome is AF detection ≥30 s duration during 28 days of cardiac rhythm monitoring. Secondary outcomes are AF detection at 1-year, recurrent cardiovascular events, and mortality and will be identified by electronic linkage and telephone follow-up. The results will guide the development of a more personalized care pathway to search for AF after ischaemic stroke or TIA. This could help to reduce cardiac rhythm monitoring for people with a low probability of AF detection and allow more intensive cardiac monitoring to be focused on people who are more likely to have AF and benefit. Participants will be consented for their data to be used in future research studies, providing a rich resource for stroke and cardiovascular research communities.

Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Stroke: 2- and 3-Year Follow-up From the Pilot Study.

OBJECTIVE: To assess whether a long-term home-based intervention using Paired VNS therapy is feasible and whether the benefits of Paired VNS therapy are maintained beyond 1 year. DESIGN: A long-term follow-up study. SETTING: Three centers in the United States and 1 in the United Kingdom. PARTICIPANTS: Adults with chronic ischemic stroke (n=15) with moderate to severe arm and hand impairment. INTERVENTIONS: Participants were implanted with a VNS device followed by 6 weeks of in-clinic therapy with Paired (Active) or control VNS followed by home-based rehabilitation through day 90 (blinded phase). The control VNS group then crossed over to receive 6 weeks of in-clinic Active VNS. Participants in both groups then continued a long-term home exercise program with self-administered Active VNS. MAIN OUTCOME MEASURES: Fugl-Meyer Assessment for Upper Extremity (FMA-UE) and Wolf Motor Function Test (WMFT) Functional scores were evaluated at the end of in-clinic therapy and day 90. Since both groups were subsequently receiving home-based rehabilitation with Active VNS during the long term, follow-up outcome assessments were pooled for the analyses at 6, 9, and 12 months, as previously reported. Here, we report pooled analysis of outcomes beyond 1 year. RESULTS: One year after Paired VNS therapy, FMA-UE improved by an average of 9.2±8.2 points, as previously reported. Overall, the 2- and 3-year FMA-UE gain from baseline was 11.4±8.7 (P<.001) and 14.8±10.2 points (P<.001), respectively. At years 2 and 3, FMA-UE improved by an additional 2.9 (P=.03 for change vs year 1, n=14) and 4.7 (P=.02 for change vs year 1, n=14) points, respectively. At year 1, 73% (11/15) of participants were responders (FMA-UE change ≥6) and by year 3, 85.7% (12/14) were responders. At years 2 and 3, the WMFT score improved by an additional 0.21 points (P=.03 for change vs year 1, n=15) and 0.42 points (P=.01 for change vs year 1, n=13), respectively. Responder rate (WMFT change ≥0.4) was 46.6% (7/15), 73.3% (11/15), and 69.2% (9/13) at years 1, 2, and 3, respectively. Long-term significant improvements were also observed for Motor Activity Log (MAL) and Stroke Impact Scale, Hand section (SIS-Hand). There were no serious long-term adverse events from the stimulation. CONCLUSIONS: Significant effects of Paired VNS therapy at 1 year were maintained at years 2 and 3, and further improvements in both impairment and function were observed in years 2 and 3. These changes were associated with improvements in measures of activity and participation.

Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study.

BACKGROUND: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain. METHODS: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment. RESULTS: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA2DS2-VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0-1.3] for each point increase; P=0.05) and hypertension (OR, 2.3 [95% CI, 1.0-5.1]; P=0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0-1.2] for each year increase; P=0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4-14.2]; P=0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4-5.5]; P=0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8-1.7]). CONCLUSIONS: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.

Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial.

BACKGROUND: Long-term loss of arm function after ischaemic stroke is common and might be improved by vagus nerve stimulation paired with rehabilitation. We aimed to determine whether this strategy is a safe and effective treatment for improving arm function after stroke. METHODS: In this pivotal, randomised, triple-blind, sham-controlled trial, done in 19 stroke rehabilitation services in the UK and the USA, participants with moderate-to-severe arm weakness, at least 9 months after ischaemic stroke, were randomly assigned (1:1) to either rehabilitation paired with active vagus nerve stimulation (VNS group) or rehabilitation paired with sham stimulation (control group). Randomisation was done by ResearchPoint Global (Austin, TX, USA) using SAS PROC PLAN (SAS Institute Software, Cary, NC, USA), with stratification by region (USA vs UK), age (≤30 years vs >30 years), and baseline Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score (20-35 vs 36-50). Participants, outcomes assessors, and treating therapists were masked to group assignment. All participants were implanted with a vagus nerve stimulation device. The VNS group received 0·8 mA, 100 µs, 30 Hz stimulation pulses, lasting 0·5 s. The control group received 0 mA pulses. Participants received 6 weeks of in-clinic therapy (three times per week; total of 18 sessions) followed by a home exercise programme. The primary outcome was the change in impairment measured by the FMA-UE score on the first day after completion of in-clinic therapy. FMA-UE response rates were also assessed at 90 days after in-clinic therapy (secondary endpoint). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT03131960. FINDINGS: Between Oct 2, 2017, and Sept 12, 2019, 108 participants were randomly assigned to treatment (53 to the VNS group and 55 to the control group). 106 completed the study (one patient for each group did not complete the study). On the first day after completion of in-clinic therapy, the mean FMA-UE score increased by 5·0 points (SD 4·4) in the VNS group and by 2·4 points (3·8) in the control group (between group difference 2·6, 95% CI 1·0-4·2, p=0·0014). 90 days after in-clinic therapy, a clinically meaningful response on the FMA-UE score was achieved in 23 (47%) of 53 patients in the VNS group versus 13 (24%) of 55 patients in the control group (between group difference 24%, 6-41; p=0·0098). There was one serious adverse event related to surgery (vocal cord paresis) in the control group. INTERPRETATION: Vagus nerve stimulation paired with rehabilitation is a novel potential treatment option for people with long-term moderate-to-severe arm impairment after ischaemic stroke. FUNDING: MicroTransponder.

Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients.

BACKGROUND: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. METHODS: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. RESULTS: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 µm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 µm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. CONCLUSIONS: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.

Risk factors mediating the effect of body mass index and waist-to-hip ratio on cardiovascular outcomes: Mendelian randomization analysis.

BACKGROUND: Higher body mass index (BMI) and waist-to-hip ratio (WHR) increase the risk of cardiovascular disease, but the extent to which this is mediated by blood pressure, diabetes, lipid traits, and smoking is not fully understood. METHODS: Using consortia and UK Biobank genetic association summary data from 140,595 to 898,130 participants predominantly of European ancestry, Mendelian randomization mediation analysis was performed to investigate the degree to which systolic blood pressure (SBP), diabetes, lipid traits, and smoking mediated an effect of BMI and WHR on the risk of coronary artery disease (CAD), peripheral artery disease (PAD) and stroke. RESULTS: The odds ratio of CAD per 1-standard deviation increase in genetically predicted BMI was 1.49 (95% CI 1.39 to 1.60). This attenuated to 1.34 (95% CI 1.24 to 1.45) after adjusting for genetically predicted SBP (proportion mediated 27%, 95% CI 3% to 50%), to 1.27 (95% CI 1.17 to 1.37) after adjusting for genetically predicted diabetes (41% mediated, 95% CI 18% to 63%), to 1.47 (95% CI 1.36 to 1.59) after adjusting for genetically predicted lipids (3% mediated, 95% -23% to 29%), and to 1.46 (95% CI 1.34 to 1.58) after adjusting for genetically predicted smoking (6% mediated, 95% CI -20% to 32%). Adjusting for all the mediators together, the estimate attenuated to 1.14 (95% CI 1.04 to 1.26; 66% mediated, 95% CI 42% to 91%). A similar pattern was observed when considering genetically predicted WHR as the exposure, and PAD or stroke as the outcome. CONCLUSIONS: Measures to reduce obesity will lower the risk of cardiovascular disease primarily by impacting downstream metabolic risk factors, particularly diabetes and hypertension. Reduction of obesity prevalence alongside control and management of its mediators is likely to be most effective for minimizing the burden of obesity.

Evaluation of the enhanced upper limb therapy programme within the Robot-Assisted Training for the Upper Limb after Stroke trial: descriptive analysis of intervention fidelity, goal selection and goal achievement.

OBJECTIVE: To report the fidelity of the enhanced upper limb therapy programme within the Robot-Assisted Training for the Upper Limb after stroke (RATULS) randomized controlled trial, the types of goals selected and the proportion of goals achieved. DESIGN: Descriptive analysis of data on fidelity, goal selection and achievement from an intervention group within a randomized controlled trial. SETTING: Out-patient stroke rehabilitation within four UK NHS centres. SUBJECTS: 259 participants with moderate-severe upper limb activity limitation (Action Research Arm Test 0-39) between one week and five years post first stroke. INTERVENTION: The enhanced upper limb therapy programme aimed to provide 36 one-hour sessions, including 45 minutes of face-to-face therapy focusing on personal goals, over 12 weeks. RESULTS: 7877/9324 (84%) sessions were attended; a median of 34 [IQR 29-36] per participant. A median of 127 [IQR 70-190] repetitions were achieved per participant per session attended. Based upon the Canadian Occupational Performance Measure, goal categories were: self-care 1449/2664 (54%); productivity 374/2664 (14%); leisure 180/2664 (7%) and 'other' 661/2664 (25%). For the 2051/2664 goals for which data were available, 1287 (51%) were achieved, ranging between 27% by participants more than 12 months post stroke with baseline Action Research Arm Test scores 0-7, and 88% by those less than three months after stroke with scores 8-19. CONCLUSIONS: Intervention fidelity was high. Goals relating to self-care were most commonly selected. The proportion of goals achieved varied, depending on time post stroke and baseline arm activity limitation.

Liver Fibrosis Indices and Outcomes After Primary Intracerebral Hemorrhage.

Background and Purpose- Cirrhosis-clinically overt, advanced liver disease-is associated with an increased risk of hemorrhagic stroke and poor stroke outcomes. We sought to investigate whether subclinical liver disease, specifically liver fibrosis, is associated with clinical and radiological outcomes in patients with primary intracerebral hemorrhage. Methods- We performed a retrospective cohort study using data from the Virtual International Stroke Trials Archive-Intracerebral Hemorrhage. We included adult patients with primary intracerebral hemorrhage presenting within 6 hours of symptom onset. We calculated 3 validated fibrosis indices-Aspartate Aminotransferase-Platelet Ratio Index, Fibrosis-4 score, and Nonalcoholic Fatty Liver Disease Fibrosis Score-and modeled them as continuous exposure variables. Primary outcomes were admission hematoma volume and hematoma expansion. Secondary outcomes were mortality, and the composite of major disability or death, at 90 days. We used linear and logistic regression models adjusted for previously established risk factors. Results- Among 432 patients with intracerebral hemorrhage, the mean Aspartate Aminotransferase-Platelet Ratio Index, Fibrosis-4, and Nonalcoholic Fatty Liver Disease Fibrosis Score values on admission reflected intermediate probabilities of fibrosis, whereas standard hepatic assays and coagulation parameters were largely normal. After adjusting for potential confounders, Aspartate Aminotransferase-Platelet Ratio Index was associated with hematoma volume (ß, 0.20 [95% CI, 0.04-0.36]), hematoma expansion (odds ratio, 1.6 [95% CI, 1.1-2.3]), and mortality (odds ratio, 1.8 [95% CI, 1.1-2.7]). Fibrosis-4 was also associated with hematoma volume (ß, 0.27 [95% CI, 0.07-0.47]), hematoma expansion (odds ratio, 1.9 [95% CI, 1.2-3.0]), and mortality (odds ratio, 2.0 [95% CI, 1.1-3.6]). Nonalcoholic Fatty Liver Disease Fibrosis Score was not associated with any outcome. Indices were not associated with the composite of major disability or death. Conclusions- In patients with largely normal liver chemistries, 2 liver fibrosis indices were associated with admission hematoma volume, hematoma expansion, and mortality after intracerebral hemorrhage.

Robot assisted training for the upper limb after stroke (RATULS): a multicentre randomised controlled trial.

BACKGROUND: Loss of arm function is a common problem after stroke. Robot-assisted training might improve arm function and activities of daily living. We compared the clinical effectiveness of robot-assisted training using the MIT-Manus robotic gym with an enhanced upper limb therapy (EULT) programme based on repetitive functional task practice and with usual care. METHODS: RATULS was a pragmatic, multicentre, randomised controlled trial done at four UK centres. Stroke patients aged at least 18 years with moderate or severe upper limb functional limitation, between 1 week and 5 years after their first stroke, were randomly assigned (1:1:1) to receive robot-assisted training, EULT, or usual care. Robot-assisted training and EULT were provided for 45 min, three times per week for 12 weeks. Randomisation was internet-based using permuted block sequences. Treatment allocation was masked from outcome assessors but not from participants or therapists. The primary outcome was upper limb function success (defined using the Action Research Arm Test [ARAT]) at 3 months. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN69371850. FINDINGS: Between April 14, 2014, and April 30, 2018, 770 participants were enrolled and randomly assigned to either robot-assisted training (n=257), EULT (n=259), or usual care (n=254). The primary outcome of ARAT success was achieved by 103 (44%) of 232 patients in the robot-assisted training group, 118 (50%) of 234 in the EULT group, and 85 (42%) of 203 in the usual care group. Compared with usual care, robot-assisted training (adjusted odds ratio [aOR] 1·17 [98·3% CI 0·70-1·96]) and EULT (aOR 1·51 [0·90-2·51]) did not improve upper limb function; the effects of robot-assisted training did not differ from EULT (aOR 0·78 [0·48-1·27]). More participants in the robot-assisted training group (39 [15%] of 257) and EULT group (33 [13%] of 259) had serious adverse events than in the usual care group (20 [8%] of 254), but none were attributable to the intervention. INTERPRETATION: Robot-assisted training and EULT did not improve upper limb function after stroke compared with usual care for patients with moderate or severe upper limb functional limitation. These results do not support the use of robot-assisted training as provided in this trial in routine clinical practice. FUNDING: National Institute for Health Research Health Technology Assessment Programme.

Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial.

BACKGROUND: Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage. METHODS: MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046. FINDINGS: Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0-3 at 365 days (adjusted risk difference 4% [95% CI -4 to 12]; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0·33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012). INTERPRETATION: For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons. FUNDING: National Institute of Neurological Disorders and Stroke and Genentech.

Diabetes drugs and stroke risk: Intensive versus conventional glucose-lowering strategies, and implications of recent cardiovascular outcome trials.

People with diabetes mellitus are at higher risk of ischaemic stroke and worse outcomes thereafter. However, whether it is better to prescribe intensive glucose-lowering treatment compared with conventional treatment in people with diabetes to prevent recurrent stroke is debated. It is also crucial to consider whether specific antidiabetic agents are more efficacious and safer than others for prevention of stroke. In this review, we provide an overview of the efficacy of intensive and conventional glucose-lowering treatment in post-stroke management. Our conclusion is that the overall evidence for a beneficial effect of intensive glycaemic control on risk of stroke is limited. We also discuss evidence from recent large clinical trials of thiazolidinediones and new antidiabetic medications, including dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose co-transporter-2 inhibitors. On the basis of the findings of these trials, our conclusion is that pioglitazone and the GLP-1RA class (other than short-acting lixisenatide) are likely to lessen the occurrence of cerebrovascular disease (by mechanisms not dependent on glucose-lowering per se), whereas there is no consistent evidence for other drug classes.

Investigating the Relationship between Cerebral Blood Flow and Cognitive Function in Hemodialysis Patients.

BACKGROUND: The immediate and longer-term effects of hemodialysis on cerebral circulation, cerebral structure, and cognitive function are poorly understood. METHODS: In a prospective observational cohort study of 97 adults (median age 59 years) receiving chronic hemodialysis, we used transcranial Doppler ultrasound to measure cerebral arterial mean flow velocity (MFV) throughout dialysis. Using a well validated neuropsychological protocol, we assessed cognitive function during and off dialysis and after 12 months of treatment. We also used brain magnetic resonance imaging (MRI) to assess atrophy, white matter hyperintensities (WMHs), and diffusion parameters, and tested correlations between MFV, cognitive scores, and changes on MRI. RESULTS: MFV declined significantly during dialysis, correlating with ultrafiltrate volumes. Percentage of decline in MFV correlated with intradialytic decline in cognitive function, including global function, executive function, and verbal fluency. At follow-up, 73 patients were available for repeat testing, 34 of whom underwent repeat MRI. In a subgroup of patients followed for 12 months of continued dialysis, percentage of decline in MFV correlated significantly with lower global and executive function and with progression of WMH burden (a marker of small vessel disease). Twelve of 15 patients who received renal transplants during follow-up had both early and follow-up off-dialysis assessments. After transplant, patients' memory (on a delayed recall test) improved significantly; increased fractional anisotropy of white matter (a measure of cerebral diffusion) in these patients correlated with improving executive function. CONCLUSIONS: Patients undergoing hemodialysis experience transient decline in cerebral blood flow, correlating with intradialytic cognitive dysfunction. Progressive cerebrovascular disease occurred in those continuing dialysis, but not in transplanted patients. Cognitive function and cerebral diffusion improved after transplant.