OBJECTIVE: This study aimed to evaluate the cytochrome P450 (CYP)-mediated drug-drug interaction (DDI) potential of kinase inhibitors with warfarin and direct oral anticoagulants (DOACs).
METHODS: An in vitro CYP probe substrate cocktail assay was used to study the inhibitory effects of fifteen kinase inhibitors on CYP2C9, 3A, and 1A2. Then, DDI predictions were performed using both mechanistic static and physiologically-based pharmacokinetic (PBPK) models.
RESULTS: Linsitinib, masitinib, regorafenib, tozasertib, trametinib, and vatalanib were identified as competitive CYP2C9 inhibitors (Ki = 1.4, 1.0, 1.1, 3.8, 0.5, and 0.1 μM, respectively). Masitinib and vatalanib were competitive CYP3A inhibitors (Ki = 1.3 and 0.2 μM), and vatalanib noncompetitively inhibited CYP1A2 (Ki = 2.0 μM). Moreover, linsitinib and tozasertib were CYP3A time-dependent inhibitors (KI = 26.5 and 400.3 μM, kinact = 0.060 and 0.026 min-1, respectively). Only linsitinib showed time-dependent inhibition of CYP1A2 (KI = 13.9 μM, kinact = 0.018 min-1). Mechanistic static models identified possible DDI risks for linsitinib and vatalanib with (S)-/(R)-warfarin, and for masitinib with (S)-warfarin. PBPK simulations further confirmed that vatalanib may increase (S)- and (R)-warfarin exposure by 4.37- and 1.80-fold, respectively, and that linsitinib may increase (R)-warfarin exposure by 3.10-fold. Mechanistic static models predicted a smaller risk of DDIs between kinase inhibitors and apixaban or rivaroxaban. The greatest AUC increases (1.50-1.74) were predicted for erlotinib in combination with apixaban and rivaroxaban. Linsitinib, masitinib, and vatalanib were predicted to have a smaller effect on apixaban and rivaroxaban AUCs (AUCR 1.22-1.53). No kinase inhibitor was predicted to increase edoxaban exposure.
CONCLUSIONS: Our results suggest that several kinase inhibitors, including vatalanib and linsitinib, can cause CYP-mediated drug-drug interactions with warfarin and, to a lesser extent, with apixaban and rivaroxaban. The work provides mechanistic insights into the risk of DDIs between kinase inhibitors and anticoagulants, which can be used to avoid preventable DDIs in the clinic.

BACKGROUND: Since several studies have examined the use of direct oral anticoagulants (DOACs) in treating patients with splanchnic vein thrombosis (SVT), we conducted a meta-analyses to assess the safety and efficacy of DOACs compared to vitamin K antagonists (VKAs) in this population.
METHODS: We conducted a comprehensive search using the PubMed, Embase, and Cochrane Library databases until June 2024. We used odds ratios (ORs) and 95% confidence intervals (CIs) as the effect measures to compare DOACs with VKAs.
RESULTS: A total of 9 observational studies were included. The pooled analysis revealed that a trend towards higher complete recanalization rates with DOACs (71.4%) compared to VKAs (55.3%), though not statistically significant (OR 1.95; 95%CI 0.70 to 5.44). For SVT extension, a significant effect was observed favoring DOACs (OR 0.12; 95%CI 0.03 to 0.54). No significant differences were found in other efficacy outcomes or safety outcomes, except for major bleeding, which was significantly lower with DOACs (OR 0.27; 95%CI 0.13 to 0.56).
CONCLUSIONS: DOACs are superior to VKAs in SVT extension and major bleeding, suggesting that DOACs may be a favorable treatment option in the treatment of SVT.

BACKGROUND: Acute venous thromboembolism (VTE) in children presents unique challenges due to the limitations of standard anticoagulation therapies. Herein, we aimed to systematically review randomized controlled trials (RCTs) evaluating the efficacy and safety of direct oral anticoagulants (DOACs) in pediatric patients with acute VTE.
METHODS: PubMed and Embase databases were searched for RCTs comparing DOACs to standard anticoagulation in pediatric VTE patients. Efficacy outcomes included VTE recurrence and all-cause mortality, while safety outcomes comprised major bleeding and other adverse events.
RESULTS: Three RCTs with 790 participants were included. When compared with standard anticoagulation, DOACs demonstrated a reduced risk of VTE recurrence (risk difference[RD] = -3%, 95% confidence interval[CI]: -6% to 0%, P = 0.04) and an increased risk of any adverse event (RD = 8%, 95% CI: 1% to 14%, P = 0.02). No significant differences were found in all-cause mortality, major bleeding, clinically relevant non-major bleeding, or total bleeding between the DOAC and control groups.
CONCLUSIONS: DOACs, primarily dabigatran and rivaroxaban, are non-inferior to standard anticoagulants in reducing VTE recurrence in pediatric patients, with comparable safety profiles. Further research is essential to confirm these findings.

BACKGROUND: Direct oral anticoagulants (DOACs) have been widely applied in adults for thrombosis prophylaxis. However, the effect of DOACs in pediatric patients with congenital or acquired heart diseases who need anticoagulation therapy remains unclear.
METHODS: We systematically searched the databases of PubMed, Embase, and the Cochrane Library, as well as the ClinicalTrials.gov registry and the World Health Organization\'s International Clinical Trials Registry Platform until June 2024 to identify relevant randomized clinical trials (RCTs). If the number of included studies was less than 5, we performed a narrative review to assess the effect of DOACs in pediatric patients.
RESULTS: Four studies were included. In the UNIVERSE study, thrombotic events occurred in 2% of the rivaroxaban group and 9% of the aspirin group, with bleeding events in 36% and 41%, respectively. The ENNOBLE-ATE study showed no thromboembolic events in the edoxaban group and 1.7% in the SOC group (rate difference: -0.07%, 95% CI: -0.22 to 0.07%). Major bleeding rates were similar (rate difference: -0.03%, 95% CI: -0.18 to 0.12%). The SAXOPHONE trial showed no thromboembolic events in either group and similar major bleeding rates (-0.8%, 95% CI: -8.1 to 3.3%). In the DIVERSITY trial, 81% of dabigatran patients achieved the primary outcome versus 59.3% in the SOC group (Odds ratio: 0.342, 95% CI: 0.081-1.229). No major bleeding occurred in either group.
CONCLUSIONS: Existing studies suggest that the use of DOACs hold promise as an effective and safe alternative for preventing and treating thromboembolism in pediatric patients with heart conditions.

UNASSIGNED: Vitamin K antagonists (VKAs) have been recommended as first-line anticoagulants for patients with left ventricular thrombosis (LVT). Direct oral anticoagulants (DOACs) are used as an alternative to the standard of care in anticoagulation. The aim of this meta-analysis was to compare the efficacy and safety of VKAs and DOACs in the treatment of patients with LVT.
UNASSIGNED: Studies were identified by searching the PubMed, Web of Science, and Embase. The main outcomes included stroke or systemic embolism (SSE), thrombus resolution, and bleeding events. The pooled risk ratio (RR) with 95% confidence intervals (CIs) was estimated with fixed effect or random effect models.
UNASSIGNED: Seventeen studies were included. Pooled estimate showed that DOACs had comparable efficacy in prevention of SSE (RR = 0.96, 95% CI: 0.80, 1.16; p = 0.677) and thrombus resolution as compared with VKAs (RR = 1.07, 95% CI: 0.97, 1.18; p = 0.193). DOACs significantly decreased the risk of stroke in patients with LVT (RR = 0.68, 95% CI: 0.47, 1.00; p = 0.048). However, this effect was not observed in the sensitive analysis by high-quality studies (RR = 0.69, 95% CI: 0.47, 1.02; p = 0.06). In terms of safety outcomes, DOACs had similar risk of bleeding events (RR = 1.12, 95% CI: 0.80, 1.57; p = 0.386) and clinically relevant bleeding events (RR = 0.49, 95% CI: 0.23, 1.03; p = 0.060). Meta-regression analysis demonstrated that none of the variables (study design, concomitant antiplatelet medication, duration of follow-up, primary cause of LVT, sample size, types of DOACs) had an impact on the risk of SSE, thrombus resolution and bleeding events. Subgroup analysis based on the use of antiplatelet and treatment switching revealed that there were no significant differences among patients with different treatment regimens.
UNASSIGNED: Based on the present evidence, both DOACs and VKA offered similar effective and safe outcomes in patients with LVT.

UNASSIGNED: Recommendations for drug treatment of left ventricular thrombus (LVT) are based on the ST-segment elevation myocardial infarction (STEMI) guidelines; however, the etiology of LVT has changed. Due to the lack of evidence regarding LVT treatment in the heart failure population, current heart failure guidelines do not cover LVT treatment. We sought to review the etiology of LVT and changes in antithrombotic therapy over the previous 12 years and explore the impact of anticoagulation treatment from a single center\'s experience.
UNASSIGNED: From January 2009 to June 2021, we studied 1675 patients with a discharge diagnosis of LVT at a single center to investigate the clinical characteristics, incidence of all-cause death, cardiovascular death, ischemic stroke, major adverse cardiac and cerebrovascular events (MACCE), systemic embolism (SE), and major bleeding events. Patients were divided into an anticoagulant group and a non-anticoagulant group according to whether they received oral anticoagulant therapy at discharge.
UNASSIGNED: The study included 909 patients (anticoagulation, 510; no anticoagulation, 399). While overall antiplatelet therapy dramatically decreased, more patients with LVT received oral anticoagulation in 2021 (74.0%) than in 2009 (29.6%). In addition, more than half of the patients had heart failure with reduced ejection fraction (HFrEF) each year. The all-cause mortality was 17.3% during 3.8 years of follow-up. The incidences of cardiovascular death, stroke, MACCE, SE, and major bleeding were 16.0%, 3.3%, 19.8%, 5.1%, and 1.7%, respectively. The anticoagulation group had a significantly higher proportion of dilated cardiomyopathy than the non-anticoagulation group (24.7% vs. 5.5%, p < 0.001), and a lower LVEF (34.0 vs. 41.0, p < 0.001). The anticoagulation group also had a higher probability of adverse events on long-term follow-up (p > 0.05). A multivariable competing risk regression model found no significant difference in all six endpoints between the groups (all p > 0.05). Similar results were found by matched and weighted data analysis. Diabetes mellitus (hazard ratio (HR), 1.42; 95% confidence interval (CI), 1.04-1.93; p = 0.027), renal insufficiency (HR, 2.36; 95% CI, 1.60-3.50; p < 0.001), history of previous stroke (HR, 1.60; 95% CI, 1.13-2.29; p = 0.009), and HFrEF (HR, 2.54; 95% CI, 1.78-3.64; p < 0.001) were predictors of increased risk of MACCE.
UNASSIGNED: Heart failure, rather than acute myocardial infarction, is currently the primary cause of LVT. A trend towards better prognosis in the no anticoagulation group was noted. Multivariable, matching and weighting analysis showed no improvement in prognosis with anticoagulant therapy. Our study does not negate the efficacy of anticoagulation but suggests the need to strengthen the management of anticoagulation in order to achieve better efficacy.

UNASSIGNED: Studies on the use of direct oral anticoagulants (DOACs) for preventing venous thromboembolism (VTE) in hospitalized cancer patients are lacking. Therefore, we conducted a multicenter retrospective cohort study to evaluate the efficacy and safety of DOACs versus low-molecular-weight heparin (LMWH) for the primary prevention of VTE in hospitalized cancer patients.
UNASSIGNED: Clinical outcomes included thrombosis, VTE, other thrombosis, all bleeding, major bleeding, nonmajor bleeding, and all-cause death. A 1:1 cohort of rivaroxaban and LMWH patients was created by propensity score matching.
UNASSIGNED: A total of 2,385 cancer patients were included in this study. During the 3-month follow-up period, 129 (5.4%) thrombosis events occurred, 63 (2.7%) of which were VTEs and 66 (2.8%) of which were other thrombosis events. All bleeding occurred in 163 (6.8%) patients, 68 (2.9%) had major bleeding, and 95 (4.0%) had nonmajor bleeding. All-cause deaths occurred in 113 (4.7%) patients. After adjusting for various confounders, the incidence of thrombosis and other thromboses was significantly lower in the rivaroxaban group than in the LMWH group [OR 0.543, 95% CI (0.343-0.859), p = 0.009; OR 0.461, 95% CI (0.241-0.883), p = 0.020]. There were no significant differences in incidence of VTE, total bleeding, major bleeding, nonmajor bleeding, or all-cause death.
UNASSIGNED: In oncology patients receiving thromboprophylaxis, rivaroxaban has a lower incidence of thrombosis and other thrombosis and a similar incidence of VTE as LMWH and does not increase the risk of bleeding. Rivaroxaban may be an attractive alternative to LMWH for preventing VTE in hospitalized cancer patients.

UNASSIGNED: Limited understanding exists regarding the hemorrhagic risk resulting from potential interactions between P-glycoprotein (P-gp) inhibitors and direct oral anticoagulants (DOACs). Utilizing the Food and Drug Administration Adverse Event Reporting System (FAERS) data, we analyzed hemorrhagic adverse events (AEs) linked with the co-administration of P-gp inhibitors and DOACs, aiming to offer guidance for their safe and rational use.
UNASSIGNED: Hemorrhagic events associated with P-gp inhibitors in combination with DOACs were scrutinized from the FAERS database. Hemorrhagic signals mining was performed by estimating the reported odds ratios (RORs), corroborated by additive and multiplicative models and a combination risk ratio (PRR) model.
UNASSIGNED: Our analysis covered 4,417,195 cases, revealing 11,967 bleeding events associated with P-gp inhibitors. We observed a significantly higher risk of bleeding with the combination of apixaban and felodipine (ROR 118.84, 95% CI 78.12-180.79, additive model 0.545, multiplicative model 1.253, PRR 22.896 (2450.141)). Moreover, consistent associations were found in the co-administration analyzes of rivaroxaban with dronedarone and diltiazem, and apixaban with losartan, telmisartan, and simvastatin.
UNASSIGNED: Our FAERS data analysis unveils varying degrees of bleeding risk associated with the co-administration of P-gp inhibitors and DOACs, underscoring the importance of vigilance about them in clinical practice.

BACKGROUND: Direct oral anticoagulants (DOACs) are increasingly prescribed for life-long anticoagulation in chronic thromboembolic pulmonary hypertension (CTEPH) patients, despite not being recommended in the guidelines. This study aims to evaluate the efficacy and safety of DOACs in CTEPH patients.
METHODS: From May 2013 to December 2022, patients who were first diagnosed with CTEPH in Fuwai Hospital and started long-term anticoagulation treatment with warfarin or DOACs were retrospectively included and followed up until (1) death, (2) transition to other kinds of anticoagulants, or (3) discontinuation of anticoagulation. Propensity score matching was used to balance confounding bias of baseline characteristics. All-cause death, major bleeding, clinically relevant nonmajor bleeding and venous thromboembolism (VTE) recurrence were obtained and analysed.
RESULTS: After propensity score matching, 115 patients taking warfarin and 206 patients taking DOACs were included in our study and followed up for 5.5 [3.4, 7.1] years. There was no significant difference of survival between the warfarin and the DOAC group (p = 0.77). The exposure adjusted event rate of major bleeding (0.3 %/person-year vs 0.4 %/person-year, p = 0.705) and clinically relevant nonmajor bleeding (3.1 %/person-year vs 3.2 %/person-year, p > 0.999) was similar between two groups. The exposure adjusted rate of VTE recurrence was significantly higher in the DOAC group (1.5 %/person-year vs 0.3 %/person-year, p = 0.030).
CONCLUSIONS: In anticoagulation of CTEPH patients, DOACs have similar survival rate, similar risk of bleeding but higher risk of VTE recurrence than warfarin.

BACKGROUND: There are currently three strategies for the duration of LMWH lead-in before DOACs in patients with acute PE: one is at least 5 days, the other is at least 3 days, and the last one is less than 3 days. Which one is the best is yet unknown.
METHODS: We divided non-high-risk PE patients into short-LMWH (LMWH <3 days), intermediate-LMWH (LMWH 3-5 days), and long-LMWH (LMWH >5 days) groups, in a 1:1:2 ratio by using propensity score matching. Primary outcomes were a composite of mortality including all-cause and PE-related mortality, VTE recurrence, and major bleeding, as well as each one of them, at 3-month after PE diagnosis.
RESULTS: The short-LMWH group (N = 504) had higher 3-month composite primary outcome (129 [25.6%] vs 67 [13.3%], P < 0.001), all-cause mortality (112 [22.2%] vs 39 [7.7%], P < 0.001), and PE-related mortality (48 [9.5%] vs 17 [3.4%], P < 0.001), than the intermediate-LMWH group (N = 504). The short-LMWH group also had higher 3-month composite primary outcome (129 [25.6%] vs 151 [15.0%], P < 0.001), all-cause mortality (112 [22.2%] vs 90 [8.9%], P < 0.001), and PE-related mortality (48 [9.5%] vs 41 [4.1%], P < 0.001) than the long-LMWH group (N = 1008). The VTE recurrence and major bleeding rates were similar between the short-LMWH and intermediate-LMWH groups, and between the short-LMWH and long-LMWH groups. The intermediate-LMWH and long-LMWH groups had similar 3-month primary outcomes rates in whole or in part with each other.
CONCLUSIONS: For patients with non-high-risk acute PE, the optimal duration of initial LMWH lead-in before switching to DOACs could be 3 to 5 days.