Extended-duration Prophylaxis Research Articles

Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients.

The risk of cytomegalovirus (CMV) infection in solid organ transplant recipients has resulted in the frequent use of prophylaxis to prevent the clinical syndrome associated with CMV infection. This is an update of a review first published in 2005 and updated in 2008 and 2013. To determine the benefits and harms of antiviral medications to prevent CMV disease and all-cause death in solid organ transplant recipients. We contacted the information specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 5 February 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. We included randomised controlled trials (RCTs) and quasi-RCTs comparing antiviral medications with placebo or no treatment, comparing different antiviral medications or different regimens of the same antiviral medications for CMV prophylaxis in recipients of any solid organ transplant. Studies examining pre-emptive therapy for CMV infection are studied in a separate review and were excluded from this review. Two authors independently assessed study eligibility, risk of bias and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. This 2024 update found four new studies, bringing the total number of included studies to 41 (5054 participants). The risk of bias was high or unclear across most studies, with a low risk of bias for sequence generation (12), allocation concealment (12), blinding (11) and selective outcome reporting (9) in fewer studies. There is high-certainty evidence that prophylaxis with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment is more effective in preventing CMV disease (19 studies: RR 0.42, 95% CI 0.34 to 0.52), all-cause death (17 studies: RR 0.63, 95% CI 0.43 to 0.92), and CMV infection (17 studies: RR 0.61, 95% CI 0.48 to 0.77). There is moderate-certainty evidence that prophylaxis probably reduces death from CMV disease (7 studies: RR 0.26, 95% CI 0.08 to 0.78). Prophylaxis reduces the risk of herpes simplex and herpes zoster disease, bacterial and protozoal infections but probably makes little to no difference to fungal infection, acute rejection or graft loss. No apparent differences in adverse events with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment were found. There is high certainty evidence that ganciclovir, when compared with aciclovir, is more effective in preventing CMV disease (7 studies: RR 0.37, 95% CI 0.23 to 0.60). There may be little to no difference in any outcome between valganciclovir and IV ganciclovir compared with oral ganciclovir (low certainty evidence). The efficacy and adverse effects of valganciclovir or ganciclovir were probably no different to valaciclovir in three studies (moderate certainty evidence). There is moderate certainty evidence that extended duration prophylaxis probably reduces the risk of CMV disease compared with three months of therapy (2 studies: RR 0.20, 95% CI 0.12 to 0.35), with probably little to no difference in rates of adverse events. Low certainty evidence suggests that 450 mg/day valganciclovir compared with 900 mg/day valganciclovir results in little to no difference in all-cause death, CMV infection, acute rejection, and graft loss (no information on adverse events). Maribavir may increase CMV infection compared with ganciclovir (1 study: RR 1.34, 95% CI: 1.10 to 1.65; moderate certainty evidence); however, little to no difference between the two treatments were found for CMV disease, all-cause death, acute rejection, and adverse events at six months (low certainty evidence). Prophylaxis with antiviral medications reduces CMV disease and CMV-associated death, compared with placebo or no treatment, in solid organ transplant recipients. These data support the continued routine use of antiviral prophylaxis in CMV-positive recipients and CMV-negative recipients of CMV-positive organ transplants.

Neoadjuvant Chemotherapy is Associated with Increased Risk of Postoperative DVT After Distal Pancreatectomy for Pancreatic Adenocarcinoma: a NSQIP Analysis.

Venous thromboembolism (VTE) remains a persistent source of postoperative morbidity despite prevention and mitigation efforts. Cancer, surgery, and chemotherapy are known risk factors for VTE. Existing literature suggests that neoadjuvant therapy (NAT) may contribute to increased VTE risk in the postoperative period, but few authors specifically examine this relationship in distal pancreatic adenocarcinoma (PDAC). In this study, we analyze the association of NAT and postoperative VTE in patients who underwent distal pancreatectomy (DP) for PDAC. Using the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database, we analyzed the Procedure Targeted files for pancreatectomy from 2014 to 2020. Adults with PDAC who underwent DP were grouped by receipt of NAT. The primary outcome was the rate of deep venous thrombosis (DVT) and the secondary outcome was the rate of pulmonary embolism (PE). We performed univariate and multivariate logistic regression analysis to determine risk factors associated with postoperative DVT. There were 4327 patients with PDAC who underwent DP. Of these, 1414 (32.7%) had NAT. Receipt of NAT was significantly associated with postoperative DVT requiring therapy (3.5% vs. 2.3%, p = 0.02), but was not associated with PE (p = 0.42). On MVA, NAT was associated with a 73% greater chance of developing postoperative DVT [odds ratio (OR) 1.73, 95% CI 1.18-2.55]. Patients who receive NAT prior to DP for PDAC are 73% more likely to develop postoperative DVT compared with upfront resection. As NAT becomes more commonplace, these high-risk patients should be prioritized for guideline-recommended extended duration prophylaxis.

Clinical Issues-January 2023.

Janus kinase inhibitor therapy and venous thromboembolism risk factors Key words: Janus kinase (JAK) inhibitor, tofacitinib, inflammatory bowel disease (IBD), ulcerative colitis, extended-duration prophylaxis. Identifying validated venous thromboembolism risk assessment tools Key words: venous thromboembolism (VTE) protocol, Caprini risk assessment model (RAM), risk identification, clinical workflow, bleeding risk. Timing of the preoperative venous thromboembolism risk assessment Key words: Caprini risk assessment model (RAM), venous thromboembolism (VTE) risk, patient assessment, presurgical testing visit, family history. Communicating venous thromboembolism and bleeding risk after surgery Key words: venous thromboembolism (VTE) risk, bleeding risk, hand over, postanesthesia care unit RN, intraoperative events.

National Adherence to Guidelines for Antimicrobial Prophylaxis for Patients Undergoing Radical Cystectomy.

The sentinel reference for antibiotic prophylaxis for radical cystectomy with ileal conduit in the AUA Guidelines reports data from 2003-2013 and has not been updated in the interim. Here, we assess adherence to antibiotic prophylaxis guidelines among patients undergoing radical cystectomy with ileal conduit for bladder cancer using a large national database. As a secondary objective, we assess the association between antimicrobial use and postoperative infection during the index admission following cystectomy. The Premier Healthcare Database was queried for all patients undergoing cystectomy with ileal conduit with diagnosis of bladder cancer between 2015 and 2020. Antibiotics used and the duration of use was determined by charge codes and grouped as guidelines-based or not according to 2019 AUA Guidelines. Association with infectious complications was assessed by logistic mixed effects regression models. Among 6,708 patients undergoing cystectomy with ileal conduit, only 28% (1,843/6,708) were given prophylaxis according to AUA guidelines; 1.8% (121/6,708) of patients received an antifungal and 37% (2,482/6,708) received extended duration prophylaxis beyond postoperative day 1. Patients who received guidelines-based prophylaxis were less likely to be diagnosed with a urinary tract infection (21% vs 24%, P = .04), pyelonephritis (5.1% vs 7.7%, P < .001), bacterial infection (24% vs 27%, P = .03), or pneumonia (12% vs 17%, P < .001). There was no statistically significant difference in clostridium difficile infection between guidelines-based and nonguidelines-based prophylaxis (3.2% vs 3.7%, P = .32). In a multivariable logistic regression adjusting for age, race, insurance, and hospital and provider characteristics, nonguideline antibiotic prophylaxis (OR 1.27 [1.12, 1.43], P < .001) was associated with an increased odds of infectious events, whereas a robotic approach (OR 0.82 [0.73, 0.92], P < .001) was associated with lower odds. Seventy-three percent of patients fail to receive guideline-based antibiotic prophylaxis when undergoing radical cystectomy with conduit, which was largely driven by extended duration antibiotic use. Despite the shorter duration of antibiotics, we found that guideline-based prophylaxis was associated with a 25% decrease in the odds of infectious complications. While residual confounding is possible, these data support current AUA guidelines and suggest a need for outreach to improve guideline adherence.

This Month in Adult Urology

This Month in Adult Urology

Provider perceptions of extended venous thromboembolism prophylaxis for hospitalized medically ill patients

BackgroundAlmost one-fourth of medically ill patients may remain at risk for venous thromboembolism (VTE) following hospital discharge, yet few receive extended-duration VTE prophylaxis. MethodsThis qualitative study at a single academic medical center assessed hospitalists’ perceptions of and barriers to implementation of extended-duration VTE prophylaxis following hospital discharge for the medically ill with the purpose of generating topics and hypotheses for future study. A focus group was conducted using semi-structured facilitator template to guide the discussion. Anonymous verbatim data transcribed from focus group participants were summarized using thematic analysis. ResultsFifteen hospitalist providers at University of Utah Hospital participated in this focus group. Themes uncovered during the session included perceived low burden of post-hospitalization VTE; lack of compelling evidence supporting the net clinical benefit of extended-duration prophylaxis; concern for high medication cost; practical uncertainty about prescribing extended-duration prophylaxis; and added risk of complications (bleeding events, transitions of care confusion, polypharmacy). ConclusionsThis group of providers believed post-hospitalization VTE risk in the medically ill is not sufficiently high to justify potential risks of extended-duration VTE prophylaxis and that a strong case for net clinical benefit and cost-effectiveness has not been made. These qualitative data are hypothesis-generating and future research should clearly define and quantify the timing and risk of VTE following hospitalization for medical illness in a real-world population, validate practical VTE and bleeding risk stratification schema, and explore cost-effectiveness of extended-duration prophylaxis. Ultimately, providers seek a clear message of which patients derive net clinical benefit from extended-duration VTE prophylaxis.

Venous Thromboembolism in COVID-19: Towards an Ideal Approach to Thromboprophylaxis, Screening, and Treatment

Purpose of ReviewNovel coronavirus disease 2019 (COVID-19) has been associated with an increased risk of arterial and venous thromboembolic (VTE) diseases. However, there is a limited amount of data regarding the prevention and management of VTE in severe hospitalized COVID-19 patients.Recent FindingsIn this article, we review currently available clinical data, and mechanisms for COVID-associated coagulopathy, and propose algorithms for screening, prevention (including extended-duration prophylaxis), and treatment of these patients.SummaryAlthough these recommendations are subject to change given rapidly evolving data, we provide a framework that can guide clinicians in managing thrombotic complications in this challenging condition.

Extended versus inpatient thromboprophylaxis with heparins following major open abdominopelvic surgery for malignancy: a systematic review of efficacy and safety

BackgroundPatients undergoing open abdominopelvic procedures for malignancy are at high risk of postoperative venous thromboembolism (VTE). This risk can be mitigated with prophylaxis; however, optimum duration in this population remains unknown. Our objective was to conduct a systematic review of contemporary literature on the use of heparin thromboprophylaxis following major open pelvic surgery for malignancy, comparing the efficacy and safety of extended duration to inpatient treatment.MethodsA study protocol describing search strategy and inclusion and exclusion criteria was developed and registered with PROSPERO. A literature review was conducted in accordance with the protocol.ResultsLiterature review identified only 4 studies directly comparing extended and inpatient duration prophylaxis, with a combined population of 3198 and 3135 patients for VTE rate and bleeding events, respectively. Despite many studies reporting lower VTE rates in patients receiving extended prophylaxis, no statistically significant difference in rates of postoperative VTE (p = 0.18) or bleeding complications (p = 0.43) was identified between patients receiving extended duration prophylaxis and those receiving inpatient only prophylaxis.ConclusionOn the review of contemporary literature, no significant difference was found in rates of postoperative VTE or bleeding complications between patients receiving extended duration heparin VTE prophylaxis and those receiving inpatient prophylaxis after open abdominopelvic surgery for malignancy.This raises the question of how extended duration prophylaxis has become common practice in this population, and whether this needs to be re-evaluated.

EDITORIAL COMMENT

The authors have conducted informative and important health services research on the “trends in extended-duration pharmacological prophylaxis (EDPP) to prevent venous thromboembolism (VTE) following radical cystectomy (RC)” using the national administrative claims database for the period 2012-2017. 1 URL-D-19-01447R1. 2019. Google Scholar Allowing for limitations of methodology using such databases, it was notable that a low proportion (19%) of cases received EDPP overall in the study period. Encouragingly, there was an improving time-trend from 9% utilization in 2012 to 26% in 2017. However, given that VTE following radical abdominal and/or pelvic surgery for cancer is a major cause of morbidity, mortality and cost, the findings of the current study portray an unfavorable picture for the current state of clinical practice with respect to EDPP utilization. Indeed, provided there are no contraindications, most international and/or national guidelines recommend the use of EDPP in this setting for high-risk cases. 2 Tikkinen KAO Craigie S Agarwal A et al. Procedure-specific risks of thrombosis and bleeding in urological cancer surgery: systematic review and meta-analysis. Eur Urol. 2018; 73: 242-251 Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar ,3 Key NS Bohlke K Falanga A Venous thromboembolism Prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update summary. J Oncol Practice. 2019; (Jop1900368) Crossref PubMed Scopus (19) Google Scholar The AUA Best Practice Statement from 2008 highlights the importance of thromboprophylaxis following RC, amongst other urological procedures, but falls short of touching upon the subject of EDPP in that context. 4 Forrest JB Clemens JQ Finamore P et al. AUA best practice statement for the prevention of deep vein thrombosis in patients undergoing urologic surgery. J Urol. 2009; 181: 1170-1177 Crossref PubMed Scopus (90) Google Scholar However, the evidence is accumulating to issue clear guidelines in support of EDPP, particularly as over 50% of symptomatic VTEs occur after discharge from hospital. 5 Sagalovich D Say R Kaouk J Mehrazin R The role of extended venous thromboembolism prophylaxis following urologic pelvic surgery. Urol Oncol. 2018; 36: 83-87 Crossref PubMed Scopus (5) Google Scholar , 6 VanDlac AA Cowan NG Chen Y et al. Timing, incidence and risk factors for venous thromboembolism in patients undergoing radical cystectomy for malignancy: a case for extended duration pharmacological prophylaxis. J Urol. 2014; 191: 943-947 Crossref PubMed Scopus (76) Google Scholar , 7 Kukreja JE Levey HR Scosyrev E et al. Effectiveness and safety of extended-duration prophylaxis for venous thromboembolism in major urologic oncology surgery. Urol Oncol. 2015; 33 (387.e387-316) Crossref PubMed Scopus (35) Google Scholar Lower compliance to EDPP use may in part be due to underappreciation of the risks in the absence of clear guidelines. 8 Sterious S Simhan J Uzzo RG et al. Familiarity and self-reported compliance with american urological association best practice recommendations for use of thromboembolic prophylaxis among american urological association Members. J Urol. 2013; 190: 992-998 Crossref PubMed Scopus (40) Google Scholar By highlighting the current trends in EDPP utilization after RC, the current study provides opportunities to look more closely into this issue and update the guidelines in relation to EDPP use following major urological oncological surgery, including RC.

Effectiveness and safety of inpatient versus extended venous thromboembolism (VTE) prophylaxis with heparin following major pelvic surgery for malignancy: protocol for a systematic review

BackgroundVenous thromboembolism (VTE) is a common postoperative complication associated with significant morbidity and mortality. The use of prophylactic heparin postoperatively reduces this risk, and the use of extended duration prophylaxis is becoming increasingly common. Malignancy and pelvic surgery both independently further increase the risk of postoperative VTE and patients undergoing major pelvic surgery for malignancy are at particularly high risk of VTE. However, the optimum duration of prophylaxis specifically in this population currently remains unclear.MethodsWe will conduct a systematic review of literature in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0.,2011) to evaluate current evidence of the effectiveness and safety of inpatient versus extended VTE prophylaxis with heparin (all forms) following major pelvic surgery for malignancy. We will search PubMed, EMBASE, and the Cochrane Library. Regarding safety, Food and Drug Administration (FDA), and Therapeutic Goods Administration (TGA) websites will be searched, including all levels of evidence. Results will be the postoperative timeframe in which a VTE event can be considered to have been provoked by the surgery, and the number of patients needed to treat with both inpatient and extended prophylaxis to prevent a VTE event in this timeframe, comparing these to determine if there is a significant benefit from extended prophylaxis.DiscussionThis systematic review will aim to identify the postoperative period in which patients undergoing major pelvic surgery for malignancy are at further increased risk of VTE as a result of their surgery and the optimum duration of heparin VTE prophylaxis with heparin to reduce this risk. Determining this will allow evidence-based recommendations to be made for the optimum duration of heparin VTE prophylaxis post major pelvic surgery for malignancy, leading to improved standards of care that are consistent between different providers and institutions.Systematic review registrationIn accordance with guidelines, our systematic review was submitted to PROSPERO for consideration of registration on 16/12/17 and was registered on 12/1/18 with the registration number CRD42018068961, and it was last updated on December 1, 2018.

Development of the IRIS-AR strategy: an intervention to improve rates of accrual and retention for the VTE-PRO randomized controlled trial

BackgroundThe Venous Thromboembolism Prophylaxis (VTE-PRO) randomized trial is a pilot study evaluating the impact of extended-duration prophylaxis on venous thromboembolic events in patients undergoing lung cancer resection. Enrolled VTE-PRO participants self-inject either low-molecular weight heparin or a saline placebo for 30 days postoperatively. Study outcomes include feasibility, incidence of venous thromboembolism, and venous thromboembolism-related morbidity and mortality. Initial analyses demonstrated low rates of accrual and retention for the VTE-PRO pilot. Therefore, the purpose of the current study was to develop a knowledge translation intervention to improve VTE-PRO pilot trial accrual and retention.MethodsEligible participants were surveyed to identify the barriers to VTE-PRO participation. The Theoretical Domains Framework was used to categorize these barriers. Barriers were mapped to the capabilities, opportunities, and behavior (COM-B) behavioral change wheel to identify potential interventions to support trial accrual and retention. The resulting knowledge translation intervention was titled Inform, Remind, Involve and Support to improve Accrual and Retention (IRIS-AR). Key informant interviews with patients were held to refine and confirm the validity of identified barriers and perceived acceptability of the proposed IRIS-AR intervention. Institutional Review Board approval was granted for this study.ResultsThe resulting intervention included: information booklets and counseling sessions to identify unique participant challenges to trial participation (Inform); daily reminders to administer injections (Remind); involvement of family/caregivers in study processes (Involve); and leverage of an existing home-care nursing program to provide injection support when needed (Support). Twenty-six key informant participants were interviewed. The most common barriers to trial participation included lack of social support and fear of needle injection. Participants generally supported use of information booklets, involvement of family/caregivers, and support by a home-care nursing program; however, not all supported the use of daily reminders.ConclusionDeveloped using theory and integrated knowledge translation, the IRIS-AR presents a patient-centered intervention that leverages existing programs to promote trial engagement. The proposed strategy can likely be adapted to improve compliance with other patient-directed interventions.Trial registrationClinicalTrials.gov, NCT02334007. Registered on 8 January 2015.

Thromboprophylaxis Strategies in Acute Medically Ill Patients

We review pivotal clinical trials of extended-duration venous thromboembolism (VTE) prophylaxis strategies in acute medically ill patients. For VTE prophylaxis in medically ill patients, current guidelines recommend the use of parenteral anticoagulants during hospitalization but not for extended duration prophylaxis. In 2017, betrixaban was approved for VTE prophylaxis in acute medically ill patients based on the results of the APEX trial. The MARINER trial missed its primary endpoint of reducing the composite of symptomatic VTE and VTE-related mortality with rivaroxaban compared with placebo. It did show that rivaroxaban halved the symptomatic VTE rate compared with placebo and did achieve its secondary endpoint. The EXCLAIM, ADOPT, and MAGELLAN trials did not demonstrate a net clinical benefit in reduction of VTE events due to an increase in bleeding events. The risk of VTE remains high in acute medically ill patients after hospital discharge. Based on the results of the APEX trial which showed a reduction in VTE, the FDA approved betrixaban for use in acute medically ill patients for extended duration VTE prophylaxis. Next steps are to implement the findings from APEX and MARINER into clinical practice to reduce recurrent VTE, lower healthcare cost, and reduce rehospitalization.

Anticoagulation in Venous Thromboembolism Prophylaxis in Medically Ill Patients: Potential Impact of NOACs.

While substantial evidence supports the use of standard-duration injectable anticoagulants for venous thromboembolism (VTE) prophylaxis, consensus is mixed about which agents may be preferred in acutely ill patients with ongoing need of VTE prophylaxis past the first 10-day duration of hospital stay and post-discharge. Non-vitamin K antagonist oral anticoagulants (NOACs) provide Factor Xa inhibition to prevent the thrombin generation essential in thromboembolism development, but evidence for the efficacy and safety of most NOACs is conflicting regarding extended-duration prophylaxis. Enoxaparin, a preferred injectable anticoagulant in standard-duration VTE prophylaxis, has shown an increased risk of major bleeding events when used in extended-duration prophylaxis, which outweighs its benefit. Rivaroxaban has demonstrated efficacy in extended-duration prophylaxis, but both rivaroxaban and apixaban have shown increased risks of major bleeding. Betrixaban remains the only NOAC approved in the USA for extended-duration VTE prophylaxis, and it demonstrates efficacy, with fewer adverse effects than other NOACs. This review evaluates the appropriateness of different NOAC agents compared with current therapies for the extended-duration VTE prophylaxis setting in medically ill populations.

PCV91 - VENOUS THROMBOEMBOLISM PROPHYLAXIS STRATEGIES FOR ELECTIVE TOTAL KNEE REPLACEMENT SURGERY: A COST-UTILITY ANALYSIS TO INFORM NICE CLINICAL GUIDELINE RECOMMENDATION

To assess the cost effectiveness of venous thromboembolism (VTE) primary prophylaxis strategies for people undergoing elective total knee replacement (eTKR) from the English National Health Service perspective to inform NICE guideline NG89 recommendation. Cost-utility analysis (CUA) was undertaken to compare 13 VTE prophylaxis strategies. These included pharmacological (low molecular-weight heparin (LMWH), fondaparinux, rivaroxaban, apixaban, dabigatran, aspirin), mechanical (anti-embolism stockings (AES), intermittent pneumatic compression (IPC), foot pumps) and combined strategies, used for different durations, as well as no prophylaxis. The analysis was undertaken in accordance with NICE Reference Case. A decision analytic model was developed in Microsoft Excel 2010®. Structure, inputs and assumptions were agreed with NICE guideline committee members. Baseline risks of events were based on published analysis of the National Joint Registry (NJR) data. Relative efficacy was based on systematic review and network meta-analysis. Incremental net monetary benefit (INMB) was calculated at a cost-effectiveness threshold of £20,000/quality-adjusted life-year (QALY). The model was run probabilistically. Deterministic sensitivity analyses (SAs) were also undertaken to assess the model robustness. Overall, strategies consisting of a single prophylaxis option and those used for standard duration (10-14 days) were more cost-effective compared to combined and/or extended duration prophylaxis strategies. The most cost-effective strategy was foot pump (INMB = £353 [95% CI: -£101 to £665]). This was followed by aspirin (low dose) (INMB = £281 [95% CI: -£195 to £703]). However, there was high uncertainty around the relative ranking of the interventions. The most cost-effective option did not change in all SAs. In people undergoing eTKR, foot pump was the most cost-effective strategy, followed by low-dose aspirin. However, the results are highly uncertain, precluding making a definitive conclusion regarding the relative cost effectiveness of these strategies. Other factors, including patient preferences, should be taken into account when making decisions regarding the choice of prophylaxis strategy in this population.

Improving adherence to recommended venous thromboembolic prophylaxis in abdominal and pelvic oncologic surgery

BackgroundWe reviewed rates of adherence to the American College of Chest Physicians guidelines for venous thromboembolism prophylaxis in abdominal and pelvic oncologic surgery at our community hospital compared with rates statewide. MethodsWe completed a retrospective review of adult patients undergoing abdominal or pelvic oncologic surgery from January 1, 2015 to December 31, 2016, compared with statewide data from the Michigan Surgical Quality Collaborative during the same period. Educational intervention included creation of hospital guidelines and presentations reviewing American College of Chest Physicians guidelines and hospital adherence rates. A short-term observation of extended-duration venous thromboembolism prophylaxis rates was completed after the intervention. ResultsThe rates of in-hospital venous thromboembolism prophylaxis (general surgery: 93.7%, n = 106; gynecology: 40.0%, n = 32) were comparable to statewide in-hospital prophylaxis rates (89.6% general surgery, 41.8% gynecology). Five patients (4.5%) were prescribed extended-duration prophylaxis, which was lower than statewide rates (20.3%). In comparison, there was a statistically significant improvement in the rate of extended prophylaxis in the 6 months following intervention to 23.6% (n = 5, P < .0005). ConclusionThe rates of extended-duration venous thromboembolism prophylaxis prescription were lower than the state average at our community hospital; however, the short-term evaluation revealed significant improvement after intervention.

Betrixaban for prevention of venous thromboembolism in acute medically ill patients.

Venous thromboembolism (VTE) is a common, potentially preventable cause of morbidity and mortality among acute medically ill patients. More than half of VTE events in this population occur after hospital discharge. Thus, providing extended-duration VTE prophylaxis from in-hospital through the post-discharge continuum may improve the quality of care in patients at risk of VTE. Betrixaban is a new oral, once-daily factor Xa inhibitor approved by the United States (US) Food and Drug Administration (FDA) for extended-duration prophylaxis of VTE in acute medically ill patients. The clinical efficacy and safety of betrixaban in acute medically ill patients perceived to be at high risk for VTE were evaluated in a large, randomized, double-blind, active-controlled, multinational clinical trial [Acute Medically Ill VTE Prevention With Extended Duration Betrixaban (APEX)]. Patients were randomized to receive subcutaneous enoxaparin (10 ± 4 days) or oral betrixaban (35–42 days) plus matching placebos. The primary efficacy outcome was a composite of asymptomatic proximal deep vein thrombosis and symptomatic VTE; the primary safety measure was major bleeding. Extended-duration betrixaban reduced VTE events without an increase in major bleeding in the modified intent-to-treat analysis. Post hoc analyses of the APEX trial provided further evidence to support the efficacy and safety of betrixaban in reducing all-cause ischaemic stroke, fatal or irreversible ischaemic or bleeding events, as well as reducing VTE-related rehospitalization. In summary, analyses of the APEX study demonstrated a positive benefit–risk profile for extended prophylaxis of VTE with betrixaban in acute medically ill patients. This is likely to have important public health and health economic implications.

Betrixaban: A New Oral Factor Xa Inhibitor for Extended Venous Thromboembolism Prophylaxis in High-Risk Hospitalized Patients.

To review the pharmacology, pharmacokinetics, efficacy, and safety of the factor Xa (FXa) inhibitor betrixaban for extended-duration prophylaxis of acute medically ill patients with venous thromboembolism (VTE) risk factors. A MEDLINE/PubMed (January 1990 to October 2017) search was conducted using the following keywords: betrixaban, PRT054021, FXa inhibitor, novel oral anticoagulant, NOAC, direct oral anticoagulant, DOAC, and target specific oral anticoagulant, TSOAC. References of identified articles were searched by hand for additional relevant citations. We included English-language articles evaluating betrixaban pharmacology, pharmacokinetics, efficacy, or safety in human subjects for VTE prophylaxis. Betrixaban is a FXa inhibitor that decreases prothrombinase activity and thrombin generation. Betrixaban efficacy and safety has been compared with that of enoxaparin for prophylaxis of VTE in acutely ill medical patients. In the APEX trial and substudies, extended-duration betrixaban was superior in efficacy to standard-duration enoxaparin in patients at high risk for VTE, including those with elevated D-dimer levels (≥2× upper limit of normal) and of older age (≥75 years). Betrixaban is noninferior to enoxaparin in rates of major bleeding, but the former is associated with more clinically relevant nonmajor bleeding events. Betrixaban is the first oral agent approved for extended-duration VTE prophylaxis in acutely ill hospitalized patients. Extended-duration thromboprophylaxis with betrixaban reduces the risk of VTE compared with standard-duration thromboprophylaxis with enoxaparin but is associated with increased risk of bleeding.

The Safety and Efficacy of Full Versus Reduced Dose Betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention with Extended Duration Betrixaban (APEX) Trial

Background: The exposure of all the currently licenced DOACs is increased in renal impairment and by certain drug interactions. The Acute Medically Ill VTE (Venous Thromboembolism) Prevention with Extended Duration Betrixaban (APEX) trial assessed the safety and efficacy of extended-duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among acutely ill medical patients. The full 80 mg dose of betrixaban was halved to 40 mg among subjects with severe renal insufficiency (calculated creatinine clearance <30ml/min), or receiving a concomitant strong P-glycoprotein (P-gp) inhibitor.Objectives and Methods: The goal of this analysis is to assess the efficacy and safety of full (80 mg) and reduced dose (40 mg) betrixaban relative to enoxaparin in the APEX trial. Subjects were stratified into the two dose groups prior to randomization according to the pre-specified dosing criteria. The primary efficacy outcome was the composite of asymptomatic proximal and symptomatic venous thromboembolism (proximal or distal deep-vein thrombosis, symptomatic nonfatal pulmonary embolism, or death from venous thromboembolism). The principal safety outcome was major bleeding.Results: The median concentration of betrixaban among subjects administered the 80 mg dose was higher than that of the 40 mg dose (19 ng/ml vs 11 ng/ml, p<0.0001). In the primary analysis Cohort 1 (the elevated D-dimer +ve patients), the primary efficacy outcome was significantly reduced among subjects treated with 80 mg of extended dose betrixaban vs enoxaparin [6.3% (95/1516) vs 8.4% (130/1549), RRR = 0.26 (0.04-0.42), p=0.023]. A similar reduction was observed in the entire modified Intention to Treat (mITT) population [4.87% (122/2506) vs 7.06% (181/2562), RRR = 0.30 (0.13 - 0.44), p=0.001]. In contrast, among subjects receiving 40 mg of betrixaban there was no significant difference in the primary outcomes compared with enoxaparin across Cohorts 1, 2, and 3. There was no excess of major bleeding associated with administration of either the full 80 mg dose or the reduced 40 mg dose of betrixaban as compared with enoxaparin.Conclusion: For extended duration prophylaxis against VTE in hospitalized medically ill patients, the full 80 mg dose of extended duration betrixaban achieves higher serum concentrations than the 40 mg dose and is associated with improved efficacy across all cohorts relative to standard dose enoxaparin, without an excess risk of major bleeding. Based upon the approximate halving of plasma concentrations in this analysis and the lack of improvement in clinical outcomes, the reduced 40 mg dose may have been excessively downwardly adjusted. Conversely, the 80 mg dose was efficacious in all cohorts, including cohort 1. The inclusion of the 40 mg dose in the primary analysis may explain at least in part the marginal statistical result in the original report. DisclosuresCohen:Takeda: Consultancy; Medscape: Speakers Bureau; XO1: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Speakers Bureau; Portola: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; NHS: Membership on an entity’s Board of Directors or advisory committees; Lifeblood: Membership on an entity’s Board of Directors or advisory committees; Department of Health: Membership on an entity’s Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Janssen: Consultancy; Aspen: Consultancy, Speakers Bureau; Boehringer Ingelheim: Consultancy, Speakers Bureau; Colation to Prevent Venous Thromboembolism: Other: Founder; Leo Pharma: Consultancy; UK Government Health Select Committee: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Consultancy, Honoraria, Speakers Bureau; ONO: Consultancy, Honoraria. Goldhaber:Portola: Consultancy. Hull:Portola: Consultancy. Hernandez:Portola: Consultancy. Gold:Portola Pharmaceuticals: Employment. Wiens:Portola: Employment, Equity Ownership. Harrington:Portola: Consultancy. Gibson:Portola: Consultancy.

Extended-duration versus short-duration pharmacological thromboprophylaxis in acutely Ill hospitalized medical patients: a systematic review and meta-analysis of randomized controlled trials.

Extended-duration pharmacological thromboprophylaxis, for at least 28 days, is effective for the prevention of symptomatic venous thromboembolism (VTE) in high-risk surgical patients but is of uncertain benefit in hospitalized medical patients. We aimed to evaluate the efficacy and safety of extended-duration thromboprophylaxis in hospitalized medical patients. We conducted a systematic PubMed, Medline and EMBASE literature search until June 2016 and a meta-analysis of randomized controlled trials which compared extended-duration with short-duration thromboprophylaxis in hospitalized medical patients. Four randomized controlled trials comparing extended-duration prophylaxis (24-47 days) with short-duration prophylaxis (6-14 days) in a total of 34,068 acutely ill hospitalized medical patients were included. When compared with short-duration prophylaxis, extended-duration prophylaxis was associated with a decrease in symptomatic proximal or distal deep vein thrombosis (DVT) [relative risk (RR) = 0.52; 95% confidence interval (Cl): 0.35-0.77: p = 0.001; absolute risk reduction (ARR) = 0.32%, number needed to treat (NNT) = 313], and symptomatic non-fatal pulmonary embolism (RR = 0.61; 95% Cl 0.38-0.99: p = 0.04; ARR = 0.16%; NNT = 625), an increase in major bleeding (RR = 2.08; 95% Cl 1.50-2.90: p < 0.0001, absolute risk increase = 0.41%, number needed to harm = 244), and no significant reduction in VTE-related mortality (RR = 0.69; 95% Cl 0.45-1.06: p = 0.09) or all-cause mortality (RR = 1.00; 95% CI 0.89-1.12; p = 0.95). There was heterogeneity for major bleeding due to results from the APEX trial (no difference between betrixaban and enoxaparin). Compared with short-duration thromboprophylaxis, extended-duration treatment reduces the risk for symptomatic DVT and non-fatal pulmonary embolism. Extended treatment with apixaban, enoxaparin and rivaroxaban but not betrixaban increases the risk for major bleeding.

Cost-Effectiveness of Extended Duration Venous Thromboembolism Prophylaxis in High Risk Urological Oncology Surgical Patients

IntroductionMajor urological oncology surgery carries a significant risk of postoperative venous thromboembolism events, resulting in major morbidity, possible mortality and substantial costs. We determined the incremental cost-effectiveness for in-hospital and low molecular weight heparin extended duration prophylaxis for venous thromboembolism prevention in patients at high risk following major urological oncology surgery. MethodsA decision analytical model was developed to compare inpatient hospital costs, venous thromboembolism incidence within 365 days and outcomes associated with extended duration prophylaxis for 4 prophylaxis strategies. The 4 strategies grouped by protocol adherence were 1) per protocol in-hospital prophylaxis with extended duration prophylaxis in 88 cases, 2) per protocol in-hospital prophylaxis without extended duration prophylaxis in 42, 3) not per protocol in-hospital prophylaxis with extended duration prophylaxis in 80 and 4) not per protocol in-hospital prophylaxis without extended duration prophylaxis in 99. Between June 2011 and March 2014, 707 patients underwent major urological oncology surgery. Using the Caprini risk score 309 patients were at high risk. ResultsThe group 1 strategy was the dominant (most effective) strategy when the probability of preventing venous thromboembolism with extended duration prophylaxis was greater than 80%. Effectiveness for preventing venous thromboembolism was most influenced by the group 2 venous thromboembolism incidence rate. Costs in group 1 vs group 2 were calculated at $1,531 vs $1,563. Using the incremental cost-effectiveness ratio to compare groups 1 and 2, which were the 2 groups with the closest costs and effectiveness, an overall cost savings of $1,390 per patient was seen. ConclusionsCompared with competing strategies in-hospital and extended duration prophylaxis for venous thromboembolism prevention in patients at high risk undergoing major urological oncology surgery is effective to prevent venous thromboembolism and it is cost saving.