Extended-duration Thromboprophylaxis Research Articles

Efficacy and Safety of Extended Duration Postoperative Thromboprophylaxis with Low-Molecular-Weight-Heparin Among Subgroups of Patients Undergoing Surgical Resection of Colorectal Cancer: A Post-Hoc Analysis of the Periop-01 Trial

Background: Clinical practice guidelines suggest the use of extended duration of postoperative thromboprophylaxis to prevent venous thromboembolic (VTE) complications after any cancer-related major abdominal or pelvic surgeries. However, recent trials including patients undergoing surgical resection of colorectal cancer have reported relatively low rates of symptomatic VTE. Hence, the risk and benefits of extended postoperative thromboprophylaxis need to be carefully assessed in this patient population. We sought to determine the impact of extended duration thromboprophylaxis with low-molecular-weight-heparin on VTE and bleeding events among different subgroups of patients undergoing surgical resection of localized colorectal cancer. Methods: This is a pre-planned post-hoc analysis of the PERIOP-01 randomized controlled trial which compared extended (up to 6 weeks) to standard duration (in hospital only) of perioperative thromboprophylaxis with tinzaparin (4500 IU SC daily) in patients undergoing surgical resection of localized colorectal cancer. Subgroup analyses were performed based on different baseline characteristics. The primary efficacy and safety outcomes were objectively documented major VTE and combination of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) events, respectively. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using the Cox proportional hazards model to compare the treatment effect accounting for clustering at study center level. Results: A total of 614 patients were randomized in the PERIOP-01 trial (307 in the extended and 307 in the standard duration thromboprophylaxis groups). Overall, the mean age of the participants was 61 years, 41% of them were women, and most patients were white (90%). Type of primary cancer was well-balanced with 311 patients having rectal cancer (51%), whereas 303 (49%) had primary colon cancer. During the study period, major VTE events occurred in 2% and 1% of the extended- and standard-duration prophylaxis groups, respectively (P=0.8). Combination of MB and CRNMB events occurred in 3% of each group. No specific characteristics were found to be associated with a decreased risk of major VTE among patients on extended duration thromboprophylaxis (Figure 1). Patients with colon cancer resection receiving extended thromboprophylaxis were at an increased risk of bleeding complication compared to patients with rectal cancer (HR 2.57, 95%CI 1.25-5.3) (Figure 1). Other characteristics that may be associated with an increased risk of bleeding among patient on extended thromboprophylaxis included age >= 75 (HR 2.37, 95%CI 0.47-11.98) and male sex (HR 2.13, 95%CI 0.2-23.17), although these characteristics were not statistically significant. Conclusions: In the PERIOP-01 trial, extended thromboprophylaxis didn't reduce the risk of major VTE in any subgroups of patients. On the other hand, extended duration of thromboprophylaxis may be associated with an increased bleeding risk among male, elderly patients, and those with colon cancer.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial

ObjectiveTo determine the efficacy and safety of extended duration perioperative thromboprophylaxis by low molecular weight heparin when assessing disease-free survival in patients undergoing resection for colorectal cancer.DesignMulticentre, open label, randomised...

Periop-01: A randomized controlled trial of extended perioperative tinzaparin to improve disease-free survival in patients with resectable colorectal cancer.

124 Background: Cancer patients undergoing surgical resection of their tumor are hypercoagulable beyond the period of hospitalization. Preclinical studies demonstrate that the postoperative hypercoagulable state promotes metastases, an effect that is abrogated by administration of perioperative low molecular-weight heparin (LMWH). Methods: We conducted a randomized, open label clinical trial to determine if extended duration thromboprophylaxis using subcutaneous LMWH (tinzaparin 4,500 IU daily), beginning at decision to operate and continuing for 56 days postoperatively, compared to inpatient postoperative thromboprophylaxis only, increased the 3-year disease-free survival (DSF) in patients undergoing resection for colorectal cancer. Secondary outcomes included 5-year overall survival (OS), postoperative bleeding and venous thromboembolism (VTE). Results: Trial recruitment was stopped prematurely after 614 of the planned 1075 patients were registered, following a pre-defined interim analysis for futility. The intention-to-treat analysis included 602 patients with demographics in the table. The 3-year DFS was 78.9% (63/299 recurrences) in the tinzaparin group and 80.5% (59/303 recurrences) in the control group (hazard ratio (HR) 1.09; [95% CI 0.91,1.31; p=0.3]). The 5-year OS was 91.3% in the tinzaparin group and 92.4% in the control group (HR 1.08; [95% CI 0.66,1.79; p=0.1]). The incidence of postoperative VTE was 1.7% and 1.3% in the tinzaparin and control groups, respectively (HR 1.3; [95% CI 0.30,5.69; p=0.7]. The incidence of major bleeding in the first postoperative week was 0.3% and 2% in the tinzaparin and control groups, respectively (HR 0.16; [95% CI 0.02,1.15; p=0.07]. Conclusions: Extended duration perioperative anticoagulation with tinzaparin did not improve DFS or OS in colorectal cancer patients undergoing surgical resection. The incidences of postoperative bleeding and VTE were low. Funded by Canadian Institute of Health Research and Leo Pharma Clinical trial information: NCT01455831. [Table: see text]

Extended-duration thromboprophylaxis after ventral hernia repair: a risk model to predict venous thrombotic events after hospital discharge

BackgroundVenous thromboembolism (VTE) is a major source of morbidity and mortality after ventral hernia surgery, but the risk of VTE after discharge has not been reported.Study designData from the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) were used to investigate the risk of post-discharge VTE. Current procedural terminology (CPT) codes identified all reported patients who underwent ventral hernia repair from 2011 to 2017. We created a multivariable regression model for post-discharge VTE, using the 2011–2016 dataset to develop the model and 2017 as a validation set. The prediction model was used to create a risk calculator as a mobile application.ResultsThe rate of VTE after surgery was 0.62% (878 of 141,065) with 48% occurring after discharge from the hospital. The final predictor model consisted of eight variables: age > 60 years, male sex, body mass index (BMI) ≥ 35 kg/m2), operative time > 2 h, concurrent panniculectomy, post-operative hospitalization > 1 day, presence of bleeding disorder, and emergency operation. The model had good calibration and discrimination (Hosmer–Lemeshow goodness-of-fit test, p = 0.71; c-statistic = 0.71). Threshold analysis showed a strategy of extended-duration thromboprophylaxis was optimized when the risk of post-discharge VTE was > 0.3%.ConclusionForty-eight percent of VTEs after ventral hernia repair occur after discharge, particularly in older, male, obese patients undergoing longer and complex operations that require hospitalization > 1 day. Post-discharge thromboprophylaxis should be considered in these patients, particularly when risk of VTE exceeds 0.3%.

Post‐discharge thrombosis and bleeding in medical patients: A novel risk score derived from ubiquitous biomarkers

BackgroundSome hospitalized medical patients experience venous thromboembolism (VTE) following discharge. Prophylaxis extended beyond hospital discharge (extended duration thromboprophylaxis [EDT]) may reduce this risk. However, EDT is costly and can cause bleeding, so selecting appropriate patients is essential. We formerly reported the performance of a mortality risk prediction score (Intermountain Risk Score [IMRS]) that was minimally predictive of 90‐day hospital‐associated venous thromboembolism (HA‐VTE) and major bleeding (HA‐MB). We used the components of the IMRS to calculate de novo risk scores to predict 90‐day HA‐VTE (HA‐VTE IMRS) and major bleeding (HA‐MB IMRS). MethodsFrom 45 669 medical patients we randomly assigned 30 445 to derive the HA‐VTE IMRS and the HA‐MB IMRS. Backward stepwise regression and bootstrapping identified predictor covariates from the blood count and basic chemistry. These candidate variables were split into quintiles, and the referent quintile was that with the lowest event rate for HA‐VTE and HA‐MB; respectively. A clinically relevant rate of HA‐VTE and HA‐MB was used to inform outcome rates. Performance was assessed in the derivation set of 15 224 patients. ResultsThe HA‐VTE IMRS and HA‐MB IMRS area under the receiver operating curve (AUC) in the derivation set were 0.646, and 0.691, respectively. In the validation set, the HA‐VTE IMRS and HA‐MB IMRS AUCs were 0.60 and 0.643. ConclusionsRisk scores derived from components of routine labs ubiquitous in clinical care identify patients that are at risk for 90‐day postdischarge HA‐VTE and major bleeding. This may identify a subset of patients with high HA‐VTE risk and low HA‐MB risk who may benefit from EDT.

Extended thromboprophylaxis following major abdominal/pelvic cancer-related surgery: A systematic review and meta-analysis of the literature

BackgroundPostoperative venous thromboembolism (VTE) is a significant source of morbidity and mortality in cancer patients undergoing major abdominopelvic surgery. Many guidelines recommend the use of extended duration postoperative low molecular weight heparin (LMWH) thromboprophylaxis, although the evidence for its overall safety and efficacy is unclear. AimsWe sought to assess the 30-day postoperative rates of VTE and bleeding complications following major abdominopelvic cancer surgery and to explore the potential risks and benefits of extended duration thromboprophylaxis with LMWH in such setting. MethodsA systematic search of the literature was conducted. Observational studies and RCTs of adult patients that underwent abdominopelvic cancer surgery were included. Pooled proportions for the outcome measures and pooled relative risks for the extended duration thromboprophylaxis analyses were generated. ResultsA total of 68 studies (1,631,118 patients) were included in the analysis. The 30-day postoperative rate of VTE was 1.7% (95%CI: 1.5 to 1.9, I2 = 98%). The postoperative rate of clinically-relevant bleeding complications was 3.5% (95%CI: 1.6 to 6.1, I2 = 99%). Extended duration thromboprophylaxis was associated with a significant reduction in the incidence of clinical VTE (1.0% vs 2.1%; Risk ratio (RR) 0.48, 95%CI: 0.31 to 0.74; I2 = 0), without a significant increase in clinically-relevant bleeding (4.0% vs. 4.9%; RR 1.0, 95%CI: 0.66 to 1.5, I2 = 0). ConclusionsThe overall risk of symptomatic VTE within 30 days of surgery was relatively low. Extended LMWH thromboprophylaxis following major abdominopelvic cancer surgery was associated with a reduced incidence of clinical VTE without an increase in clinically-relevant bleeding.

A clinical focus on the use of extended-duration thromboprophylaxis in medically ill patients.

This review describes and analyzes literature to provide recommendations for use of extended-duration thromboprophylaxis (EDT) in medically ill patients. Guidelines recommend pharmacologic thromboprophylaxis for patients at increased thrombosis risk during hospitalization and recommend against extending thromboprophylaxis beyond hospitalization. Despite these recommendations, observational data demonstrate that venous thromboembolism (VTE) risk persists following hospital discharge. A MEDLINE literature search was performed to identify original research evaluating the safety and efficacy of EDT. Eight meta-analyses and 5 randomized controlled trials-each varying in the agents studied (enoxaparin, rivaroxaban, apixaban, and betrixaban)-were selected for inclusion. Collectively, the evaluated data demonstrates that EDT reduces the incidence of VTE at the expense of increasing the risk of major bleeding and without providing mortality reduction. Variations in enrollment criteria, differences in EDT strategies, and uncertainty regarding proper patient selection limit the applicability of EDT in practice. Rivaroxaban and betrixaban gained Food and Drug Administration (FDA) approval on the basis of results of the APEX and MARINER trials and a post hoc analysis of the MAGELLEN trial results. Although a number of agents are FDA approved for use in EDT, clinicians must carefully weigh the risks vs benefits of EDT with these agents until studies demonstrate a more favorable risk-benefit profile. Evidence to support EDT in medically ill patients is inconclusive and has highlighted the need for an individualized approach. The reviewed evidence supports guideline recommendations from both the American College of Chest Physicians and the American Society of Hematology that recommend against routine use of EDT in the majority of medically ill patients. Future studies are needed to optimize the risk-benefit profile of EDT and to ensure proper patient selection.

Thromboprophylaxis practice patterns and beliefs among physicians treating patients with abdominopelvic cancers at a Canadian centre.

There is inadequate high-quality evidence on thromboprophylaxis for patients undergoing surgery for abdominopelvic cancer. We surveyed physicians who treat patients with abdominopelvic cancer to determine current thromboprophylaxis practice patterns and to determine where research is needed. We created an online survey with questions on thromboprophylaxis topics, including type of thromboprophylaxis used, timing of initial thromboprophylaxis dose, use of thromboprophylaxis during chemotherapy, use of extended-duration thromboprophylaxis and areas for future research. The survey questions were reviewed by external content experts to ensure they were appropriate and relevant. Surgeons, thrombosis experts and medical oncologists who manage patients with abdominopelvic cancers at 1 large Canadian academic centre were invited to complete the survey between January and April 2019. Of the 57 physicians invited, 42 (74%) completed the survey, including 27 surgeons (response rate 79%), 9 thrombosis experts (response rate 75%) and 6 medical oncologists (response rate 55%). Most surgeons (22 [82%]) reported using mechanical thromboprophylaxis, whereas only 1 thrombosis expert (11%) recommended mechanical thromboprophylaxis. There was substantial variability in the timing of the initial dose of thromboprophylaxis, with 9/10 urologists (90%) and all 7 general surgeons giving the first dose intraoperatively, and three-quarters of thoracic surgeons (3/4 [75%]), gynecologists (3/4 [75%]) and thrombosis experts (7/9 [78%]) starting thromboprophylaxis after surgery. All medical oncologists believed chemotherapy increases the risk of venous thromboembolism, but 4 (67%) reported that they do not routinely prescribe thromboprophylaxis owing to bleeding concerns. Most respondents (35/38 [92%]) felt there was a need for more research on thromboprophylaxis and indicated willingness to participate in future clinical trials. Variability exists in contemporary thromboprophylaxis practice patterns among physicians treating patients with abdominopelvic cancer. Future research is needed to standardize care and improve outcomes for patients.

Identification and Outcomes of Hospitalized Medically Ill Patients Who Are Candidates for Extended Duration Thromboprophylaxis.

Background Extended duration thromboprophylaxis (ET) for approximately 30 days can effectively and safely reduce venous thromboembolism (VTE) risk in appropriately selected medically ill patients. We sought to estimate the proportion of hospitalized medically ill patients potentially qualifying for ET and assess their post-discharge clinical and economic outcomes using a large claims database. Methods Using MarketScan claims from January 2012 to September 2018, we identified medically ill patients hospitalized with a primary diagnosis of heart failure, respiratory insufficiency, ischemic stroke, infection, or inflammatory disease and ≥1-additional risk factor for VTE. Patients < 40 years old, a length-of-stay < 3 or >30 days, receiving oral anticoagulation prior to index hospitalization or having an indication for full-dose anticoagulation were excluded, as were patients deemed high-risk for bleeding due to active, in-hospital treated cancer, gastroduodenal ulcer or bleeding within the prior 3 months, bronchiectasis, pulmonary cavitation or hemorrhage, or dual antiplatelet therapy use. Results We identified 2,782,988 patients ≥40 years of age and admitted for a high-risk medical illness. Of these, 724,531 patients (26.0%) were identified as ET candidates. Patients' VTE risk appeared highest in the first 30 days post-discharge (1,532/724,531, 0.2%). Adjusted post-index hospitalization costs (2018 US$) for patients with a VTE within 30 days were higher than those without VTE (Δ = $32,623 at 30 days, Δ = $43,325 at 90 days, Δ = $53,668 at 365 days; p < 0.001 for all). Conclusion Post-discharge VTE in high-risk patients with medical illness is associated with substantially increased costs.

DERIVATION AND VALIDATION OF THE HA-VTE AND HA-MB INTERMOUNTAIN RISK SCORES FROM UBIQUITOUS CLINICAL BIOMARKERS TO PREDICT 90-DAY HOSPITAL-ASSOCIATED VENOUS THROMBOEMBOLISM AND MAJOR BLEEDING AMONG MEDICAL PATIENTS

SESSION TITLE: Late-breaking Abstracts SESSION TYPE: Original Investigations PRESENTED ON: October 18-21, 2020 PURPOSE: Identify hospitalized medical patients who at discharge have significant risk for hospital-associated venous thromboembolism (HA-VTE) or major bleeding (HA-MB) to inform extended-duration thromboprophylaxis (EDT) decision-making. METHODS: The Intermountain risk score (IMRS) is a highly predictive mortality risk estimation tool derived from components of the complete blood count (CBC) and basic metabolic panel (BMP). While minimally predictive for the outcome of 90-day HA-VTE [Snyder,L 2020] we hypothesized that IMRS components from the CBC and BMP could be re-weighted to be more predictive of HA-VTE and major bleeding (“HA-VTE IMRS” & “HA-MB IMRS”). To do so, a dataset of 45,669 medical patients who survived hospitalization in which 1038 (1.6%) VTE and 611 (1.3%) major bleeding events were recorded (as determined using validated natural language processing in EMR interrogation [Evans,RS 2010]) was split into a derivation (2/3) and validation (1/3) cohort. In the derivation set the CBC and BMP candidate variables were split into quintiles, and the referent quintile was determined as that with the lowest event rate. Backward stepwise regression in 500 bootstrapped samples was performed to identify predictors from the BMP and CBC candidate variables. A Cox model was fit in the derivation dataset with the variables included in 80%, 70%, 60%, and 50% of bootstrapped samples; these models were compared using likelihood ratio tests to determine if the additional variables included at each threshold significantly improved model fit. Coefficients from the Cox model were used to assign weights for the quintiles to generate the HA-VTE IMRS and HA-MB IMRS cutoff thresholds. Covariates selected for the final VTE model were: RDW, BUN, age, glucose, WBC, platelet count, RBC and sodium. Covariates selected for the final major bleeding model were: RDW, age, creatinine, MPV, Sodium, and RBC. RESULTS: In the derivation set 563/30,445 patients experienced HA-VTE and 399/30,445 experienced HA-MB. The HA-VTE IMRS ≥ 7 generated an AUC=0.603 and the HA-MB IMRS ≥ 8 generated an AUC=0.624. In the validation set 137/5242 had VTE in the HA-VTE IMRS ≥ 7 cohort vs. 160/9982 with a HA-VTE IMRS < 7 (2.6% vs 1.6%; HR=1.69; 95% CI 1.35-2.13; AUC=0.60). 135/7101 had MB in the HA-MB IMRS ≥ 8 cohort vs. 67/8123 with a HA-MB IMRS < 8 (1.9% vs. 0.8%; HR=2.35; 95% CI 1.75-3.16; AUC=0.64). CONCLUSIONS: HA-VTE and HA-MB risk may be estimated electronically at the time of hospital discharge based on components of the CBC and BMP. This information may inform decision-making regarding the prescription of EDT. CLINICAL IMPLICATIONS: If validated, this electronic program may be deployed in an EMR to calculate 90-day HA-VTE risk at the time of discharge with no additional time or expense based on laboratory values that are ubiquitously available and could inform decision-making regarding extended duration thromboprophylaxis for medical patients. DISCLOSURES: Consultant relationship with BD Please note: $5001 - $20000 Added 07/17/2020 by Joseph Bledsoe, source=Web Response, value=Consulting fee No relevant relationships by masarret fazili, source=Web Response PI of research grant relationship with AstraZeneca Please note: $20001 - $100000 Added 07/17/2020 by Benjamin Horne, source=Web Response, value=Grant/Research Support PI of research grant relationship with GlaxoSmithKline Please note: $1-$1000 Added 07/17/2020 by Benjamin Horne, source=Web Response, value=Grant/Research Support PI of research grant relationship with CareCentra Please note: $1-$1000 Added 07/17/2020 by Benjamin Horne, source=Web Response, value=Grant/Research Support Owner of intellectual property relationship with Alluceo Please note: $1-$1000 Added 07/17/2020 by Benjamin Horne, source=Web Response, value=IP was licensed Owner of intellectual property relationship with CareCentra Please note: $1-$1000 Added 07/17/2020 by Benjamin Horne, source=Web Response, value=IP was licensed No relevant relationships by James Lloyd, source=Web Response No relevant relationships by Gregory Snow, source=Web Response Research contract (no longer active) relationship with BMS/Pfizer Please note: $1-$1000 Added 07/17/2020 by Scott Stevens, source=Web Response, value=Grant/Research Support No relevant relationships by Scott Woller, source=Web Response

Predicting postdischarge hospital‐associated venous thromboembolism among medical patients using a validated mortality risk score derived from common biomarkers

BackgroundDischarged medical patients are at risk for venous thromboembolism (VTE). It is difficult to identify which discharged patients would benefit from extended duration thromboprophylaxis. The Intermountain Risk Score is a prediction score derived from discrete components of the complete blood cell count and basic metabolic panel and is highly predictive of 1‐year mortality. We sought to ascertain if the Intermountain Risk Score might also be predictive of 90‐day postdischarge hospital‐associated VTE (HA‐VTE). MethodsWe applied the Intermountain Risk Score to 60 064 medical patients who survived 90 days after discharge and report predictiveness for HA‐VTE. Area under the receiver operating curve analyses were performed. We then assessed whether the Intermountain Risk Score improved prediction of 2 existing VTE risk assessment models. ResultsThe Intermountain Risk Score poorly predicted HA‐VTE (area under the curve = 0.58; 95% confidence interval [CI], 0.56‐0.60). Each clinical risk assessment model was superior to the Intermountain Risk Score (UTAH area under the curve, 0.63; Kucher area under the curve, 0.62; Intermountain Risk Score area under the curve, 0.58; P < .001 for each comparison). Adding the Intermountain Risk Score to these scores did not substantially improve the performance of either risk assessment model (UTAH + Intermountain Risk Score, 0.65; Kucher + Intermountain Risk Score, 0.64). ConclusionThe Intermountain Risk Score demonstrated poor predictiveness for HA‐VTE when compared to existing risk assessment models. Adding the Intermountain Risk Score to existing risk assessment models did not improve upon either risk assessment model alone to justify the added complexity.

Thromboprophylaxis after bariatric surgery.

BackgroundVenous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a known cause of morbidity and mortality after bariatric surgery. However, the data concerning appropriate thromboprophylaxis after bariatric surgery is uncertain. The objective of this study was to evaluate the efficacy and safety of extended duration thromboprophylaxis in post-bariatric surgery patients.MethodsWe conducted a retrospective study of consecutive patients who underwent bariatric surgery from November 2014 to October 2018 at King Fahad General Hospital in Jeddah, Saudi Arabia. All included patients were treated with extended duration thromboprophylaxis.ResultsWe identified 374 patients who underwent bariatric surgery during the study period. Of these, 312 patients (83%) were followed for at least 3 months. The most common type of surgery was a laparoscopic sleeve gastrectomy (N=357) and the median weight was 110 kg. The cumulative incidence of symptomatic postoperative VTE at 3 months was 0.64% (95% confidence interval, 0.20–1.52). All events occurred after hospital discharge. The most commonly used pharmacological prophylaxis (91%) for VTE prevention after bariatric surgery was enoxaparin 40 mg subcutaneously twice daily for 10–14 days after hospital discharge. There were no reported cases of bleeding or VTE related mortality after 3 months.ConclusionExtended thromboprophylaxis after bariatric surgery appears to be an effective and safe strategy for VTE prevention. Large prospective studies are needed to evaluate the optimal thromboprophylaxis regimen after bariatric surgery.

Extended duration of thromboprophylaxis for medically ill patients: a systematic review and meta-analysis of randomised controlled trials.

The benefit of extended-duration thromboprophylaxis in patients hospitalised for acute medical illness beyond hospital stay remains controversial. To perform a meta-analysis of randomised controlled trials (RCT) in order to examine the efficacy and safety of extended-duration anticoagulation for venous-thromboembolism (VTE) prophylaxis in this high-risk population. An electronic database search was conducted to include all RCT comparing between extended-duration versus short-duration prophylactic anticoagulation in medically ill patients. The primary efficacy outcome was the composite events of asymptomatic deep vein thrombosis (DVT), symptomatic VTE and death from VTE-related causes. Five RCT were included totalling 40 124 patients, with a mean age of 71 years and 51% were male. In comparison to standard-duration therapy, extended-duration thromboprophylaxis was associated with a significant reduction in the primary efficacy outcome (risk ratio (RR) 0.75; 95% confidence interval (CI) 0.67-0.85; P < 0.01), symptomatic VTE (RR 0.53; 95% CI 0.33-0.84; P < 0.01) and asymptomatic DVT (RR 0.81; 95% CI 0.71-0.94; P < 0.01). However, there were no significant differences between both groups with regard to VTE-related death (RR 0.81; 95% CI 0.60-1.10; P = 0.18) or all-cause death (RR 0.97; 95% CI 0.88-1.08; P = 0.64). In contrast, extended-duration thromboprophylaxis was associated with an increased risk of major bleeding (RR 2.04; 95% CI 1.42-2.91; P < 0.01) and non-major clinically relevant bleeding (RR 1.81; 95% CI 1.29-2.53; P < 0.01). Among hospitalised medically ill patients, prolonging venous thromboprophylaxis was associated with a decreased risk of composite events of the primary efficacy outcome and increased risk of bleeding with no significant difference in VTE-related death.

Extended Duration Thromboprophylaxis for Venous Thromboembolism in High-Risk Ventral Hernia Patients: The Time Has Come

Kumar, Sandhya B. MD; YC. Lin, Matthew MD, FACS; Carter, Jonathan T. MD, FACS Author Information

The use of direct oral anticoagulants for extended duration thromboprophylaxis in medically ill patients: a systematic review and meta-analysis.

The extended use of thromboprophylaxis with direct oral anticoagulants (DOACs) for more than 30days has been evaluatedas an alternative for the standard duration thromboprophylaxis (7-10days) with low molecular weight heparin in medically ill patientsto reduce the risk of venous thromboembolism (VTE) after hospital discharge. EMBASE and MEDLINE were searched for studies evaluating extended duration thromboprophylaxis with DOACs versus standard thromboprophylaxis with enoxaparin in medically ill patients through October 2018. Search was limited to randomized-controlled trials. Symptomatic VTE, VTE-related death, anddeath from any cause,and major and clinically relevant non-major bleeding were used to assess the efficacy and safety, respectively. The Mantel-Haenszel random-effects model risk ratio (RR) and corresponding 95% CIs were calculated using the metan routine in Stata (version 14.2) to estimate the pooled treatment effects. Heterogeneity was assessed by the I2 statistics. Four studies met the inclusion criteria. DOACs were superior to enoxaparin in preventing symptomatic VTE (RR = 0.59, 95% CI 0.44-0.79). There were no significant differences in thromboprophylactic efficacy between extended and standard thromboprophylaxis as to VTE-related death (RR = 0.81, 95% CI 0.60-1.10) and death from any cause (RR = 0.98, 95% CI 0.87-1.09). Compared to the standard duration, extended thromboprophylaxis was associated with approximately two-fold greater risk of major (RR = 1.95, 95% CI 1.25-3.04), and clinically relevant non-major (RR = 1.81, 95% CI 1.29-2.53) bleeding. The superior efficacy was diminished by the unfortunate safety profile. Therefore, we continue to support both the American Society of Hematology (ASH) and the American College of Chest Physicians (ACCP) guidelines recommendation against the extended use of thromboprophylaxis beyond the hospital stay.

Extended prophylaxis for venous thromboembolism after hospitalization for medical illness: A trial sequential and cumulative meta-analysis.

BackgroundThe efficacy, safety, and clinical importance of extended-duration thromboprophylaxis (EDT) for prevention of venous thromboembolism (VTE) in medical patients remain unclear. We compared the efficacy and safety of EDT in patients hospitalized for medical illness.Methods and findingsElectronic databases of PubMed/MEDLINE, EMBASE, Cochrane Central, and ClinicalTrials.gov were searched from inception to March 21, 2019. We included randomized clinical trials (RCTs) reporting use of EDT for prevention of VTE. We performed trial sequential and cumulative meta-analyses to evaluate EDT effects on the primary efficacy endpoint of symptomatic VTE or VTE-related death, International Society on Thrombosis and Haemostasis (ISTH) major or fatal bleeding, and all-cause mortality. The pooled number needed to treat (NNT) to prevent one symptomatic or fatal VTE event and the number needed to harm (NNH) to cause one major or fatal bleeding event were calculated.Across 5 RCTs with 40,247 patients (mean age: 67–77 years, proportion of women: 48%–54%, most common reason for admission: heart failure), the duration of EDT ranged from 24–47 days. EDT reduced symptomatic VTE or VTE-related death compared with standard of care (0.8% versus 1.2%; risk ratio [RR]: 0.61, 95% confidence interval [CI]: 0.44–0.83; p = 0.002). EDT increased risk of ISTH major or fatal bleeding (0.6% versus 0.3%; RR: 2.04, 95% CI: 1.42–2.91; p < 0.001) in both meta-analyses and trial sequential analyses. Pooled NNT to prevent one symptomatic VTE or VTE-related death was 250 (95% CI: 167–500), whereas NNH to cause one major or fatal bleeding event was 333 (95% CI: 200–1,000). Limitations of the study include variation in enrollment criteria, individual therapies, duration of EDT, and VTE detection protocols across included trials.ConclusionsIn this systematic review and meta-analysis of 5 randomized trials, we observed that use of a post-hospital discharge EDT strategy for a 4-to-6-week period reduced symptomatic or fatal VTE events at the expense of increased risk of major or fatal bleeding. Further investigations are still required to define the risks and benefits in discrete medically ill cohorts, evaluate cost-effectiveness, and develop pathways for targeted implementation of this postdischarge EDT strategy.Trial registrationPROSPERO CRD42018109151.

Extended-Duration Use of Direct Oral Anticoagulants to Prevent VTE in Acutely III Medical Patients.

OBJECTIVE: To evaluate current clinical evidence for the use of direct oral anticoagulants (DOACs) for extended-duration thromboprophylaxis in the acutely ill medical population for venous thromboembolism (VTE) and bleeding events.<br/> DATA SOURCES: Were obtained through a MEDLINE/PubMed search for clinical trials conducted from March 2008 to 2018 using relevant key words. Limitations of English and human subjects were applied to search results.<br/> STUDY SELECTION AND DATA EXTRACTION: Forty-one articles were identified, and abstracts reviewed by the authors for inclusion of the study population (acutely ill medical patients) and VTE outcomes. Clinical studies evaluating the use of DOACs for extended duration of VTE prevention in acutely ill medical patients were included in the review, resulting in three clinical trials and two subgroup analyses. The participants enrolled had an overall mean age of 71.4 years.<br/> DATA SYNTHESIS: The DOAC trials collectively demonstrated a positive outcome in composite endpoints of VTE prevention with extended-duration thromboprophylaxis in acutely ill medical patients compared with enoxaparin. As for safety, rivaroxaban and apixaban trials reported more major bleeding events compared with enoxaparin. The betrixaban trial demonstrated no difference in bleeding compared with enoxaparin.<br/> CONCLUSION: DOACs reduced the number of VTE events in acutely ill medical patients on extended-duration thromboprophylaxis, but with an overall increased bleeding risk. An individualized patient approach based on risk factors should be utilized for treatment with extended-duration DOAC in the older adult population with recent hospitalization.

Extended-Duration Use of Direct Oral Anticoagulants to Prevent VTE in Acutely III Medical Patients

OBJECTIVE: To evaluate current clinical evidence for the use of direct oral anticoagulants (DOACs) for extended-duration thromboprophylaxis in the acutely ill medical population for venous thromboembolism (VTE) and bleeding events.<br/> DATA SOURCES: Were obtained through a MEDLINE/PubMed search for clinical trials conducted from March 2008 to 2018 using relevant key words. Limitations of English and human subjects were applied to search results.<br/> STUDY SELECTION AND DATA EXTRACTION: Forty-one articles were identified, and abstracts reviewed by the authors for inclusion of the study population (acutely ill medical patients) and VTE outcomes. Clinical studies evaluating the use of DOACs for extended duration of VTE prevention in acutely ill medical patients were included in the review, resulting in three clinical trials and two subgroup analyses. The participants enrolled had an overall mean age of 71.4 years.<br/> DATA SYNTHESIS: The DOAC trials collectively demonstrated a positive outcome in composite endpoints of VTE prevention with extended-duration thromboprophylaxis in acutely ill medical patients compared with enoxaparin. As for safety, rivaroxaban and apixaban trials reported more major bleeding events compared with enoxaparin. The betrixaban trial demonstrated no difference in bleeding compared with enoxaparin.<br/> CONCLUSION: DOACs reduced the number of VTE events in acutely ill medical patients on extended-duration thromboprophylaxis, but with an overall increased bleeding risk. An individualized patient approach based on risk factors should be utilized for treatment with extended-duration DOAC in the older adult population with recent hospitalization.

Betrixaban for Extended Venous Thromboembolism Prophylaxis in High-Risk Hospitalized Patients: Putting the APEX Results into Practice.

Acutely ill hospitalized medical patients remain at high thromboembolic risk for several weeks after discharge. Previous trials with extended-duration thromboprophylaxis using enoxaparin, apixaban, and rivaroxaban failed to achieve acceptable net clinical benefit, largely due to excess of major bleeding. Betrixaban is a novel factor Xa inhibitor with unique pharmacokinetic properties, including low renal clearance, long half-life, and low peak-to-trough ratio. The phase III APEX trial (N=7513) compared a betrixaban 160mg loading dose followed by 80mg once daily for 35-42days, with enoxaparin 40mg once daily for 6-14days; the betrixaban dose was reduced for renal impairment or a concomitant strong P-glycoprotein (P-gp) inhibitor. The primary efficacy endpoint of composite thrombotic events was not different between treatment arms in cohort 1 (D-dimer ≥ 2×upper limit of normal). Subsequent exploratory analyses showed a statistically significant difference favoring betrixaban for symptomatic venous thromboembolism and net clinical benefit in the overall population. For the primary safety outcome, betrixaban did not significantly increase major bleeding compared with enoxaparin. Based on available data from the APEX trial and subanalyses, the use of betrixaban in patients similar to those enrolled in the APEX trial can reduce the risk of thromboembolic events without increasing the risk of major bleeding. Patients who may benefit more from betrixaban therapy include those with elevated D-dimer, history of venous thromboembolism, hospitalized for ischemic stroke, hospitalized for heart failure with N-terminal pro-B-type natriuretic peptide ≥ 1975ng/L, or two or more VTE risk factors. Reduced-dose betrixaban does not appear to provide the same clinical utility as full-dose betrixaban.