Dasatinib induces endothelial dysfunction leading to impaired recovery from ischaemia.

Chronic myeloid leukaemia (CML) management is complicated by treatment-emergent vascular adverse events seen with tyrosine kinase inhibitors (TKIs) such as nilotinib, dasatinib and ponatinib. Pleural effusion and pulmonary arterial hypertension (PAH) have been associated with dasatinib treatment. Endothelial dysfunction and impaired angiogenesis are hallmarks of PAH. In this study, we explored, at cellular and whole animal levels, the connection between dasatinib exposure and disruption of endothelial barrier integrity and function, leading to impaired angiogenesis. Understanding the mechanisms whereby dasatinib initiates PAH will provide opportunities for intervention and prevention of such adverse effects, and for future development of safer TKIs, thereby improving CML management.

Effectiveness of the BNT162b2mRNA COVID-19 vaccine in patients with hematological neoplasms in a nationwide mass vaccination setting.

Evidence regarding the effectiveness of COVID-19 vaccine in patients with impaired immunity is limited. Initial observations suggest a lower humoral response in these patients. We evaluated the relative effectiveness of the mRNA BNT162b2 vaccine in patients with hematological neoplasms compared with matched controls. Data on patients with hematological neoplasms after 2 vaccine doses were extracted and matched 1:1 with vaccinated controls. Subpopulation analyses focused on patients receiving therapy for hematological neoplasm, patients without treatment who were only followed, and recipients of specific treatments. The analysis focused on COVID-19 outcomes from days 7 through 43 after the second vaccine dose in these areas: documented COVID-19 infection by polymerase chain reaction; symptomatic infection; hospitalizations; severe COVID-19 disease; and COVID-19-related death. In a population of 4.7 million insured people, 32 516 patients with hematological neoplasms were identified, of whom 5017 were receiving therapy for an active disease. Vaccinated patients with hematological neoplasms, compared with vaccinated matched controls, had an increased risk of documented infections (relative risk [RR] 1.60, 95% CI 1.12-2.37); symptomatic COVID-19 (RR 1.72, 95% CI 1.05-2.85); COVID-19-related hospitalizations (RR 3.13, 95% CI 1.68-7.08); severe COVID-19 (RR 2.27, 95% CI 1.18-5.19); and COVID-19-related death (RR 1.66, 95% CI 0.72-4.47). Limiting the analysis to patients on hematological treatments showed a higher increased risk. This analysis shows that vaccinated patients with hematological neoplasms, in particular patients receiving treatment, suffer from COVID-19 outcomes more than vaccinated individuals with intact immune system. Ways to enhance COVID-19 immunity in this patient population, such as additional doses, should be explored.

Efficacy and safety of rivaroxaban versus apixaban for venous thromboembolism: A systematic review and meta-analysis of observational studies.

BACKGROUND: Direct-acting oral anticoagulants (DOACs) including rivaroxaban and apixaban are preferred over vitamin K antagonists for the treatment of venous thromboembolism (VTE). We conducted a systematic review and a meta-analysis to compare the efficacy and safety of rivaroxaban versus apixaban in the treatment of VTE. METHODS: We conducted an electronic search for studies that directly compared treatment with rivaroxaban and apixaban in adult patients with VTE. The relative risks (RRs) and 95% confidence intervals (CIs) were estimated and pooled using a fixed-effect model unless significant heterogeneity was present (I2 > 40%), then random-effects model was used. The primary efficacy and safety outcomes were recurrent VTE (rVTE) and major bleeding events, respectively. RESULTS: Nine observational studies were included in our meta-analysis, assessing 24,156 patients for apixaban and 38,847 for rivaroxaban. Pooling of data for our primary efficacy outcome showed a trend towards lower risk of rVTE with apixaban compared to rivaroxaban (RR 0.77, 95% CI 0.57-1.04, I2 = 53%). Analysis of our primary safety outcome showed a significantly lower risk of major bleeding with apixaban compared to rivaroxaban (RR 0.68, 95% CI 0.61-0.76, I2 = 0%). Apixaban was associated with significantly decreased risk of net clinical harm, clinically relevant non major bleeding (CRNMB) and any bleeding, compared to rivaroxaban (RR 0.75, 95% CI 0.61-0.92, I2 = 50%; RR 0.58, 95% CI 0.50-0.67, I2 = 7%; RR 0.64, 95% CI 0.59-0.70, I2 = 0%, respectively). CONCLUSIONS: Apixaban is associated with a significantly lower risk of major bleeding compared to rivaroxaban for treatment of VTE. Given the limitations of the existing evidence, further interventional studies comparing the two drugs are needed.

Arterial and Venous Thromboembolism in ALK-Rearrangement-Positive Non-small Cell Lung Cancer: A Population-Based Cohort Study.

INTRODUCTION: There is scarce data regarding the incidence of venous thromboembolism (VTE) and arterial thromboembolism (ATE) in the molecular subtypes of non-small cell lung cancer (NSCLC). We aimed to investigate the association between Anaplastic Lymphoma Kinase (ALK)-positive NSCLC and thromboembolic events. METHODS: A retrospective population-based cohort study of the Clalit Health Services database, included patients with NSCLC diagnosed between 2012 and 2019. Patients exposed to ALK-tyrosine-kinase inhibitors (TKIs) were defined as ALK-positive. The outcome was VTE (at any site) or ATE (stroke or myocardial infarction) 6 months prior to the diagnosis of cancer, until 5 years post-diagnosis. The cumulative incidence of VTE and ATE and hazard-ratios (HR) with 95% CIs were calculated (at 6- 12- 24 and 60-months), using death as a competing risk. Cox proportional hazards multivariate regression was performed, with the Fine and Gray correction for competing risks. RESULTS: The study included 4762 patients, of which 155 (3.2%) were ALK-positive. The overall 5-year VTE incidence was 15.7% (95% CI, 14.7-16.6%). ALK-positive patients had a higher VTE risk compared to ALK-negative patients (HR 1.87 [95% CI, 1.31-2.68]) and a 12-month VTE incidence of 17.7% (13.9-22.7%) compared to 9.9% (9.1-10.9%) in ALK-negative patients. The overall 5-year ATE incidence was 7.6% [6.8-8.6%]. ALK positivity was not associated with ATE incidence (HR 1.24 [0.62-2.47]). CONCLUSIONS: In this study, we observed a higher VTE risk, but not ATE risk, in patients with ALK-rearranged NSCLC relative to those without ALK rearrangement. Prospective studies are warranted to evaluate thromboprophylaxis in ALK-positive NSCLC.

Direct oral anticoagulants in patients with venous thromboembolism and hematological malignancies.

Data are needed on direct oral anticoagulants (DOACs) for the treatment of venous thromboembolism (VTE) in hematological malignancies (HM). Retrospective studies to date lacked a control group and did not focus on patients with VTE. Out aim was to assess the incidence of VTE recurrence and bleeding in HM patients treated with low molecular weight heparin (LMWH) or DOACs for acute VTE. This is a retrospective cohort study including patients with active HM and newly-diagnosed VTE, indexed on the first day of anticoagulation and followed for 12 months. The outcome was a composite of recurrent VTE, major bleeding or clinically relevant non-major bleeding. Cumulative incidence [95% confidence interval (CI)] was calculated for each anticoagulation group (LMWH, DOAC) and hazard ratios (HR) were calculated using cox-proportional hazards model, with death as a competing risk. 143 HM patients treated with LMWH (96) or DOACs (47) for acute VTE were included. The most common HM types were lymphoma in 83 (58%) and plasma cell dyscrasia in 32 (22.3%). The 12-month cumulative incidence of the composite outcome was 24.2% (95% CI 15.9-33.5%; n = 22) in the LMWH group and 18.5% (8.5-31.5%; n = 8) in the DOAC group (HR 1.51 [0.695-3.297]). Two recurrent VTE occurred (both in the DOAC group while off-treatment). Nine (9.4%) LMWH-treated patients had major bleeding compared to 1 (2.1%) DOAC-treated patient (HR 4.85 [0.64-36.56]). This study generates the hypothesis that DOACs may be a safe and effective alternative to LMWH for VTE in patients with HM types represented in the study.

Prevalence and Clinical Characteristics of Paraproteinemia Associated with Chronic Myeloid Leukemia.

INTRODUCTION: Data regarding the prevalence of paraproteinemia in patients with chronic myeloid leukemia (CML) are lacking. METHODS: To evaluate for the prevalence of paraproteinemia, we undertook this cross-sectional study among consecutive chronic-phase CML patients. Complete blood count, chemistry, immunoglobulins, serum-free light chains, serum-protein electrophoresis and immunofixation were collected. Further analyses evaluated whether various patient-, disease-, and treatment-related variables are associated with paraproteinemia. RESULTS: One hundred patients, median age 63.5 (IQR 48.1-72) years were recruited. Median time from CML diagnosis to enrollment was 6.3 (IQR 2.3-11.3) years. Monoclonal protein was detected in 8 patients (8%), diagnosed with smoldering multiple myeloma (SMM, n = 2) and low-risk monoclonal gammopathy of undetermined significance (MGUS, n = 6). Six patients were on tyrosine kinase inhibitor treatment, 2 were in treatment-free remission. The only covariate associated with paraproteinemia was the presence of anemia, albeit with borderline statistical significance in univariate analysis (p = 0.053) and when adjusted for age (p = 0.056). CONCLUSIONS: In this largest study so far describing the prevalence of paraproteinemia among CML patients, we found MGUS prevalence to be higher than the 3.2% expected prevalence in the general population above 50 years and a non-negligible prevalence of SMM (2%). Screening for paraproteinemia in CML patients, especially in the presence of anemia, should be considered.

Exacerbation of immune thrombocytopenia following initial and booster vaccination with Pfizer-BioNTech COVID-19 vaccine.

As the immune thrombocytopenia exacerbation rate after booster COVID-19 vaccines is unknown, we explore the rates after first, second and booster Pfizer-BioNTech COVID-19 vaccines. A retrospective study of adult ITP patients, receiving 1-3 vaccines was performed. The primary outcome was clinical ITP exacerbation defined as platelet count decrease requiring initiation/escalation of ITP treatment and/or new medical attention due to bleeding, within 3 months. Secondary outcome was any clinically relevant platelet decrease during the 3 months post-vaccination. The study included 93 ITP patients receiving 1 (n = 2), 2 (n = 22) or 3 (n = 69) vaccines. ITP exacerbation occurred in 2/93 (2.2%) patients following initial vaccination and in 3/69 (4.3%) following booster dose. Clinically relevant platelet decreases after initial doses occurred in 8/72 (11.1%) patients and in 8/39 (20.5%) after the booster. Clinical ITP exacerbation after booster doses did not follow clinical exacerbation after initial doses. Half of patients with clinically relevant platelet decreases after booster dose also had clinically relevant decreases following initial vaccination. We concluded that clinical ITP exacerbation is infrequent following Pfizer-BioNTech COVID-19 vaccine. Clinical exacerbation after booster doses was not preceded by clinical exacerbation after initial doses. Clinically relevant platelet decreases after booster doses occur frequently in patients with clinically relevant decreases after initial doses.

Targeted therapies for immune thrombocytopenic purpura: a meta-analysis of randomized controlled trials.

Several targeted therapies have been approved in recent years for second-line treatment of immune thrombocytopenic purpura (ITP), providing an alternative to rituximab and splenectomy. The extent to which these drugs reduce bleeding risk has not been well defined. Targeted therapies recently approved for the treatment of ITP in adults were identified through a search of recently published professional guidelines. Randomized controlled trials (RCTs) supporting regulatory approval were identified through a search of drug labels on FDA@gov. Odds ratios (ORs) and associated 95% confidence intervals (CIs) were computed for pre-specified efficacy outcomes including platelet recovery to ≥ 50,000/µL, major and minor bleeding events, and survival. ORs for all adverse events were also computed. Four targeted therapies were identified, including three thrombopoietin receptor agonists and one tyrosine kinase inhibitor. Six RCTs, comprising 752 patients, were included in the meta-analysis. More patients treated with targeted therapies for ITP as compared to placebo achieved platelet counts over ≥ 50,000/µL (OR 8.29, 95% CI 5.59-12.29). Compared to placebo, targeted therapies for ITP were associated with significantly lower odds for major bleeding (OR 0.43, 95% CI 0.21-0.91), minor bleeding (OR 0.66, 95% CI 0.45-0.97), and with numerically lower mortality rates (OR 0.24, 95% CI 0.05-1.07). The odds for adverse events were comparable between the two arms (OR 1.43 95% CI 0.76-2.67). Compared to placebo, targeted therapies for ITP increase platelet counts, decrease bleeding events, and show a trend towards lower mortality, without increased toxicity. These findings support their use as a second-line ITP treatment.

Management and Outcome of Venous Thrombosis in Patients with Myeloproliferative Neoplasms: Data from the Israeli MPN Working Group.

The BCR-ABL-negative myeloproliferative neoplasms (MPN) are associated with high incidence of venous thrombosis and a significant rate of recurrent events, but there is no consensus regarding their management. In this retrospective study, we analyzed 96 patients with MPN-related venous thrombosis. The index venous thrombosis occurred at a median age of 58 years (IQR 37-71), with 58% of the events involving unusual sites. Patients who were on antiplatelet agents at the time of index thrombosis tended to be older than patients who were not receiving antiplatelets at the time of index thrombosis. The majority of index thromboses occurring after the diagnosis of MPN had uncontrolled blood counts at the time of event and were not receiving antithrombotic agents. Following the thrombotic episode, 75% of patients received long-term anticoagulation. At a median follow-up of 3.4 years, the recurrence rate was 14%. Thrombophilia was significantly more prevalent among patients with recurrent thrombosis compared to patients without recurrence (p < 0.01). Patients who developed a recurrent event early were more likely to have thrombophilia (either inherited or antiphospholipid antibodies), and controlled blood counts, and were likely to receive anticoagulation at the time of recurrence compared to patients with later recurrences. Thrombophilia may contribute to venous thrombosis recurrence, especially early after the index venous thrombosis. Suboptimal anticoagulation and blood count control are factors associated with late venous thrombosis recurrence.

Anticoagulation in patients with atrial fibrillation, thrombocytopenia and hematological malignancy.

Managing anticoagulation in hematological malignancy patients with atrial fibrillation and thrombocytopenia is a clinical challenge with limited data. We aimed to identify anticoagulation management strategies and evaluate bleeding and thrombosis rates associated with each approach. A retrospective cohort study in Israel and the Netherlands was conducted. Patients with hematological malignancy and atrial fibrillation were indexed when platelets were < 50 × 109/L and followed for 30 days. The cohort included 61 patients of whom 42 (69%) had anticoagulation held at index. On multivariate analysis, holding anticoagulation was associated with age < 65 years and atrial fibrillation diagnosed within 30 days prior index. Clinically relevant bleeding was diagnosed in 7 (16.7%) and 1 (5.3%) of patients who had anticoagulation held and continued respectively, while arterial thromboembolism occurred in 1 patient in each group (2.4% and 5.3%, respectively). All-cause mortality rate was high at 45%. Accordingly, the 30-day bleeding risk may outweigh the risk of arterial thromboembolism in hematological malignancy, platelets < 50 × 109/L and atrial fibrillation.

Thrombosis, anticoagulation and outcomes in malignant superior vena cava syndrome.

Anticoagulation is often used in superior vena cava syndrome (SVCS) associated with cancer (i.e malignant SVCS), even without thrombosis, but its effect on outcomes has not been reported. We aimed to determine factors and outcomes associated with thrombosis and anticoagulation in malignant SVCS. Patients with malignant SVCS diagnosed on computerized tomography (CT) were retrospectively included, indexed at diagnosis and followed for 6 months using medical records. The cohort included 183 patients with malignant SVCS of which 153 (84%) were symptomatic. Thirty of the 127 patients (24%) with a reviewable baseline CT had thrombosis of the SVC or tributaries at diagnosis. Patients with baseline thrombosis more often had symptomatic SVCS (p < 0.01). 70% (21/30) of patients with thrombosis and 52% (49/97) of those without thrombosis at baseline received anticoagulation, most often at therapeutic doses. Thrombosis occurred in 5/39 patients with anticoagulation (13%) compared to 2/18 (11%) of those without, during follow-up (p = 0.85). Anticoagulation was associated with a reduction in risk of SVC stent placement during follow-up that did not reach statistical significance (HR 0.47, 95% CI 0.2-1.13, p = 0.09). Major bleeding occurred in 7 (4%) patients, six of whom received anticoagulation (four therapeutic and two intermediate dose). Neither thrombosis nor anticoagulation affected survival. Anticoagulation is commonly used as primary prevention but its benefit remains to be proven. The role of reduced-dose anticoagulation in non-thrombotic malignant SVCS should be prospectively assessed.

Computed Tomography Findings Associated With 30-Day Mortality in Patients With Malignant Superior Vena Cava Syndrome.

OBJECTIVE: The objective of this study was to identify radiological and clinical factors associated with early mortality in malignant superior vena cava syndrome (SVCS). MATERIALS AND METHODS: Chest computed tomography studies of 127 patients with malignancy-associated SVCS were retrospectively reviewed. Involvement of SVC and tributaries, pleural and pericardial effusions, pulmonary artery involvement, and ancillary findings were documented. Univariate and multivariate models determined associations between radiological and clinical variables, and 30-day mortality. RESULTS: Thirty-day mortality rate was 16.5% (n = 21). Factors associated with 30-day mortality on univariate analysis included age, cancer stage, SVCS clinical severity, left jugular vein obstruction, number of involved veins, pulmonary arteries involvement, and presence of pleural effusions. Age, SVCS clinical severity, number of veins involved, and pleural effusions were positively associated with 30-day mortality on multivariate analysis. CONCLUSIONS: Selected clinical and radiological variables are associated with early death in malignant SVCS. These factors may identify a subgroup of patients who may benefit from treatment escalation.

[ADHERENCE TO ORAL ANTI-CANCER DRUGS IN HEMATO-ONCOLOGY].

INTRODUCTION: Non-adherence to medical treatment is prevalent in the context of potentially life-saving treatment for diseases such as cancer. Estimates of non-adherence to oral anti-cancer therapy range between 27% and 63% in studies of cancer patients. This represents a growing challenge, due to the paradigm shift in anti-cancer treatment from parenteral chemotherapy to oral anti-cancer drugs. The importance of adherence to medical treatment is highlighted by the World Health Organization which considers non-adherence to be a major public health concern. Studies in several malignancies have shown an adverse effect of nonadherence on treatment response, survival and quality of life, accompanied by an increase in health-care related costs. The clinical vignette accompanying this review demonstrates the complexity of management of adherence to oral anticancer therapy, through an example of an elderly chronic myeloid leukemia patient, non-adherent to serial tyrosine kinase inhibitors (imatinib, dasatinib). Her non-adherence was explained by subtle socio-demographic, patient-related and treatment-related factors, which in hindsight could have already been identified at diagnosis, resulting in preemptive management of these barriers and adherence. Routine management by the hematologist, using education alone resulted in improvement of adherence, which was predictably short-lived. Our use of a multilevel and multidisciplinary adherence-enhancing intervention, incorporating feedback based on electronic monitoring of adherence, resulted in improved adherence and treatment response in this patient. This exemplifies the contemporary evidence-based approach to non-adherence to oral-anticancer therapy.

First line treatment with newer tyrosine kinase inhibitors in chronic myeloid leukemia associated with deep and durable molecular response - systematic review and meta-analysis.

BACKGROUND: The choice of a specific tyrosine kinase inhibitor (TKI) as first line treatment in chronic myeloid leukemia (CML) is complex and influenced by multiple factors. We published a meta-analysis examining the role of newer TKIs as first line treatment in chronic phase CML. In view of the recently published data, we decided to update it. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials comparing first line treatment with imatinib to the newer TKIs (nilotinib, dasatinib, bosutinib and ponatinib). We searched MEDLINE, conference proceedings and databases of ongoing trials up to August 2015. RESULTS: Our search yielded eight trials including 3554 patients. Treatment with the newer TKIs significantly improved major molecular response (MMR) at all time points and increased the rate of complete molecular response (CMR) at 12 and 24 months [relative risk (RR) 2.58, 95% CI 1.98-3.37, six trials and RR 2.05, 95% CI 1.63-2.58, three trials, respectively]. Early molecular response at three months was better with the newer TKIs (RR 1.33, 95% CI 1.26-1.40, six trials). Importantly, progression rate to accelerated or blastic phase was significantly lower with the newer TKIs at 12, 24 months and 5 years. Yet, there was no difference in all-cause mortality. The risk of adverse events requiring treatment discontinuation increased with the newer TKIs. CONCLUSIONS: With a longer follow-up, the newer TKIs remain more potent than imatinib, yet with no significant effect on survival. As CMR is a prerequisite for treatment discontinuation and cure, the newer TKIs favor treatment cessation.

High-Intensity Induction Chemotherapy Is Feasible for Elderly Patients with Acute Myeloid Leukemia.

BACKGROUND: The prognosis of elderly patients with acute myeloid leukemia (AML) is poor, and the best treatment is controversial. Since the majority of AML patients are older than 60 years, identification of those who might benefit from intensive treatment is essential. METHODS: Data from electronic charts of consecutive AML patients treated in our center were analyzed. Eligibility criteria included newly diagnosed de novo or secondary AML, an age of 60 years or older, and intensive induction treatment. RESULTS: Sixty-two patients were included in the analysis. Forty-six patients (74%) achieved complete remission (CR) after 1-2 intensive induction courses. Twenty of them received consolidation with conventional chemotherapy, 20 proceeded to allogeneic hematopoietic cell transplantation (allo-HCT), and 6 were ineligible for further treatment. The projected overall survival (OS) at 2 and 3 years was 28 and 23%, respectively. A normal karyotype, CR achievement, and allo-HCT were associated with improved OS, while an Eastern Cooperative Oncology Group performance status of 0-1 was borderline associated. The median survival and disease-free survival at 2 years was 18.7 months and 49%, respectively, for patients who underwent allo-HCT in CR1, compared to 12.8 months and 25%, respectively, for those who did not. CONCLUSION: Based on our data, selected eligible elderly AML patients might benefit from intensive treatment.

Adherence-related issues in adolescents and young adults with hematological disorders.

Nonadherence to medical recommendations is a widespread problem well documented in a multitude of clinical settings. Nonadherence may adversely affect clinical outcomes such as survival and quality of life and increase health-care-related costs. An understanding of the factors driving nonadherence is key to developing effective adherence-enhancing interventions (AEIs). There are ongoing attempts in contemporary adherence research to better define the various components of adherence, to find optimal measures of adherence and correlations with clinical outcomes, and to create a classification system for AEIs. Nonadherence is also widely prevalent among adolescents and young adults (AYAs) with chronic hematological diseases, affecting up to 50% of patients and increasing with age. Combined use of objective (i.e. electronic monitoring, EM) and subjective (i.e. self-report) measures of adherence may be the preferred approach to assess adherence. The unique physical, social and emotional aspects of the AYA life stage are closely related to intricate causes of nonadherence in AYAs such as problems in transition to adult care. Until proven otherwise, the empirical target in AYAs with hematological disorders should be perfect adherence. Multilevel AEIs, EM feedback and behavioral interventions are among the most effective types of AEIs. Despite the magnitude of the problem, only a handful of AEIs have been evaluated among AYAs with hematological disorders. Thus, this is a field with unmet needs warranting high-quality trials using standardized and well-specified assessment methods and interventions. This review discusses the prevalence, definition, causes and clinical implications of nonadherence among AYAs with hematological disorders, along with strategies to measure and improve adherence.

Cancer and arterial thrombosis: therapeutic options.

A State of the Art lecture titled "Cancer and Arterial Thrombosis: Therapeutic Options" was presented at the International Society on Thrombosis and Haemostasis Congress in 2023. This State of the Art review delves into the complex relationship between cancer and arterial thromboembolism (ATE), encompassing acute coronary syndrome, ischemic strokes, and peripheral arterial disease. The burden of cancer-associated ATE is not well defined, but studies indicate elevated risks, particularly in the 6 months after a cancer diagnosis. Incidence varies among cancer subtypes, with lung cancer displaying the highest rates. Additionally, the pathophysiology of cancer-associated ATE involves a multifaceted interplay of cancer-induced hypercoagulopathy, cancer therapy-related thrombosis, and personal risk factor contributors. ATEs are clinically heterogeneous and in the context of cancer have particular mechanistic differences compared with ATE patients without cancer. This requires modifications in approach and tailored management considerations. Specific etiologies contributing to ATE, such as coronary vasospasm and non-bacterial-thrombotic endocarditis, need to be considered. The diagnosis of cancer alone usually does not contraindicate patients to standard guideline-based therapies for the management of ATE, although nuances in treatment may need to be considered in light of the underlying cancer. Atrial fibrillation in cancer patients further complicates the thrombotic landscape. Cancer patients with atrial fibrillation are at a higher risk of ATE, necessitating careful consideration of anticoagulation therapy as clinical benefits and bleeding risks need to be weighed. ATE may also be a presenting sign of underlying malignancy, which requires increased awareness and focused clinical evaluation for cancer in selected cases. Finally, we summarize relevant new data on this topic presented during the 2023 International Society on Thrombosis and Haemostasis Congress.

Drug-Drug Interactions Between Glucagon-Like Peptide 1 Receptor Agonists and Oral Medications: A Systematic Review.

BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP1RAs) are used in the treatment of diabetes and obesity. Their slowing effect of gastric emptying might change oral drug absorption, potentially affecting pharmacokinetics, particularly in the case of medications with a narrow therapeutic index. PURPOSE: The purpose of this systematic review is to summarize data on drug-drug interactions between GLP1RAs and oral drugs. DATA SOURCES: The PubMed and EMBASE databases were searched up to November, 1st 2023. STUDY SELECTION: We selected pharmacokinetic studies of any injectable GLP1RA given with an oral medication, and product prescribing sheets reporting data without access to the original study. DATA EXTRACTION: Two authors independently extracted the data. DATA SYNTHESIS: Twenty-two reports and six prescribing sheets were included. Treatment with GLP1RAs resulted in unaffected or reduced Cmax and delayed tmax of drugs with high solubility and permeability (warfarin, contraceptive pills, acetaminophen), drugs with high solubility and low permeability (angiotensin converting enzyme inhibitors), drugs with low solubility and high permeability (statins) and drugs with low solubility and permeability (digoxin). However, the use of GLP1RAs did not exert clinically significant changes in the AUC or differences in clinically relevant endpoints. LIMITATIONS: The major limitations of the studies that are included in this systematic review are the enrollment of healthy subjects and insufficient data in conditions that might affect pharmacokinetics (e.g., kidney dysfunction). CONCLUSIONS: To conclude, reduced Cmax and delayed tmax of drugs co-administered with GLP1RAs are consistent with the known delayed gastric output by the latter. Nevertheless, the overall drug exposure was not considered clinically significant. Dose adjustments are probably not required for simultaneous use of GLP1RAs with oral medications. Still, results should be carefully generalized to cases of background kidney dysfunction or when using drugs with narrow therapeutic index. The study is registered in PROSPERO: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022332339 .

Comparison of direct oral anticoagulants versus low-molecular-weight heparin in primary and metastatic brain cancers: a meta-analysis and systematic review.

BACKGROUND: The safety and efficacy of direct-acting oral anticoagulants (DOACs) for therapeutic anticoagulation in the setting of primary or metastatic brain cancer is not known. OBJECTIVES: To conduct a meta-analysis and systematic review of studies that compare the risk of intracranial hemorrhage (ICH) in patients with brain cancer treated with DOACs vs low-molecular-weight heparin (LMWH). METHODS: A literature search was conducted using PubMed, EMBASE, and Cochrane databases. Summary statistics were obtained by calculating the risk ratio (RR), and heterogeneity across studies was estimated using the I2 statistic. A total of 10 retrospective studies (n = 1638) met criteria for inclusion. The primary endpoint was the pooled RR for ICH in patients with brain tumors receiving anticoagulation with DOACs compared with those receiving LMWH. Secondary analyses included the risk of fatal ICH in each subgroup. RESULTS: The pooled RR for ICH in patients receiving DOACs vs those receiving LMWH was 0.65 (95% CI, 0.36-1.17; P = .15; I2 = 50%). In studies evaluating primary brain cancer, there was a reduction in risk of ICH with DOACs (RR, 0.35; 95% CI, 0.18-0.69; P = .003; I2 = 0%). In patients with metastatic brain cancer, there was no difference in the risk of ICH with the type of anticoagulation (RR, 1.05; 95% CI, 0.71-1.56; P = .80; I2 = 0%). The overall risk of fatal ICH was not different between anticoagulants. CONCLUSION: The risk of ICH in patients with brain cancer receiving therapeutic anticoagulation varies by anticoagulation agent and diagnosis of primary or metastatic disease.