Rate Of Venous Thromboembolic Events Research Articles

Safety Profile of Upadacitinib up to 3 Years in Psoriatic Arthritis: An Integrated Analysis of Two Pivotal Phase 3 Trials.

IntroductionThis integrated analysis describes the safety profile of upadacitinib, an oral Janus kinase inhibitor, at 15 and 30 mg once daily for up to 3 years of exposure in patients with active psoriatic arthritis (PsA) who had a prior inadequate response or intolerance to ≥ 1 non-biologic or biologic disease-modifying antirheumatic drug.MethodsSafety data were pooled and analyzed from two randomized, placebo-controlled phase 3 trials. Both trials evaluated upadacitinib 15 mg and 30 mg once daily, and one trial also evaluated adalimumab 40 mg every other week. Treatment-emergent adverse events (TEAEs) and laboratory data were summarized for four groups: pooled placebo, pooled upadacitinib 15 mg, pooled upadacitinib 30 mg, and adalimumab. TEAEs were reported as exposure-adjusted event rates (events per 100 patient-years [E/100 PY]) up to a data cut-off of June 29, 2020.ResultsA total of 2257 patients received ≥ 1 dose of upadacitinib 15 mg (N = 907) or 30 mg (N = 921) for 2504.6 PY of exposure or adalimumab (N = 429) for 549.7 PY of exposure. Upper respiratory tract infection, nasopharyngitis, and increased creatine phosphokinase (CPK) were the most common TEAEs with upadacitinib. Rates of malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs), and deaths were similar across treatment groups. Rates of herpes zoster (HZ) and opportunistic infections (OI; excluding tuberculosis, HZ, and oral candidiasis) were higher with upadacitinib versus adalimumab. Serious infection, anemia, and CPK elevations were most frequent with upadacitinib 30 mg. Potentially clinically significant laboratory abnormalities were uncommon.ConclusionsUpadacitinib 15 mg and adalimumab had similar safety profiles with the exception of HZ and OIs, consistent with what was observed in rheumatoid arthritis. Rates of malignancies, MACEs, VTEs, and deaths were comparable among patients receiving upadacitinib and adalimumab. No new safety risks emerged with longer-term exposure to upadacitinib.Trial Registration NumbersSELECT-PsA 1: NCT03104400; SELECT-PsA 2: NCT03104374.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00410-z.

Effects of Marijuana Use in Patients with Orthopaedic Trauma.

The use of cannabis and cannabis-related products has increased dramatically in the last 2 decades. As states continue to legalize cannabis products, it is important for surgeons to understand the effects they may have on patients who have sustained orthopaedic trauma. Cannabinoids have been shown to decrease the severity of certain symptoms related to traumatic brain injury as well as posttraumatic stress disorder. Cannabinoids can modulate the body's endocannabinoid system, which can play an important role in bone homeostasis. Activation of cannabinoid receptors has been shown to be bone-protective in adults. Venous thromboembolism is a major concern for trauma patients. Cannabis use has been linked to overall increased rates of venous thromboembolism events. Literature regarding human-based cannabis studies is sparse; however, the growing field is opening new opportunities for research of this topic.

Real-World Anticoagulant Use and Incidence of Venous Thromboembolism and Major Bleeding in Children

Children generally have a lower risk of venous thromboembolism (VTE) than adults, but those with acute and chronic conditions requiring hospitalization and surgical procedures are at increased risk. Anticoagulant use in children has not been systematically studied, and limited data exist. This study aimed to provide data on the conditions associated with use of anticoagulants, the type of anticoagulant used in children, and the incidence of thromboembolism and major bleeding events reported in this population. To increase understanding of the use of anticoagulant therapies in children with at-risk conditions, 3 health claims databases in the United States were analyzed to describe the characteristics of use of heparins, warfarin, and direct oral anticoagulants (DOACs). Cumulative drug exposure was determined for continuous exposure, defined as >30 days. Unadjusted event rates of VTE and major bleeding after exposure to these therapies were reported. The data were presented descriptively and are not intended for comparison or to imply any causation. Anticoagulants were infrequently used in the pediatric population, including at any time point after Fontan surgery for congenital heart disease. Heparins were used most frequently in the population overall and especially for patients aged <12 years. DOACs were used least often and primarily for patients ages 12 to <18 years. Among pediatric patients exposed to anticoagulants, unadjusted incidence rates of VTE per 1000 person-years of exposure ranged from 30.8 to 34.0 for all DOACs, 21.6 to 46.2 for warfarin, and 6.0 to 7.3 for heparins. Rates per 1000 person-years for major bleeding ranged from 0 to 4.9 for all DOACs, 4.3 to 6.7 for warfarin, and 3.7 to 4.6 for heparins. With results from clinical trials evaluating DOACs in the pediatric population expected in the next 2 years, these descriptive real-world data may provide a baseline understanding of current prescribing patterns and outcomes associated with the use of DOACs and other anticoagulants in routine pediatric clinical practice. This information represents the use of real-world evidence and may function as the benchmark for evaluating changes in prescription practices and potential outcomes in the future.

Sex‐, Race‐ and Ethnicity‐Based Differences in Thromboembolic Events Among Adults Hospitalized With COVID‐19

BackgroundPatients hospitalized with COVID‐19 have an increased risk of thromboembolic events. Whether sex, race or ethnicity impacts these events is unknown. We studied the association between sex, race, and ethnicity and venous and arterial thromboembolic events among adults hospitalized with COVID‐19.Methods and ResultsWe used the American Heart Association Cardiovascular Disease COVID‐19 registry. Primary exposures were sex and race and ethnicity, as defined by the registry. Primary outcomes were venous thromboembolic events and arterial thromboembolic events. We used logistic regression for risk adjustment. We studied 21 528 adults hospitalized with COVID‐19 across 107 centers (54.1% men; 38.1% non‐Hispanic White, 25.4% Hispanic, 25.7% non‐Hispanic Black, 0.5% Native American, 4.0% Asian, 0.4% Pacific Islander, and 5.9% other race and ethnicity). The rate of venous thromboembolic events was 3.7% and was more common in men (4.2%) than women (3.2%; P<0.001), and in non‐Hispanic Black patients (4.9%) than other races and ethnicities (range, 1.3%–3.8%; P<0.001). The rate of arterial thromboembolic events was 3.9% and was more common in men (4.3%) than women (3.5%; P=0.002), and in non‐Hispanic Black patients (5.0%) than other races and ethnicities (range, 2.3%–4.7%; P<0.001). Compared with men, women were less likely to experience venous thromboembolic events (adjusted odds ratio [OR], 0.71; 95% CI, 0.61–0.83) and arterial thromboembolic events (adjusted OR, 0.76; 95% CI, 0.66–0.89). Compared with non‐Hispanic White patients, non‐Hispanic Black patients had the highest likelihood of venous thromboembolic events (adjusted OR, 1.27; 95% CI, 1.04–1.54) and arterial thromboembolic events (adjusted OR, 1.35; 95% CI, 1.11–1.65).ConclusionsMen and non‐Hispanic Black adults hospitalized with COVID‐19 are more likely to have venous and arterial thromboembolic events. These subgroups may represent at‐risk patients more susceptible to thromboembolic COVID‐19 complications.

The Impact of Risk-Adjusted Heparin Regimens on the Outcome of Patients with COVID-19 Infection. A Prospective Cohort Study.

Background. According to recent guidelines, all hospitalized patients with COVID-19 should receive pharmacological prophylaxis for venous thromboembolism (VTE), unless there are specific contraindications. However, the optimal preventive strategy in terms of intensity of anticoagulation for these patients is not well established. Objectives. To investigate the impact of individualized regimens of enoxaparin on the development of VTE and on the risk of major bleeding complications during hospitalization in patients with COVID-19 infection. Methods. All consecutive patients admitted to the medical wards of six Italian hospitals between 15 September and 15 October 2020 with COVID-19 infection of moderate severity were administered enoxaparin in subcutaneous daily doses adjusted to the Padua Prediction Score stratification model: No heparin in patients scoring less than 4, 4000 IU daily in those scoring 4, 6000 IU in those scoring 5, and 8000 in those scoring six or more. Objective tests were performed in patients developing clinical symptoms of deep vein thrombosis and/or pulmonary embolism. Bleeding complications were defined according to the ISTH classification. Results. From the 154 eligible patients, enoxaparin was administered in all: 4000 IU in 73 patients, 6000 IU in 53, and 8000 IU in the remaining 28. During the course of hospitalization, 27 patients (17.5%) died. VTE developed in 14 of the 154 patients (9.1%; 95% CI, 4.6% to 13.6%), and was fatal in 1. Major bleeding complications developed in 35 patients (22.7%; 95% CI, 16.1% to 29.3%), and were fatal in 8. Conclusions. Despite the use of risk-adjusted doses of enoxaparin, the rate of VTE events was consistent with that reported in contemporary studies where fixed-dose low-molecular-weight heparin was used. The unexpectedly high risk of bleeding complications should induce caution in administering enoxaparin in doses higher than the conventional low ones.

ABCL-230: Prevalence, Patterns, and Predictors of Venous Thromboembolic Events in Patients Undergoing Salvage Chemotherapy and Autologous Stem Cell Transplant for Relapsed Lymphomas

The majority of relapsed or refractory lymphoma patients undergo salvage chemotherapy and autologous stem cell transplant (ASCT). Data on venous thromboembolic events (VTEs) in this setting are scarce. This study aims to evaluate the incidence, pattern, and risk factors for VTEs in this group of patients across the continuum of their care. The medical records of adult patients, aged ≥ 18 years, who were diagnosed and treated at our institution from 2007 to 2017 with refractory or relapsed lymphoma and received salvage therapy followed by high-dose chemotherapy and autologous stem cell transplant were retrospectively reviewed. A total of 216 patients, with a median age of 31 (range: 19–60) years, were identified. In total, 36 (16.7%) patients had VTE, mostly in the upper extremity (n=28, 77.8%); 50.0% were related to central venous catheter. Thrombosis rates were higher among patients with high lactate dehydrogenase (LDH) (29.2% <i>vs</i> 5.9%, p< 0.001), mediastinal involvement (25.9% <i>vs</i> 11.5%, p=0.025) and in patients with longer hospital stay (22.1% <i>vs</i> 9.5%, p=0.036). In multivariate analysis, high LDH (OR: 7.66; 95% CI: 2.79–21.04, p<0.001) and mediastinal involvement (OR, 3.64; 95% CI: 1.53–8.70, p=0.002) were associated with significantly higher rates of VTE. In conclusion, patients with relapsed lymphoma undergoing ASCT are at higher risk for VTE, especially those with high LDH and mediastinal involvement. Thromboprophylaxis might be considered in these settings.

Observed risk of recurrent bleeding and thromboembolic disease in COVID-19 patients with gastrointestinal bleeding.

Background and study aim COVID-19 patients are at increased risk for venous thromboembolism (VTE) requiring the use of anticoagulation. Gastrointestinal bleeding (GIB) is increasingly being reported, complicating the decision to initiate or resume anticoagulation as providers balance the risk of thrombotic disease with the risk of bleeding. Our study aimed to assess rebleeding rates in COVID-19 patients with GIB and determine whether endoscopy reduces these rebleeding events. We also report 30-day VTE and mortality rates. Methods This was a retrospective study evaluating 56 COVID-19 patients with GIB for the following outcomes: 30-day rebleeding rate, 30-day VTE rate, effects of endoscopic intervention on the rate of rebleeding, and 30-day mortality. Results The overall rates of VTE and rebleeding events were 27 % and 41 %, respectively. Rebleeding rates in patients managed conservatively was 42 % compared with 40 % in the endoscopy group. Overall, 87 % of those who underwent invasive intervention resumed anticoagulation vs. 55 % of those managed medically ( P = 0.02). The all-cause 30-day mortality and GIB-related deaths were 32 % and 9 %, respectively. Mortality rates between the endoscopic and conservative management groups were not statistically different (25 % vs. 39 %; P = 0.30). Conclusions Although rebleeding rates were similar between the endoscopic and conservative management groups, patients who underwent intervention were more likely to restart anticoagulation. While endoscopy appeared to limit the duration that anticoagulation was withheld, larger studies are needed to further characterize its direct effect on mortality outcomes in these complex patients.

Thromboembolic events in pregnant and puerperal women after COVID-19 lockdowns: A retrospective cohort study.

ObjectiveTo explore the indirect impact of the COVID‐19 pandemic on patterns of pregnancy‐related venous thromboembolism (VTE) events, mediated by population mobility restrictions during lockdown periods.MethodsPregnancy‐related VTE hospitalizations were identified through a code‐targeted search of the Hadassah Medical Center's computerized database. A manual analysis of relevant medical records was performed, and cases diagnosed throughout the year 2020 were compared to those diagnosed during 2019 and 2018. Statistical analyses studied obstetrical outcomes, as well as the extent and treatment of VTE events during the COVID‐19 pandemic compared to those of preceding years, stratified by pre‐, intra‐, and post‐lockdown periods.ResultsThe incidence of pregnancy‐related thromboembolic events during 2020 was 0.16% of all deliveries, significantly higher than in 2018 and 2019 (0.06% and 0.1%, respectively; P < 0.05). Higher rates of VTE events were found during post‐lockdown periods in 2020, compared with corresponding time periods in 2019 and 2018.ConclusionThe present data suggest that lockdown periods impact pregnancy‐related VTE hospitalizations, possibly as a result of restricted population mobility. Increased awareness of this undesirable outcome may aid health policymakers in the continuing struggle with epidemics.

Venous Thromboembolism Among Patients With Inflammatory Bowel Diseases is Not Related to Increased Thrombophilia: A Case-Control Study.

The aim was to assess whether thrombophilia significantly contributes to the risk of venous thromboembolic events (VTEs) in patients with inflammatory bowel disease (IBD). Patients with IBD have a high risk of VTE. The underlying mechanism has been only partially defined. A case-control study in adults with IBD and an episode of VTE (IBD-VTE) were matched and compared with non-IBD patients with a VTE (non-IBD-VTE). The study population was comprised of patients seen in 2 tertiary medical centers in Israel between 2000 and 2013. Characteristics of IBD and risk factors for VTE were retrieved from medical charts, and a comprehensive thrombophilia panel was completed in all patients. Forty-four IBD-VTE cases (27 Crohn's disease) were matched with 127 non-IBD-VTE controls. The majority of VTE had a clear etiology and were considered provoked events. Provoked and unprovoked VTE rates were not different between the 2 groups. Likewise, thrombophilia rates were similar among patients with IBD-VTE and controls (40.9% vs. 53.5%, respectively, P=0.14). However, among patients with unprovoked VTE, thrombophilia rates were significantly lower in the IBD-VTE group compared with controls (42.1% vs. 70.7%, respectively, P=0.03). Among patients with IBD-VTE, an unprovoked event, and negative thrombophilia, 77% had active inflammation at the time of VTE. Thrombophilia rates are similar among patients with IBD-VTE and controls but are less common among patients with unprovoked IBD-VTE. This finding suggests that either inflammation or other novel pathways drive VTE in patients with IBD.

Thromboembolic safety profile of low-dose estradiol (valerate) in combined hormonal preparations: Implications for the development of new hormonal endometriosis and uterine fibroid therapies

Background: Several promising new medications containing low-dose estradiol (E2) in combination with a progestin and an additional component, such as gonadotropin-releasing hormone antagonists, are currently being developed for use in pre-menopausal women. Objective: This pooled analysis was designed to estimate the thromboembolic safety profile of E2 and its ester, estradiol valerate (E2Val), when used in combined hormonal treatments in a pre-menopausal population. Methods: Data regarding users of combined oral contraceptives (COCs) and combined menopausal hormonal therapy (MHT) containing either E2/E2Val or ethinylestradiol (EE) ⩽ 30 µg were retrieved from five large prospective, non-interventional, cohort studies in Europe, US, and Canada with similar study design but differing medication cohorts. Propensity score sub-classification was applied to balance baseline parameters between cohorts and time-to-event analysis of venous thromboembolic events (VTE) was carried out based on the extended Cox model to calculate crude and adjusted hazard ratios (HR). Results: (1) Crude incidence rates of VTE were higher in MHT users compared to pre-menopausal COC users, (2) the VTE risk in menopausal users of E2/E2Val-norethindrone acetate was not higher than that in menopausal users of E2/E2Val-progestin (adjusted HR 0.71; 95% confidence interval, 0.41-1.26) and (3) the VTE risk in pre-menopausal users of E2/E2Val-progestin was similar, or lower, than pre-menopausal users of EE⩽30µg-progestin (adjusted HR 0.49; 95% confidence interval, 0.28–0.84). Conclusion: Our data presents a solid safety assessment of combined hormonal preparations containing E2/E2Val. We conclude that the risk of E2/E2Val-norethindrone acetate in pre-menopausal users is unlikely to be higher than the known risk of COCs containing EE ⩽ 30 µg-progestin.

Andexanet Alfa or Prothrombin Complex Concentrate for Factor Xa Inhibitor Reversal in Acute Major Bleeding: A Systematic Review and Meta-Analysis.

To combine evidence on andexanet alfa and prothrombin complex concentrates for factor Xa inhibitor-associated bleeding to guide clinicians on reversal strategies. Embase, Pubmed, Web of Science, and the Cochrane Library. Observational studies and randomized clinical trials studying hemostatic effectiveness of andexanet alfa or prothrombin complex concentrate for acute reversal of factor Xa inhibitor-associated hemorrhage. Two independent reviewers extracted the data from the studies. Visualization and comparison of hemostatic effectiveness using Sarode et al or International Society of Thrombosis and Hemostasis Scientific and Standardization Committee criteria at 12 and 24 hours, (venous) thrombotic event rates, and inhospital mortality were performed by constructing Forest plots. Exploratory analysis using a logistic mixed model analysis was performed to identify factors associated with effectiveness and venous thromboembolic event. A total of 21 studies were included (andexanet: 438 patients; prothrombin complex concentrate: 1,278 patients). The (weighted) mean effectiveness for andexanet alfa was 82% at 12 hours and 71% at 24 hours. The (weighted) mean effectiveness for prothrombin complex concentrate was 88% at 12 hours and 76% at 24 hours. The mean 30-day symptomatic venous thromboembolic event rates were 5.0% for andexanet alfa and 1.9% for prothrombin complex concentrate. The mean 30-day total thrombotic event rates for andexanet alfa and prothrombin complex concentrate were 10.7% and 3.1%, respectively. Mean inhospital mortality was 23.3% for andexanet versus 15.8% for prothrombin complex concentrate. Exploratory analysis controlling for potential confounders did not demonstrate significant differences between both reversal agents. Currently, available evidence does not unequivocally support the clinical effectiveness of andexanet alfa or prothrombin complex concentrate to reverse factor Xa inhibitor-associated acute major bleeding, nor does it permit conventional meta-analysis of potential superiority. Neither reversal agent was significantly associated with increased effectiveness or a higher rate of venous thromboembolic event. These results underscore the importance of randomized controlled trials comparing the two reversal agents and may provide guidance in designing institutional guidelines.

Arterial events, venous thromboembolism, thrombocytopenia, and bleeding after vaccination with Oxford-AstraZeneca ChAdOx1-S in Denmark and Norway: population based cohort study

ObjectiveTo assess rates of cardiovascular and haemostatic events in the first 28 days after vaccination with the Oxford-AstraZeneca vaccine ChAdOx1-S in Denmark and Norway and to compare them with rates...

AB143. SOH21AS080. Venous thromboembolic event rates and extended thromboprophylaxis post colorectal resections

AB143. SOH21AS080. Venous thromboembolic event rates and extended thromboprophylaxis post colorectal resections

Abstract PS13-24: CDK 4/6 inhibitors are associated with a high incidence of thrombotic events in real world practice

Abstract Background: Cyclin dependent kinase (CDK) 4/6 inhibitors combined with endocrine therapy are an integral therapy for advanced hormone receptor positive breast cancer. Rates of venous thromboembolic events (VTE) were between 1-5% in clinical trials leading to CDK 4/6 inhibitor approval. Abemaciclib currently carries an FDA warning for VTE risk. However, rates of thrombosis in real world practice remain poorly described. We aim to better define the thrombotic risk associated with CDK 4/6 inhibitors, expanding to evaluate venous and arterial events. Additionally, factors that predispose to thrombosis while on CDK 4/6 inhibitors are unclear. We hypothesize the Khorana thrombosis risk score may predict which patients will experience thrombosis on CDK 4/6 therapy. Methods: We conducted a retrospective analysis of breast cancer patients aged ≥18 years who were prescribed a CDK 4/6 inhibitor (palbociclib, ribociclib, abemiciclib) at the Knight Cancer Institute and affiliated clinics between February 2015 and March 2020. Venous and arterial thrombosis occurring during treatment or within 30 days of discontinuation were included. We collected data including pre-treatment lab values, age, BMI, prior thrombosis, and smoking status and calculated a Khorana risk score for each patient. Utilizing univariate and multivariate logistic regression we compared these variables in patients who developed thrombosis and those who did not. We calculated overall survival of the two groups. Results: There were 270 patients included in the analysis and 29 patients (10.7%) developed a thrombotic event. Of these, 66% were venous, 28% were arterial, and 10% experienced &amp;gt;1 clot. Ribociclib had the highest incidence of thrombosis; 17%, followed by palbociclib; 9% and abemaciclib; 5% (Table 1). Multivariate analysis evaluating risk factors for thrombosis did not find any statistically significant predictors of thrombosis (Table 2). Khorana scores did not predict which patients experienced thrombosis. Median overall survival did not significantly differ between those who developed thrombosis and those who did not (23 months vs 17.5 months respectively, p value = 0.37). Discussion: Incidence of thrombosis in our institutional analysis is higher than reported in clinical trials. Interestingly, we found arterial thrombosis comprised over one-third of events. Patients on ribociclib experienced the highest incidence of thrombosis, suggesting the FDA thrombosis warning may need to be expanded to the drug class. Khorna scores were not predictive of thrombosis risk in our population, however only 1% of study patients had a high risk score over 2. Larger, real world studies are needed to define the risk of thrombosis with CDK 4/6 inhibitors. The role of prophylactic anticoagulation is yet to be defined in this patient population. TABLE 1: Incidence of thrombosisCumulative Incidence:Total CDK 4/6 inhibitor populationn = 270Number of thrombotic events29 (11%)Total arterial8 (28%)Total venous19 (66%)Total arterial + venous2 (6.9%)Incidence by CDK4/6 inhibitorAbemaciclib (n = 20)1 (5%)Palbociclib (n = 233)22 (9.4%)Ribociclib (n = 17)3 (17.6%)Site of eventFirst thrombotic eventn = 26CVA2 (6.9%)CVA + DVT1 (3.5%)CVA + MI1 (3.5%)DVT10 (34.5%)MI1 (3.5%)PE4 (13.8%)PE + DVT2 (7%)Line associated DVT1 (3.5%)Retinal vein thrombosis1 (3.5%)TIA3 (10.3%)Second thrombotic eventn = 3DVT1 (3.5%)PE + MI1 (3.5%)TIA1 (3.5%) TABLE 2 Predictors of thrombosisCharacteristicOR95% CIP-ValueAge1.020.98 - 1.060.28BMI1.040.98 - 1.10.24Hemoglobin0.830.69 - 1.000.06History of thrombosis1.910.72 - 5.090.20Platelet1.00.99 - 1.010.86Smoking2.610.75 - 9.110.13WBC0.970.84 - 1.110.64 Citation Format: Malinda West, Claire Smith, Tia Kohs, Ramin Amirsoltani, Jessica Ribkoff, Joshua Choung, Alison Palumbo, Joseph Shatzel. CDK 4/6 inhibitors are associated with a high incidence of thrombotic events in real world practice [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-24.

Abstract PS10-17: Palbociclib (P) in combination with fulvestrant (F) or letrozole (L) in endocrine-sensitive patients (pts) with hormone receptor (HR)[+]/HER2[-] metastatic breast cancer (MBC): detailed safety analysis from a multicenter, randomized, open-label, phase II trial (PARSIFAL)

Abstract Background: P led to a meaningful improvement in clinical outcomes when used in combination with endocrine therapy for first- or later-line regimen in HR[+]/HER2[-] MBC. Grade 3-4 neutropenia was the most common adverse event (AE) in the P-containing regimens. Although venous thromboembolic events (VTE) have been rarely reported in registrational trials, a systematic review and meta-analysis of randomized controlled trials demonstrated a higher rate of these AEs. Moreover, rare but severe cases of interstitial lung disease (ILD)/pneumonitis have been observed during post-approval use of P. Here, we present a comprehensive toxicity profile of pts included in the PARSIFAL study, with particular emphasis given to AEs of special interest of the overall safety population. Methods: A total of 486 pts with HR[+]/HER2[-] MBC with no prior therapy in the advanced setting and endocrine sensitive criteria (relapse &amp;gt;12 months [mo] after the end of adjuvant endocrine therapy or diagnosed with de novo metastatic disease) were randomly assigned 1:1 to receive P (oral 125 mg/day [d]; 3 weeks on/1 week off) plus either F (intramuscular injection 500 mg/d; d 0, 14, 28, and then every 28 ds) or L (oral 2.5 mg/d). Pts were stratified by visceral involvement and type of disease presentation (de novo/recurrent). Safety assessments included blood analysis and collection of vital signs at screening, d1 of each cycle, and end of treatment/withdrawal. Severity was graded as per the NCI Common Terminology Criteria for Adverse Events v.4.03. Results: The incidence rate of any grade, grade 3-4, and serious AEs was 99.6%, 80.9%, and 29.9%, respectively, in the FP arm, and 99.2%, 78.5%, and 21.1% in the LP arm. Discontinuations due to AEs were 5.4% in the FP arm and 2.1% in the LP arm. Neutropenia, leukopenia, anemia, asthenia, arthralgia, fatigue, and diarrhea were the most frequent AEs in both arms. Febrile neutropenia was reported in 1.2% (3 pts) and 0.4% (1 patient) in the FP and LP arms, respectively. The rate of VTE of any grade was 5.8% (14 pts) in the FP arm and 4.5% (11 pts) in the LP arm (p = 0.531). Among 18 pts who had grade ≥ 3 pulmonary embolism (PE), the incidence reported in the FP and LP arms was 5% (12 pts) vs 2.5% (6 pts), respectively, and many of them (n=16, 88.9%) were unrelated PE. Asymptomatic grade 3 PE was reported in 10 pts of the entire study population on every 3-mo CT scan. Further, in 5 pts PE was detected in the context of progressive disease. Median time from the first dose of study drugs to occurrence of PE was 4.1 mo (range 1.4-32.0 mo) in the FP arm and 7 mo (range 1.8-19.3 mo) in the LP arm. Analysis of baseline characteristics in the whole population revealed that older pts had a significantly increased risk for developing PE (69.5 years [range 47-84 years]; p &amp;lt; 0.01). ECOG performance status, menopausal status, metastatic disease, visceral involvement, number of disease sites, and prior therapies including antithrombotic agents did not significantly increase the risk for developing PE. Grade 3 ILD/pneumonitis was rarely observed in the FP and LP arms (0.8% vs 1.2%, respectively) with no grade 4 AE. Conclusions: First-line treatment with FP and LP for HR[+]/HER2[-] MBC in the PARSIFAL study confirmed the favorable safety profile, with neutropenia representing the most common AE. Although rare, ILD/pneumonitis can be a side effect of P-based regimens. VTE and PE incidence rates were low and consistent with age-specific analyses from PALOMA trials and breast cancer population. Early detection of these AEs may assist in optimizing their management. Citation Format: José Manuel Pérez-García, Antonio Llombart-Cussac, Meritxell Bellet, Florence Dalenc, Miguel J. Gil Gil, Manuel Ruiz Borrego, Joaquín Gavilá, Miguel Sampayo-Cordero, Elena Aguirre, Peter Schmid, Frederik Marmé, Serena Di Cosimo, Joseph Gligorov, Andreas Schneeweiss, Joan Albanell, Pilar Zamora, Duncan Wheatley, Eduardo Martínez-De Dueñas, Vicente Carañana, Kepa Amillano, Andrea Malfettone, Javier Cortés. Palbociclib (P) in combination with fulvestrant (F) or letrozole (L) in endocrine-sensitive patients (pts) with hormone receptor (HR)[+]/HER2[-] metastatic breast cancer (MBC): detailed safety analysis from a multicenter, randomized, open-label, phase II trial (PARSIFAL) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-17.

Discordant reporting of VTE in pancreatic cancer: A systematic review and meta‐analysis of thromboprophylaxis versus chemotherapeutic trials

BackgroundDespite the frequency of venous thromboembolism (VTE) in pancreatic cancer, it is inconsistently reported as an adverse event in clinical trials. We hypothesized that reported rates of VTE in pancreatic cancer clinical trials are influenced by the objectives of the trial, with higher rates reported in thromboprophylaxis compared with chemotherapeutic trials. We performed a systematic review and meta‐analysis of randomized, controlled trials (RCT) in pancreatic cancer to quantify differences in reported rates of VTE in thromboprophylaxis and chemotherapeutic trials. MethodsWe systematically searched MEDLINE, EMBASE, and Clinicaltrials.gov. Eligible thromboprophylaxis RCTs were required to report rates of thrombosis in non‐anticoagulant pancreatic cancer cohorts. Eligible chemotherapy studies were RCTs evaluating chemotherapy regimens in advanced pancreatic cancer and reported thrombosis as adverse events. Pooled event rates of VTE and arterial thrombosis were calculated using a random‐effects model. ResultsThe pooled VTE rate in 13 chemotherapy studies (5694 patients) was 5.9% (95% confidence interval [CI], 3.9‐9.0%) compared with 16.5% (95% CI, 11.7%‐23.3%; P < .001) in 9 thromboprophylaxis studies (631 patients). The pooled symptomatic VTE rate from chemotherapy studies was 5.4% (95% CI, 3.5%‐8.3%), which was significantly lower than the pooled rate from thromboprophylaxis studies of 10.5% (95% CI, 7.3%‐14.9%; P = .02). ConclusionThe VTE incidence reported in chemotherapy RCTs in pancreatic cancer is significantly lower than reported in thromboprophylaxis studies. This finding highlights the underrecognition of VTE in chemotherapeutic trials and emphasizes the need to standardize approaches towards monitoring and reporting of VTE in clinical trials.

Venous thromboembolism in ANCA-associated vasculitis: a population-based cohort study.

To determine incidence rate and predictors of venous thromboembolic events (VTE) in a population-based cohort with ANCA-associated vasculitis (AAV). The study comprised 325 patients diagnosed with AAV from 1997 to 2016. All cases of VTE from prior to vasculitis diagnosis to the end of the study period were identified. The BVAS was used to assess disease activity at diagnosis. Venous thromboembolisms occurring in a period beginning 3 months prior to AAV diagnosis were considered to be AAV-related. The standardized incidence ratio (SIR) and 95% CI of VTE were calculated using the incidence rate in the general population. Fifty-nine patients (18%) suffered 64 VTE events. Of these, 48 (81%) suffered AAV-related VTE [deep vein thrombosis (n = 23), pulmonary embolism (n = 18) and other (n = 9)]. The incidence rate of AAV-related VTE was 2.4 per 100 person-years (95% CI 1.7, 3.0) during 2039 person-years of follow-up. The incidence during the first 3 months post-AAV diagnosis was 20.4 per 100 person-years (95% CI 11.5, 29.4), decreasing to 8.9 (95% CI 0.2, 17.6) and 1.5 (95% CI 0.0, 3.5) in months 4-6 and months 7-12 post-AAV diagnosis, respectively. The SIR was 34.2 (95% CI 20.2, 48.1) for deep vein thrombosis and 10.4 (95% CI 5.6, 15.1) for pulmonary embolism. In multivariate Cox regression analyses, only age and BVAS were predictive of VTE. The incidence rate and SIR of AAV-related VTE is high, and higher early in the course of the disease. Vasculitis activity and age are positively associated with VTE.

Patient's compliance is a contributor to failure of extended antithrombotic prophylaxis in colorectal surgery: prospective cohort study.

Venous thromboembolic events (VTE) continue to be a major source of morbidity following colorectal surgery. Selective extended VTE prophylaxis for high-risk patients is recommended; however, provider compliance is low. The purpose of this study is to evaluate whether the "global" extended use of enoxaparin in all colorectal patients is feasible and safe. This is a prospective study conducted at a tertiary care center. All Patients undergoing elective colorectal procedures from November 1, 2017 to October 31, 2018 were discharged on 30days of enoxaparin. Safety of use and patient compliance were examined. Total of 270 patients received extended prophylaxis during the study period (100% of intended patients) with five VTE recorded (1.85%). There was no significant difference in rates of VTE or complications when compared to years of selective prophylaxis (1.26% for 2016, 2.32% for 2017). Only 64% of patients reported full compliance. Global use of extended enoxaparin prophylaxis is safe, but does not decrease rates of VTE when compared to selective use. Patient's non-adherence is likely a significant contributing factor.

Biologically Active Tissue Factor-Bearing Larger Ectosome-Like Extracellular Vesicles in Malignant Effusions from Ovarian Cancer Patients: Correlation with Incidence of Thrombosis.

The development of malignant effusions such as ascites reflects a massive progression of a malignant disease. In patients with ovarian carcinoma, a high amount of ascites (>500 mL) is an independent negative prognostic marker. The composition and constituents of ascites reflect the inflammatory environment of the underlying tumor. Increased cellular resistance of ascites-derived tumor cells and the development of venous thromboembolic events (VTE) are major risks for these patients, especially in patients with advanced ovarian carcinoma. In this study, we discuss the release of tissue factor-bearing extracellular vesicles (TF+ EVs) from tumor cells into the environment (ascites fluid) and their systemic spreading as a possible causal explanation of the pathologic coagulation status in these patients. We obtained ascites from patients with advanced ovarian carcinoma, collected during surgery or therapeutic paracentesis (n = 20). Larger ectosome-like EVs were isolated using sequential centrifugation, quantified by high-resolution flow cytometry and analyzed using nanoparticle tracking analysis. Furthermore, the pro-coagulant properties (TF activity) of EVs were determined. Compared to published TF activities of EVs from healthy persons, TF activities of EVs derived from ascites of patients with ovarian cancer were very high, with a median of 80 pg/mL. The rate of VTE, as reported in the patient files, was high as well (35%, 7 out of 20). Furthermore, all but one patient with VTE had EV concentrations above the median within their ascetic fluid (p < 0.02). Since VTE continues to be a frequent cause of death in cancer patients, prophylactic antithrombotic treatment might be worth considering in these patients. However, given the risk of bleeding, more clinical data are warranted. Although the study is too small to enable reaching a conclusion on direct clinical implementation, it can well serve as a proof of principle and a rationale to initiate a prospective clinical study with different patient subgroups. We also show ex vivo that these larger ectosome-like EVs induce intracellular ERK phosphorylation and tumor cell migration, which is not directly related to their pro-coagulative potency, but might help to understand why cancer patients with thromboembolic events have a poorer prognosis.

Cancer in pregnancy increases the risk of venous thromboembolism: a nationwide cohort study.

To investigate if cancer in pregnancy causes a higher risk of venous thromboembolism (VTE) during pregnancy and postpartum compared with pregnant women without cancer. A historical prospective cohort study using data from nationwide registries. We assessed all pregnancies in Denmark between 1 January 1977 and 31 December 2017. We linked information concerning cancer diagnosis, pregnancy and VTE diagnosis and potential confounders. Event rates of VTE for women with pre-pregnancy cancer, cancer in pregnancy and without cancer were calculated per 10000 pregnancies and compared using logistic regression analysis. Occurrence of VTE during pregnancy or the postpartum period. A total of 3581214 pregnancies were included in the study and we found 1330 women with cancer in pregnancy. In pregnant women with cancer, the event rate of VTE was 75.2 per 10000 pregnancies compared with 10.7 per 10000 pregnancies in the no cancer group. The findings correspond to an increased adjusted odds ratio of 6.50 (95% CI3.5-12.1) in the cancer in pregnancy group in comparison with the no cancer group. Women with cancer in pregnancy have a markedly higher risk of pregnancy-associated VTE compared with women without cancer. In pregnancy-related VTE risk assessment, the presence of cancer alone may be sufficient to indicate thromboprophylaxis. Cancer in pregnancy increases the risk of VTE during pregnancy and the postpartum period.