Direct oral anticoagulant concentrations and adherence in stroke patients.

No therapeutic ranges linking drug concentrations of apixaban and rivaroxaban to clinical outcomes have been defined. We investigated whether direct oral anticoagulant (DOAC) concentrations among patients admitted to hospital with symptoms of stroke differed between those later verified to suffer an ischaemic cerebrovascular event (stroke or transient ischaemic attack) and those having other diagnoses (control group). Serum concentrations in 102 patients on DOAC for atrial fibrillation (84%) and thromboembolic disease (16%) were measured within 24 h of the acute event, employing ultra-high performance liquid chromatography with tandem mass spectrometry. We converted all concentrations to standardized trough levels. DOAC concentrations were lower in the 64 patients with verified ischaemic cerebrovascular event than in the 30 controls, 255 ± 155 versus 329 ± 144 nmol/L (p = 0.029), despite no statistically significant difference in self-reported adherence and daily dosages. Calculated concentrations were 5.4-596 nmol/L (median = 229 nmol/L) in the ischaemic stroke group and 41-602 nmol/L (median = 316 nmol/L) in controls. CHA2 DS2 -VASc score was significantly higher in the ischaemic stroke group than in controls (4.9 ± 1.6 versus 4.1 ± 1.7; p = 0.007). These results may suggest that patients with high cerebrovascular risk might benefit from higher DOAC levels than those with a lower risk.

Use of lipid-lowering therapy after ischaemic stroke and expected benefit from intensification of treatment.

OBJECTIVES: Elevated low-density lipoprotein cholesterol (LDL-C) increases the risk of recurrent cardiovascular disease (CVD) events. We examined use of lipid-lowering therapy (LLT) following ischaemic stroke, and estimated benefits from guideline-based up-titration of LLT. METHODS: The Norwegian COgnitive Impairment After STroke (Nor-COAST) study, a multicentre prospective cohort study, collected data on LLT use, dose intensity and LDL-C levels for 462 home-dwelling patients with ischaemic stroke. We used the Secondary Manifestations of Arterial Disease-Reduction of Atherothrombosis for Continued Health (SMART-REACH) model to estimate the expected benefit of up-titrating LLT. RESULTS: At discharge, 92% received LLT (97% statin monotherapy). Patients with prestroke dementia and cardioembolic stroke aetiology were less likely to receive LLT. Older patients (coefficient -3 mg atorvastatin per 10 years, 95% CI -6 to -0.5) and women (coefficient -5.1 mg atorvastatin, 95% CI -9.2 to -0.9) received lower doses, while individuals with higher baseline LDL-C, ischaemic heart disease and large artery stroke aetiology received higher dose intensity. At 3 months, 45% reached LDL-C ≤1.8 mmol/L, and we estimated that 81% could potentially reach the target with statin and ezetimibe, resulting in median 5 (IQR 0-12) months of CVD-free life gain and median 2% 10-year absolute risk reduction (IQR 0-4) with large interindividual variation. CONCLUSION: Potential for optimisation of conventional LLT use exists in patients with ischaemic stroke. Awareness of groups at risk of undertreatment and objective estimates of the individual patient's benefit of intensification can help personalise treatment decisions and reduce residual cholesterol risk. TRIAL REGISTRATION NUMBER: NCT02650531.

Estimation of recurrent atherosclerotic cardiovascular event risk in patients with established cardiovascular disease: the updated SMART2 algorithm.

AIMS: The 10-year risk of recurrent atherosclerotic cardiovascular disease (ASCVD) events in patients with established ASCVD can be estimated with the Secondary Manifestations of ARTerial disease (SMART) risk score, and may help refine clinical management. To broaden generalizability across regions, we updated the existing tool (SMART2 risk score) and recalibrated it with regional incidence rates and assessed its performance in external populations. METHODS AND RESULTS: Individuals with coronary artery disease, cerebrovascular disease, peripheral artery disease, or abdominal aortic aneurysms were included from the Utrecht Cardiovascular Cohort-SMART cohort [n = 8355; 1706 ASCVD events during a median follow-up of 8.2 years (interquartile range 4.2-12.5)] to derive a 10-year risk prediction model for recurrent ASCVD events (non-fatal myocardial infarction, non-fatal stroke, or cardiovascular mortality) using a Fine and Gray competing risk-adjusted model. The model was recalibrated to four regions across Europe, and to Asia (excluding Japan), Japan, Australia, North America, and Latin America using contemporary cohort data from each target region. External validation used data from seven cohorts [Clinical Practice Research Datalink, SWEDEHEART, the international REduction of Atherothrombosis for Continued Health (REACH) Registry, Estonian Biobank, Spanish Biomarkers in Acute Coronary Syndrome and Biomarkers in Acute Myocardial Infarction (BACS/BAMI), the Norwegian COgnitive Impairment After STroke, and Bialystok PLUS/Polaspire] and included 369 044 individuals with established ASCVD of whom 62 807 experienced an ASCVD event. C-statistics ranged from 0.605 [95% confidence interval (CI) 0.547-0.664] in BACS/BAMI to 0.772 (95% CI 0.659-0.886) in REACH Europe high-risk region. The clinical utility of the model was demonstrated across a range of clinically relevant treatment thresholds for intensified treatment options. CONCLUSION: The SMART2 risk score provides an updated, validated tool for the prediction of recurrent ASCVD events in patients with established ASCVD across European and non-European populations. The use of this tool could allow for a more personalized approach to secondary prevention based upon quantitative rather than qualitative estimates of residual risk.

Risk Stratification in Patients with Ischemic Stroke and Residual Cardiovascular Risk with Current Secondary Prevention.

PURPOSE: Suboptimal secondary prevention in patients with stroke causes a remaining cardiovascular risk desirable to reduce. We have validated a prognostic model for secondary preventive settings and estimated future cardiovascular risk and theoretical benefit of reaching guideline recommended risk factor targets. PATIENTS AND METHODS: The SMART-REACH (Secondary Manifestations of Arterial Disease-Reduction of Atherothrombosis for Continued Health) model for 10-year and lifetime risk of cardiovascular events was applied to 465 patients in the Norwegian Cognitive Impairment After Stroke (Nor-COAST) study, a multicenter observational study with two-year follow-up by linkage to national registries for cardiovascular disease and mortality. The residual risk when reaching recommended targets for blood pressure, low-density lipoprotein cholesterol, smoking cessation and antithrombotics was estimated. RESULTS: In total, 11.2% had a new event. Calibration plots showed adequate agreement between estimated and observed 2-year prognosis (C-statistics 0.63, 95% confidence interval 0.55-0.71). Median estimated 10-year risk of recurrent cardiovascular events was 42% (Interquartile range (IQR) 32-54%) and could be reduced to 32% by optimal guideline-based therapy. The corresponding numbers for lifetime risk were 70% (IQR 63-76%) and 61%. We estimated an overall median gain of 1.4 (IQR 0.2-3.4) event-free life years if guideline targets were met. CONCLUSION: Secondary prevention was suboptimal and residual risk remains elevated even after optimization according to current guidelines. Considerable interindividual variation in risk exists, with a corresponding variation in benefit from intensification of treatment. The SMART-REACH model can be used to identify patients with the largest benefit from more intensive treatment and follow-up.

The Impact of Vascular Risk Factors on Post-stroke Cognitive Impairment: The Nor-COAST Study.

Introduction: Post-stroke cognitive impairment (PSCI) is common, but evidence on the impact of vascular risk factors is lacking. We explored the association between pre-stroke vascular risk factors and PSCI and studied the course of PSCI. Materials and Methods: Vascular risk factors were collected at baseline in stroke survivors (n = 635). Cognitive assessments of attention, executive function, memory, language, and the Montreal Cognitive Assessment (MoCA) were performed at 3 and/or 18 months post-stroke. Stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS). PSCI was measured with global z; MoCA z-score; and z-score of the four assessed cognitive domains. Mixed-effect linear regression was applied with global z, MoCA z-score, and z-scores of the cognitive domains as dependent variables. Independent variables were the vascular risk factors (hypertension, hypercholesterolemia, smoking, diabetes mellitus, atrial fibrillation, coronary heart disease, previous stroke), time, and the interaction between these. The analyses were adjusted for age, education, and sex. There were between 5 and 25% missing data for the variables for PSCI. Results: Mean age was 71.6 years (SD 11.7); 42% were females; and the mean NIHSS score at admittance was 3.8 (SD 4.8). Regardless of vascular risk factors, global z, MoCA, and all the assessed cognitive domains were impaired at 3 and 18 months, with MoCA being the most severely impaired. Atrial fibrillation (AF) was associated with poorer language at 18 months and coronary heart disease (CHD) with poorer MoCA at 18 months (LR = 12.80, p = 0.002, and LR = 8.32, p = 0.004, respectively). Previous stroke was associated with poorer global z and attention at 3 and 18 months (LR = 15.46, p < 0.001, and LR = 16.20, p < 0.001). In patients without AF, attention improved from 3 to 18 months, and in patients without CHD, executive function improved from 3 to 18 months (LR = 10.42, p < 0.001, and LR = 9.33, p = 0.009, respectively). Discussion: Our findings indicate that a focal stroke lesion might be related to pathophysiological processes leading to global cognitive impairment. The poorer prognosis of PSCI in patients with vascular risk factors emphasizes the need for further research on complex vascular risk factor interventions to prevent PSCI.