Impaired glucose metabolism and the risk of vascular events and mortality after ischemic stroke: A systematic review and meta-analysis.

BACKGROUND: Diabetes mellitus (DM), prediabetes, and insulin resistance are highly prevalent in patients with ischemic stroke (IS). DM is associated with higher risk for poor outcomes after IS. OBJECTIVE: Investigate the risk of recurrent vascular events and mortality associated with impaired glucose metabolism compared to normoglycemia in patients with IS and transient ischemic attack (TIA). METHODS: Systematic literature search was performed in PubMed, Embase, Cochrane Library on 21st March 2024 and via citation searching. Studies that comprised IS or TIA patients and exposures of impaired glucose metabolism were eligible. Study Quality Assessment Tool was used for risk of bias assessment. Covariate adjusted outcomes were pooled using random-effects meta-analysis. MAIN OUTCOMES: Recurrent stroke, cardiac events, cardiovascular and all-cause mortality and composite of vascular outcomes. RESULTS: Of 10,974 identified studies 159 were eligible. 67% had low risk of bias. DM was associated with an increased risk for composite events (pooled HR (pHR) including 445,808 patients: 1.58, 95% CI 1.34-1.85, I2 = 88%), recurrent stroke (pHR including 1.161.527 patients: 1.42 (1.29-1.56, I2 = 92%), cardiac events (pHR including 443,863 patients: 1.55, 1.50-1.61, I2 = 0%), and all-cause mortality (pHR including 1.031.472 patients: 1.56, 1.34-1.82, I2 = 99%). Prediabetes was associated with an increased risk for composite events (pHR including 8,262 patients: 1.50, 1.15-1.96, I2 = 0%) and recurrent stroke (pHR including 10,429 patients: 1.50, 1.18-1.91, I2 = 0), however, not with mortality (pHR including 9,378 patients, 1.82, 0.73-4.57, I2 = 78%). Insulin resistance was associated with recurrent stroke (pHR including 21,363 patients: 1.56, 1.19-2.05, I2 = 55%), but not with mortality (pHR including 21,363 patients: 1.31, 0.66-2.59, I2 = 85%). DISCUSSION: DM is associated with a 56% increased relative risk of death after IS and TIA. Risk estimates regarding recurrent events are similarly high between prediabetes and DM, indicating high cardiovascular risk burden already in precursor stages of DM. There was a high heterogeneity across most outcomes.

Efficacy and safety of aspirin plus clopidogrel versus aspirin alone in ischemic stroke or high-risk transient ischemic attack: A meta-analysis of randomized controlled trials.

Background: Antiplatelet therapy plays an important role in reducing the risk of stroke recurrence in patients with mild ischemic stroke or high-risk transient ischemic attack (TIA). However, data regarding the effectiveness and safety of using aspirin plus clopidogrel in dual antiplatelet therapy (DAPT) compared to aspirin alone in mild ischemic stroke is limited. Methods: PubMed/MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) that compared DAPT to aspirin alone started within 72 hours in mild ischemic stroke or high-risk TIA. We used a random effects model to pool risk ratios (RRs) along with 95% CIs for clinical outcomes. Results: Four RCTs with 16,547 patients were included in this study. DAPT significantly reduced the risk of recurrent stroke by 26% (RR: 0.74; 95% CI: 0.67-0.83; p < 0.00001), ischemic stroke by 28% (RR: 0.72; 95% CI: 0.65-0.80; p < 0.00001), and major adverse cardiovascular events (MACE) by 24% (RR: 0.76; 95% CI: 0.68-0.84; p < 0.00001) compared to aspirin monotherapy. However, DAPT was associated with a significantly increased risk of moderate or severe bleeding (RR: 1.88; 95% CI: 1.10-3.23; p = 0.02) compared to aspirin alone. No significant differences were observed for hemorrhagic stroke (RR: 1.77; 95% CI: 0.96-3.29; p = 0.07), all-cause mortality (RR: 1.25; 95% CI: 0.87-1.80; p = 0.23), cardiovascular mortality (RR: 1.38; 95% CI: 0.81-2.33; p = 0.23), and myocardial infarction (RR: 1.63; 95% CI: 0.77-3.46; p = 0.20). Conclusion: DAPT involving aspirin plus clopidogrel reduces stroke recurrence and MACE but can lead to an increased risk of moderate or severe bleeding compared to aspirin monotherapy. (PROSPERO ID: CRD42024499310).

Incidence, Predictors, and Prognostic Impact of Neurologic Events After TAVR According to VARC-3 Criteria.

BACKGROUND: The Valve Academic Research Consortium (VARC)-3 definition for neurologic events after transcatheter aortic valve replacement (TAVR) lacks clinical validation. OBJECTIVES: This study sought to determine the incidence, predictors, and clinical impact of neurologic events following TAVR as defined by VARC-3 criteria. METHODS: This was a multicenter study including 2,924 patients with severe aortic stenosis undergoing TAVR. Based on Neurologic Academic Research Consortium (NeuroARC) classification, neurologic events were classified as NeuroARC type 1 (stroke), NeuroARC type 2 (covert central nervous system injury), and NeuroARC type 3 (transient ischemic attack and delirium). Baseline, procedural, and follow-up data were prospectively collected in a dedicated database. RESULTS: After a median follow-up of 13 (7-37) months, neurologic events occurred in 471 patients (16.1%), NeuroARC type 1, 2, and 3 in 37.4%, 4.7%, and 58.0% of cases, respectively, and the majority (58.6%) were periprocedural. Advanced age, chronic kidney disease, atrial fibrillation, major vascular complications, and in-hospital bleeding determined an increased risk of periprocedural events (P < 0.03 for all). Neurologic events occurring during the periprocedural time frame were independently associated with a substantial increase in mortality at 1 year after the intervention (HR: 1.91; 95% CI: 1.23-2.97; P = 0.004). However, although NeuroARC type 1 was associated with an increased mortality risk (IRR: 3.38; 95% CI: 2.30-5.56; P < 0.001 and IRR: 21.7; 95% CI: 9.63-49.1; P < 0.001 for ischemic and hemorrhagic stroke, respectively), the occurrence of NeuroARC type 3 events had no impact on mortality. CONCLUSIONS: Neurologic events after TAVR were associated with poorer short- and long-term survival. This correlation was related to the type of NeuroARC event defined by the VARC-3 criteria. Given the negative impact on clinical outcomes, every attempt should be made to reduce the risk of neurologic complications after TAVR.

Monocyte Chemoattractant Protein-1, Inflammatory Biomarkers, and Prognosis of Patients With Ischemic Stroke or Transient Ischemic Attack: Fndings From a Nationwide Registry Study.

BACKGROUND: Recent Mendelian randomization and meta-analysis highlight the relevance of MCP-1 (monocyte chemoattractant protein-1) in stroke. We aimed to investigate the associations between MCP-1 and clinical outcomes in patients with ischemic stroke or transient ischemic attack and test whether inflammation mediates or jointly contributes to the relationships. METHODS AND RESULTS: A total of 10 700 patients from the Third China National Stroke Registry study were included. Multivariable Cox regression was used for recurrent stroke and all-cause death, and logistic regression was used for poor functional outcome. Mediation analyses were performed to clarify whether inflammation mediates the associations. After adjusting for potential confounders, low MCP-1 level (<337.6 pg/mL) was associated with a reduced risk of all-cause death (hazard ratio [HR], 0.65 [95% CI, 0.51-0.82]) and poor functional outcome (odds ratio, 0.81 [95% CI, 0.70-0.94]) but was not associated with recurrent stroke (HR, 1.10 [95% CI, 0.95-1.27]), compared with high MCP-1 level (≥337.6 pg/mL). The association between MCP-1 and all-cause death was partially mediated by highly sensitive C-reactive protein, interleukin-6, and YKL-40 (Chitinase-3-like protein 1; mediated proportion: 7.4%, 10.5%, and 7.4%, respectively). The corresponding mediated proportion for poor functional outcome was 9.9%, 17.1%, and 7.1%, respectively. Patients with combined high levels of MCP-1 and inflammatory biomarkers had the highest risks of all-cause death and poor functional outcome. CONCLUSIONS: Low plasma MCP-1 level was associated with decreased risks of all-cause mortality and poor functional outcome after ischemic stroke or transient ischemic attack. Inflammation partially mediated and jointly contributed to the associations.

Physical activity modification following a Transient Ischemic Attack in individuals with diabetes.

BACKGROUND: Individuals with diabetes exhibit a higher risk of cardiovascular disease and mortality compared to healthy individuals. Following a transient ischemic attack (TIA) the risk of stroke and death increase further. Physical activity engagement after a TIA is an effective way of secondary prevention. However, there's a lack of research on how individuals with diabetes modify physical activity levels and how these adjustments impact survival post-TIA. This study aimed to determine the extent to which individuals with diabetes alter their physical activity levels following a TIA and to assess the impact of these changes on mortality. METHODS: This was a nationwide longitudinal study, employing data from national registers in Sweden spanning from 01/01/2003 to 31/12/2019. Data were collected 2 years retro- and prospectively of TIA occurrence, in individuals with diabetes. Individuals were grouped based on decreasing, remaining, or increasing physical activity levels after the TIA. Cox proportional hazards models were fitted to evaluate the adjusted relationship between change in physical activity and all-cause, cardiovascular, and non-cardiovascular mortality. RESULTS: The final study sample consisted of 4.219 individuals (mean age 72.9 years, 59.4% males). Among them, 35.8% decreased, 37.5% kept steady, and 26.8% increased their physical activity after the TIA. A subsequent stroke occurred in 6.7%, 6.4%, and 6.1% of individuals, while death occurred in 6.3%, 7.3%, and 3.7% of individuals, respectively. In adjusted analyses, participants who increased their physical activity had a 45% lower risk for all-cause mortality and a 68% lower risk for cardiovascular mortality, compared to those who decreased their physical activity. CONCLUSIONS: Positive change in physical activity following a ΤΙΑ was associated with a reduced risk of mortality. Increased engagement in physical activity should be promoted after TIA, thereby actively supporting individuals with diabetes in achieving improved health outcomes.

Long-term risk factors of recurrent stroke, myocardial infarction and death in patients leaving hospital with a diagnosis of ischemic stroke or TIA.

Objectives. The prevalence of patients with prior stroke is increasing globally. Accordingly, there is a need for up-to-date evidence of patient-related prognostic factors for stroke recurrence, post stroke myocardial infarction (MI) and death based on long-term follow-up of stroke survivors. For this purpose, the RIALTO study was established in 2004. Design. A prospective cohort study in which patients diagnosed with ischemic stroke (IS) or transient ischemic attack (TIA) in three Copenhagen hospitals were included. Data were collected from medical records and by structured interview. Data on first stroke recurrence, first MI and all-cause death were extracted from the Danish National Patient Registry and the Danish Civil Registration System. Results. We included 1215 patients discharged after IS or TIA who were followed up by register data from April 2004 to end of 2018 giving a median follow-up of 3.5-6.9 years depending on the outcome. At the end of follow-up 406 (33%) patients had been admitted with a recurrent stroke, 100 (8%) had a MI and 822 (68%) had died. Long-term prognostic predictors included body mass index, diabetes, antihypertensive and lipid lowering treatment, smoking, a sedentary lifestyle as well as poor self-rated health and psychosocial problems. Conclusions. Long-term risk of recurrent stroke and MI remain high in patients discharged with IS or TIA despite substantial improvements in tertiary preventive care in recent decades. Continued attention to the patient risk profile among patients surviving the early phase of stroke, including comorbidities, lifestyle, and psychosocial challenges, is warranted.

Cervicocerebral Atherosclerosis Burden Increases Long-Term Mortality in Patients With Ischemic Stroke or Transient Ischemic Attack.

BACKGROUND: The influence of burden of atherosclerosis in the brain supplying arteries on mortality in patients with acute ischemic stroke or transient ischemic attack is poorly known. We assessed whether total burden of atherosclerosis within cervicocerebral arteries is associated with long-term mortality. METHODS AND RESULTS: A total of 406 patients (median age, 71.8 years; 57.9% male) with acute ischemic stroke or transient ischemic attack were included and their cervicocerebral arteries imaged with computed tomography angiography. The presence of atherosclerotic findings was scored for 25 artery segments and points were summed as a Cervicocerebral Atherosclerosis Burden (CAB) score, analyzed as quartiles. Data on all-cause mortality came from Statistics Finland. After a median follow-up of 7.3 years, 147 (33.5%) patients had died. Compared with surviving patients, those who died had a higher median CAB score (5, interquartile range 2-10 versus 11, 7-16; P<0.001). Cumulative mortality increased from 8.9% (95% CI, 7.0-10.8) in the lowest to 61.4% (95% CI, 55.4-67.4) in the highest quartile of CAB score. Adjusted for demographics, cardiovascular risk factors, secondary preventive medication, and admission National Institute of Health Stroke Scale score, every CAB score point increased probability of death by 3%. Analyzed in quartiles, the highest CAB quartile was associated with a 2.5-fold likelihood of all-cause mortality. CONCLUSIONS: The main findings of our study were the increasing mortality with the total burden of computed tomography angiography-defined atherosclerosis in the brain supplying arteries after ischemic stroke or transient ischemic attack and that the CAB score-integrating this pathology-independently increased all-cause mortality.

Complications of Carotid Interventions for Symptomatic Lesions after Systemic Thrombolysis.

BACKGROUND: Series detailing complications after carotid endarterectomy (CEA) and transfemoral carotid stenting (tfCAS) for patients presenting with neurologic symptoms that are treated with systemic thrombolysis (ST) are sparse. We sought to determine if treatment with ST was associated with a higher rate of post-carotid intervention complications. METHODS: A multispecialty, institutional, prospectively maintained database was queried for symptomatic patients treated with CEA or tfCAS from 2007 to 2019. The primary outcomes of interest were bleeding complications (access/wound complications, hematuria, intracranial hemorrhage) or need for reintervention, stroke, and death. We compared rates of these outcomes between patients who were and were not treated with ST. To adjust for preoperative patient factors and confounding variables, propensity scores for assignment to ST and non-ST were calculated. RESULTS: There were 1,139 patients included (949 [82%] CEA and 190 [17%] tfCAS. All treated lesions were symptomatic (550 [48%] stroke, 603 [52%] transient ischemic attack). Fifty-six patients (5%) were treated with ST. Fifteen of 56 patients also underwent catheter-based intervention for stroke. ST was administered 0 to 1 day preoperatively in 21 (38%) patients, 2 to 6 days preoperatively in 27 (48%) patients, and greater than 6 days preoperatively in 8 (14%) patients. ST patients were more likely to present with stroke (93% vs. 45%; P < 0.001) and have higher preoperative Rankin scores. Unadjusted rate of bleeding/return to operating room was 3% for ST group and 3% for non-ST group (P = 0.60). Unadjusted rate of stroke was 4% for ST group and 3% for the non-ST group (P = 0.91), while perioperative mortality was 5% for ST group and 1% for non-ST group (P = 0.009). After adjusting for patient factors, preoperative antiplatelet/anticoagulation, and operative factors, ST was not associated with an increased odds of perioperative bleeding/return to the operating room (odds ratio 0.37; 95% confidence interval: 0.02-1.63; P = 0.309) or stroke (odds ratio 0.62; 95% confidence interval: 0.16-2.40; P = 0.493). CONCLUSIONS: ST does not convey a higher risk of complications after CEA or tfCAS. After controlling for other factors, patients that received ST had similar rates of local complications and stroke when compared to non-ST patients. Early carotid intervention is safe in patients that have received ST, and delays should be avoided in symptomatic patients given the high risk of recurrent stroke.

A case management intervention in stroke care: Evaluation of a quasi-experimental study.

BACKGROUND: Patients with initial stroke or transient ischemic attack (TIA) are at high risk for further strokes, death or cardiovascular events. Even the first-ever stroke is associated with a high chance of disability and need for assistance. The risk of long-term health care demands increases with each subsequent event. Although the inpatient sector already provides a high standard of care in Germany, it can be difficult to obtain cross-sectoral aftercare. Thus, the study investigated whether a structured case management program can avoid stroke recurrences. METHODS: The study was conducted with a quasi-experimental study design in three regions in North Rhine-Westphalia. Patients with first-ever stroke or TIA were eligible to participate. The intervention group was prospectively recruited and supported by a case manager during a one-year follow-up. Optimal Full Matching was used to generate a control group based on statutory claims data. The primary outcome was the stroke recurrence. Recurrence and mortality were analysed by using Cox regression; other secondary outcomes were examined with test-based procedures and with logistic regressions. Additionally, subgroup analyses were performed. RESULTS: From June 2018 to March 2020, 1,512 patients were enrolled in the intervention group. Claims data from 19,104 patients have been transmitted for establishing the control group. After the matching process, 1,167 patients of each group were included in the analysis. 70 recurrences (6.0%) occurred in the intervention group and 67 recurrences (5.7%) in the control group. With a hazard ratio of 1.06 (95% CI: [1.42-0.69]; p=0.69), no significant effect was found for the primary outcome. With regard to the secondary outcome mortality, 36 patients in the intervention group and 46 in the control group died (3.1% vs. 3.9%). Again, there was no significant effect (HR: 0.86; 95% CI: [0.58-1.28], p=0.46). DISCUSSION: Based on the present findings, the case management approach for stroke patients evaluated here was unable to demonstrate an improvement in health care. Potential effects of case management might not be adequately depicted in short observation periods. Thus, future studies should consider longer observation periods. CONCLUSION: A panel of experts should discuss whether the core approach of case management to support cost-intensive individual cases is contrary to a broad implementation with a one-size-fits-all intervention for stroke patients. In this case, further research should focus on more specific study populations.

Efficacy and safety of oral factor Xa inhibitors versus vitamin-K antagonists in the early phase after acute ischemic stroke or TIA in the real-world setting: The PRODAST study.

INTRODUCTION: Factor Xa (FXa) inhibitors are superior to vitamin K antagonists (VKAs) in terms of avoiding hemorrhagic complications. However, no robust data are available to date as to whether this also applies to the early phase after stroke. In this prospective registry study, we aimed to investigate whether anticoagulation with FXa inhibitors in the early phase after acute ischemic stroke or transient ischemic attack (TIA) is associated with a lower risk of major bleeding events compared with VKAs. MATERIALS AND METHODS: The Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) study is a prospective, multicenter, observational, post-authorization safety study at 86 German stroke units between July 2015 and November 2020. Primary outcome was a major bleeding event during hospital stay. Secondary endpoints were recurrent strokes, recurrent ischemic strokes, TIA, systemic/pulmonary embolism, myocardial infarction, death and the composite endpoint of stroke, systemic embolism, life-threatening bleeding and death. RESULTS: In total, 10,039 patients have been recruited. 5,874 patients were treated with FXa inhibitors and 1,050 patients received VKAs and were eligible for this analysis. Overall, event rates were low. We observed 49 major bleeding complications during 33,297 treatment days with FXa-inhibitors (rate of 14.7 cases per 10,000 treatment days) and 16 cases during 7,714 treatment days with VKAs (rate of 20.7 events per 10,000 treatment days), translating into an adjusted hazard ratio (aHR) of 0.70 (95% confidence interval (95% CI): 0.37-1.32) in favor of FXa inhibitors. Hazards for ischemic endpoints (63 vs 17 strokes, aHR: 0.96 (95% CI: 0.53-1.74), mortality (33 vs 6 deaths, aHR: 0.87 (95% CI: 0.33-2.34)) and the combined endpoint (154 vs 39 events, aHR: 0.99 (95% CI: 0.65-1.41) were not substantially different. DISCUSSION AND CONCLUSION: This large real-world study shows that FXa inhibitors appear to be similarly effective in terms of bleeding events and ischemic endpoints compared to VKAs in the early post-stroke phase of hospitalization. However, the results need to be interpreted with caution due to the low precision of the estimates.

Prognostic value of serum albumin to creatinine ratio in patients undergoing carotid artery stenting.

BACKGROUND: We aimed to investigate the prognostic value of serum albumin-to-creatinine ratio (sACR) in carotid artery stenting (CAS) patients regarding in-hospital and 5-year outcomes. METHODS: This is a retrospective study. Baseline characteristics were compared between patients by admission albumin to creatinine ratio and categorized accordingly: T1, T2 and T3. 609 patients were included in the study. Serum albumin and creatinine levels at hospital admission were used to calculate the sACR. The primary endpoint was all-cause mortality. MACE consisted of stroke, transient ischemic attack (TIA), myocardial infarction (MI) and death. All follow-up data were obtained from electronic medical records or by interview. The study was terminated after 60 months of follow-up. RESULTS: Serum albumin levels were found to be significantly lower in T1, while creatinine was found to be significantly higher in T1. T1 has the lowest sACR while T3 has the highest. In hospital, ipsilateral stroke, major stroke, MI and death were significantly higher in T1. In long-term outcomes, ipsilateral stroke, major stroke, and death were significantly higher in T1. CONCLUSIONS: Low sACR values at hospital admission was independently associated with in-hospital and long-term mortality and major stroke in patients underwent CAS.

Stroke in the very old: A study from the Philippine Neurological Association One Database.

OBJECTIVE: The very old, although a minority in many populations, experience stroke with distinct risk factors and more complications. We sought to understand the profile, stroke subtypes, risk factors and outcomes among the very old compared to younger stroke patients in our population in the Philippine Neurological Association One Database-Stroke (PNA1DB-Stroke). METHODS: The PNA1DB-Stroke registry (clinicaltrial.gov NCT04972058) is a multi-centre, prospective database of all patients hospitalised for transient ischaemic attack or acute stroke in 11 neurology residency training institutions. RESULTS: Of the 6314 patients with stroke, 463 (7%) were 80 years or older, and among them, 320 (69%) were women. Traditional risk factors were more frequent in the very old compared to the younger group (hypertension 76% vs. 66%, diabetes mellitus 26% vs. 19%, previous stroke 14% vs. 10%, atrial fibrillation 13% vs. 3%; p ≤ .005), while current smoking (5%) and excess alcohol consumption (4%) were less common than in younger stroke patients (p < .001). Overall, in-hospital fatality was not remarkably increased in our very old compared to younger stroke patients, with comparable rates between cases of ischaemic stroke (18%) and intracerebral haemorrhage (20%). However, they had longer hospital stay (mean 13.4 ± 17.2 days vs. 10.9 ± 15.4 days, p = .001), had more medical complications (p < .001) and were more functionally dependent at discharge (p < .0001). CONCLUSIONS: Very old stroke patients have relatively more risk factors for stroke. In-hospital fatality rates are comparable between ischaemic and haemorrhagic strokes. Risk factor modification, prevention of medical complications and optimisation of functional recovery are potential strategies in managing stroke in the very old.

Effect of Stenting Plus Medical Therapy vs Medical Therapy Alone on Risk of Stroke and Death in Patients With Symptomatic Intracranial Stenosis: The CASSISS Randomized Clinical Trial.

Importance: Prior randomized trials have generally shown harm or no benefit of stenting added to medical therapy for patients with symptomatic severe intracranial atherosclerotic stenosis, but it remains uncertain as to whether refined patient selection and more experienced surgeons might result in improved outcomes. Objective: To compare stenting plus medical therapy vs medical therapy alone in patients with symptomatic severe intracranial atherosclerotic stenosis. Design, Setting, and Participants: Multicenter, open-label, randomized, outcome assessor-blinded trial conducted at 8 centers in China. A total of 380 patients with transient ischemic attack or nondisabling, nonperforator (defined as nonbrainstem or non-basal ganglia end artery) territory ischemic stroke attributed to severe intracranial stenosis (70%-99%) and beyond a duration of 3 weeks from the latest ischemic symptom onset were recruited between March 5, 2014, and November 10, 2016, and followed up for 3 years (final follow-up: November 10, 2019). Interventions: Medical therapy plus stenting (n = 176) or medical therapy alone (n = 182). Medical therapy included dual-antiplatelet therapy for 90 days (single antiplatelet therapy thereafter) and stroke risk factor control. Main Outcomes and Measures: The primary outcome was a composite of stroke or death within 30 days or stroke in the qualifying artery territory beyond 30 days through 1 year. There were 5 secondary outcomes, including stroke in the qualifying artery territory at 2 years and 3 years as well as mortality at 3 years. Results: Among 380 patients who were randomized, 358 were confirmed eligible (mean age, 56.3 years; 263 male [73.5%]) and 343 (95.8%) completed the trial. For the stenting plus medical therapy group vs medical therapy alone, no significant difference was found for the primary outcome of risk of stroke or death (8.0% [14/176] vs 7.2% [13/181]; difference, 0.4% [95% CI, -5.0% to 5.9%]; hazard ratio, 1.10 [95% CI, 0.52-2.35]; P = .82). Of the 5 prespecified secondary end points, none showed a significant difference including stroke in the qualifying artery territory at 2 years (9.9% [17/171] vs 9.0% [16/178]; difference, 0.7% [95% CI, -5.4% to 6.7%]; hazard ratio, 1.10 [95% CI, 0.56-2.16]; P = .80) and 3 years (11.3% [19/168] vs 11.2% [19/170]; difference, -0.2% [95% CI, -7.0% to 6.5%]; hazard ratio, 1.00 [95% CI, 0.53-1.90]; P > .99). Mortality at 3 years was 4.4% (7/160) in the stenting plus medical therapy group vs 1.3% (2/159) in the medical therapy alone group (difference, 3.2% [95% CI, -0.5% to 6.9%]; hazard ratio, 3.75 [95% CI, 0.77-18.13]; P = .08). Conclusions and Relevance: Among patients with transient ischemic attack or ischemic stroke due to symptomatic severe intracranial atherosclerotic stenosis, the addition of percutaneous transluminal angioplasty and stenting to medical therapy, compared with medical therapy alone, resulted in no significant difference in the risk of stroke or death within 30 days or stroke in the qualifying artery territory beyond 30 days through 1 year. The findings do not support the addition of percutaneous transluminal angioplasty and stenting to medical therapy for the treatment of patients with symptomatic severe intracranial atherosclerotic stenosis. Trial Registration: ClinicalTrials.gov Identifier: NCT01763320.

Comparison of Drug-Eluting Stent With Bare-Metal Stent in Patients With Symptomatic High-grade Intracranial Atherosclerotic Stenosis: A Randomized Clinical Trial.

Importance: In-stent restenosis (ISR) is the primary reason for stroke recurrence after intracranial stenting in patients who were treated with a standard bare-metal stent (BMS). Whether a drug-eluting stent (DES) could reduce the risk of ISR in intracranial atherosclerotic stenosis (ICAS) remains unclear. Objective: To investigate whether a DES can reduce the risk of ISR and stroke recurrence in patients with symptomatic high-grade ICAS. Design, Settings, and Participants: A prospective, multicenter, open-label randomized clinical trial with blinded outcome assessment was conducted from April 27, 2015, to November 16, 2018, at 16 medical centers in China with a high volume of intracranial stenting. Patients with symptomatic high-grade ICAS were enrolled, randomized, and followed up for 1 year. Intention-to-treat data analysis was performed from April 1 to May 22, 2021. Interventions: Patients were randomly assigned to receive DES (NOVA intracranial sirolimus-eluting stent system) or BMS (Apollo intracranial stent system) treatment in a 1:1 ratio. Main Outcomes and Measures: The primary efficacy end point was ISR within 1 year after the procedure, which was defined as stenosis that was greater than 50% of the luminal diameter within or immediately adjacent to (within 5 mm) the implanted stent. The primary safety end point was any stroke or death within 30 days after the procedure. Results: A total of 263 participants (194 men [73.8%]; median [IQR] age, 58 [52-65] years) were included in the analysis, with 132 participants randomly assigned to the DES group and 131 to the BMS group. The 1-year ISR rate was lower in the DES group than in the BMS group (10 [9.5%] vs 32 [30.2%]; odds ratio, 0.24; 95% CI, 0.11-0.52; P < .001). The DES group also had a significantly lower ischemic stroke recurrence rate from day 31 to 1 year (1 [0.8%] vs 9 [6.9%]; hazard ratio, 0.10; 95% CI, 0.01-0.80; P = .03). No significant difference in the rate of any stroke or death within 30 days was observed between the DES and BMS groups (10 [7.6%] vs 7 [5.3%]; odds ratio, 1.45; 95% CI, 0.54-3.94; P = .46). Conclusions and Relevance: This trial found that, compared with BMSs, DESs reduced the risks of ISR and ischemic stroke recurrence in patients with symptomatic high-grade ICAS. Further investigation into the safety and efficacy of DESs is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02578069.

Stroke Among Patients Hospitalized With COVID-19: Results From the American Heart Association COVID-19 Cardiovascular Disease Registry.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) may be associated with increased risk for ischemic stroke. We present prevalence and characteristics of strokes in patients with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection enrolled in the American Heart Association COVID-19 Cardiovascular Disease Registry. METHODS: In this quality improvement registry study, we examined demographic, baseline clinical characteristics, and in-hospital outcomes among hospitalized COVID-19 patients. The primary outcomes were ischemic stroke or transient ischemic attack (TIA) and in-hospital death. RESULTS: Among 21 073 patients with COVID-19 admitted at 107 hospitals between January 29, 2020, and November 23, 2020, 160 (0.75%) experienced acute ischemic stroke/TIA (55.3% of all acute strokes) and 129 (0.61%) had other types of stroke. Among nonischemic strokes, there were 44 (15.2%) intracerebral hemorrhages, 33 (11.4%) subarachnoid hemorrhages, 21 (7.3%) epidural/subdural hemorrhages, 2 (0.7%) cerebral venous sinus thromboses, and 24 (8.3%) strokes not otherwise classified. Asians and non-Hispanic Blacks were overrepresented among ischemic stroke/TIA patients compared with their overall representation in the registry, but adjusted odds of stroke did not vary by race. Median time from COVID-19 symptom onset to ischemic stroke was 11.5 days (interquartile range, 17.8); median National Institutes of Health Stroke Scale score was 11 (interquartile range, 17). COVID-19 patients with acute ischemic stroke/TIA had higher prevalence of hypertension, diabetes, and atrial fibrillation compared with those without stroke. Intensive care unit admission and mechanical ventilation were associated with higher odds of acute ischemic stroke/TIA, but older age was not a predictor. In adjusted models, acute ischemic stroke/TIA was not associated with in-hospital mortality. CONCLUSIONS: Ischemic stroke risk did not vary by race. In contrast to the association between older age and death from COVID-19, ischemic stroke risk was the highest among middle-aged adults after adjusting for comorbidities and illness severity, suggesting a potential mechanism for ischemic stroke in COVID-19 independent of age-related atherosclerotic pathways.

The impact of carotid lesion calcification on outcomes of carotid artery stenting.

OBJECTIVE: The impact of carotid artery lesion calcification on adverse events following carotid artery stenting is not well-studied. Few reports associated heavily calcified lesions with high risk of perioperative stroke following transfemoral carotid artery stenting (TFCAS). With the advent of transcarotid artery revascularization (TCAR), we aimed to compare the outcomes of these two procedures stratified by the degree of lesion calcification. METHODS: Our cohort was derived from the Vascular Quality Initiative database for carotid artery stenting. Patients with missing information on the degree of carotid artery calcification were excluded. Patients were stratified into two groups: >50% (heavy) calcification and ≤50% (no/mild) calcification. The Student t test and the χ2 test were used to compare patients' baseline characteristics and crude outcomes, as appropriate. Clinically relevant and statistically significantly variables on univariable analysis were added to a logistic regression model clustered by center identifier. RESULTS: A total of 11,342 patients were included. Patients with >50% calcification were older, had more comorbidities, and more contralateral occlusion. There were more patients with prior ipsilateral carotid endarterectomy in the ≤50% calcification group. In patients who underwent TCAR, there were no significant differences between those who had >50% vs ≤50% carotid calcification in the odds of in-hospital adverse outcomes. However, in patients with heavy calcification who underwent TFCAS, there was a 50% to 60% increase in the odds of stroke (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.04-2.5; P = .03), stroke/transient ischemic attack (TIA) (OR, 1.6; 95% CI, 1.1-2.3; P = .013), and stroke/death (OR, 1.5; 95% CI, 1.02-2.08; P = .039). Compared with TFCAS in patients with heavy calcification, TCAR was associated with a 40% to 90% reduction in the odds of contralateral stroke (OR, 0.13; 95% CI, 0.04-0.4; P = .001), contralateral stroke/TIA (OR, 0.3; 95% CI, 0.1-0.87; P = .024), any stroke/TIA (OR, 0.6; 95% CI, 0.38-0.91; P = .02), death (OR, 0.3; 95% CI, 0.13-0.72; P = .006), stroke/death (OR, 0.5; 95% CI, 0.32-0.8; P = .004), and stroke/death/myocardial infarction (OR, 0.58; 95% CI, 0.39-0.87; P = .008). There were no significant differences in the odds of stroke and myocardial infarction. CONCLUSIONS: In this retrospective analysis of patients undergoing TFCAS vs TCAR in the Vascular Quality Initiative database, TCAR demonstrated favorable outcomes compared with TFCAS among patients with calcification greater than 50% of the carotid circumference. Advance burden of carotid artery calcification was associated with worse outcomes in patients undergoing TFCAS but not TCAR. These results are consistent with previously demonstrated superiority of flow reversal compared with distal embolic protection devices. Further research is needed to assess long-term outcomes and confirm the durability of TCAR in heavily calcified lesions.

Comparison of Ticagrelor vs Clopidogrel in Addition to Aspirin in Patients With Minor Ischemic Stroke and Transient Ischemic Attack: A Network Meta-analysis.

Importance: Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is effective in preventing recurrent strokes after minor ischemic stroke or transient ischemic attack (TIA). However, there is emerging evidence for the use of ticagrelor and aspirin, and the 2 DAPT regimens have not been compared directly. Objective: To compare ticagrelor and aspirin with clopidogrel and aspirin in patients with acute minor ischemic stroke or TIA in the prevention of recurrent strokes or death. Data Sources: MEDLINE, Embase, and Cochrane from database inception until February 2021. Study Selection: Randomized clinical trials that enrolled adults with acute minor ischemic stroke or TIA and provided the mentioned interventions within 72 hours of symptom onset, with a minimum follow-up of 30 days. Data Extraction and Synthesis: PRISMA guidelines for network meta-analyses were followed. Two reviewers independently extracted data and appraised risk of bias. Fixed-effects models were fit using a bayesian approach to network meta-analysis. Between-group comparisons were estimated using hazard ratios (HRs) with 95% credible intervals (95% CrIs). Surface under the cumulative rank curve plots were produced. Main Outcomes and Measures: The primary outcome was a composite of recurrent stroke or death up to 90 days. Secondary outcomes include major bleeding, mortality, adverse events, and functional disability. A sensitivity analysis was performed at 30 days for the primary outcome. Results: A total of 4014 citations were screened; 5 randomized clinical trials were included. Data from 22 098 patients were analyzed, including 5517 in the clopidogrel and aspirin arm, 5859 in the ticagrelor and aspirin arm, and 10 722 in the aspirin arm. Both clopidogrel and aspirin (HR, 0.74; 95% CrI, 0.65-0.84) and ticagrelor and aspirin (HR, 0.79; 95% CrI, 0.68-0.91) were superior to aspirin in the prevention of recurrent stroke and death. There was no statistically significant difference between clopidogrel and aspirin compared with ticagrelor and aspirin (HR, 0.94; 95% CrI, 0.78-1.13). Both DAPT regimens had higher rates of major hemorrhage than aspirin alone. Clopidogrel and aspirin was associated with a decreased risk of functional disability compared with aspirin alone (HR, 0.82; 95% CrI, 0.74-0.91) and ticagrelor and aspirin (HR, 0.85; 95% CrI, 0.75-0.97). Conclusions and Relevance: DAPT combining aspirin with either ticagrelor or clopidogrel was superior to aspirin alone, but there was no statistically significant difference found between the 2 regimens for the primary outcome.

Hospital Readmissions and Mortality Among Fee-for-Service Medicare Patients With Minor Stroke or Transient Ischemic Attack: Findings From the COMPASS Cluster-Randomized Pragmatic Trial.

Background Mortality and hospital readmission rates may reflect the quality of acute and postacute stroke care. Our aim was to investigate if, compared with usual care (UC), the COMPASS-TC (Comprehensive Post-Acute Stroke Services Transitional Care) intervention (INV) resulted in lower all-cause and stroke-specific readmissions and mortality among patients with minor stroke and transient ischemic attack discharged from 40 diverse North Carolina hospitals from 2016 to 2018. Methods and Results Using Medicare fee-for-service claims linked with COMPASS cluster-randomized trial data, we performed intention-to-treat analyses for 30-day, 90-day, and 1-year unplanned all-cause and stroke-specific readmissions and all-cause mortality between INV and UC groups, with 90-day unplanned all-cause readmissions as the primary outcome. Effect estimates were determined via mixed logistic or Cox proportional hazards regression models adjusted for age, sex, race, stroke severity, stroke diagnosis, and documented history of stroke. The final analysis cohort included 1069 INV and 1193 UC patients (median age 74 years, 80% White, 52% women, 40% with transient ischemic attack) with median length of hospital stay of 2 days. The risk of unplanned all-cause readmission was similar between INV versus UC at 30 (9.9% versus 8.7%) and 90 days (19.9% versus 18.9%), respectively. No significant differences between randomization groups were seen in 1-year all-cause readmissions, stroke-specific readmissions, or mortality. Conclusions In this pragmatic trial of patients with complex minor stroke/transient ischemic attack, there was no difference in the risk of readmission or mortality with COMPASS-TC relative to UC. Our study could not conclusively determine the reason for the lack of effectiveness of the INV. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02588664.

Association Between Plasma Trimethyllysine and Prognosis of Patients With Ischemic Stroke.

Background Trimethyllysine, a trimethylamine N-oxide precursor, has been identified as an independent cardiovascular risk factor in acute coronary syndrome. However, limited data are available to examine the role of trimethyllysine in the population with stroke. We aimed to examine the relationship between plasma trimethyllysine levels and stroke outcomes in patients presenting with ischemic stroke or transient ischemic attack. Methods and Results Data of 10 027 patients with ischemic stroke/transient ischemic attack from the CNSR-III (Third China National Stroke Registry) and 1-year follow-up data for stroke outcomes were analyzed. Plasma levels of trimethyllysine were measured with mass spectrometry. The association between trimethyllysine and stroke outcomes was analyzed using Cox regression models. Mediation analysis was performed to examine the mediation effects of risk factors on the associations of trimethyllysine and stroke outcomes. Elevated trimethyllysine levels were associated with increased risk of cardiovascular death (quartile 4 versus quartile 1: adjusted hazard ratio [HR], 1.72; 95% CI, 1.03-2.86) and all-cause mortality (quartile 4 versus quartile 1: HR, 1.97; 95% CI, 1.40-2.78) in multivariate Cox regression model. However, no associations were found between trimethyllysine and nonfatal stroke recurrence or nonfatal myocardial infarction. Trimethyllysine was associated with cardiovascular death independent of trimethylamine N-oxide. Both estimated glomerular filtration rate and hs-CRP (high-sensitivity C-reactive protein) had significant mediation effects on the association of trimethyllysine with cardiovascular death, with a mediation effect of 37.8% and 13.4%, respectively. Conclusions Elevated trimethyllysine level is associated with cardiovascular death among patients with ischemic stroke/transient ischemic attack. Mediation analyses propose that trimethyllysine contributes to cardiovascular death through inflammation and renal function, suggesting a possible pathomechanistic link.

Variant rs6749447 (T > G) in the serine threonine kinase gene is associated with cardiovascular complications, the Tampere adult population cardiovascular risk study.

ABSTRACT: We have previously shown an association of STK39 (serine threonine kinase) rs6749447 (T > G) with hypertension in the Tampere adult population cardiovascular risk study in 50-year-old subjects. These 1196 subjects were followed up to the age of 65 years to determine whether rs6749447 is also associated with coronary artery disease (CAD), transient ischemic attack (TIA), or early cardiovascular death.DNA samples were collected by buccal swabs and genotypes were determined by PCR. Hypertension, TIA, and CAD were determined by questionnaire and the National Hospital Discharge Registry. Outcomes for death were collected from the National Statistics Centre. Linkage disequilibrium analysis and gene expression correlations for rs6749447 were done in silico.After following the subjects up to the age of 60 years the rs6749447 G-allele still associated with hypertension (P = .009). The variation did not associate with CAD (P = .959). The risk for TIA was 5.2-fold among G-allele carriers compared to TT genotype even after adjusting for body mass index (P = .036, 95% CI 1.11-24.59). After follow-up of the subjects to the age of 65 years, adjusting for body mass index, the G-allele was associated with 3.2-fold risk of premature cardiovascular death (P = .049, 95% CI 1.00-10.01).In conclusion, the STK39 genetic variant rs6749447 was significantly associated with TIA and premature cardiovascular death in a Finnish cohort. The in silico results of linkage disequilibrium and gene expression analyses also showed associations that were distinct from the retention of salt effect on kidneys proposed earlier for this intronic variation.