Sodium Glucose Transporter 2 Inhibitors Versus Metformin on Cardiovascular and Renal Outcomes in Patients With Diabetes With Low Cardiovascular Risk: A Nationwide Cohort Study.

BACKGROUND: This study investigated whether initial SGLT2 (sodium-glucose cotransporter 2) inhibitor-based treatment is superior to metformin-based regimens as a primary prevention strategy among low-risk patients with diabetes. METHODS AND RESULTS: In this nationwide cohort study, a total of 38 496 patients with diabetes with low cardiovascular risk were identified (age 62.0±11.6 years, men 50%) from January 1 to December 31, 2016. Patients receiving SGLT2 inhibitors-based and metformin-based regimens were 1:2 matched by propensity score. Study outcomes included all-cause mortality, cardiovascular death, hospitalization for heart failure, stroke, and progression to end-stage renal disease. Compared with 1928 patients receiving metformin-based regimens, 964 patients receiving SGLT2 inhibitor-based regimens had similar all-cause mortality (hazard ratio [HR], 0.75 [95% CI, 0.51-1.12]), cardiovascular death (HR, 0.69 [95% CI, 0.25-1.89]), hospitalization for heart failure (HR, 1.06 [95% CI, 0.59-1.92]), stroke (HR, 0.78 [95% CI, 0.48-1.27]), and progression to end-stage renal disease (HR, 0.88 [95% CI, 0.32-2.39]). However, SGLT2 inhibitors were associated with a lower risk of all-cause mortality (HR, 0.47 [95% CI, 0.23-0.99]; P for interaction=0.008) and progression to end-stage renal disease (HR, 0.22 [95% CI, 0.06-0.82]; P for interaction=0.04) in patients under the age of 65. CONCLUSIONS: In comparison to metformin-based regimens, SGLT2 inhibitor-based regimens showed a similar risk of all-cause mortality and adverse cardiorenal events. SGLT2 inhibitors might be considered as first-line therapy in select low-risk patients, for example, younger patients with diabetes.

Cost-Effectiveness of Increased Use of Dual Antiplatelet Therapy After High-Risk Transient Ischemic Attack or Minor Stroke.

BACKGROUND: Rates of dual antiplatelet therapy (DAPT) after high-risk transient ischemic attack or minor ischemic stroke (TIAMIS) are suboptimal. We performed a cost-effectiveness analysis to characterize the parameters of a quality improvement (QI) intervention designed to increase DAPT use after TIAMIS. METHODS AND RESULTS: We constructed a decision tree model that compared current national rates of DAPT use after TIAMIS with rates after implementing a theoretical QI intervention designed to increase appropriate DAPT use. The base case assumed that a QI intervention increased the rate of DAPT use to 65% from 45%. Costs (payer and societal) and outcomes (stroke, myocardial infarction, major bleed, or death) were modeled using a lifetime horizon. An incremental cost-effectiveness ratio <$100 000 per quality-adjusted life year was considered cost-effective. Deterministic and probabilistic sensitivity analyses were performed. From the payer perspective, a QI intervention was associated with $9657 in lifetime cost savings and 0.18 more quality-adjusted life years compared with current national treatment rates. A QI intervention was cost-effective in 73% of probabilistic sensitivity analysis iterations. Results were similar from the societal perspective. The maximum acceptable, initial, 1-time payer cost of a QI intervention was $28 032 per patient. A QI intervention that increased DAPT use to at least 51% was cost-effective in the base case. CONCLUSIONS: Increasing DAPT use after TIAMIS with a QI intervention is cost-effective over a wide range of costs and proportion of patients with TIAMIS treated with DAPT after implementation of a QI intervention. Our results support the development of future interventions focused on increasing DAPT use after TIAMIS.

Cardiomyopathy in Patients With Acute Ischemic Stroke and Methamphetamine Use: Relevance for Cardioembolic Stroke and Outcome.

BACKGROUND: Methamphetamine use has emerged as a major risk factor for cardiovascular and cerebrovascular disease in young adults. The aim of this study was to investigate a possible association of methamphetamine use with cardioembolic stroke. METHODS AND RESULTS: We performed a retrospective study of patients with acute ischemic stroke admitted at our medical center between 2019 and 2022. All patients were screened for methamphetamine use and cardiomyopathy, defined as left ventricular ejection fraction ≤45%. Among 938 consecutive patients, 46 (4.9%) were identified as using methamphetamine. Compared with the nonmethamphetamine group (n=892), the methamphetamine group was significantly younger (52.8±9.6 versus 69.7±15.2 years; P<0.001), included more men (78.3% versus 52.8%; P<0.001), and had a significantly higher rate of cardiomyopathy (30.4% versus 14.0%; P<0.01). They were also less likely to have a history of atrial fibrillation (8.7% versus 33.4%; P<0.01) or hyperlipidemia (28.3% versus 51.7%; P<0.01). Compared with patients with cardiomyopathy without methamphetamine use, the patients with cardiomyopathy with methamphetamine use had significantly lower left ventricular ejection fraction (26.0±9.59% versus 32.47±9.52%; P<0.01) but better functional outcome at 3 months, likely attributable to significantly younger age and fewer comorbidities. In the logistic regression model of clinical variables, methamphetamine-associated cardiomyopathy was found to be significantly associated with cardioembolic stroke (odds ratio, 1.79 [95% CI, 1.04-3.06]; P<0.05). CONCLUSIONS: We demonstrate that methamphetamine use is significantly associated with cardiomyopathy and cardioembolic stroke in young adults.

Thrombolysis for Wake-Up Stroke Versus Non-Wake-Up Unwitnessed Stroke: EOS Individual Patient Data Meta-Analysis.

BACKGROUND: Stroke with unknown time of onset can be categorized into 2 groups; wake-up stroke (WUS) and unwitnessed stroke with an onset time unavailable for reasons other than wake-up (non-wake-up unwitnessed stroke, non-WUS). We aimed to assess potential differences in the efficacy and safety of intravenous thrombolysis (IVT) between these subgroups. METHODS: Patients with an unknown-onset stroke were evaluated using individual patient-level data of 2 randomized controlled trials (WAKE-UP [Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke], THAWS [Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes With Alteplase at 0.6 mg/kg]) comparing IVT with placebo or standard treatment from the EOS (Evaluation of Unknown-Onset Stroke Thrombolysis trial) data set. A favorable outcome was prespecified as a modified Rankin Scale score of 0 to 1 at 90 days. Safety outcomes included symptomatic intracranial hemorrhage at 22 to 36 hours and 90-day mortality. The IVT effect was compared between the treatment groups in the WUS and non-WUS with multivariable logistic regression analysis. RESULTS: Six hundred thirty-four patients from 2 trials were analyzed; 542 had WUS (191 women, 272 receiving alteplase), and 92 had non-WUS (42 women, 43 receiving alteplase). Overall, no significant interaction was noted between the mode of onset and treatment effect (P value for interaction=0.796). In patients with WUS, the frequencies of favorable outcomes were 54.8% and 45.5% in the IVT and control groups, respectively (adjusted odds ratio, 1.47 [95% CI, 1.01-2.16]). Death occurred in 4.0% and 1.9%, respectively (P=0.162), and symptomatic intracranial hemorrhage in 1.8% and 0.3%, respectively (P=0.194). In patients with non-WUS, no significant difference was observed in favorable outcomes relative to the control (37.2% versus 29.2%; adjusted odds ratio, 1.76 [0.58-5.37]). One death and one symptomatic intracranial hemorrhage were reported in the IVT group, but none in the control. CONCLUSIONS: There was no difference in the effect of IVT between patients with WUS and non-WUS. IVT showed a significant benefit in patients with WUS, while there was insufficient statistical power to detect a substantial benefit in the non-WUS subgroup. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: CRD42020166903.

Efficacy, safety, and cost-effectiveness analysis of Cerebrolysin in acute ischemic stroke: A rapid health technology assessment.

This study conducts a rapid health technology assessment to systematically evaluate the effectiveness, safety, and cost-effectiveness of Cerebrolysin as an adjunctive therapy for acute ischemic stroke to provide evidence-based medicine for clinical decisions of Cerebrolysin. All systematic reviews/meta-analyses, pharmacoeconomic studies, and health technology assessment reports of Cerebrolysin for the treatment of acute ischemic stroke before August 17, 2023, were retrieved from PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Wanfang, Weipu, Sinomed database and the official website of health technology assessment. According to the inclusion and exclusion criteria, 2 researchers independently carried out screening, data extraction, and quality evaluation and descriptively analyzed the results of the included studies. A total of 14 pieces of literature were incorporated, comprising 8 systematic reviews/meta-analyses and 6 pharmacoeconomic studies. In terms of effectiveness, compared to control groups, the use of Cerebrolysin as a treatment for acute ischemic stroke demonstrates certain advantages, including enhancement in total efficacy rate, neurological function, upper limb motor dysfunction, and facilitation of the recovery of activities of daily living. Especially in patients with moderate to severe acute ischemic stroke, Cerebrolysin has demonstrated the ability to enhance neurological function recovery and ameliorate disabilities. Regarding safety, adverse reactions were mild or comparable to those in the control group. The primary findings of economic studies reveal that advocating for the use of Cerebrolysin offers certain cost-effectiveness advantages. Cerebrolysin contributes to improved clinical efficacy and evaluation indexes while demonstrating favorable safety and economic benefits.

Optimizing warfarin dosing for patients with atrial fibrillation using machine learning.

While novel oral anticoagulants are increasingly used to reduce risk of stroke in patients with atrial fibrillation, vitamin K antagonists such as warfarin continue to be used extensively for stroke prevention across the world. While effective in reducing the risk of strokes, the complex pharmacodynamics of warfarin make it difficult to use clinically, with many patients experiencing under- and/or over- anticoagulation. In this study we employed a novel implementation of deep reinforcement learning to provide clinical decision support to optimize time in therapeutic International Normalized Ratio (INR) range. We used a novel semi-Markov decision process formulation of the Batch-Constrained deep Q-learning algorithm to develop a reinforcement learning model to dynamically recommend optimal warfarin dosing to achieve INR of 2.0-3.0 for patients with atrial fibrillation. The model was developed using data from 22,502 patients in the warfarin treated groups of the pivotal randomized clinical trials of edoxaban (ENGAGE AF-TIMI 48), apixaban (ARISTOTLE) and rivaroxaban (ROCKET AF). The model was externally validated on data from 5730 warfarin-treated patients in a fourth trial of dabigatran (RE-LY) using multilevel regression models to estimate the relationship between center-level algorithm consistent dosing, time in therapeutic INR range (TTR), and a composite clinical outcome of stroke, systemic embolism or major hemorrhage. External validation showed a positive association between center-level algorithm-consistent dosing and TTR (R2 = 0.56). Each 10% increase in algorithm-consistent dosing at the center level independently predicted a 6.78% improvement in TTR (95% CI 6.29, 7.28; p < 0.001) and a 11% decrease in the composite clinical outcome (HR 0.89; 95% CI 0.81, 1.00; p = 0.015). These results were comparable to those of a rules-based clinical algorithm used for benchmarking, for which each 10% increase in algorithm-consistent dosing independently predicted a 6.10% increase in TTR (95% CI 5.67, 6.54, p < 0.001) and a 10% decrease in the composite outcome (HR 0.90; 95% CI 0.83, 0.98, p = 0.018). Our findings suggest that a deep reinforcement learning algorithm can optimize time in therapeutic range for patients taking warfarin. A digital clinical decision support system to promote algorithm-consistent warfarin dosing could optimize time in therapeutic range and improve clinical outcomes in atrial fibrillation globally.

Can the combination of antiplatelet or alteplase thrombolytic therapy with argatroban benefit patients suffering from acute stroke? a systematic review, meta-analysis, and meta-regression.

BACKGROUND: The effectiveness of administering argatroban as a treatment approach following antiplatelet therapy or alteplase thrombolytic therapy in patients with acute stroke is presently uncertain. However, it is important to highlight the potential benefits of combining this medication with known thrombolytics or antiplatelet therapy. One notable advantage of argatroban is its short half-life, which helps minimize excessive anticoagulation and risk of bleeding complications in inadvertent cases of hemorrhagic stroke. By conducting a meticulous review and meta-analysis, we aim to further explore the common use of argatroban and examine the plausible advantages of combining this medication with established thrombolytic and antiplatelet therapies. METHOD: In this study, we performed a rigorous and methodical search for both randomized controlled trials and retrospective analyses. Our main objective was to analyze the impact of argatroban on the occurrence of hemorrhagic events and the mRS scores of 0-2. We utilized a meta-analysis to assess the relative risk (RR) associated with using argatroban versus not using it. RESULTS: In this study, we analyzed data from 11 different studies, encompassing a total of 8,635 patients. Out of these patients, 3999(46.3%) received argatroban treatment while the remaining 4636(53.7%)did not. The primary outcome of 90-day functional independence (modified Rankin scale (mRS) score≤2) showed that the risk ratio (RR) for patients using argatroban after alteplase thrombolytic therapy compared to those not using argatroban was(RR, 1.00 ([95% CI, 0.92-1.09]; P = 0.97), indicating no statistical significance. However, for patients using argatroban after antiplatelet therapy, was (RR,1.09 [95% CI, 1.04-1.14]; P = 0.0001), which was statistically significant. In terms of hemorrhagic events, the RR for patients using argatroban compared to those not using argatroban was (RR,1.08 [95% CI, 0.88-1.33]; P = 0.46), indicating no statistical significance. CONCLUSION: The results of this study suggest that further research into combination therapy with argatroban and antiplatelet agents may be warranted, however more rigorous RCTs are needed to definitively evaluate the effects of combination treatment.

When anticoagulation management in atrial fibrillation becomes difficult: Focus on chronic kidney disease, coagulation disorders, and cancer.

Anticoagulation therapy (AT) is fundamental in atrial fibrillation (AF) treatment but poses challenges in implementation, especially in AF populations with elevated thromboembolic and bleeding risks. Current guidelines emphasize the need to estimate and balance thrombosis and bleeding risks for all potential candidates of antithrombotic therapy. However, administering oral AT raises concerns in specific populations, such as those with chronic kidney disease (CKD), coagulation disorders, and cancer due to lack of robust data. These groups, excluded from large direct oral anticoagulants trials, rely on observational studies, prompting physicians to adopt individualized management strategies based on case-specific evaluations. The scarcity of evidence and specific guidelines underline the need for a tailored approach, emphasizing regular reassessment of risk factors and anticoagulation drug doses. This narrative review aims to summarize evidence and recommendations for challenging AF clinical scenarios, particularly in the long-term management of AT for patients with CKD, coagulation disorders, and cancer.

Radon Exposure, Clonal Hematopoiesis, and Stroke Susceptibility in the Women's Health Initiative.

BACKGROUND AND OBJECTIVES: Studies suggest that clonal hematopoiesis of indeterminate potential (CHIP) may increase risk of hematologic malignancy and cardiovascular disease, including stroke. However, few studies have investigated plausible environmental risk factors for CHIP such as radon, despite the climate-related increases in and documented infrequency of testing for this common indoor air pollutant.The purpose of this study was to estimate the risk of CHIP related to radon, an established environmental mutagen. METHODS: We linked geocoded addresses of 10,799 Women's Health Initiative Trans-Omics for Precision Medicine (WHI TOPMed) participants to US Environmental Protection Agency-predicted, county-level, indoor average screening radon concentrations, categorized as follows: Zone 1 (>4 pCi/L), Zone 2 (2-4 pCi/L), and Zone 3 (<2 pCi/L). We defined CHIP as the presence of one or more leukemogenic driver mutations with variant allele frequency >0.02. We identified prevalent and incident ischemic and hemorrhagic strokes; subtyped ischemic stroke using Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria; and then estimated radon-related risk of CHIP as an odds ratio (OR) and 95% CI using multivariable-adjusted, design-weighted logistic regression stratified by age, race/ethnicity, smoking status, and stroke type/subtype. RESULTS: The percentages of participants with CHIP in Zones 1, 2, and 3 were 9.0%, 8.4%, and 7.7%, respectively (ptrend = 0.06). Among participants with ischemic stroke, Zones 2 and 1 were associated with higher estimated risks of CHIP relative to Zone 3: 1.39 (1.15-1.68) and 1.46 (1.15-1.87), but not among participants with hemorrhagic stroke: 0.98 (0.68-1.40) and 1.03 (0.70-1.52), or without stroke: 1.04 (0.74-1.46) and 0.95 (0.63-1.42), respectively (pinteraction = 0.03). Corresponding estimates were particularly high among TOAST-subtyped cardioembolism: 1.78 (1.30-2.47) and 1.88 (1.31-2.72), or other ischemic etiologies: 1.37 (1.06-1.78) and 1.50 (1.11-2.04), but not small vessel occlusion: 1.05 (0.74-1.49) and 1.00 (0.68-1.47), respectively (pinteraction = 0.10). Observed patterns of association among strata were insensitive to attrition weighting, ancestry adjustment, prevalent stroke exclusion, separate analysis of DNMT3A driver mutations, and substitution with 3 alternative estimates of radon exposure. DISCUSSION: The robust elevation of radon-related risk of CHIP among postmenopausal women who develop incident cardioembolic stroke is consistent with a potential role of somatic genomic mutation in this societally burdensome form of cerebrovascular disease, although the mechanism has yet to be confirmed.

Hypoglycemia and Cardiovascular Outcomes in the CARMELINA and CAROLINA Trials of Linagliptin: A Secondary Analysis of Randomized Clinical Trials.

Importance: Previous studies have reported an association between hypoglycemia and cardiovascular (CV) events in people with type 2 diabetes (T2D), but it is unclear if this association is causal or identifies a high-risk patient phenotype. Objective: To evaluate the associations between hypoglycemia and CV outcomes. Design, Setting, and Participants: This secondary analysis was a post hoc assessment of the multinational, double-blind CARMELINA (Cardiovascular and Renal Microvascular Outcome Study With Linagliptin; 2013-2016) and CAROLINA (Cardiovascular Outcome Trial of Linagliptin vs Glimepiride in Type 2 Diabetes; 2010-2018) randomized clinical trials of the antihyperglycemic drug, linagliptin, a dipeptidyl peptidase 4 inhibitor. Participants were adults with T2D at high CV risk with or without high kidney risk. By design, participants in the CARMELINA trial had longer duration of T2D and had a higher CV risk than participants in the CAROLINA trial. Data analyses were conducted between June 2021 and June 2023. Intervention: Linagliptin or placebo in the CARMELINA trial, and linagliptin or glimepiride in the CAROLINA trial. Main Outcomes and Measures: The primary outcome for both trials was CV death, myocardial infarction (MI), or stroke (3-point major adverse CV events [3P-MACE]). For the present analyses, hospitalization for heart failure (HF) was added. Hypoglycemia was defined as plasma glucose less than 54 mg/dL or severe hypoglycemia (episodes requiring the assistance of another person). Associations between the first hypoglycemic episode and subsequent CV events and between nonfatal CV events (MI, stroke, hospitalization for HF) and subsequent hypoglycemic episodes were assessed using multivariable Cox proportional hazards regression models. Sensitivity analyses explored the risk of CV events within 60 days after each hypoglycemic episode. Results: In the CARMELINA trial (6979 patients; 4390 males [62.9%]; mean [SD] age, 65.9 [9.1] years), there was an association between hypoglycemia and subsequent 3P-MACE plus hospitalization for HF (hazard ratio [HR], 1.23; 95% CI, 1.04-1.46) as well as between nonfatal CV events and subsequent hypoglycemia (HR, 1.39; 95% CI, 1.06-1.83). In the CAROLINA trial (6033 patients; 3619 males (60.0%); mean [SD] age, 64.0 [9.5] years), there was no association between hypoglycemia and subsequent 3P-MACE plus hospitalization for HF (HR, 1.00; 95% CI, 0.76-1.32) and between nonfatal CV events and subsequent hypoglycemia (HR, 1.44; 95% CI, 0.96-2.16). In analyses of CV events occurring within 60 days after hypoglycemia, there was either no association or too few events to analyze. Conclusions and Relevance: This study found bidirectional associations between hypoglycemia and CV outcomes in the CARMELINA trial but no associations in either direction in the CAROLINA trial, challenging the notion that hypoglycemia causes adverse CV events. The findings from the CARMELINA trial suggest that both hypoglycemia and CV events more likely identify patients at high risk for both. Trial Registration: ClinicalTrials.gov Identifier: NCT01897532 (CARMELINA) and NCT01243424 (CAROLINA).

Quality of Life After Intravenous Thrombolysis for Acute Ischemic Stroke: Results From the AcT Randomized Controlled Trial.

BACKGROUND: Recent evidence from thrombolysis trials indicates the noninferiority of intravenous tenecteplase to intravenous alteplase with respect to good functional outcomes in patients with acute stroke. We examined whether the health-related quality of life (HRQOL) of patients with acute stroke differs by the type of thrombolysis treatment received. In addition, we examined the association between the modified Rankin Scale score 0 to 1 and HRQOL and patient-reported return to prebaseline stroke functioning at 90 days. METHODS: Data were from all patients included in the AcT trial (Alteplase Compared to Tenecteplase), a pragmatic, registry-linked randomized trial comparing tenecteplase with alteplase. HRQOL at 90-day post-randomization was assessed using the 5-item EuroQOL questionnaire (EQ5D), which consists of 5 items and a visual analog scale (VAS). EQ5D index values were estimated from the EQ5D items using the time tradeoff approach based on Canadian norms. Tobit regression and quantile regression models were used to evaluate the adjusted effect of tenecteplase versus alteplase treatment on the EQ5D index values and VAS score, respectively. The association between return to prebaseline stroke functioning and the modified Rankin Scale score 0 to 1 and HRQOL was quantified using correlation coefficient (r) with 95% CI. RESULTS: Of 1577 included in the intention-to-treat analysis patients, 1503 (95.3%) had complete data on the EQ5D. Of this, 769 (51.2%) were administered tenecteplase and 717 (47.7%) were female. The mean EQ5D VAS score and EQ5D index values were not significantly higher for those who received intravenous tenecteplase compared with those who received intravenous alteplase (P=0.10). Older age (P<0.01), more severe stroke assessed using the National Institutes of Health Stroke Scale (P<0.01), and longer stroke onset-to-needle time (P=0.004) were associated with lower EQ5D index and VAS scores. There was a strong association (r, 0.85 [95% CI, 0.81-0.89]) between patient-reported return to prebaseline functioning and modified Rankin Scale score 0 to 1 Similarly, there was a moderate association between return to prebaseline functioning and EQ5D index (r, 0.45 [95% CI, 0.40-0.49]) and EQ5D VAS scores (r, 0.42 [95% CI, 0.37-0.46]). CONCLUSIONS: Although there is no differential effect of thrombolysis type on patient-reported global HRQOL and EQ 5D-5L index values in patients with acute stroke, sex- and age-related differences in HRQOL were noted in this study. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

Incidence and outcomes of high bleeding risk patients with type 1 and type 2 myocardial infarction in a community-based cohort: Application of the Academic Research Consortium High Bleeding Risk Criteria.

BACKGROUND AND AIMS: The incidence and outcomes of high bleeding risk (HBR) patients in a community cohort according to the Academic Research Consortium (ARC) criteria is not known. We hypothesized that HBR is common and associated with worse outcomes for all-comers with myocardial infarction. METHODS: We prospectively collected all patients with cardiac troponin T > 99th percentile upper limit of normal (≥0.01 ng/mL) in Olmsted County between 2003 and 2012. Events were retrospectively classified as type 1 myocardial infarction (T1MI), type 2 myocardial infarction (T2MI), or myocardial injury. Patients were further classified as HBR based on the "ARC-HBR definition." Outcomes included all-cause mortality, cardiovascular mortality, recurrent MI, stroke, and major bleeding. RESULTS: 2419 patients were included in the final study; 1365 were classified as T1MI and 1054 as T2MI. Patients were followed for a median of 5.5 years. ARC-HBR was more common in T2MI than T1MI (73% vs 46%, p < 0.001). Among patients with T1MI, HBR was associated with higher all-cause mortality (HR 3.7, 95% CI 3.2-4.5, p < 0.001), cardiovascular mortality (4.7, 3.6-6.3, p < 0.001), recurrent MI (2.1, 1.6-2.7, p < 0.001), stroke (4.9, 2.9-8.4, p < 0.001), and major bleeding (6.5, 3.7-11.4, p < 0.001). For T2MI, HBR was similarly associated with higher all-cause mortality (HR 2.1, 95% CI 1.8-2.5, p < 0.001), cardiovascular mortality (2.7, 1.8-4.0, p < 0.001), recurrent MI (1.7, 1.1-2.6, p = 0.02) and major bleeding (HR 15.6, 3.8-63.8, p < 0.001). CONCLUSION: HBR is common among unselected patients with T1MI and T2MI and is associated with increased overall and cardiovascular mortality, recurrent cardiovascular events, and major bleeding on long-term follow up.

Rises in Hematocrit Are Associated With an Increased Risk of Major Adverse Cardiovascular Events in Men Starting Testosterone Therapy: A Retrospective Cohort Claims Database Analysis.

PURPOSE: Elevated hematocrit (Hct) can result in increased risk of major adverse cardiovascular events (MACE) in men receiving testosterone therapy (TTh). However, the impact of the magnitude of the change in Hct from baseline after starting TTh has never been assessed. MATERIALS AND METHODS: To assess whether an increase in Hct after initiating TTh is associated with an increased risk of MACE within 3 and 24 months of initiating TTh, we queried the TriNetX Research network database for men over the age of 18 with Hct values obtained within 6 months before starting TTh, and who had follow-up Hct measurements within 3 and 24 months after beginning TTh from 2010 to 2021. Men with and without a subsequent increase in Hct after initiating TTh were propensity matched. MACE was defined as myocardial infarction, stroke, or death. RESULTS: After matching, 10,511 men who experienced an any increase in Hct after initiating TTh and an equal number of controls who did have an increase in Hct were included. Compared to controls who did not have an increase in Hct after starting TTh, the men who had an increase in subsequent Hct had a significantly increased risk of MACE compared to men with no change in Hct. CONCLUSIONS: We demonstrate that increases in Hct from baseline are associated with increased risk of MACE, compared to men whose Hct remains stable while receiving TTh.

Comparative safety of tenecteplase vs alteplase for acute ischemic stroke.

INTRODUCTION: Tenecteplase has been compared to alteplase in acute stroke randomized trials, with similar outcomes and safety measures, but higher doses of tenecteplase have been associated with higher hemorrhage rates in some studies. Limited data are available on the safety of tenecteplase outside of clinical trials. METHODS: We examined the safety measures of intracranial hemorrhage, angioedema, and serious extracranial adverse events in a 21-hospital integrated healthcare system that switched from alteplase (0.9 mg/kg, maximum dose 90 mg) to tenecteplase (0.25 mg/kg, maximum dose 25 mg) for acute ischemic stroke. RESULTS: Among 3,689 subjects, no significant differences were seen between tenecteplase and alteplase in the rate of intracranial hemorrhage (ICH), parenchymal hemorrhage, or volume of parenchymal hemorrhage. Symptomatic hemorrhage (sICH) was not different between the two agents: sICH by NINDS criteria was 2.0 % for alteplase vs 2.3 % for tenecteplase (P = 0.57), and sICH by SITS criteria was 0.8 % vs 1.1 % (P = 0.39). Adjusted logistic regression models also showed no differences between tenecteplase and alteplase: the odds ratio for tenecteplase (vs alteplase) modeling sICH by NINDS criteria was 0.9 (95 % CI 0.33 - 2.46, P = 0.83) and the odds ratio for tenecteplase modeling sICH by SITS criteria was 1.12 (95 % CI 0.25 - 5.07, P = 0.89). Rates of angioedema and serious extracranial adverse events were low and did not differ between tenecteplase and alteplase. Elapsed door-to-needle times showed a small improvement after the switch to tenecteplase (51.8 % treated in under 30 min with tenecteplase vs 43.5 % with alteplase, P < 0.001). CONCLUSION: In use outside of clinical trials, complication rates are similar between tenecteplase and alteplase. In the context of a stroke telemedicine program, the rates of hemorrhage observed with either agent were lower than expected based on prior trials and registry data. The more easily prepared tenecteplase was associated with a lower door-to-needle time.

Fine Particulate Matter Exposure, Genetic Susceptibility, and the Risk of Incident Stroke: A Prospective Cohort Study.

BACKGROUND: Both genetic factors and environmental air pollution contribute to the risk of stroke. However, it is unknown whether the association between air pollution and stroke risk is influenced by the genetic susceptibilities of stroke and its risk factors. METHODS: This prospective cohort study included 40 827 Chinese adults without stroke history. Satellite-based monthly fine particulate matter (PM2.5) estimation at 1-km resolution was used for exposure assessment. Based on 534 identified genetic variants from genome-wide association studies in East Asians, we constructed 6 polygenic risk scores for stroke and its risk factors, including atrial fibrillation, blood pressure, type 2 diabetes, body mass index, and triglyceride. The Cox proportional hazards model was applied to evaluate the hazard ratios and 95% CIs for the associations of PM2.5 and polygenic risk score with incident stroke and the potential effect modifications. RESULTS: Over a median follow-up of 12.06 years, 3147 incident stroke cases were documented. Compared with the lowest quartile of PM2.5 exposure, the hazard ratio (95% CI) for stroke in the highest quartile group was 2.72 (2.42-3.06). Among individuals at high genetic risk, the relative risk of stroke was 57% (1.57; 1.40-1.76) higher than those at low genetic risk. Although no statistically significant interaction was found, participants with both the highest PM2.5 and high genetic risk showed the highest risk of stroke, with ≈4× that of the lowest PM2.5 and low genetic risk group (hazard ratio, 3.55 [95% CI, 2.84-4.44]). Similar upward gradients were observed in the risk of stroke when assessing the joint effects of PM2.5 and genetic risks of blood pressure, type 2 diabetes, body mass index, atrial fibrillation, and triglyceride. CONCLUSIONS: Long-term exposure to PM2.5 was associated with a higher risk of incident stroke across different genetic susceptibilities. Our findings highlighted the great importance of comprehensive assessment of air pollution and genetic risk in the prevention of stroke.

Persistent brain exposure to high sodium induces stroke onset by upregulation of cerebral microbleeds and oxidative stress in hypertensive rats.

High salt intake induces hypertension and enhances stroke onset. However, whether an increase in brain sodium exposure itself is harmful and has poor prognosis remains unknown. Therefore, we employed hypertensive rats that underwent intracerebroventricular (ICV) infusion of sodium for 28 days and evaluated stroke onset and related cytotoxic brain injuries. Forty-seven spontaneously hypertensive stroke-prone (SHRSP) and 39 normotensive rats (Wistar Kyoto rats [WKY]) underwent persistent ICV infusion of the following four solutions: artificial cerebrospinal fluid, 0.9%, 2.7%, and 9% saline for 28 days. We evaluated stroke onset and all-cause mortality between SHRSP and WKY at each ICV sodium concentration as the primary endpoints. Our secondary objective was to explore histological brain injuries associated with SHRSP induced by high sodium ICV. The results indicated that ICV infusion of 2.7% and 9% sodium showed a significant increase in stroke onset, decrease in body weight, and increase rate of brain water content in SHRSP compared to WKY. Increased blood pressure was not observed for ICV infusion of high sodium, while serum sodium concentration was significantly increased in SHRSP compared to WKY. Histological evaluations revealed that higher sodium infusion significantly increased the number of activated microglia, superoxide, neuronal cell loss, and microbleeds compared to WKY and SHRSP with 0.9% sodium. We conclude that persistent exposure to high sodium in the brain is one of the risk factors for stroke onset upregulating cerebral microbleeds and oxidative stress in hypertensive rats.