Embolic stroke of undetermined source: identification of patient subgroups for oral anticoagulation treatment.
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SUBMITTER: Greeve I
PROVIDER: S-EPMC8552842 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivePrevention of recurrent stroke in patients with embolic stroke of undetermined source (ESUS) is challenging. The advent of safer anticoagulation in the form of direct oral anticoagulants (DOACs) has prompted exploration of prophylactic anticoagulation for all ESUS patients, rather than anticoagulating just those with documented atrial fibrillation (AF). However, recent trials have failed to demonstrate a clinical benefit, while observing increased bleeding. We modeled the economic impact of anticoagulating ESUS patients without documented AF across multiple geographies.MethodsCRYSTAL-AF trial data were used to assess ischaemic stroke event rates in ESUS patients confirmed AF-free after long-term monitoring. Anticipated bleeding event rates (including both minor and major bleeds) with aspirin, dabigatran 150 mg, and rivaroxaban 20 mg were sourced from published meta-analyses, whilst a 30% ischaemic stroke reduction for both DOACs was assumed. Cost data for clinical events and pharmaceuticals were collected from the local payer perspective.ResultsCompared with aspirin, dabigatran and rivaroxaban resulted in 17.9 and 29.9 additional bleeding events per 100 patients over a patient's lifetime, respectively. Despite incorporating into our model the proposed 30% reduction in ischaemic stroke risk, both DOACs were cost-additive over patient lifetime, as the costs of bleeding events and pharmaceuticals outweighed cost savings associated with the reduction in ischaemic strokes. DOACs added £5953-£7018 per patient (UK), €6683-€7368 (Netherlands), €4933-€9378 (Spain), AUD$5353-6539 (Australia) and $26,768-$32,259 (US) of payer cost depending on the agent prescribed. Additionally, in the U.S. patient pharmacy co-payments ranged from $2468-$12,844 depending on agent and patient plan. In all settings, cost-savings could not be demonstrated even when the modelling assumed 100% protection from recurrent ischaemic strokes, due to the very low underlying risk of recurrent ischaemic stroke in this population (1.27 per 100 patient-years).ConclusionsAnticoagulation of non-AF patients may cause excess bleeds and add substantial costs for uncertain benefits, suggesting a personalised approach to anticoagulation in ESUS patients.
| S-EPMC8015049 | biostudies-literature
Project description:Background and Purpose- The RE-SPECT ESUS trial (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) tested the hypothesis that dabigatran would be superior to aspirin for the prevention of recurrent stroke in patients with embolic stroke of undetermined source. This exploratory subgroup analysis investigates the impact of age, renal function (both predefined), and dabigatran dose (post hoc) on the rates of recurrent stroke and major bleeding. Methods- RE-SPECT ESUS was a multicenter, randomized, double-blind trial of dabigatran 150 or 110 mg (for patients aged ≥75 years and/or with creatinine clearance 30 to <50 mL/minute) twice daily compared with aspirin 100 mg once daily. The primary outcome was recurrent stroke. Results- The trial, which enrolled 5390 patients from December 2014 to January 2018, did not demonstrate superiority of dabigatran versus aspirin for prevention of recurrent stroke in patients with embolic stroke of undetermined source. However, among the population qualifying for the lower dabigatran dose, the rate of recurrent stroke was reduced with dabigatran versus aspirin (7.4% versus 13.0%; hazard ratio, 0.57 [95% CI, 0.39-0.82]; interaction P=0.01). This was driven mainly by the subgroup aged ≥75 years (7.8% versus 12.4%; hazard ratio, 0.63 [95% CI, 0.43-0.94]; interaction P=0.10). Stroke rates tended to be lower with dabigatran versus aspirin with declining renal function. Risks for major bleeding were similar between treatments, irrespective of renal function, but with a trend for lower bleeding rates with dabigatran versus aspirin in older patients. Conclusions- In subgroup analyses of RE-SPECT ESUS, dabigatran reduced the rate of recurrent stroke compared with aspirin in patients qualifying for the lower dose of dabigatran. These results are hypothesis-generating. Aspirin remains the standard antithrombotic treatment for patients with embolic stroke of undetermined source. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.
| S-EPMC7379165 | biostudies-literature
Project description:One-quarter to one-third of ischemic strokes have no established mechanism after standard diagnostic evaluation and are classified as embolic stroke of undetermined source (ESUS). Failure of randomized trials to demonstrate a benefit of direct oral anticoagulants over aspirin for the treatment of ESUS as a single homogeneous entity has led to renewed interest by stroke experts to divide ESUS into subgroups. Emerging data suggest that active cancer, which is present in 5% to 10% of patients with ESUS, is a distinct and important subgroup of ESUS with unique clinical characteristics, underlying pathophysiologies, and treatment and prognostic considerations. Furthermore, the prevalence of cancer-related ESUS is expected to increase as patients with cancer, even those with distant metastases, survive longer due to improvements in cancer treatments. In this topical review, we examine the epidemiological link between ESUS and cancer, the clinical features and potential mechanistic underpinnings of ESUS with cancer (with a focus on novel biomarkers and their relationship to recurrent stroke and other thromboembolic events), and the potential treatment strategies for cancer-related ESUS. We include a critical appraisal of existing data and ongoing or planned clinical trials of different antithrombotic approaches. As cancer-related ESUS is a dynamic disease with variable course, we recommend close collaboration between neurologists and oncologists to develop individualized management plans.
| S-EPMC7902455 | biostudies-literature
Project description:PurposeWe performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of direct oral anticoagulation (DOAC) compared with antiplatelet therapy for secondary stroke prevention in adult patients with embolic stroke of undetermined source (ESUS).MethodWe searched major databases (Embase, MEDLINE, CINAHL, CENTRAL, and Web of Science) for RCTs published until March 2021. The primary outcome was recurrent stroke, and the main safety outcomes were major bleeding and clinically relevant non-major bleeding (CRNB). We assessed risk of bias using the Cochrane Risk of Bias tool. We used a random-effects model to determine pooled risk ratios and 95% confidence intervals in the datasets and key subgroups.FindingsOur search identified two RCTs, involving a total of 12,603 patients with ESUS. Anticoagulation with dabigatran or rivaroxaban compared with aspirin did not reduce the risk of recurrent stroke (RR, 0.96 [0.76-1.20]) or increase major bleeding (RR, 1.77 [0.80-3.89]) but significantly increased the composite of major or clinically relevant non-major bleeding (RR, 1.57 [1.26-1.97]). Prespecified subgroup analysis demonstrated consistent results according to age and sex. Additional post-hoc subgroup analyses demonstrated consistent results according to prior stroke and presence of a patent foramen ovale but suggested that DOACs reduced recurrent stroke in patients with an estimated glomerular filtration rate (eGFR) <50 and 50-80 ml/min but not in those with eGFR >80 ml/min (interaction P = 0.0234).Discussion/conclusionDirect oral anticoagulations are not more effective than aspirin in preventing stroke recurrence in patients with ESUS and increase bleeding.RegistrationPROSPERO ID: CRD42019138593.
| S-EPMC9134773 | biostudies-literature
Project description:Background: The objective of this study was to evaluate if anticoagulation therapy reduces recurrent stroke in embolic stroke of undetermined source (ESUS) patients with left atrial enlargement (LAE) or abnormal markers of coagulation and hemostatic activity (MOCHA) compared to antiplatelet therapy. Methods: ESUS patients from January 1, 2017, to June 30, 2019, underwent outpatient cardiac monitoring and the MOCHA profile (serum d-dimer, prothrombin fragment 1.2, thrombin-antithrombin complex, and fibrin monomer). Anticoagulation was offered to patients with abnormal MOCHA (≥2 elevated markers) or left atrial volume index 40 mL/m2. Patients were evaluated for recurrent stroke or major hemorrhage at routine clinical follow-up. We compared this patient cohort (cohort 2) to a historical cohort (cohort 1) who underwent the same protocol but remained on antiplatelet therapy. Results: Baseline characteristics in cohort 2 (n = 196; mean age = 63 ± 16 years, 59% female, 49% non-White) were similar to cohort 1 (n = 42) except that cohort 2 had less diabetes (43 vs. 24%, p = 0.01) and more tobacco use (26 vs. 43%, p = 0.04). Overall, 45 patients (23%) in cohort 2 initiated anticoagulation based on abnormal MOCHA or LAE. During mean follow-up of 13 ± 10 months, cohort 2 had significantly lower recurrent stroke rates than cohort 1 (14 vs. 3%, p = 0.009) with no major hemorrhages. Conclusions: Anticoagulation therapy in a subgroup of ESUS patients with abnormal MOCHA or severe LAE may be associated with a reduced rate of recurrent stroke compared to antiplatelet therapy. A prospective, randomized study is warranted to validate these results.
| S-EPMC8215436 | biostudies-literature
Project description:So far, there has been no generally accepted diagnostic and therapeutic algorithm for patients with embolic stroke of undetermined source (ESUS). As recent clinical trials on secondary stroke prevention in ESUS did not support the use of oral anticoagulation and the concept of ESUS comprises heterogeneous subgroups of patients, including a wide age range, concomitant patent foramen ovale (PFO), variable cardiovascular risk factors as well as a variable probability for atrial fibrillation (AF), an individualized clinical approach is needed. In this context, we here present a case of recurrent stroke in a young patient with ESUS and PFO. During treatment according to our Catch-up-ESUS registry study, prolonged cardiac monitoring diagnosed AF, and PFO closure was omitted.
| S-EPMC7036551 | biostudies-literature
Project description:Background We aimed to assess the prevalence and degree of overlap of potential embolic sources (PES) in patients with embolic stroke of undetermined source (ESUS). Methods and Results In a pooled data set derived from 3 prospective stroke registries, patients were categorized in ≥1 groups according to the PES that was/were identified. We categorized PES as follows: atrial cardiopathy, atrial fibrillation diagnosed during follow-up, arterial disease, left ventricular disease, cardiac valvular disease, patent foramen ovale, and cancer. In 800 patients with ESUS (43.1% women; median age, 67.0 years), 3 most prevalent PES were left ventricular disease, arterial disease, and atrial cardiopathy, which were present in 54.4%, 48.5%, and 45.0% of patients, respectively. Most patients (65.5%) had >1 PES, whereas only 29.7% and 4.8% of patients had a single or no PES, respectively. In 31.1% of patients, there were ≥3 PES present. On average, each patient had 2 PES (median, 2). During a median follow-up of 3.7 years, stroke recurrence occurred in 101 (12.6%) of patients (23.3 recurrences per 100 patient-years). In multivariate analysis, the risk of stroke recurrence was higher in the atrial fibrillation group compared with other PES, but not statistically different between patients with 0 to 1, 2, or ≥3 PES. Conclusions There is major overlap of PES in patients with ESUS. This may possibly explain the negative results of the recent large randomized controlled trials of secondary prevention in patients with ESUS and offer a rationale for a randomized controlled trial of combination of anticoagulation and aspirin for the prevention of stroke recurrence in patients with ESUS. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02766205.
| S-EPMC6761628 | biostudies-literature
Project description: Not available
| S-EPMC8189862 | biostudies-literature
Project description:Background and purposeOne-fifth of ischemic strokes are embolic strokes of undetermined source (ESUS). Their theoretical causes can be classified as cardioembolic versus noncardioembolic. This distinction has important implications, but the categories' proportions are unknown.MethodsUsing data from the Cornell Acute Stroke Academic Registry, we trained a machine-learning algorithm to distinguish cardioembolic versus non-cardioembolic strokes, then applied the algorithm to ESUS cases to determine the predicted proportion with an occult cardioembolic source. A panel of neurologists adjudicated stroke etiologies using standard criteria. We trained a machine learning classifier using data on demographics, comorbidities, vitals, laboratory results, and echocardiograms. An ensemble predictive method including L1 regularization, gradient-boosted decision tree ensemble (XGBoost), random forests, and multivariate adaptive splines was used. Random search and cross-validation were used to tune hyperparameters. Model performance was assessed using cross-validation among cases of known etiology. We applied the final algorithm to an independent set of ESUS cases to determine the predicted mechanism (cardioembolic or not). To assess our classifier's validity, we correlated the predicted probability of a cardioembolic source with the eventual post-ESUS diagnosis of atrial fibrillation.ResultsAmong 1083 strokes with known etiologies, our classifier distinguished cardioembolic versus noncardioembolic cases with excellent accuracy (area under the curve, 0.85). Applied to 580 ESUS cases, the classifier predicted that 44% (95% credibility interval, 39%-49%) resulted from cardiac embolism. Individual ESUS patients' predicted likelihood of cardiac embolism was associated with eventual atrial fibrillation detection (OR per 10% increase, 1.27 [95% CI, 1.03-1.57]; c-statistic, 0.68 [95% CI, 0.58-0.78]). ESUS patients with high predicted probability of cardiac embolism were older and had more coronary and peripheral vascular disease, lower ejection fractions, larger left atria, lower blood pressures, and higher creatinine levels.ConclusionsA machine learning estimator that distinguished known cardioembolic versus noncardioembolic strokes indirectly estimated that 44% of ESUS cases were cardioembolic.
| S-EPMC8034802 | biostudies-literature
Project description:BackgroundFrom a therapeutic viewpoint, it is important to differentiate the underlying causes of embolism in patients with cryptogenic stroke, such as aortic arch atheroma, patent foramen ovale, and paroxysmal atrial fibrillation. We investigated the clinical and radiological characteristics of these 3 common causes of cryptogenic embolism to develop models for decision making in etiologic workups.Methods and resultsA total of 321 consecutive patients with acute infarcts from cryptogenic embolism were included. Patients were divided into 3 groups-aortic arch atheroma (n=40), patent foramen ovale (n=153), and paroxysmal atrial fibrillation (n=128)-based on extensive cardiologic workups. We used a multinomial logistic regression analysis to detect the clinical and diffusion-weighted imaging factors associated with the probability of aortic arch atheroma, patent foramen ovale, and paroxysmal atrial fibrillation. Clinical and radiological features differed among the groups. The patent foramen ovale group had a healthy vascular risk factor profile and showed posterior circulation involvement compared with other groups (P<0.01). In contrast, paroxysmal atrial fibrillation-related strokes had higher initial National Institutes of Health Stroke Scale (NIHSS) scores and larger lesions than the other groups (P<0.001). The aortic arch atheroma group had clinical features similar to those of the paroxysmal atrial fibrillation group but showed small lesions scattered in multiple vascular territories (P<0.001). Multivariate regression analysis revealed that age, initial NIHSS score, lesion size (≥20 mm), multiple (≥3) lesions, and involvement of posterior circulation or multiple vascular territories differentiated the 3 groups (pseudo, R(2)=0.656). The prediction ability of this model was validated in the external validation cohort (n=117, area under the curve 0.78).ConclusionsOur data indicate that patients with cryptogenic embolic stroke show distinct clinical and radiological features depending on the underlying causes.
| S-EPMC4943271 | biostudies-literature