Venous thromboembolism chemical prophylaxis after skull base surgery.

PURPOSE: There is no guidance surrounding postoperative venous thromboembolism (VTE) prophylaxis using pharmacological agents (chemoprophylaxis) in patients undergoing skull base surgery. The aim of this study was to compare VTE and intracranial haematoma rates after skull base surgery in patients treated with/without chemoprophylaxis. METHODS: Review of prospective quaternary centre database including adults undergoing first-time skull base surgery (2009-2020). VTE was defined as deep vein thrombosis (DVT) and pulmonary embolism (PE) within 6 months of surgery. Multivariate logistic regression was used to determine factors predictive of postoperative intracranial haematoma/VTE. Propensity score matching (PSM) was used in group comparisons. RESULTS: One thousand five hundred fifty-one patients were included with a median age of 52 years (range 16-89 years) and female predominance (62%). Postoperative chemoprophylaxis was used in 81% of patients at a median of 1 day postoperatively. There were 12 VTE events (1.2%), and the use of chemoprophylaxis did not negate the risk of VTE entirely (p > 0.99) and was highest on/after postoperative day 6 (9/12 VTE events). There were 18 intracranial haematomas (0.8%), and after PSM, chemoprophylaxis did not significantly increase the risk of an intracranial haematoma (p > 0.99). Patients administered chemoprophylaxis from postoperative days 1 and 2 had similar rates of intracranial haematomas (p = 0.60) and VTE (p = 0.60), affirmed in PSM. CONCLUSION: Postoperative chemoprophylaxis represents a relatively safe strategy in patients undergoing skull base surgery. We advocate a personalised approach to chemoprophylaxis and recommend it on postoperative days 1 or 2 when indicated.

Menopausal hormone therapy and risk of venous thromboembolism: The story so far.

Menopausal hormone therapy (MHT) is known to increase the risk of venous thromboembolism (VTE), which includes deep vein thrombosis, pulmonary embolism, and less frequently cerebral vein thrombosis, but the absolute risk for a given patient is very low. After starting MHT, the risk of VTE seems to be at its highest, declining to the non-HRT user baseline level of risk after stopping. Whether estrogen-only or estrogen-progestin HRT combination is linked to a similar risk of VTE is unclear from the available evidence. The aim of this study is to evaluate the risks of developing VTE in relation to different types as well as different modes of administration of MHT through a database search including PubMed, MEDLINE, Google Scholar, Cochrane Library, and others in order to provide the women carers with the up-to-date and evidence-based guidelines and recommendations while counseling the post-menopausal women enquiring on use of hormonal therapies either to alleviate the menopausal symptoms or to prevent the long-term sequelae of estrogen deficiency.

On sait que l'hormonothérapie ménopausique (MHT) augmente le risque de thromboembolie veineuse (TEV), qui comprend la thrombose veineuse profonde, l'embolie pulmonaire et, moins fréquemment, la thrombose veineuse cérébrale, mais le risque absolu pour un patient donné est très faible. Après le début du MHT, le risque de TEV semble être à son plus haut niveau, diminuant jusqu'au niveau de risque de base des non-utilisatrices de THS après l'arrêt. Les preuves disponibles ne permettent pas de savoir si un THS à base d'œstrogène seul ou d'association œstroprogestative est lié à un risque similaire de TEV. Le but de cette étude est d'évaluer les risques de développer une TEV par rapport à différents types ainsi qu'à différents modes d'administration du MHT grâce à une recherche dans des bases de données comprenant PubMed, MEDLINE, Google Scholar, Cochrane Library et autres afin de fournir aux femmes les soignants avec les lignes directrices et recommandations à jour et fondées sur des preuves tout en conseillant les femmes ménopausées qui se renseignent sur l'utilisation de thérapies hormonales, soit pour soulager les symptômes de la ménopause, soit pour prévenir les séquelles à long terme d'une carence en œstrogènes.

Fragility and long-term clinical outcomes in patients with venous thromboembolism receiving direct oral anticoagulants: From the COMMAND VTE REGISTRY-2.

INTRODUCTION: There is limited data on the safety of direct oral anticoagulants (DOACs) in fragile patients with venous thromboembolism (VTE). MATERIALS AND METHODS: We used the COMMAND VTE Registry-2 enrolling patients with acute symptomatic VTE. The study population consisted of 3928 patients receiving DOACs, who were divided into fragile (2136 patients) and non-fragile groups (1792 patients). Fragility was defined as patients of age ≥ 75 years, creatinine clearance level ≤ 50 ml/min, and/or body weight ≤ 50 kg. RESULTS: The fragile group significantly more often received reduced doses of DOACs compared to the non-fragile group (51 % and 19 %, P < 0.001). The cumulative 5-year incidence of major bleeding was numerically higher in the fragile group than the non-fragile group (15.0 % and 11.1 %, P = 0.052), even with no significant excess risk after adjusting for confounders (HR 1.03, 95%CI 0.81-1.31, P = 0.78). The cumulative 5-year incidence of clinically relevant bleeding was significantly higher in the fragile group than the non-fragile group (28.6 % and 19.6 %, P < 0.001), even after adjusting for confounders (HR 1.28, 95%CI 1.08-1.53, P = 0.005). There was no significant difference in cumulative 5-year incidence of recurrent VTE between the groups (9.6 % and 8.9 %, P = 0.68), which was consistent after adjusting for confounders (HR 1.13, 95%CI 0.84-1.51, P = 0.41). CONCLUSIONS: Among VTE patients receiving DOACs, fragile patients were associated with a numerically higher rate of major bleeding and a significantly increased risk of clinically relevant bleeding, but not an increased risk of recurrent VTE.

The risk and burden of thromboembolic and hemorrhagic events in patients with malignant gliomas receiving bevacizumab.

PURPOSE: Bevacizumab has evolved as an integral treatment option for patients with high-grade gliomas. Little is known about clinical risk factors that predispose patients with high-grade gliomas receiving bevacizumab to VTE or ICH. We sought to characterize the clinical risk factors associated with risk of either event. METHODS: In this multi-institutional retrospective study, we first evaluated patients with high-grade gliomas who were treated with bevacizumab at University of Texas MD Anderson Cancer Center from 2015-2021. We compared clinical and treatment-related factors among three cohorts: those who developed VTE, ICH, or neither. We further compared survival outcomes of these patients from the time of bevacizumab initiation. Then to further confirm our results in a non-cancer center hospital setting we evaluated patients from two Ascension Seton Hospitals in Austin, Texas which are affiliated with Dell Medical School at the University of Texas at Austin from 2017-2022. RESULTS: We found that the presence of cerebral macrobleeding, defined as a magnetic susceptibility of > 1 cm3 on magnetic resonance imaging, was highly associated with risk of developing ICH after initiation of bevacizumab. Development of ICH was significantly associated with poorer survival outcomes. We did not find a statistically significant effect of VTE on survival after bevacizumab initiation. CONCLUSION: In order to stratify the risk for developing ICH before the initiation of bevacizumab, we recommend to assess for the presence of cerebral macrobleeding as it is associated with ICH development.

Does anticoagulation in combination with immunosuppressive therapy prevent recurrent thrombosis in Behçet's disease?

Vascular involvement in Behçet's disease (BD) occurs in up to 50% of patients. The main mechanism of thrombosis is inflammation. Thus, immunosuppressants (IS) are the mainstay of therapy, and adding anticoagulation (AC) is controversial. In daily practice, we observed that patients who received AC in combination with IS experienced less recurrent thrombosis and decided to investigate our BD patients retrospectively. We hypothesized that adding AC to immunosuppressive therapy may lower the risk of recurrent thrombosis. Treatment at the time of first or recurrent thrombotic events was recorded. Events under the only IS and IS + AC treatments were compared. There were 40 patients (33 males). The most common types of first vascular events were deep vein thrombosis (77.5%) followed by pulmonary embolism (PE) (52.5%). One patient did not receive any treatment. Among the 39 patients, 32 received glucocorticoid and at least one of the azathioprine, or cyclophosphamide, anti-TNF, 5 received monotherapy with azathioprine, 1 received monotherapy with corticosteroid, and the remaining 1 received monotherapy with cyclophosphamide. In total, 22 patients (55%) experienced 27 recurrent venous thromboembolism (VTE) events. Two (7.4%) events while only on AC, 2 (7.4%) events while on AC + IS, and 15 (55.5%) events occurred while on only IS. Eight (19.6%) patients were not receiving any treatment during relapses. The recurrence rate was statistically significantly lower in the IS + AC treatment group compared to IS alone. In conclusion, IS are the mainstay of treatment for BD, and adding AC may help to lower the recurrence risk of thrombotic events.

The value of performance status in predicting venous thromboembolism in lung cancer patients treated with immune checkpoint inhibitors.

INTRODUCTION: The incidence of venous thromboembolism (VTE) is notably high in lung cancer patients, particularly among those treated with immune checkpoint inhibitors (ICIs). Previous studies have focused on the relationship between Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) and VTE risk in immune checkpoint inhibitor therapy, but available evidence is inconsistent. METHODS: The clinical data of lung cancer patients treated with ICIs were collected and analyzed from West China Hospital between January 2018 and March 2022. ECOG PS score was measured on admission. The primary outcome was the incidence of VTE, encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE). Multivariate logistic regression analysis was conducted to calculate the odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: A total of 1115 lung cancer patients receiving ICIs were eligible for this study, VTE developed in 105 (9.4%) during the 12-month follow-up, of which 95 (8.5%) had DVT,14 (1.3%) had definite PE. Poor ECOG PS (PS ≥ 2) was associated with an increased risk for VTE (OR = 5.405, 95% CI = 3.067-9.525, P < 0.001), DVT (OR = 4.669, 95% CI = 2.588-8.427, P < 0.001) and PE (OR = 8.413, 95% CI = 2.565-27.600, P < 0.001) after multivariable adjustment in the study cohort. CONCLUSION: VTE occurred in 9.4% of lung cancer patients treated with ICIs, and poor performance status was associated with an increased risk of VTE.

Effect of Aspirin Versus Low-Molecular-Weight Heparin Thromboprophylaxis on Medication Satisfaction and Out-of-Pocket Costs: A Secondary Analysis of a Randomized Clinical Trial.

BACKGROUND: Current guidelines recommend low-molecular-weight heparin for thromboprophylaxis after orthopaedic trauma. However, recent evidence suggests that aspirin is similar in efficacy and safety. To understand patients' experiences with these medications, we compared patients' satisfaction and out-of-pocket costs after thromboprophylaxis with aspirin versus low-molecular-weight heparin. METHODS: This study was a secondary analysis of the PREVENTion of CLots in Orthopaedic Trauma (PREVENT CLOT) trial, conducted at 21 trauma centers in the U.S. and Canada. We included adult patients with an operatively treated extremity fracture or a pelvic or acetabular fracture. Patients were randomly assigned to receive 30 mg of low-molecular-weight heparin (enoxaparin) twice daily or 81 mg of aspirin twice daily for thromboprophylaxis. The duration of the thromboprophylaxis, including post-discharge prescription, was based on hospital protocols. The study outcomes included patient satisfaction with and out-of-pocket costs for their thromboprophylactic medication measured on ordinal scales. RESULTS: The trial enrolled 12,211 patients (mean age and standard deviation [SD], 45 ± 18 years; 62% male), 9725 of whom completed the question regarding their satisfaction with the medication and 6723 of whom reported their out-of-pocket costs. The odds of greater satisfaction were 2.6 times higher for patients assigned to aspirin than those assigned to low-molecular-weight heparin (odds ratio [OR]: 2.59; 95% confidence interval [CI]: 2.39 to 2.80; p < 0.001). Overall, the odds of incurring any out-of-pocket costs for thromboprophylaxis medication were 51% higher for patients assigned to aspirin compared with low-molecular-weight heparin (OR: 1.51; 95% CI: 1.37 to 1.66; p < 0.001). However, patients assigned to aspirin had substantially lower odds of out-of-pocket costs of at least $25 (OR: 0.15; 95% CI: 0.12 to 0.18; p < 0.001). CONCLUSIONS: Use of aspirin substantially improved patients' satisfaction with their medication after orthopaedic trauma. While aspirin use increased the odds of incurring any out-of-pocket costs, it protected against costs of ≥$25, potentially improving health equity for thromboprophylaxis. LEVEL OF EVIDENCE: Therapeutic Level II . See Instructions for Authors for a complete description of levels of evidence.

Tofacitinib Is Associated With Increased Risk of Postoperative Venous Thromboembolism in Patients With Ulcerative Colitis.

BACKGROUND: In 2019, the Food and Drug Administration issued a black box warning for increased risk of venous thromboembolism in patients with rheumatoid arthritis exposed to tofacitinib. There are limited data regarding postoperative venous thromboembolism risk in patients with ulcerative colitis exposed to tofacitinib. OBJECTIVE: To assess whether preoperative exposure to tofacitinib is associated with increased odds of postoperative venous thromboembolism. DESIGN: Retrospective review. SETTINGS: Tertiary academic medical center. PATIENTS: Consecutive patients exposed to tofacitinib within 4 weeks before total abdominal colectomy or total proctocolectomy, with or without ileostomy, from 2014 to 2021, matched 1:2 for tofacitinib exposure or no exposure. INTERVENTION: Tofacitinib exposure versus no exposure. MAIN OUTCOME MEASURES: Ninety-day postoperative venous thromboembolism rate. RESULTS: Forty-two patients with tofacitinib exposure and 84 case-matched patients without tofacitinib exposure underwent surgery for medically refractory ulcerative colitis. Nine (22.0%) tofacitinib-exposed patients and 7 (8.5%) unexposed patients were diagnosed with venous thromboembolism within 90 days of surgery. In univariate logistic regression, patients exposed to tofacitinib had 3.01 times increased odds of developing venous thromboembolism within 90 days after surgery compared to unexposed patients ( p = 0.04; 95% CI, 1.03-8.79). Other venous thromboembolism risk factors were not significantly associated with venous thromboembolisms. Venous thromboembolisms in both groups were most commonly portomesenteric vein thromboses (66.7% in the tofacitinib-exposed group and 42.9% in the unexposed group) and were diagnosed at a mean of 23.2 days (range, 3-90 days) postoperatively in the tofacitinib-exposed group and 7.9 days (1-19 days) in the unexposed group. There were no statistically significant differences in location or timing between the 2 groups. LIMITATIONS: Retrospective nature of the study and associated biases. Reliance on clinically diagnosed venous thromboembolisms may underreport the true incidence rate. CONCLUSIONS: Tofacitinib exposure before surgery for medically refractory ulcerative colitis is associated with 3 times increased odds of venous thromboembolism compared with patients without tofacitinib exposure. See Video Abstract . TOFACITINIB SE ASOCIA CON UN MAYOR RIESGO DE TROMBOEMBOLISMO VENOSO POSTOPERATORIO EN PACIENTES CON COLITIS ULCEROSA: ANTECEDENTES:En 2019, la FDA emitió una advertencia de recuadro negro sobre un mayor riesgo de tromboembolismo venoso en pacientes con artritis reumatoide expuestos a tofacitinib. Hay datos limitados sobre el riesgo de tromboembolismo venoso postoperatorio en pacientes con colitis ulcerosa expuestos a tofacitinib.OBJETIVO:Evaluar si la exposición preoperatoria a tofacitinib se asocia con mayores probabilidades de tromboembolismo venoso postoperatorio.DISEÑO:Revisión retrospectiva.LUGARES:Centro médico académico terciario.PACIENTES:Pacientes consecutivos expuestos a tofacitinib dentro de las 4 semanas previas a la colectomía abdominal total o proctocolectomía total, con o sin ileostomía, entre 2014 y 2021, emparejados 1:2 para exposición a tofacitinib o ninguna exposición.INTERVENCIÓN(S):Exposición a tofacitinib versus ninguna exposición.PRINCIPALES MEDIDAS DE RESULTADO:Tasa de tromboembolismo venoso posoperatorio a los 90 días.RESULTADOS:Cuarenta y dos pacientes con exposición a tofacitinib y 84 pacientes de casos similares sin exposición a tofacitinib se sometieron a cirugía por colitis ulcerosa médicamente refractaria. Nueve (22,0%) pacientes expuestos a tofacitinib y 7 (8,5%) pacientes no expuestos fueron diagnosticados con tromboembolismo venoso dentro de los 90 días posteriores a la cirugía. En la regresión logística univariada, los pacientes expuestos a tofacitinib tuvieron 3,01 veces más probabilidades de desarrollar un tromboembolismo venoso dentro de los 90 días posteriores a la cirugía en comparación con los no expuestos ( p = 0,04, IC del 95 %: 1,03-8,79). Otros factores de riesgo de tromboembolismo venoso no se asociaron significativamente con el tromboembolismo venoso. Los tromboembolismos venosos en ambos grupos fueron más comúnmente trombosis de la vena portomesentérica (66,7% en los expuestos a tofacitinib y 42,9% en los no expuestos) y se diagnosticaron en una media de 23,2 días (rango, 3-90 días) después de la operación en los expuestos a tofacitinib y 7,9 días. (1-19 días) en los grupos no expuestos, respectivamente. No hubo diferencias estadísticamente significativas en la ubicación o el momento entre los dos grupos.LIMITACIONES:Carácter retrospectivo del estudio y sesgos asociados. La dependencia de tromboembolismos venosos diagnosticados clínicamente puede subestimar la tasa de incidencia real.CONCLUSIONES:La exposición a tofacitinib antes de la cirugía para la colitis ulcerosa médicamente refractaria se asocia con probabilidades 3 veces mayores de tromboembolismo venoso en comparación con los pacientes sin exposición a tofacitinib. (Traducción-Dr. Mauricio Santamaria ).

Oral anticoagulant safety in family practice: prognostic accuracy of Bleeding Risk Scores (from the CACAO study).

BACKGROUND: To assess bleeding risk of patients treated by oral anticoagulants, several scores have been constructed to assist physicians in the evaluation of the benefit risk. Most of these scores lack a strong enough level of evidence for use in family practice. OBJECTIVE: To assess the predictive prognostic accuracy of 13 scores designed to assess the risk of major or clinically relevant non-major (CRNM) bleeding events in a French ambulatory cohort receiving Vitamin-K antagonists (VKA) or direct oral anticoagulants (DOACs) in a family practice setting. METHODS: CACAO (Comparison of Accidents and their Circumstances with Oral Anticoagulants) was a multicentre prospective cohort of ambulatory patients prescribed oral anticoagulants. We selected patients from the cohort who had received an oral anticoagulant because of non-valvular atrial fibrillation (NVAF) and/or venous thromboembolism (VTE) to be followed during one year by their GP. The following scores were calculated: mOBRI, Shireman, Kuijer, HEMORR2HAGES, ATRIA, HAS-BLED, RIETE, VTE-BLEED, ACCP score, Rutherford, ABH-Score, GARFIEL-AF, and Outcomes Registry for Better InformedTreatment of Atrial Fibrillation (ORBIT). Prognostic accuracy was assessed by using receiver operating characteristic curves and c-statistics. RESULTS: During 1 year, 3,082 patients were followed. All of the scores demonstrated only poor to moderate ability to predict major bleeding or CRNM in NVAF patients on DOACs (c-statistic: 0.41-0.66 and 0.45-0.58), respectively. The results were only slightly better for patients prescribed VKA (0.47-0.66 and 0.5-0.55, respectively) in this indication. The results were also unsatisfactory in patients treated for VTE. CONCLUSION: None of the scores demonstrated satisfactory discriminatory ability when used in family practice. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02376777.

Venous Thromboembolic Risk of Estradiol Valerate-Dienogest Compared with Ethinyl Estradiol-Levonorgestrel Combined Oral Contraceptives.

This pooled analysis compared the risk of venous thromboembolism (VTE) associated with combined oral contraceptives (COCs) containing estradiol (E2) valerate-dienogest with those containing ethinyl E2-levonorgestrel. Data were retrieved from two large, prospective, observational cohort studies. Propensity score subclassification was applied to balance baseline parameters between the COC user cohorts. Crude and adjusted hazard ratios (HRs) were calculated based on the extended Cox model. The pooled data set included 11,616 E2 valerate-dienogest users and 18,681 ethinyl E2-levonorgestrel users, contributing 17,932 and 29,140 women-years of observation, respectively. A significantly decreased VTE risk in E2 valerate-dienogest COCs compared with ethinyl E2-levonorgestrel COCs was observed (propensity score-stratified HR 0.46, 95% CI, 0.22-0.98). This pooled analysis expands data from a previous postauthorization safety study and provides valuable real-world safety information on the relative safety of current COCs.

COVID-19 and Antipsychotic Therapy: Unraveling the Thrombosis Risk.

In the context of the COVID-19 pandemic, this study investigates the potential correlation between the increased use of antipsychotic medications and the rising incidence of venous thromboembolism (VTE). As psychiatric disorders surged, the consequential escalation in antipsychotic drug use raised concerns about thrombotic risks. We conducted a comprehensive literature review using PubMed, focusing on articles that intersected COVID-19, antipsychotic medication, and thrombosis. This approach allowed for a nuanced examination of the historical and recent data on antipsychotic drugs and their association with thrombotic events. Our findings reveal a notable link between the use of antipsychotic medications, particularly second-generation antipsychotics, and an increased risk of VTE, including pulmonary embolism and deep vein thrombosis. This association was evident, despite variations in study designs and populations. The study underscores the need for cautious medication management in psychiatric care, especially during pandemic conditions like COVID-19, to mitigate thrombotic risks. It advocates a personalized approach to prescribing antipsychotics, considering individual patient factors and comorbidities, to balance the benefits against potential thrombotic complications.

Does hormone therapy exacerbate other venous thromboembolism risk factors?

OBJECTIVE: Postmenopausal symptoms in women at higher risk for venous thromboembolism (VTE) due to comorbidities are often undertreated because of concerns that hormone therapy (HT) may increase VTE risk; however, it is unclear how much HT impacts risk of VTE when compared with other risk factors. METHODS: This is a case-control study in a commercial claims database from 2007 to 2019. Women aged 50 to 64 years (n = 223,949) were classified as cases if they had an International Classification of Diseases code indicating an acute VTE plus a filled prescription for an anticoagulant, placement of intravascular vena cava filter, or death within 30 days of diagnosis. Controls were matched 10:1 to each case by index date and age. Risk factors and comorbidities present within the year before index were examined. Exposure was defined as a HT prescription within 60 days before index. RESULTS: There were 20,359 VTE cases and 203,590 matched controls. A conditional logistic regression indicated that the greatest risks for VTE were from metastatic cancer (odds ratio [OR], 13.66; 95% CI, 12.64-14.75), hospitalization/surgery (OR, 8.51; 95% CI, 8.09-8.96), trauma (OR, 3.52; 95% CI, 3.32-3.73), comorbidity burden (OR, 3.51; 95% CI, 3.34-3.69), history of hypercoagulable condition (OR, 3.10; 95% CI, 2.87-3.36), and varicose veins (OR, 2.87; 95% CI, 2.56-3.22). Regarding hormone exposure, we observed ORs of 1.51 (95% CI, 1.43-1.60) for any recent hormone exposure; 1.13 (95% CI, 1.04-1.23; number needed to harm, 4,274) for unopposed estrogen menopausal HT; 1.23 (95% CI, 1.10-1.38; number needed to harm, 2,440) for combined menopausal HT; and 5.22 (95% CI, 4.67-5.84) for combined hormonal contraceptives compared with no recent HT exposure. CONCLUSIONS: Hormone therapy exposure did not appear to adversely influence other risk factors, and exposure generally played a minor role in VTE risk. Contraceptives, however, were a strong risk factor.

Short-Term Cardiovascular Complications in Dermatology Patients Receiving JAK-STAT Inhibitors: A Meta-Analysis of Randomized Clinical Trials.

Importance: Evolving evidence suggests that patients receiving Janus kinase-signal transducer and activator of transcription inhibitors (JAK-STATi) may be at higher risk of major adverse cardiovascular events (MACE) and venous thromboembolism (VTE). Most existing literature has focused on indications that may confer a higher MACE and VTE risk than that among patients with isolated dermatological indications. Objective: To evaluate risk of MACE, VTE, serious adverse events (SAEs), and tolerability of systemic JAK-STATi compared with placebo, in those with a dermatologic indication. Data Sources: A systematic review of the literature was carried out to June 2023, using databases Embase, MEDLINE, SCOPUS, Cochrane Library of Registered Trials, and registered Clinical Trials. The analysis was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. The analysis itself took place in June 2023. Study Selection: Placebo-controlled randomized clinical trials that compared systemic JAK-STATi with placebo, and investigated the safety in patients with alopecia areata, psoriasis, vitiligo, atopic dermatitis, lichen planus or hidradenitis suppurativa. Data Extraction and Synthesis: Study selection and data extraction by 2 authors working independently using a standardized template. Crude numbers for MACE, VTE, SAEs, and study discontinuation due to treatment emergent adverse events (TEAEs) were pooled and underwent meta-analysis. Main Outcomes and Measures: Incidence of MACE, VTE, SAE, and study discontinuation due to TEAEs. Analysis of these values against person exposure years to determine the incidence rate (IR). Risk ratios (RRs) compared incidence rates among treatment and placebo comparator arms. Results: Forty-five randomized clinical trials were eligible for inclusion, with 12 996 patients receiving active JAK-STATi therapy and 4925 allocated to placebo treatment. Meta-analysis found no significant increase in MACE (I2 = 0.00%; RR, 0.47; 95% CI, 0.28-0.80) or VTE (I2 = 0.00%; RR, 0.46; 95% CI, 0.26-0.80) between placebo and JAK-STATi comparator arms. There was also no significant difference in SAEs (I2 = 12.38%; RR, 0.92; 95% CI, 0.72-1.20) and discontinuations between JAK-STATi and placebo (I2 = 23.55%; RR, 0.94; 95% CI, 0.76-1.19). Conclusions and Relevance: This meta-analysis did not identify a significant increase in the risk of MACE and VTE in dermatology patients receiving JAK-STATi for median duration of 16 weeks. The results of this review suggest there is insufficient evidence that JAK-STATi confer an increased risk of cardiovascular complications in dermatological patients, especially when used for short time frames.

Cardiovascular health and the menopause, metabolic health.

Estrogen depletion following menopause predisposes to increased risk of cardiovascular disease (CVD), mainly due to ischemic heart disease. This is mostly evident in cases with premature menopause. The pathophysiological basis for this atherosclerotic process is the accumulation of several risk factors, such as abdominal obesity, atherogenic dyslipidemia, insulin resistance and arterial hypertension. The presence of vasomotor symptoms may further augment this risk, especially in women younger than 60 years. Menopausal hormone therapy (MHT) exerts many beneficial effects on lipid profile and glucose homeostasis as well as direct arterial effects, and may reduce CVD risk if initiated promptly (i.e.,<60 years or within ten years of the final menstrual period). Transdermal estradiol and micronized progesterone or dydrogesterone are the safest regimens in terms of venous thromboembolic events (VTE) and breast cancer risk. In any case, an individualized approach, taking into account the patient's total CVD, VTE and breast cancer risk, is recommended.

Cardiovascular and Venous Thromboembolic Risk With JAK Inhibitors in Immune-Mediated Inflammatory Skin Diseases: A Systematic Review and Meta-Analysis.

Importance: Janus kinase (JAK) inhibitors are an effective treatment option for patients with certain skin-related conditions, such as atopic dermatitis, alopecia areata, and vitiligo, but there is a current US Food and Drug Administration (FDA) boxed warning label for oral and topical JAK inhibitors regarding increased risk of major adverse cardiovascular events (MACE), venous thromboembolism (VTE), serious infections, malignant neoplasm, and death. However, this boxed warning was precipitated by results of the Oral Rheumatoid Arthritis Trial (ORAL) Surveillance study, which only included patients with rheumatoid arthritis, and the same association may not be observed in dermatologic conditions. Objective: To determine the risk of all-cause mortality, MACE, and VTE with JAK inhibitors in patients with dermatologic conditions. Data Sources: PubMed and ClinicalTrials.gov were searched from database inception to April 1, 2023. Study Selection: This review included phase 3 randomized clinical trials with a placebo/active comparator group of JAK inhibitors used for a dermatologic indication with FDA approval or pending approval or with European Union or Japanese approval. Studies without a comparison group, case reports, observational studies, and review articles were excluded. Data Extraction and Synthesis: This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Adverse events using odds ratios (ORs) and 95% CIs were calculated using a random-effects model and the DerSimonian-Laird method. Studies were screened, data abstracted, and quality assessed by 2 independent authors. The protocol was prospectively registered with PROSPERO. Main Outcomes and Measures: Primary outcomes were a composite of adjudicated MACE and all-cause mortality, and VTE. Results: The analysis included 35 randomized clinical trials with 20 651 patients (mean [SD] age, 38.5 [10.1] years; male, 54%) and a mean (SD) follow-up time of 4.9 (2.68) months. Findings did not show a significant difference between JAK inhibitors and placebo/active comparator in composite MACE and all-cause mortality (OR, 0.83; 95% CI, 0.44-1.57) or VTE (OR, 0.52; 95% CI, 0.26-1.04). Conclusions and Relevance: In this systematic review and meta-analysis, use of JAK inhibitors was not associated with increased risk of all-cause mortality, MACE, and VTE compared to the placebo/active comparator groups. Additional trials with long-term follow-up are needed to better understand the safety risks of JAK inhibitors used for dermatologic indications.

Venous Thromboembolism: Review of Clinical Challenges, Biology, Assessment, Treatment, and Modeling.

Venous thromboembolism (VTE) is a massive clinical challenge, annually affecting millions of patients globally. VTE is a particularly consequential pathology, as incidence is correlated with extremely common risk factors, and a large cohort of patients experience recurrent VTE after initial intervention. Altered hemodynamics, hypercoagulability, and damaged vascular tissue cause deep-vein thrombosis and pulmonary embolism, the two permutations of VTE. Venous valves have been identified as likely locations for initial blood clot formation, but the exact pathway by which thrombosis occurs in this environment is not entirely clear. Several risk factors are known to increase the likelihood of VTE, particularly those that increase inflammation and coagulability, increase venous resistance, and damage the endothelial lining. While these risk factors are useful as predictive tools, VTE diagnosis prior to presentation of outward symptoms is difficult, chiefly due to challenges in successfully imaging deep-vein thrombi. Clinically, VTE can be managed by anticoagulants or mechanical intervention. Recently, direct oral anticoagulants and catheter-directed thrombolysis have emerged as leading tools in resolution of venous thrombosis. While a satisfactory VTE model has yet to be developed, recent strides have been made in advancing in silico models of venous hemodynamics, hemorheology, fluid-structure interaction, and clot growth. These models are often guided by imaging-informed boundary conditions or inspired by benchtop animal models. These gaps in knowledge are critical targets to address necessary improvements in prediction and diagnosis, clinical management, and VTE experimental and computational models.

Comparison of clinical outcomes among patients with isolated axial vs muscular calf vein thrombosis: A systematic review and meta-analysis.

OBJECTIVE: Thrombi in the axial calf veins have quite different anatomical and physiological characteristics from that in the muscular calf veins, but their treatment was usually addressed in the same manner. We performed a meta-analysis of randomized and cohort studies to compare clinical outcomes among patients with isolated axial vs muscular calf deep vein thrombosis (DVT). METHODS: Recurrent venous thromboembolism (VTE) was selected as the primary outcome. Resolution, proximal propagation of calf DVT, pulmonary embolism (PE), major bleeds, and clinically relevant non-major bleeds were separately analyzed as secondary outcomes. Data were pooled and compared with risk ratio (RR) and 95% confidence interval (CI). RESULTS: Thirteen studies, consisting of 4889 patients, met the inclusion criteria and were included for analysis. A greater rate of recurrent VTE (FE model: RR, 1.23; 95% CI, 1.00-1.53; I2 = 29%), resolution (FE model: RR, 1.32; 95% CI, 1.01-1.72; I2 = 31%), proximal propagation (FE model: RR, 1.63; 95% CI, 1.10-2.41; I2 = 40%), and PE (FE model: RR, 2.79; 95% CI, 1.31-5.95; I2 = 0%) in the axial group compared with the muscular group. There was no difference in the pooled estimates for major bleeds (FE model: RR, 1.09; 95% CI, 0.61-1.95; I2 = 0%), and clinically relevant non-major bleeds (FE model: RR, 1.80; 95% CI, 0.93-3.48) in the axial and muscular arms. CONCLUSIONS: Patients with calf DVT limited to muscular veins might have a lower rate of recurrent VTE, resolution, proximal propagation, and PE vs those with axial calf vein involvement and exhibited similar safety outcomes.

Lenalidomide in the treatment of anti-myelin-associated glycoprotein neuropathy: A phase 1 study to identify the maximum tolerated dose.

BACKGROUND: Anti-myelin-associated glycoprotein (MAG) neuropathy is a debilitating demyelinating polyneuropathy with no approved therapies. Our primary objective was to ascertain lenalidomide safety and maximum tolerated dose (MTD) in anti-MAG neuropathy. METHODS: This phase 1b, open-label, single-arm, dose-finding trial was conducted from 2019 through 2022. The original design included a dose-escalation/extension phase followed by a dose-expansion phase. Three doses of lenalidomide were evaluated: 10, 15, and 25 mg. The main outcome was the MTD. RESULTS: Eleven patients enrolled (10 men), with a mean age of 67.6 years (SD = 6.18, range 58-77 years) and mean disease duration of 8.5 years (SD = 10.9, range 1-40 years). The study terminated early due to higher-than-expected non-dose-limiting toxicity venous thromboembolism (VTE) events. The calculated MTD was 25 mg (posterior mean of toxicity probability was 0.01 with a 95% credible interval of 0.00, 0.06), but a recommended phase 2 dose of 15 mg was advised. For secondary exploratory outcomes, only EQ-5D (-0.95, 95% CI -1.81 to -0.09) and total IgM (-162 mg/dL, 95% CI -298 to -26) showed signs of improvement by month 12. CONCLUSIONS: Lenalidomide was associated with higher-than-expected VTE events in anti-MAG neuropathy patients, despite a calculated MTD of 25 mg. A recommended phase 2 dose of 15 mg was advised. Lenalidomide did not improve disability or impairment at 12 months, although this study was not powered for efficacy. The risks of long term lenalidomide may outweigh benefit for patients with anti-MAG neuropathy. Any future efficacy study should address VTE risk, as current myeloma guidelines appear inadequate. TRIAL REGISTRATION: Lenalidomide in Anti-MAG Neuropathy: Phase 1b Study, ClinicalTrials.gov Identifier: NCT03701711, https://clinicaltrials.gov/ct2/show/NCT03701711. First submitted October 10, 2018. First patient enrolled in January 2019.