Ischemic stroke in patients on dabigatran: a role for rescue thrombectomy?

Introduction: Artificial intelligence is emerging as an adjunct promising tool in medicine. ChatGPT, an AI chatbot that uses machine learning to create human-like dialogue, has shown strong potential in the medical field, specifically aiding professionals in clinical reasoning and diagnosis. We aim to assess the ability of ChatGPT to guide the decision for intravenous thrombolysis (IVT) in patients with acute ischemic strokes (AIS). Methods: The performance of ChatGPT in clinical decision making for IVT was compared with that of a board-certified stroke neurologist using artificially created AIS scenarios, covering a broad range of indications and contraindications. ChatGPT was asked to act like an acute stroke clinical decision tool and to answer with a “yes” or “no” along with a 1-sentence justification for its answer. The accuracy and interpretation skills of ChatGPT and the stroke neurologist were analyzed by a blinded assessor, with more than 10 years of experience in stroke neurology. Results: Out of the 20 scenarios, ChatGPT’s decision to pursue or withhold IVT was deemed congruent with that of the stroke neurologist’s in 16 scenarios (80%). Based on the blinded assessor’s judgement, two clinical decisions made by ChatGPT and one clinical decision made by the stroke neurologist were rendered wrong. In one case, chatGPT’s reasoning was deemed to be incorrect but the correct clinical decision was made not to provide IVT. In another case, both the stroke neurologist and ChatGPT gave reasonable explanations despite different clinical decisions, both deemed plausible by the assessor. Overall, both chatGPT’s decision to pursue or withhold IVT and the explanation it provided were deemed accurate by the assessor in 17 scenarios (85%). Conclusion: This study shows that ChatGPT performed well in most scenarios, potentially reinforcing its ability to guide clinical decision making for IVT in AIS patients. However, ChatGPT is still prone to errors, as shown by its inability to consistently depict contraindications for IVT, and may still not be ready for independent use.

Randomized controlled trials for the use of alteplase in acute ischemic stroke have excluded or had little representation of patients with prestroke disability, and the benefit of alteplase in this population remains uncertain. We performed a systematic review and meta-analysis to examine the outcomes of thrombolysis in patients with premorbid disability. We performed a systematic review in accordance with the Meta-Analysis of Observational Studies in Epidemiology guidelines and retrieved studies reporting intravenous thrombolysis (IVT) in patients with prestroke disability (modified Rankin Scale score, 3-5) with acute ischemic stroke, either compared with untreated patients or treated patients without premorbid disability. The primary outcome was the return to premorbid disability at 90 days. Secondary outcomes included rate and odds ratio of favorable functional outcome at 90 days (modified Rankin Scale score 0-2 or return to premorbid modified Rankin Scale), symptomatic intracerebral hemorrhage (sICH), and 90-day mortality. Eight articles were included involving 103 988 patients. Patients with disability treated with IVT had better odds of returning to baseline function compared with those who did not receive IVT (odds ratio, 7.26 [95% CI, 2.51-21.02]). Mortality and rates of sICH were not significantly different between patients with disability treated with IVT and those not treated, although there were numerically more sICHs in the IVT group. Return to baseline function was not significantly different between patients with and without prestroke disability (odds ratio, 1.46 [95% CI, 0.75-2.83]). The rates of sICH were not significantly different in patients with and without premorbid disability. However, mortality was 3× higher in patients with premorbid disability than in those without premorbid disability (38.2% versus 12.6%). The use of IVT in patients with disability was associated with better outcomes compared with patients who did not receive IVT without statistically significant added risks of sICH or mortality. When compared with those without disability, there was no significant difference in the return to baseline function or sICH. High-quality data comparing treated versus untreated patients with premorbid disability are needed to clarify this issue. URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42021240499.

Aim. To study in the PROFILE register the rate of new oral anticoagulants (NOAC) taking in patients with atrial fibrillation (AF) and to identify the factors influencing it. Material and methods. Patients with AF who applied to the Cardiology Center in 2013-2014 (n=111) were included into the study. The oral anticoagulants (OAC) were recommended to patients at the reference visit (n=97). Inquiry in questionnaire format was performed to assess the compliance to recommended therapy at the follow-up visit. Patients were divided into two groups according to taking/not-taking NOAC. Analysis of the facts that influence the compliance to NOAC therapy was performed. Results. At the reference visit 70 patients desired to receive NOAC. At the follow-up visit 29 (41.4%) patients refused to take NOAC. Leading causes of NOAC refusal were satisfactory with warfarin (32.6%), the high price of these drugs (23.9%), the description of adverse reactions in the patient information leaflet for medicines (15.2%), and withdrawal by physician in outpatient clinic/hospital (8.7%). Preferential provision of medicines and warfarin therapy at the time of reference visit had a negative impact on the taking of NOAC. Patients taking NOAC were more aware of the possible outcomes of their illness, the possible side effects of OAC and were more familiar with patient information leaflet for medicines. Conclusion. The study assessed NOAC taking rate and the factors influencing patients' compliance to NOAC therapy.

Drugs currently in use for the management of heparin-induced thrombocytopenia (HIT) have their limitations. Several new oral anticoagulants (NOACs) such as dabigatran, rivaroxaban and apixaban may offer attractive therapy options for HIT. Although the clinical data are sparse on this topic, we have summarized the available clinical data, discussed pertinent in-vitro studies and provided the rational and advantages of using NOACs in patients with suspected or confirmed HIT. We have also reviewed the safety and efficacy of these NOACs in patients with HIT based on published literature. We reviewed all suspected or confirmed HIT cases treated with NOACs and indexed in English language in MEDLINE and EMBASE by July 2015. The bibliography of each relevant article was searched for additional reports. In-vitro studies and other pertinent literature were briefly discussed. A total of 36 HIT patients were treated with the following NOACs: rivaroxaban (50%), dabigatran (36%) and apixaban (14%). Sixty-one percent of patients received argatroban bolus before NOACs and 3% received rivaroxaban after a lack of response with three-day course of fondaparinux. Three percent (n=1) received rivaroxaban after the patient responded to intravenous immunoglobulin for 2 days, following a lack of response to fondaparinux and bilvalirudin. In another 3% (n=1), prophylactic dose of rivaroxaban was used for 21 days and then changed to dabigatran because of persistent thrombocytopenia. All cases responded with early signs of clinical improvement and increase in platelet counts. A follow-up after a median 47 days (range 4- 450) reported no bleeding or thrombotic complications. In this review, all patients with HIT treated with NOACs responded without any bleeding or thrombotic complication. Although the argatroban bolus might have contributed to a response in some patients, response to NOAC alone in other patients and in-vitro studies provide a proof of principle that NOACs can be effective in the management of HIT. Additionally, properties such as rapid onset of action, oral administration, ease of use and a lack of need for monitoring make these drugs attractive options for HIT. However, given several limitations of prior reports, further confirmation of the results are desirable.

NOAC's It's Time to Extenuate Patient Knowledge Gaps

Background: Venous thromboembolism (VTE) is a significant healthcare burden, but is a preventable and treatable condition. The new oral anticoagulants (NOACs), apixaban, rivaroxaban, dabigatran, and edoxaban have all been shown in phase III trials to be noninferior in efficacy to standard therapies for acute VTE treatment, although there may be some differences in the bleeding rates among the NOACs. This study evaluated the net clinical benefits (NCB) of NOACs vs. standard therapies based on the AMPLIFY, EINSTEIN-Pooled analysis, RECOVER-1, RE-COVER II, and Hokusai-VTE trial results. Methods: Event rates of the primary efficacy and safety outcomes, as defined in each original trial, among VTE patients during trial periods were obtained from the published clinical trial data. Data from RECOVER-I and -II trials were combined to represent the findings for dabigatran since the two trials were of similar design. EINSTEIN-pooled (DVT and PE combined) data were used to represent findings for rivaroxaban. The combinations of rates for the primary efficacy endpoint, representing recurrent VTE or death and major bleedings (MB) were evaluated and defined as the NCB of each NOAC. Additionally, the number of VTE patients needed to treat (NNT) to avoid one event (e.g. VTE or MB) with each NOAC was also determined. Results: For patients treated in the VTE clinical trials, the differences in event rates of recurrent VTE or death for apixaban, rivaroxaban, dabigatran, and edoxaban vs. standard therapy were -0.43%, -0.23%, 0.20%, and -0.34%, respectively. The differences in event rates of MB for apixaban, rivaroxaban, dabigatran, and edoxaban vs. standard therapy were -1.26%, -0.78%, -0.43%, and -0.24%, respectively. The NCB improved for all NOAC treated patients, with those treated with apixaban (-1.69%) vs. standard therapy having the greatest NCB, followed by those treated with rivaroxaban (-1.01%), edoxaban (-0.58%), and dabigatran ( -0.23%) (Table 1). Conclusions: All NOACs were shown to be non-inferior to standard VTE treatments in clinical trials; however, apixaban may provide the optimal NCB with the lowest NNT. How these results translate into real-world outcomes or medical cost reductions will require further evaluation.

Hemorrhagic transformation (HT) is the most serious complication of intravenous thrombolysis in ischemic stroke patients. Inflammation plays a critical role in the pathological progression of HT. This study was to explore the relationship between fibrinogen-to-albumin ratio (FAR), a novel systemic inflammation biomarker, and HT after intravenous thrombolysis in patients with ischemic stroke. This retrospective study enrolled ischemic stroke patients who underwent intravenous thrombolysis between Jan 2017 to May 2022. The characteristic data of all patients at admission were retrospectively collected. The univariate and multivariate logistic regression analyses were performed to evaluate the correlation between FAR and HT after intravenous thrombolysis. The optimal cut-off value of FAR for predicting HT was determined by the receiver operating characteristic curve. A total of 363 ischemic stroke patients were enrolled in the present study. Sixty-two patients had HT after intravenous thrombolysis. In multivariate regression analysis, FAR was significantly associated with HT (odds ratio [OR], 1.105; 95% confidential interval [CI], 1.029-1.186, P = 0.006). The receiver operating characteristic curve analysis indicated FAR predicts HT after intravenous thrombolysis with an AUC of 0.613 (95%CI, 0.530-0.695; P = 0.005) and an optimal cut-off value of 0.101. The correlation between FAR and HT after intravenous thrombolysis was still observed when patients were stratified according to FAR levels. A higher FAR level was independently related to the occurrence of HT after adjusting for the potential confounding factors. Higher FAR level was independently associated with HT after intravenous thrombolysis in patients with ischemic stroke.

ABSTRACTIntroduction: This review attempts to summarise what is known about Drug-drug interactions (DDIs) of the new oral anticoagulants (NOACs) in elderly patients. The literature was searched for: ‘CYP3A4’, ‘CYP2C9’, ‘P-glycoprotein’, ‘acetylsalicylic-acid’, ‘non-steroidal anti-inflammatory’, ‘clopidogrel’, ‘ticagrelor’, ‘prasugrel’ and ‘dabigatran’, ‘rivaroxaban’, ‘edoxaban’, or ‘apixaban’. ‘Elderly’ was defined as ≥75 years.Areas covered: Publications about DDIs of NOACs were found for 35% of 140 potentially interacting drugs. Reports about DDIs of cardiovascular drugs, were most frequent, followed by anti-infective and nervous system drugs. Reports about elderly were found for only 47 patients. DDIs were reported most frequently in association with dabigatran. Dabigatran is the only NOAC interacting with proton-pump-inhibitors.Expert commentary: Dabigatran was the first NOAC approved, so it is not possible to determine whether the higher number of reports about DDIs with dabigatran compared with other NOACs is due to a higher rate of DDIs or to the length of time during which this drug has been in use. Most of the data is derived from subgroup-analyses of trials, sponsored by NOAC manufacturers, consequently there is a lack of independent data. Because of the scarcity of data, the clinical relevance of DDIs of NOACs is uncertain at present, especially in elderly patients.

Effectiveness of new oral anticoagulants (NOAC) in patients with cancer is not clearly defined. There remain concerns of doubtful benefit and chances of potential harm with newer agents. In this meta-analysis, we evaluated the efficacy and safety of NOAC in patients with cancer. PubMed, Cochrane Library, EMBASE, Web of Science, and CINAHL databases were searched from January 01, 2001 through February 28, 2013. Randomized controlled trials reporting efficacy and safety data of NOACs (rivaroxaban, dabigatran, and apixaban) with control (low-molecular-weight heparin/vitamin K antagonists/placebo) for patients with cancer were included. Primary efficacy outcome was venous thromboembolism (VTE) or VTE-related death, and primary safety outcome was clinically relevant bleeding. We used random-effects models. Six trials randomized 19,832 patients, and 1197 patients had cancer. Risk of VTE or VTE-related death was not significantly different with NOAC versus control [odds ratio (OR), 0.80; 95% confidence interval (CI), 0.39-1.65] in patients with cancer. Separate analysis for individual effects showed similar results for rivaroxaban (OR, 1.08; 95% CI, 0.60-1.94) and dabigatran (OR, 0.91; 95% CI, 0.21-3.91). Clinically relevant bleeding was not higher with NOAC compared with control (OR, 1.49; 95% CI, 0.82-2.71); individual effect of rivaroxaban showed similar results. No statistically significant difference of efficacy and safety with NOAC was found between patients with and without cancer. Rivaroxaban might be equally effective and safe as vitamin K antagonist in patients with cancer. Dabigatran is as effective as comparator; however, safety profile of dabigatran is unknown. Randomized trials of new anticoagulants specific to the cancer population are necessary, and NOAC also need to be evaluated against low-molecular-weight heparin.

Treatment with vitamin K antagonists are subject to a common iatrogenic mainly characterized by hemorrhagic stroke. Their narrow therapeutic range associated with variability largely explains this phenomenon. New oral anticoagulants (NOAC) are now available. dabigatran (Pradaxa®) is a direct and specific thrombin inhibitor. It is excreted mainly by the kidney and is the only which can be dialyzed. Rivaroxaban (Xarelto®) and apixaban (Eliquis®) are factor X activated direct inhibitors. They are highly bound to plasma proteins and are metabolized mainly by the liver, via CYP3A4. All NOAC are substrates of P-glycoprotein (P-gp). Due to pharmacological changes, some populations at risk were identified: patients with hepatic impairment, renal impairment, elderly patients or low weight. Some pharmacokinetic or pharmacodynamic drug interactions alter the concentration and the expected impact of NOAC. The NOAC does not require biological monitoring. They interfere with the routine coagulation tests which should be interpreted with caution. Specific tests exist and can be used in case of emergencies. Currently, no antidote is available. The new oral anticoagulant look promising in the elderly. However, certain rules must be followed to reduce the risk of iatrogenic.

Large clinical trials have demonstrated that new oral anticoagulants (NOACs) are at least as efficient as vitamin K antagonists (VKAs) in preventing thromboembolic events, while providing a better safety profile. The relatively stable pharmacokinetics and pharmacodynamics, the reduced reports on food and drug interactions, and the wide therapeutic windows of NOACs appear to provide a more predictable anticoagulant effect than that observed with VKAs, enabling the use of fixed doses without the need for monitoring. However, the safe implementation of NOACs may require additional judgment, and one should not have the erroneous impression that NOACs are free from interactions or that inter- and intra-individual variability is absent with NOACs. In fact, a consensus seems to have been reached concerning the usefulness of "circumstantial" testing in certain clinical scenarios. Recent data also suggest that factors such as intercurrent diseases, drug interactions, and inexplicable variability may occasionally alter the anticoagulant effect of NOACs. Furthermore, the issue of nonadherence, already high in VKA-treated patients, may represent an even greater clinical concern with NOACs, given their short half-lives. This review aims to underline the main arguments that support the need for NOAC monitoring, at least in selected categories of patients. Additionally, an overview of classic coagulation assays and novel laboratory techniques that may provide a tool for NOAC monitoring is also provided.

Background: The efficacy and safety of newer oral anticoagulants (NOAs) compared to vitamin K antagonist (VKA) in preventing the recurrence of venous thromboembolism (VTE) is well documented. However, it still needs to be determined whether this pattern holds when compared to the combination of low-molecular-weight heparin (LMWH) and VKA in patients with VTE and malignancy. Methods: For this analysis, the authors searched available databases for randomized controlled trials (RCTs) comparing the NOAs with standard treatment (combination of LMWH and VKA) in patients with VTE and those comparing NOAs with LMWH only for prevention of VTE. All these RCTs included small proportion of patients with cancer. The authors then assessed the pooled treatment effects of VTE recurrence, as well as major and non-major clinically relevant bleeding in the two groups. Results: Twelve studies met our inclusion criteria, yielding 2,054 patients. Five studies with rivaroxaban, three each with dabigatran and apixaban, and one with edoxaban compared NOAs with standard treatment. There was a non-significant reduction in VTE recurrence by the NOAs (3.95%) compared to standard treatment (5.62%) [risk ratio (RR) =0.68; 95% confidence interval (CI) =0.42–1.10; P=0.12]. The major bleeding rate with NOAs was (2.62%) compared to the corresponding rate for standard treatment (3.75%) (RR =0.66; 95% CI =0.36–1.20; P=0.17). The non-major clinically relevant bleeding rate with NOAs was (12.82%) compared to the rate for standard treatment (15.52%) (RR =0.85; 95% CI =0.65–1.10; P= 0.22). However, compared to LMWH only, both higher major (RR =2.18; 95% CI =0.32–14.80; P=0.42) and non-major clinically relevant (RR =2.39; 95% CI =0.75–7.56; P=0.14) bleeding rates were noted with NOAs use in acutely-ill hospitalized patients. Conclusions: NOAs seem to be comparable to standard treatment in both their efficacy and safety in patients with VTE and malignancy. However, increased rates of bleeding were observed with their use compared to LMWH use in acutely-ill hospitalized patients.

New oral anticoagulants (NOACs) may represent an alternative to standard therapy with vitamin K antagonists (VKA). However, up to the present, it is unknown whether these drugs are safer than VKA. The aim of this study was to perform a meta-analysis of the interventional trials with NOACs vs VKA in patients with acute venous thromboembolism (VTE) to obtain the balance between clinical efficacy and complications. A meta-analysis of double blind randomized controlled trials (RCTs) was performed. We included RCTs that compared, in acute VTE, the beneficial and harmful effects of NOACs (ximelagatran, apixaban, dabigatran, edoxaban and rivaroxaban) vs VKA (warfarin). Seven studies including 29,482 patients were selected. Compared with warfarin, recurrent VTE and death from any cause were not significantly reduced by NOACs. Myocardial infarction was significantly increased with NOACs compared with warfarin (RR 2.55; 95% CI 1.1-5.6; p = 0.02). NOACs significantly reduced the major bleedings (RR 0.63; 95% CI 0.47-0.83; p = 0.001). This meta-analysis suggests that treatment with NOACs in patients with acute VTE is not inferior to conventional therapy with warfarin for recurrent VTE and death from any cause, but there might be an increased incidence of myocardial infarction.

Introduction Computed tomography (CT) is often performed before atrial fibrillation (AF) ablation to assess the anatomy of the pulmonary veins and exclude left atrial (LA) and left atrial appendage (LAA) thrombus. With the growing use of new oral anticoagulants (NOACs), a reassessment of the need for systematic thrombus exclusion in this context seems warranted. Objective To evaluate the prevalence of thrombus in LA/LAA in pre-ablation CT in a contemporary cohort of patients predominantly anticoagulated with NOACs. Methods We evaluated 789 consecutive patients (mean age 61±12 years; 38% female; 84% with paroxysmal AF) who underwent pre-ablation CT between Oct/2015 and Oct/2019. ECG-gated CT-angiography was performed using a dual-source 64-slice CT after iodinated contrast injection. Whenever necessary, a second dedicated acquisition was made 60 seconds after the first set of images. Presence of thrombus was defined as a persistent opacification defect. For each patient, thromboembolic risk was assessed with the CHA2DS2-VASc score. Results The median interval between CT and AF ablation was 1 day (IQR 1 – 2 days). The median CHA2DS2-VASc was 2 points (IQR 0 – 3 points), with 590 patients (75%) having CHA2DS2-VASc ≥1. Among the 199 patients (25%) with CHA2DS2-VASc = 0, 118 (59,3%) were anticoagulated with a NOAC and 14 (7%) with a vitamin K antagonist; 67 (34%) were not anticoagulated. Conversely, amongst the 590 patients with CHA2DS2-VASc ≥1, 84% were anticoagulated with a NOAC (n=494), 11% used vitamin K antagonists (n=62), and 34 patients were not anticoagulated (23 with CHA2DS2-VASc = 1). On cardiac CT, 521 (66%) patients were in sinus rhythm. Overall, only one LAA thrombus was found (0.12% [1/789]; 95% CI: 0.0–0.7%) – in a patient with CHA2DS2-VASc = 0, anticoagulated with a NOAC. The median effective radiation dose was 3.2 mSv (IQR 2.1–4.8 mSv). There were 5 minor allergic reactions to iodinated contrast. No strokes were documented within the first 24 hours after ablation. Conclusion In this contemporary cohort of patients with predominantly paroxysmal AF and anticoagulated with NOAC, the prevalence of intracavitary thrombus was extremely low (0.12%). While these findings do not compromise the multipurpose role of pre-ablation CT, they should nevertheless inform future discussions on the risk/benefit and cost/benefit of performing systematic exclusion of LA/LAA thrombi prior to AF ablation. Funding Acknowledgement Type of funding source: None

Objective To compare the safety and effectiveness of intravenous thrombolysis treatment in large artery atherosclerosis (LAA) and cardioembolic (CE) strokes in patients with acute anterior circulation ischemic stroke. Methods Two hundred and thirty-eight patients with acute anterior circulation ischemic stroke, admitted to and treated with intravenous thrombolysis in our hospital from January 2017 to June 2018 were chosen in our study. These patients were divided into either a LAA group (n=158) or a CE group (n=80) according to etiological subtypes. The differences in baseline data and outcomes 90 d after the onset between the two groups were compared. Baseline data of patients in the good outcome group and the poor outcome group were compared and independent risk factors for poor outcome were determined by multivariate Logistic regression analysis. Results As compared with the patients from the LAA group, patients from the CE group had older age and higher proportion of patients combined with atrial fibrillation, with significant differences (P 0.05). Among the 238 patients, 112 were into the good outcome group and 126 were into the poor outcome group; as compared with patients from the poor outcome group, patients from the good outcome group had younger age, and lower National Institute of Health Stroke Scale (NIHSS) scores and lower levels of fasting blood glucose before and after thrombolysis, with statistically significant differences (P<0.05); multivariate Logistic regression analysis showed that older age (odds ratio [OR]=1.040, 95% confidence interval [CI]: 1.010-1.071, P=0.008) and higher NIHSS scores 24 h after thrombolysis (OR=1.259, 95%CI: 1.175-1.350, P=0.000) were independently associated with poor outcome. Conclusion The outcomes of intravenous thrombolysis in patients with acute anterior ischemic stroke are only associated with age and severity of stroke, and not associated with TOAST etiological subtypes; intravenous thrombolysis for cardiogenic stroke is safe and effective. Key words: Intravenous thrombolysis; Acute ischemic stroke; Large artery atherosclerosis; Cardiogenic stroke; Outcome