High-risk Ambulatory Patients Research Articles

Factor XI inhibitors: a new option for the prevention and treatment of cancer-associated thrombosis

Venous thromboembolism (VTE) is a relatively common complication in cancer patients with potentially dire consequences. Anticoagulants are the mainstay of treatment of cancer-associated VTE. The anticoagulants most often used are low-molecular-weight heparin (LMWH) and direct oral factor (F) Xa inhibitors, which include apixaban, edoxaban, and rivaroxaban. Most guidelines recommend primary VTE prophylaxis with LMWH, apixaban, or rivaroxaban after abdominal or pelvic cancer surgery, or in high-risk ambulatory cancer patients. Both oral FXa inhibitors and LMWH have limitations. LMWH requires daily subcutaneous injections, and because of its renal clearance, its use may be problematic in patients with severe kidney disease. The risk of bleeding with oral FXa inhibitors may be higher than with LMWH in patients with intraluminal gastrointestinal or genitourinary cancers. Other problems with oral FXa inhibitors include potential drug-drug interactions and dosing issues in patients with thrombocytopenia or severe kidney or liver disease. Therefore, there remains a need for convenient and safer anticoagulants for VTE treatment in cancer patients. FXI has emerged as a potentially safer target for anticoagulants than FXa because FXI is essential for thrombosis, but mostly dispensable for hemostasis. This review summarizes the currently available therapeutic options for cancer-associated VTE, highlights knowledge gaps, and discusses the potential of FXI inhibitors to address key unmet clinical needs in this vulnerable patient population.

Feasibility of home administration of nebulised interferon ß-1a (SNG001) for COVID-19: a remote study.

Effective therapeutics given early to high-risk ambulatory patients with coronavirus disease 2019 (COVID-19) could improve outcomes and reduce overall healthcare burden. However, conducting site visits in non-hospitalised patients, who should remain isolated, is problematic. To evaluate the feasibility of a purely remote (virtual) study in non-hospitalised patients with COVID-19; and the efficacy and safety of nebulised recombinant interferon-β1a (SNG001) in this setting. Randomised, double-blind, parallel-group study, which was conducted remotely. Eligible patients aged ≥65 years (or ≥50 years with risk factors) with COVID-19 and not requiring hospital admission were recruited remotely. They were randomised to SNG001 or placebo once-daily via nebuliser for 14 days. The main outcomes were assessments of feasibility and safety, which were all conducted remotely. Of 114 patients treated, 111 (97.4%) completed 28 days of follow-up. Overall compliance to study medication was high, with ≥13 doses taken by 89.7% and 92.9% of treated patients in the placebo and SNG001 groups, respectively. Over the course of the study, only two patients were hospitalised, both in the placebo group; otherwise there were no notable differences between treatments for the efficacy parameters. No patients withdrew owing to an adverse event, and a similar proportion of patients experienced on-treatment adverse events in the two treatment groups (64.3% and 67.2% with SNG001 and placebo, respectively); most were mild or moderate and not treatment-related. This study demonstrated that it is feasible to conduct a purely virtual study in community-based patients with COVID-19, when the study included detailed daily assessments and with medication administered via nebuliser.

Cancer-associated thrombosis and drug-drug interactions of antithrombotic and antineoplastic agents.

Venous thromboembolism (VTE) is often associated with malignant diseases and notably contributes to morbidity and mortality in patients with cancer. Cancer-associated thrombosis (CAT) brings additional costs to health expenditures and has a negative impact on oncological outcomes. Either the recurrence rate of VTE or bleeding complications are also higher in patients with cancer. Prophylactic anticoagulation has been recommended in peri-surgical periods, inpatient settings, and high-risk ambulatory patients. Although various risk stratification scores are used, none are ideal for identifying patients who can benefit from anticoagulant prophylaxis. New risk scoring systems or biomarkers are needed to identify patients who are more likely to benefit from prophylaxis with low bleeding risk. The questions about the patients who will be given prophylaxis and those who develop thromboembolism, with which drug, and how long they will be treated are still not fully answered. Anticoagulation is the cornerstone of the treatment, but management of CAT remains complex. Low molecular weight heparins and direct oral anticoagulants are effective and safe options for the treatment of CAT. Recognizing adverse effects, drug-drug interactions, and accompanying conditions that cause dose adjustment is crucial. Prevention and treatment of VTE in patients with cancer require a multidisciplinary and patient-based approach. PLAIN LANGUAGE SUMMARY: Cancer-associated thrombosis is a significant cause of mortality and morbidity in patients with cancer. Chemotherapy, surgery, and/or use of central venous access remarkably increase the risk of thrombosis. Prophylactic anticoagulation should be considered not only in inpatient follow-up and during peri-surgical period but also ambulatory patients with a high risk of thrombosis. Many parameters, such as drug-drug interactions, primary side of cancer, and comorbidities of patients should be considered when selecting anticoagulant drugs. More accurate risk stratification scores or biomarkers are still an unmet need.

Primary prevention of cancer-associated venous thrombosis: Rationale and challenges in clinical practice

Cancer-associated venous thrombosis (CAT) is a common, multifactor event known to complicate the course of cancer and jeopardize a patient's prognosis. The current guidelines regarding the prevention of CAT are sometimes considered insufficiently precise about specific situations, or are poorly applied. The expected benefits of thromboprophylaxis are balanced by the risk of major bleeding induced by anticoagulation, which implies a need to accurately identify ambulatory patients at high risk of thrombosis or hemorrhage. The Khorana score is commonly used for this, but is limited by the non-reproducibility of predicted performance across cancer types, and by the fact that antitumor treatment and cardiovascular risks are not included. The COMPASS-CAT score, which includes those two aspects, was found to be a more accurate predictor of venous thromboembolism in patients with lung cancer, and to better distinguish between patients at low or high risk of thrombosis. The frailty of patients with cancer is also a major issue, and should be taken into account when thromboprophylaxis is considered. According to current guidelines, CAT prophylaxis should be considered for hospitalized patients, those for whom surgery is scheduled, or those with pancreatic cancers. In ambulatory patients, decisions should be made according to patient, cancer and antitumoral treatment characteristics. Low molecular weight heparin is the gold standard of CAT prophylaxis. Despite increased risks of bleeding or drug-drug interactions in cancer patients, direct oral anticoagulants could be alternate options for high-risk ambulatory patients that should be accompanied by a careful global analysis of benefits, harms, and patient preferences.

Efficacy and Safety of Adintrevimab (ADG20) for the Treatment of High-Risk Ambulatory Patients With Mild or Moderate Coronavirus Disease 2019: Results From a Phase 2/3, Randomized, Placebo-Controlled Trial (STAMP) Conducted During Delta Predominance and Early Emergence of Omicron.

Safe and effective treatments are needed to prevent severe outcomes in individuals with coronavirus disease 2019 (COVID-19). We report results from STAMP, a phase 2/3, multicenter, double-blind, randomized, placebo-controlled trial of adintrevimab, an extended half-life monoclonal antibody, for treatment of high-risk ambulatory patients with mild to moderate COVID-19. Nonhospitalized, unvaccinated participants aged ≥12 years with mild to moderate COVID-19 and ≥1 risk factor for disease progression were randomized to receive a single intramuscular injection of 300 mg adintrevimab or placebo. Enrollment was paused due to the global emergence of the Omicron BA.1/BA1.1 variants, against which adintrevimab showed reduced activity in vitro. The primary efficacy endpoint was COVID-19-related hospitalization or all-cause death through day 29 in participants with COVID-19 due to laboratory-confirmed or suspected non-Omicron severe acute respiratory syndrome coronavirus 2 variants. Between 8 August 2021 and 11 January 2022, 399 participants were randomized to receive adintrevimab (n = 198) or placebo (n = 201), including 336 with COVID-19 due to non-Omicron variants. COVID-19-related hospitalization or all-cause death through day 29 occurred in 8 of 169 (4.7%) participants in the adintrevimab group and 23 of 167 (13.8%) participants in the placebo group, a 66% relative risk reduction in favor of adintrevimab (standardized risk difference, -8.7% [95% confidence interval, -14.71% to -2.67%]; P = .0047). Incidence of treatment-emergent adverse events (TEAEs) was similar between treatment groups (33.9% for adintrevimab and 39.5% for placebo). No adintrevimab-related serious TEAEs were reported. Treatment with a single intramuscular injection of adintrevimab provided protection against severe outcomes in high-risk ambulatory participants with COVID-19 due to susceptible variants, without safety concerns. Clinical Trial Registration. NCT04805671.

1113. Clinical and Virologic Outcomes with Early Adintrevimab (ADI) Monoclonal Antibody Therapy in Mild and Moderate COVID-19

Abstract Background Peak SARS-CoV-2 viral replication occurs in the upper respiratory tract in presymptomatic and early symptomatic phases. Administration of a monoclonal antibody may be most beneficial in the early time period immediately after symptom onset. Here we describe the effect of early therapy on efficacy in patients receiving ADI. Methods High risk patients with mild or moderate COVID-19 were enrolled in the ADI treatment study (STAMP), with primary endpoint of COVID-19 related hospitalization or all-cause death through Day 29 in patients with disease due to confirmed or suspected SARS-CoV-2 variants other than Omicron. Patients were randomized 1:1 to receive ADI or placebo administered by a single intramuscular (IM) injection. For this subgroup analysis, patients that had received therapy within 3 days of symptom onset were evaluated. Results In the overall population, the study met the primary endpoint demonstrating 66% relative risk reduction of COVID-19 hospitalization or all cause death in 336 patients. Among 261 patients receiving therapy within 3 days of symptom onset (n=133 ADI, n=128 placebo), ADI was associated with a statistically significant reduction in the risk of COVID-19-related hospitalization or all-cause death through Day 29 compared with placebo (4 [3%] vs. 15 [11.7%], standardized risk difference -8%, 95% CI: -14.11, -1.86, p=0.0106), demonstrating a 72% standardized relative risk reduction in favor of ADI. When given as early therapy, ADI provided a greater reduction in viral load from baseline to Day 5 compared with placebo as assessed by saliva samples, with an adjusted least-squares mean difference of -0.97 log10 copies/mL (95% CI: -1.540, -0.391; p=0.0011). No study drug related SAEs, including deaths, and no hypersensitivity reactions were reported. Conclusion Early therapy with a single dose of ADI 300 mg IM provided a 72% reduction in the risk of COVID-19 related hospitalization and all-cause death compared to placebo in high-risk ambulatory patients with mild to moderate COVID-19. Therapy within the first 3 days also led to a greater reduction in viral load compared to placebo and favorable outcomes in patients who are at high risk for progression of disease. Disclosures Kathryn Mahoney, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Kristin Narayan, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Natalia Betancourt, MS, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Yong Li, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Deepali Gupta, B.Sc, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Pamela Hawn, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Pete Schmidt, MD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Myra Popejoy, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds.

Thrombophilia Gene Mutations for the Prediction of Venous Thromboembolism in Ambulatory Cancer Patients Receiving Chemotherapy

Inherited thrombophilia and cancer are both independently known to increase the risk of venous thromboembolism (VTE) due to genetic procoagulant predisposition, tissue damage and inflammatory mediators, respectively. The role of inherited thrombophilia on the risk of VTE in cancer patients is unclear and determination of thrombophilic status is not part of clinical practice. Our objective was to determine the prevalence of common thrombophilia gene mutations and their influence on the risk of developing VTE in a cohort of moderate to high-risk ambulatory cancer patients receiving chemotherapy. We used buffy coat blood samples at the baseline visit from patients enrolled in the AVERT trial (a randomized, placebo-controlled, double-blind trial to assess the efficacy and safety of apixaban as primary thromboprophylaxis in ambulatory cancer patients with intermediate to high risk for VTE) to determine if a panel of thrombophilia gene mutations (including Prothrombin G20210A mutation, Factor XI, Fibrinogen gamma chain (FGG), SERPINA10, Factor V K858R, Factor XIII, Factor V Leiden and, ABO blood gene mutations) is associated with a diagnosis of VTE during the 7-months follow-up after randomization (which in all cases coincided with the start of chemotherapy). Bivariate tests of association were performed using the Fisher exact test. Logistic regression analysis was used to calculate unadjusted and adjusted odds ratios (OR) with 95% confidence intervals comparing heterozygous and homozygous mutations (combined) to wild type. When a gene mutation was rare or absent in the cohort, we used exact logistic regression to obtain OR estimates. We adjusted for age, sex, anticoagulation treatment group, and concomitant antiplatelet therapy. 438 patients (260 females) (76.3% of the entire cohort of 574) with available samples were included in this study. The patients' median age was 62. During the 7-months of follow-up, there were 39 VTE events including 25 deep vein thrombosis (DVT), 13 pulmonary embolisms (PE), and 1 DVT with PE. Among the 39 (8.90%) patients who suffered a VTE event, the prevalence of mutations was Prothrombin G20210A mutation: 2.56%, Factor XI: 79.5%, FGG: 31.6%, SERPINA10: 0%, Factor V K858R: 35.9%, Factor XIII: 44.7%, Factor V Leiden: 15.4% and ABO: 79.5%, compared to Prothrombin G20210A mutation: 2.01%, Factor XI: 75.2%, FGG: 42.0%, SERPINE10: 0.75%, Factor V K858R: 45.6%, Factor XIII: 43.7%, Factor V Leiden: 3.52% and ABO: 58.9% in those who did not develop a VTE (n=399, Table 1). The odds of VTE were significantly increased in patients with Factor V Leiden mutation compared to those without the mutation, in both unadjusted and adjusted models [OR: 4.99 (p=0.0020) and adjusted OR: 5.84 (p=0.0011)] (Table 2). Patients with non-O blood type also had increased odds of VTE compared to those with O blood type before and after adjustment [OR: 2.70 (p=0.0153) and adjusted OR: 2.71 (p=0.0156)] (Table 2). No other thrombophilia genes were significantly associated with the occurrence of VTE (Table 2). In conclusion, our data indicate that some thrombophilia gene mutations may be important predictors for VTE in cancer patients. The Factor V Leiden and ABO gene mutations independently predicted VTE in this cohort of moderate to high-risk ambulatory cancer patients receiving chemotherapy. Whether testing for thrombophilia gene mutations can help risk stratify or influence outcomes should be further explored in prospective studies before clinical application. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Stewardship of COVID-19 volunteers by nested trial design

Stewardship of COVID-19 volunteers by nested trial design

Disparities in COVID-19 Monoclonal Antibody Delivery: a Retrospective Cohort Study.

BackgroundDisparities in access to anti-SARS-CoV-2 monoclonal antibodies have not been well characterized.ObjectiveWe sought to explore the impact of race/ethnicity as a social construct on monoclonal antibody delivery.Design/PatientsFollowing implementation of a centralized infusion program at a large academic healthcare system, we reviewed a random sample of high-risk ambulatory adult patients with COVID-19 referred for monoclonal antibody therapy.Main MeasuresWe examined the relationship between treatment delivery, race/ethnicity, and other demographics using descriptive statistics, binary logistic regression, and spatial analysis.Key ResultsThere was no significant difference in racial composition between patients who did (n = 25) and patients who did not (n = 378) decline treatment (p = 0.638). Of patients who did not decline treatment, 64.8% identified as White, 14.8% as Hispanic/Latinx, and 11.1% as Black. Only 44.6% of Hispanic/Latinx and 31.0% of Black patients received treatment compared to 64.1% of White patients (OR 0.45, 95% CI 0.25–0.81, p = 0.008, and OR 0.25, 95% CI 0.12–0.50, p < 0.001, respectively). In multivariable analysis including age, race, insurance status, non-English primary language, county Social Vulnerability Index, illness severity, and total number of comorbidities, associations between receiving treatment and Hispanic/Latinx or Black race were no longer statistically significant (AOR 1.32, 95% CI 0.69–2.53, p = 0.400, and AOR 1.34, 95% CI 0.64–2.80, p = 0.439, respectively). However, patients who were uninsured or whose primary language was not English were less likely to receive treatment (AOR 0.16, 95% CI 0.03–0.88, p = 0.035, and AOR 0.37, 95% CI 0.15–0.90, p = 0.028, respectively). Spatial analysis suggested decreased monoclonal antibody delivery to Cook County patients residing in socially vulnerable communities.ConclusionsHigh-risk ambulatory patients with COVID-19 who identified as Hispanic/Latinx or Black were less likely to receive monoclonal antibody therapy in univariate analysis, a finding not explained by patient refusal. Multivariable and spatial analyses suggested insurance status, language, and social vulnerability contributed to racial disparities.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-022-07603-4.

Anti–SARS-CoV-2 Monoclonal Antibodies for Early COVID-19

Background Anti–SARS-CoV-2 monoclonal antibodies have been shown to reduce severe COVID-19 in high-risk ambulatory patients. Methods This operations study at 3 affiliated centers conducted from November 23, 2020, to April 30, 2021, identified and treated patients meeting criteria for anti–SARS-CoV-2 monoclonal antibody therapy. The primary study outcome was treatment of qualifying patients. Secondary outcomes included infusion complications, hospitalization/death, and symptom resolution. Results Three hundred sixty-seven patients were treated during the study period. The mean patient age was 63 years (SD, 13.47 years). A total of 201 patients (55%) were male, 276 patients (75%) were White, 54 patients (15%) were African American, 10 patients (2.7%) were Asian, and 9 patients (2.4%) identified as Latino or Hispanic. Patients had a first positive direct SARS-CoV-2 test within 10 days of infusion and met high-risk criteria with 232 patients (63%) having more than 1 risk factor. Thirty-two patients (9%) had received at least 1 dose of SARS-CoV-2 vaccination. Four patients experienced an infusion reaction. Of 236 patients reporting time to symptom resolution, 172 patients (73%) were symptom free within 5 days of infusion. Twenty patients (5%) treated were hospitalized for COVID-19 within 30 days of infusion including 1 patient death from COVID-19. Conclusions Our study demonstrates that treatment with anti–SARS-CoV-2 neutralizing monoclonal antibodies is feasible in a high-resource health care setting. Infusion was well tolerated by the majority of patients, and there were no known infusion center SARS-CoV-2 exposures.

514. Anti-SARS-CoV-2 Monoclonal Antibodies for Early COVID-19: A Real World Experience

BackgroundAnti-SARS-CoV-2 monoclonal antibodies afford prompt immunity, have demonstrated reduction in severe COVID-19 in high risk ambulatory patients, and are available through Emergency Use Authorization. Challenges exist, however, to widespread utilization. MethodsThis operations study 11/23/20-4/30/21 identified patients meeting monoclonal AB EUA criteria by test results or referral. Outreach to harder-hit neighborhoods included connecting with primary care teams and testing sites. Infusion centers with staff trained in infection control, rapid response and drug preparation were utilized. The primary study outcome was treatment of qualifying patients. Secondary outcomes included infusion complications, hospitalization/death, and symptom resolution. Investigational review board approval was obtained.Results367 patients were treated: mean age of 63, 201(55%) male, 276(75%) white, 54(15%) black. All patients had a first positive direct SARS-CoV-2 test within 10 days, 232(63%) had > 1 high-risk qualification, 32(9%) were vaccinated for SARS-CoV-2. Of patients with available zipcodes, 135(38%) had a Community Need Index >3.5 and 157(45%) a Social Vulnerability Index >0.5. 190(52%) received bamlanivimab, 93(25%) casirivimab/imdevimab, 84(23%) bamlanivimab/etesevimab. Four patients experienced infusion reaction, 1 with anaphylaxis. 172(73%) of 236 patients were symptom free at day 5. 20 patients (5%) were hospitalized for COVID-19 within 30 days with a median time from symptom onset to infusion of 7 days, 11(55%) were admitted within 24 hours, 1 died. Patient Characteristics COVID-19 course Community Need Index and Social Vulnerability Index by Zipcode ConclusionOur study demonstrates that treatment with anti-SARS-CoV-2 monoclonal antibodies is feasible in a high resource setting. There were no related SARS-CoV-2 exposures and therapy was well tolerated. Trials of anti-SARS-CoV-2 monoclonal antibodies have reported lower rates of hospitalizations in treated patients than we found. This may reflect the expanded time frame for EUA therapy as compared to clinical trials, differences in real world patients or viral variants. Given potential benefit in unvaccinated patients or those at risk for poor vaccine response, the equitable utilization of anti-SARS-CoV-2 monoclonal antibody therapy in early COVID-19 should remain a focus for researchers and clinicians. Disclosures All Authors: No reported disclosures

A Randomized, Placebo-Controlled Clinical Trial of Bamlanivimab and Etesevimab Together in High-Risk Ambulatory Patients With COVID-19 and Validation of the Prognostic Value of Persistently High Viral Load.

BackgroundBased on interim analyses and modeling data, lower doses of bamlanivimab and etesevimab together (700/1400 mg) were investigated to determine optimal dose and expand availability of treatment.MethodsThis Phase 3 portion of the BLAZE-1 trial characterized the effect of bamlanivimab with etesevimab on overall patient clinical status and virologic outcomes in ambulatory patients ≥12 years old, with mild-to-moderate coronavirus disease 2019 (COVID-19), and ≥1 risk factor for progressing to severe COVID-19 and/or hospitalization. Bamlanivimab and etesevimab together (700/1400 mg) or placebo were infused intravenously within 3 days of patients’ first positive COVID-19 test.ResultsIn total, 769 patients were infused (median age [range]; 56.0 years [12, 93], 30.3% of patients ≥65 years of age and median duration of symptoms; 4 days). By day 29, 4/511 patients (0.8%) in the antibody treatment group had a COVID-19-related hospitalization or any-cause death, as compared with 15/258 patients (5.8%) in the placebo group (Δ[95% confidence interval {CI}] = −5.0 [−8.0, −2.1], P < .001). No deaths occurred in the bamlanivimab and etesevimab group compared with 4 deaths (all COVID-19-related) in the placebo group. Patients receiving antibody treatment had a greater mean reduction in viral load from baseline to Day 7 (Δ[95% CI] = −0.99 [−1.33, −.66], P < .0001) compared with those receiving placebo. Persistently high viral load at Day 7 correlated with COVID-19-related hospitalization or any-cause death by Day 29 in all BLAZE-1 cohorts investigated.ConclusionsThese data support the use of bamlanivimab and etesevimab (700/1400 mg) for ambulatory patients at high risk for severe COVID-19. Evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants will require continued monitoring to determine the applicability of this treatment.Clinical Trials RegistrationNCT04427501.

Cost-utility analysis of apixaban compared with usual care for primary thromboprophylaxis in ambulatory patients with cancer.

Background:Apixaban (2.5 mg) taken twice daily has been shown to substantially reduce the risk of venous thromboembolism (VTE) compared with placebo for the primary thromboprophylaxis of ambulatory patients with cancer who are starting chemotherapy and are at intermediate-to-high risk of VTE. We aimed to compare the health system costs and health benefits associated with primary thromboprophylaxis using apixaban with those associated with the current standard of care (where no primary thromboprophylaxis is given), from the perspective of Canada’s publicly funded health care system in this subpopulation of patients with cancer over a lifetime horizon.Methods:We performed a cost–utility analysis to estimate the incremental cost per quality-adjusted life-year (QALY) gained with primary thromboprophylaxis using apixaban. We obtained baseline event rates and the efficacy of apixaban from the Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer Patients (AVERT) trial on apixaban prophylaxis. We estimated relative risk for bleeding, risk of complications associated with VTE treatment, mortality rates, costs and utilities from other published sources.Results:Over a lifetime horizon, apixaban resulted in lower costs to the health system (Can$7902.98 v. Can$14 875.82) and an improvement in QALYs (9.089 v. 9.006). The key driver of cost–effectiveness results was the relative risk of VTE as a result of apixaban. Results from the probabilistic analysis showed that at a willingness to pay of Can$50 000 per QALY, the strategy with the highest probability of being most cost-effective was apixaban, with a probability of 99.87%.Interpretation:We found that apixaban is a cost-saving option for the primary thromboprophylaxis of ambulatory patients with cancer who are starting chemotherapy and are at intermediate-to-high risk of VTE.

Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19

BackgroundPatients with underlying medical conditions are at increased risk for severe coronavirus disease 2019 (Covid-19). Whereas vaccine-derived immunity develops over time, neutralizing monoclonal-antibody treatment provides immediate, passive immunity and may limit disease progression and complications.MethodsIn this phase 3 trial, we randomly assigned, in a 1:1 ratio, a cohort of ambulatory patients with mild or moderate Covid-19 who were at high risk for progression to severe disease to receive a single intravenous infusion of either a neutralizing monoclonal-antibody combination agent (2800 mg of bamlanivimab and 2800 mg of etesevimab, administered together) or placebo within 3 days after a laboratory diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The primary outcome was the overall clinical status of the patients, defined as Covid-19–related hospitalization or death from any cause by day 29.ResultsA total of 1035 patients underwent randomization and received an infusion of bamlanivimab–etesevimab or placebo. The mean (±SD) age of the patients was 53.8±16.8 years, and 52.0% were adolescent girls or women. By day 29, a total of 11 of 518 patients (2.1%) in the bamlanivimab–etesevimab group had a Covid-19–related hospitalization or death from any cause, as compared with 36 of 517 patients (7.0%) in the placebo group (absolute risk difference, −4.8 percentage points; 95% confidence interval [CI], −7.4 to −2.3; relative risk difference, 70%; P<0.001). No deaths occurred in the bamlanivimab–etesevimab group; in the placebo group, 10 deaths occurred, 9 of which were designated by the trial investigators as Covid-19–related. At day 7, a greater reduction from baseline in the log viral load was observed among patients who received bamlanivimab plus etesevimab than among those who received placebo (difference from placebo in the change from baseline, −1.20; 95% CI, −1.46 to −0.94; P<0.001).ConclusionsAmong high-risk ambulatory patients, bamlanivimab plus etesevimab led to a lower incidence of Covid-19–related hospitalization and death than did placebo and accelerated the decline in the SARS-CoV-2 viral load. (Funded by Eli Lilly; BLAZE-1 ClinicalTrials.gov number, NCT04427501.)

Real-world Effectiveness and Tolerability of Monoclonal Antibody Therapy for Ambulatory Patients With Early COVID-19.

BackgroundNeutralizing monoclonal antibodies (MAbs) are a promising therapy for early coronavirus disease 2019 (COVID-19), but their effectiveness has not been confirmed in a real-world setting.MethodsIn this quasi-experimental pre-/postimplementation study, we estimated the effectiveness of MAb treatment within 7 days of symptom onset in high-risk ambulatory adults with COVID-19. The primary outcome was a composite of emergency department visits or hospitalizations within 14 days of positive test. Secondary outcomes included adverse events and 14-day mortality. The average treatment effect in the treated for MAb therapy was estimated using inverse probability of treatment weighting and the impact of MAb implementation using propensity-weighted interrupted time series analysis.ResultsPre-implementation (July–November 2020), 7404 qualifying patients were identified. Postimplementation (December 2020–January 2021), 594 patients received MAb treatment and 5536 did not. The primary outcome occurred in 75 (12.6%) MAb recipients, 1018 (18.4%) contemporaneous controls, and 1525 (20.6%) historical controls. MAb treatment was associated with decreased likelihood of emergency care or hospitalization (odds ratio, 0.69; 95% CI, 0.60–0.79). After implementation, the weighted probability that a given patient would require an emergency department visit or hospitalization decreased significantly (0.7% per day; 95% CI, 0.03%–0.10%). Mortality was 0.2% (n = 1) in the MAb group compared with 1.0% (n = 71) and 1.0% (n = 57) in pre- and postimplementation controls, respectively. Adverse events occurred in 7 (1.2%); 2 (0.3%) were considered serious.ConclusionsMAb treatment of high-risk ambulatory patients with early COVID-19 was well tolerated and likely effective at preventing the need for subsequent emergency department or hospital care.

Thromboembolic events in metastatic testicular cancer treated with cisplatin-based chemotherapy.

BACKGROUNDTesticular germ cell tumor (TGCT) is the most curable solid tumor and most common cancer among men 18-39 years. While cisplatin-based chemotherapy has significantly lengthened the survival of patients with TGCT, it is associated with a high rate of thromboembolic events (TEE).AIMTo summarize our single-center experience highlighting patients who were diagnosed with TGCT and received platinum-based chemotherapy, with special attention to those patients who suffered a TEE.METHODSA retrospective analysis of the medical records and imaging studies of 68 consecutive individuals who were diagnosed with TGCT and received platinum-based chemotherapy at our Institution in a metropolitan community between January 1, 2014 and December 31, 2019.RESULTSA total of 19 (28%) patients experienced a TEE following orchiectomy which occurred during chemotherapy in 13 (68%) of these patients. Patients with a higher pathologic stage (stage III) were significantly (P = 0.023) more likely to experience a TEE compared to patients who had a lower stage. Additionally, patients who were treated with 3 cycles of bleomycine, etoposide, and cisplatin and 1 cycle of etoposide and cisplatin or 4 cycles of etoposide and cisplatin were significantly 5 (P = 0.02) times more likely to experience a TEE compared to patients who were treated with only 3 cycles of bleomycine, etoposide, and cisplatin.CONCLUSIONDue to numerous factors that predispose to a TEE such as large retroperitoneal disease, higher clinical stage, greater number of chemotherapy cycle, central venous catheter, cigarette smoking, and possible cannabis use, high-risk ambulatory patients with TGCT treated with cisplatin-based chemotherapy may benefit from prophylactic anticoagulation. Randomized studies to evaluate the safety and efficacy of prophylactic anticoagulants are warranted in this young patient population generally devoid of medical co-morbidities.

Venous thromboembolism prophylaxis in ambulatory cancer patients initiating chemotherapy: A cost-effectiveness analysis.

7074 Background: Venous thromboembolism (VTE) is a major cause of morbidity and mortality among cancer patients. The Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer Patients (AVERT) randomized controlled trial concluded that apixaban is a safe and effective option for VTE prophylaxis in high-risk ambulatory cancer patients initiating a new chemotherapy regimen. We performed a cost-effectiveness analysis from a health system perspective to determine if apixaban is a feasible prophylactic strategy for this population. Methods: A decision model was created from a third party payer perspective with a time horizon of 6 months, based on the treatment arms of the AVERT trial: (1) apixaban 2.5 mg twice daily for 6 months during active chemotherapy versus (2) placebo. Rates of VTE (4.2% apixaban vs 10.2% placebo), major bleeding (3.5% vs 1.8%) and clinically relevant nonmajor bleeding (CRNMB) (7.3% vs 5.5%) were modeled from the results of the AVERT trial. Cost estimates for treatments and events were obtained from wholesale drug costs, previously published studies and Medicare reimbursement data, and adjusted for inflation to 2018 dollars. Quality adjusted life years were calculated based on previously published utility values for the health states of advanced cancer, DVT, PE, and major bleeding events. An exploratory analysis was performed comparing prophylactic aspirin to no prophylaxis assuming a VTE rate of 7.2%, major bleeding rate of 3.5%, and CRNMB rate of 7.3%, based on the conservative assumptions that while aspirin may not be as effective at preventing VTE, the rate of clinically significant bleeding events would be similar or greater than that of apixaban. Results: In the base case model, apixaban is more costly and more effective than placebo (ICER = $5,013,190/QALY), and the cost per VTE prevented in the apixaban arm is $33,000. In one-way sensitivity analysis, if the cost of apixaban were reduced by 40% from $3,197 to $1,250 for a 6 month course, this could potentially be a cost-effective prophylaxis strategy with an ICER less than $100,000/QALY. In the alternative analysis, aspirin dominates placebo as it is both more effective and less expensive, and remains cost-effective even when the rate of clinically recognized bleeding with aspirin exceeds 15%. Conclusions: Further investigation into less costly prophylactic options such as generic direct oral anticoagulants (once available) and aspirin is warranted prior to broader implementation of a VTE prophylaxis strategy in this population.

Assessing Full Benefit of Rivaroxaban Prophylaxis in High-Risk Ambulatory Patients with Cancer: Thromboembolic Events in the Randomized CASSINI Trial.

Introduction In the CASSINI study, rivaroxaban thromboprophylaxis significantly reduced primary venous thromboembolism (VTE) endpoints during the intervention period, but several thromboembolic events designated as secondary efficacy endpoints were not included in the primary analysis. This study was aimed to evaluate the full impact of rivaroxaban thromboprophylaxis on all prespecified thromboembolic endpoints occurring on study. Methods CASSINI was a double-blind, randomized, placebo-controlled study in adult ambulatory patients with cancer at risk for VTE (Khorana score ≥2). Patients were screened at baseline for deep-vein thrombosis (DVT) and randomized if none was found. The primary efficacy endpoint was a composite of lower extremity proximal DVT, symptomatic upper extremity, or lower extremity distal DVT, any pulmonary embolism, and VTE-related death. This analysis evaluated all prespecified thromboembolic endpoints occurring on study to determine the full benefit of rivaroxaban prophylaxis. All endpoints were independently adjudicated. Results Total thromboembolic events occurred in fewer patients randomized to rivaroxaban during the full study period (29/420 [6.9%] and 49/421 [11.6%] patients in rivaroxaban and placebo groups, respectively [hazard ratio (HR) = 0.57; 95% confidence interval (CI): 0.36–0.90; p = 0.01]; number needed to treat [NNT] = 21). Similarly, fewer patients randomized to rivaroxaban experienced thromboembolism during the intervention period (13/420 [3.1%] patients) versus placebo (38/421 [9.0%] patients; HR = 0.33; 95% CI: 0.18–0.62; p < 0.001; NNT = 17). Conclusion Our findings confirm the substantial benefit of rivaroxaban thromboprophylaxis when considering all prespecified thromboembolic events, even after excluding baseline screen-detected DVT. The low NNT, coupled with prior data demonstrating a high number needed to harm, should assist clinicians in determining the risk/benefit of thromboprophylaxis in high-risk patients with cancer.

Thromboprophylaxis in ambulatory patients with cancer

Ambulatory cancer patients receiving systemic cancer therapy are at varying risk for venous thromboembolism (VTE). The VTE risk depends on different cancer types, cancer stage, anti-cancer treatment and individual patient risk factors. Whereas pharmacologic thromboprophylaxis is recommended in most hospitalized cancer patients with an acute medical condition and in patients undergoing major cancer surgery, the role of primary thromboprophylaxis in the ambulatory setting is not clear. A VTE risk stratification using specific scoring systems, e. g. the Khorana score or the recently published CAT-score should be performed. Recently, two large randomized controlled studies using rivaroxaban (CASSINI trial) and apixaban (AVERT trial) versus placebo as primary VTE prevention in high-risk ambulatory cancer patients were published. When considered together, the two trials showed a significant benefit for the prevention of VTE with a low incidence of major bleeding. The DOAC had no effect on mortality. Primary thromboprophylaxis may be offered to high-risk outpatients with cancer, e. g. patients with advanced pancreatic carcinoma, provided there are no risk factors for bleeding and no drug-interactions. The patient's preference should also be respected. Current guidelines differ in their recommendations concerning the choice of anticoagulation. Whereas LMWH is still preferred to DOAC in the current German guideline, the ISTH guidance suggest to use DOAC in high-risk ambulatory cancer patients with no drug-drug interactions and not at high risk for bleeding. Of note, DOAC are currently not approved in this indication.

Re: Rivaroxaban for Thromboprophylaxis in High-risk Ambulatory Patients with Cancer

Re: Rivaroxaban for Thromboprophylaxis in High-risk Ambulatory Patients with Cancer