Composite Of Deep Vein Thrombosis Research Articles

Efficacy and Safety of Rivaroxaban for Postoperative Thromboprophylaxis in Patients After Bariatric Surgery

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality after bariatric surgery. Clinical end point studies on thromboprophylaxis with direct oral anticoagulants in patients undergoing bariatric surgery are lacking. To assess the efficacy and safety of a prophylactic dose of 10 mg/d of rivaroxaban for both 7 and 28 days after bariatric surgery. This assessor-blinded, phase 2, multicenter randomized clinical trial was conducted from July 1, 2018, through June 30, 2021, with participants from 3 academic and nonacademic hospitals in Switzerland. Patients were randomized 1 day after bariatric surgery to 10 mg of oral rivaroxaban for either 7 days (short prophylaxis) or 28 days (long prophylaxis). The primary efficacy outcome was the composite of deep vein thrombosis (symptomatic or asymptomatic) and pulmonary embolism within 28 days after bariatric surgery. Main safety outcomes included major bleeding, clinically relevant nonmajor bleeding, and mortality. Of 300 patients, 272 (mean [SD] age, 40.0 [12.1] years; 216 women [80.3%]; mean body mass index, 42.2) were randomized; 134 received a 7-day and 135 a 28-day VTE prophylaxis course with rivaroxaban. Only 1 thromboembolic event (0.4%) occurred (asymptomatic thrombosis in a patient undergoing sleeve gastrectomy with extended prophylaxis). Major or clinically relevant nonmajor bleeding events were observed in 5 patients (1.9%): 2 in the short prophylaxis group and 3 in the long prophylaxis group. Clinically nonsignificant bleeding events were observed in 10 patients (3.7%): 3 in the short prophylaxis arm and 7 in the long prophylaxis arm. In this randomized clinical trial, once-daily VTE prophylaxis with 10 mg of rivaroxaban was effective and safe in the early postoperative phase after bariatric surgery in both the short and long prophylaxis groups. ClinicalTrials.gov Identifier: NCT03522259.

Clinical outcomes of cancer-associated isolated superficial vein thrombosis in daily practice

BackgroundDespite significant progress in the understanding of paraneoplastic deep vein thrombosis (DVT) and pulmonary embolism (PE), little is known about the outcomes of cancer-associated superficial vein thrombosis (SVT) in daily practice. MethodsINSIGHTS-SVT was a prospective observational study on patients with acute isolated SVT. Primary outcome measure was symptomatic venous thromboembolism (VTE), a composite of DVT, PE, and SVT extension/recurrence, at 3 months. Clinically relevant bleeding was also assessed. ResultsOf 1151 patients included, 6.7 % either had active cancer at baseline or were diagnosed with cancer during 12 months of follow-up. At 3 months, symptomatic VTE had occurred in 13.0 % and 5.4 % of cancer and non-cancer patients, respectively (HR 2.6, 95 % CI 1.3–5.0). Regarding secondary outcomes, cancer patients had increased risks of DVT and PE (HR 3.9, 95 % CI 1.3–11.8) and hospitalization due to VTE (HR 11.0, 95 % CI 2.5–49.0). The rate of clinically relevant bleeding was numerically higher in the cancer cohort (3.9 % vs 1.3 %, HR 3.1, 95 % CI 0.9–10.7). At 12 months, the primary composite outcome had occurred in 15.6 % and 11.9 % of cancer and non-cancer patients, respectively (HR 1.9, 95 % CI 1.0–3.5). After adjusting for additional risk factors, including age, history of DVT/PE and cardiovascular risk factors/diseases, the association of cancer with the primary outcome remained statistically significant. ConclusionCancer patients with isolated SVT are at significant risk of symptomatic VTE. While most events occur within 3 months, the VTE risk remains elevated up to one year of follow-up.ClinicalTrials.gov identifier: NCT02699151.

Extended-Duration Low-Intensity Apixaban to Prevent Recurrence in Patients with Provoked Venous Thromboembolism and Enduring Risk Factors: Rationale and Design of the HI-PRO Trial.

Patients with acute venous thromboembolism (VTE) in the setting of transient provoking factors are typically treated with short-term anticoagulation. However, the risk of recurrence may be increased in the presence of enduring risk factors. In such patients, the optimal duration of treatment remains uncertain. HI-PRO is a single-center, double-blind randomized trial. Patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) following a major provoking factor, including major surgery or major trauma, who completed at least 3 months of standard-dose therapeutic anticoagulation and have at least one enduring risk factor (such as obesity or heart failure) will be considered for inclusion. Patients will be randomized to apixaban 2.5 mg twice daily or placebo for 12 months. The primary efficacy outcome will be symptomatic recurrent VTE-a composite of DVT and/or PE at 12 months after randomization. Secondary efficacy outcomes include a composite of death due to cardiovascular causes, nonfatal myocardial infarction, stroke or systemic embolism, major adverse limb events, or coronary or peripheral ischemia requiring revascularization at 12 months, and individual components of these outcomes. The primary safety outcome is major bleeding according to the International Society on Thrombosis and Haemostasis definition. The study plans to enroll 600 patients (300 per arm) to have 80% power for detecting a 75% relative risk reduction in the primary outcome. Active recruitment began in March 2021. HI-PRO will provide clinically meaningful data on whether patients with provoked VTE and enduring risk factors have fewer adverse clinical outcomes if prescribed low-intensity extended-duration anticoagulation.

Immune checkpoint inhibitors for cancer and venous thromboembolic events

BackgroundImmune checkpoint inhibitors (ICIs) are widely used cancer treatments. There are limited data on the risk for developing venous thromboembolism (VTE) among patients on an ICI. MethodsThis was a retrospective study of 2854 patients who received ICIs at a single academic centre. VTE events, defined as a composite of deep vein thrombosis or pulmonary embolism, were identified by individual chart review and blindly adjudicated using standard imaging criteria. A self-controlled risk-interval design was applied with an ‘at-risk period’ defined as the two-year period after and the ‘control period’, defined as the two-year before treatment. The hazard ratio (HR) was calculated using a fixed-effect proportional hazards model. ResultsOf the 2854 patients, 1640 (57.5%) were men; the mean age was 64 ± 13 years. The risk for VTE was 7.4% at 6 months and 13.8% at 1 year after starting an ICI. The rate of VTE was > 4-fold higher after starting an ICI (HR 4.98, 95% CI 3.65–8.59, p < 0.001). There was a 5.7-fold higher risk for deep vein thrombosis (HR 5.70, 95% CI 3.79–8.59, p < 0.001) and a 4.75-fold higher risk for pulmonary embolism (HR 4.75, 95% CI 3.20–7.10, p < 0.001). Comparing patients with and without a VTE event, a history of melanoma and older age predicted lower risk of VTE, while a higher Khorana risk score, history of hypertension and history of VTE predicted higher risk. ConclusionsThe rate of VTE among patients on an ICI is high and increases after starting an ICI.

Abstract 15395: Immune Checkpoint Inhibitors for Cancer Are Associated With Increased Venous Thromboembolism Events

Introduction: Immune checkpoint inhibitors (ICI) lead to immune activation, increased inflammation and cancer cell death. Both immune activation and inflammation are critical pathobiological drivers for venous thromboembolism (VTE). There are no robust data testing the effect of ICIs on the risk of developing VTE. Methods: This is a retrospective study of 2854 patients who received ICIs at Massachusetts General Hospital, Boston, MA. VTE events, defined as a composite of deep vein thrombosis (DVT) or pulmonary embolism (PE), were identified by individual chart review and were blindly adjudicated using standard criteria. A case-crossover design was applied with an “at-risk period” defined as the two-year period after and the “control period” as the two years prior to treatment. Incidence rate ratio (IRR) was calculated using Poisson’s regression. Results: Immune checkpoint inhibitor use increased VTE risk by 1.84-fold from 4.85 per 100-person years to 8.91 per 100 person-years (IRR 1.84, 95% confidence interval: 1.54 - 2.19, p &lt;0.001). Of the individual components, there was a 2.44-fold increase in DVT risk (2.30 to 5.58 per 100 person-years) and 1.68-fold increase in PE risk (2.96 to 5.00 per 100 person-years). Comparing patients with and without a VTE event, those with a VTE event after ICI initiation had a higher rate of prior VTE, lung cancer, urothelial cancer, and a higher platelet count and white blood cell count at baseline. At 6 months post ICI initiation, 165 (8.6%) patients had a VTE event and of these patients 136 (7.1%) had no prior VTE. Conclusions: Patients with cancer treated with ICIs are at increased risk of developing VTE. Whether prophylaxis for VTE among patients starting an ICI reduces this risk is unclear.

Association between ROTEM Hypercoagulable Profile and Outcome in a Cohort of Severely Ill COVID-19 Patients Under Mechanical Ventilation

Introduction: Recently published data show that COVID-19 is characterized by a hypercoagulable ROTEM profile and decreased fibrinolysis. Multiple reports suggest that severe COVID-19 infection is associated with an increased thromboembolic risk. There are limited data associating a hypercoagulable ROTEM profile and outcomes in the literature. A hypercoagulable ROTEM profile could help identify patients at risk of worse outcome and help target a study population for enhanced anticoagulation therapy or other COVID-19 therapy.Objectives: To determine if early hypercoagulability on ROTEM is associated with a higher risk of thromboembolic complications or worse outcome, in a population of mechanically ventilated COVID-19 patients transferred to a tertiary ARDS/ECMO referral center.Methods: All COVID-19 patients receiving mechanical ventilation at our center between April 3 and June 15, 2020 were assessed with ROTEM. Testing performed included at least ExTEM and FibTEM. Patients were classified as hypercoagulable (HC) or not (nHC) using the following criteria from ROTEM: ExTEM clot formation time (E_CFT)< 40 sec, alpha (∝) angle >79° and, either ExTEM or FibTEM maximum clot firmness (E_MCF or F_MCF) >70mm or >24mm, respectively. Outcomes, assessed at discharge from our ICU, included thromboembolic events (TE: composite of deep vein thrombosis, pulmonary embolism and ischemic stroke), acute kidney injury (AKI: AKIN stage >2 with or without dialysis), duration of mechanical ventilation, requirement for ECMO, and death. Difference between groups was determined using the chi-square or Fisher-exact test for categorical data and a t-test for continuous variables respectively, using p<0.05 as significant.Results: Of 59 patients included, 31 were hypercoagulable (HC) on admission. Mean (SD) age was 52 (14), and SOFA score on admission was high 15 (2). The severity of disease was similar in both groups especially for the cardiac and respiratory SOFA components (Table 1). The composite outcome of TE was not different between the groups (HC 9/31, nHC 6/28, p=0.7). The composite renal outcome was not different (HC 18/31 vs nHC 16/28). Mortality rate (29%, HC 9 vs nHC 8), and the duration of ventilation in survivors (HC 22 vs nHC 22 days) were similar in both groups. Requirement for ECMO support was similar (HC 8 vs nHC 12, p= 0.27). Patients were tested with daily viscoelastic tests and, neither fibrinolysis nor DIC were documented. All patients received TE prophylaxis and 34 received therapeutic intravenous heparin for ECMO (n=20) or TE treatment (n=14). Initial ROTEM were conducted on therapeutic heparin in 22 cases (12 HC, 10 nHC).Conclusion: Our data suggest that in a population of mechanically ventilated patients with severe COVID-19, an early hypercoagulable profile on ROTEM was not associated with an increased risk of thromboembolic events, AKI, prolonged ventilation, ECMO or death during their ICU stay.DisclosuresKarkouti:Octapharma: Research Funding; Canadian blood services: Research Funding.

The Development and Application of a Clinical Severity Scoring Model for Post-Operative Venous Thromboembolism (VTE)

Background: In studies evaluating the prevention of venous thromboembolic events (VTE - composite of deep vein thrombosis (DVT) and pulmonary embolism (PE)) following surgery, VTE is considered as a binary event (present or absent). There is no consensus in the literature in determining the clinical severity of a post-operative VTE. The objectives of our study were to derive a severity scoring model for VTE in the post-operative setting and then apply the model to outcomes from a clinical trial evaluating aspirin vs. rivaroxaban for extended prophylaxis following total hip or knee arthroplasty (EPCATII). Methods: Thirty-one clinical scenarios were written, each describing a VTE event after a total hip or knee arthroplasty procedure. Each scenario varied the severity of the patient's presenting symptoms, the extent of thrombosis observed on radiographic studies, and the presence or absence of long-term symptoms. These scenarios were incorporated into a web-based survey sent to thrombosis clinicians. Respondents were asked to score each scenario on a 9-point scale based on perceived clinical severity. Responses from 29 clinicians were analyzed using mixed-effects regression models to determine the weight of each variable on the respondents' overall severity scores. The sum of scores for each weighted factor present based on parameter estimates from the model was calculated to categorize the scenarios into high, moderate, or low clinical severity categories. The VTE clinical severity scoring model was applied independently by two clinicians to the 36 cases of confirmed VTE from the EPCAT II trial. Two further reviewers gave their clinical opinion of each case's severity. Kappa scores for inter-rater reliability, and for agreement between clinical opinion and the model were determined. The proportion of EPCAT II cases rated as mild, moderate and severe by the model were determined for rivaroxaban and aspirin groups and then compared using the Cochran-Armitage test for trend. Results: The following factors shown as parameter estimates were associated with higher levels of clinical severity: moderate (1.28, p&lt;0.0001) or severe (2.61, p&lt;0.0001) radiographic findings; high severity symptoms at initial presentation (0.72, p&lt;0.0001); presence of long-term symptoms (1.01, p&lt;0.0001); and PE compared to DVT (1.49, p&lt;0.0001). Based on these parameters, a scoring model was created using the nearest half point for each doubled parameter estimate for ease of calculation. The model classifies post-operative VTE into mild (score &lt;4.5), moderate (score 4.5-8), or severe (score &gt;8) clinical severity categories. Independent application of the model to the EPCAT II VTE cases had agreement in 33 of 36 cases (κ=0.89). The agreement between the clinical opinion and the model was 28 of the 36 cases (κ=-0.14). In all cases of disagreement, the clinical gestalt was more severe than the model. Cases randomized to rivaroxaban were scored as 10 mild (55.6%), 4 moderate (22.2%), and 4 severe (22.2%). Cases randomized to aspirin were scored as 12 mild (66.7%), 4 moderate (22.2%) and 2 severe (11.1%). There were no differences in severity of VTE between the aspirin and rivaroxaban groups (p=0.38). Conclusion: A clinical severity scoring model for post-operative VTE was created based upon scenarios rated by experienced thrombosis clinicians and validated by applying it to EPCAT II cases of VTE. This model may be useful for categorizing clinical importance of VTE in the post-operative setting. There was no apparent difference in the severity of post-operative VTE following total hip or knee arthroplasty whether aspirin or rivaroxaban was used for extended prophylaxis. Disclosures No relevant conflicts of interest to declare.

Early versus late venous thromboembolism: A secondary analysis of data from the PROPPR trial

BackgroundFactors predicting timing of post-traumatic venous thromboembolism (VTE) remain incompletely understood. Because the balance between hemorrhage and thrombosis is dynamic during a patient’s hospital course, early and late VTE may be physiologically discrete processes. This secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial aims to explore whether certain risk factors are associated with early versus late VTE. MethodsThe PROPPR trial investigated post-traumatic resuscitation with platelets, plasma, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. Multinomial regression based on a threshold determined by cubic spline analysis tested the association of clinical variables with early or late VTE, a composite of deep vein thrombosis and pulmonary embolus, adjusting for predetermined confounders. ResultsOf the 87 patients (13%) with VTE, pulmonary embolus was predominant in the first 72 hours. A statistically determined threshold at 12 days corresponded to change in odds of early versus late events. Variables associated with early VTE included plasma transfusion (risk ratio [RR] 1.14; 95% confidence interval, 1.00, 1.30; P = .05), sepsis (RR 0.05; 95% confidence interval, 1.40, 6.64; P = .01), pelvic or femur fracture (RR 2.62; 95% confidence interval, 1.00, 6.90; P = .05). Late VTE was associated with dialysis (RR 7.37; 95% confidence interval, 1.59, 34.14; P = .01), older age (RR 1.02; 95% confidence interval 1.00, 1.04; P = .05), and delayed resuscitation approaching ratios of 1:1:1 among patients randomized to 1:1:2 therapy (RR 2.06; 95% confidence interval, 0.28, 3.83; P = .02). Cyroprecipitate increased risk of early (RR 1.04, 95% confidence interval, 1.00,1.08; P < .03) and late VTE (1.05; 95% confidence interval, 1.01, 1.09; P = .01). Prolonged lagtime (coeffcient 0.06, 95% confidence interval, 0.02, 0.10; P < .01) and time-to-peak thrombin generation (coeffcient 0.04, 95% confidence interval, 0.02, 0.07; P < .01) were associated with increased risk of early VTE. ConclusionEarly and late VTE may differ in their risk factors. Defining temporal trends in VTE may allow for a more individualized approach to thromboprophylaxis.

Incidence and predictors of venous thromboembolism in medically ill hospitalized elderly cancer patients: a prospective observational study.

The aim of this study was to estimate the incidence and predictors of venous thromboembolism (VTE) in medically ill hospitalized elderly cancer patients in a single Korean tertiary hospital. Patients were examined for deep vein thrombosis (DVT) by duplex and color Doppler ultrasonography (DUS) of both legs between days 5 and 14 of their hospital stays. The primary endpoint was the incidence of VTE by day 14, which was determined via a composite of DVT detected by routine DUS and symptomatic VTE. A total of 140 patients with 31 hematologic and 109 nonhematologic malignancies were analyzed. The median age was 73years, and 45.7% of the patients were female. The median length of hospital stay was 12days. The modified Padua prediction score (PPS) ≥ 4 was 92.9%. The incidence of VTE by day 14 was 7.1%, including six proximal and four distal DVT cases. Being female, having a length of hospital stay of ≥ 13days, and having a modified Padua prediction score of ≥ 6 were risk factors of VTE in univariate analysis. The incidence of VTE was 2.3%, 7.3%, and 41.7% in patients with 0-1, 2, and 3 of these risk factors, respectively. The incidence of VTE in medically ill hospitalized elderly cancer patients was lower in Korean patients than in Western patients. However, the risk of VTE in those with more than two risk factors (female, long length of hospitalization, and high PPS) increased considerably, and pharmacologic thromboprophylaxis is warranted in these cases.

Recurrent venous thromboembolism in patients with pulmonary embolism and right ventricular dysfunction: a post-hoc analysis of the Hokusai-VTE study

In patients with pulmonary embolism, right ventricular dysfunction is associated with early mortality. The Hokusai-VTE study used N-terminal pro-brain natriuretic peptide (NT-proBNP) and right to left ventricular diameter ratio on CT as indicators of right ventricular dysfunction and reported that recurrent venous thromboembolism rates were lower with edoxaban than warfarin. The aim of the current study was to further explore the significance of right ventricular dysfunction and investigate potential explanations for the superiority of edoxaban-ie, differences in baseline clinical characteristics, duration of initial heparin treatment, bleeding rates, or quality of warfarin treatment. The Hokusai-VTE trial was a randomised, double-blind, event-driven non-inferiority trial in patients from centres in 37 countries that compared edoxaban with warfarin in the treatment of acute venous thromboembolism. Patients received treatment for at least 3 months and up to a maximum of 12 months. Patients were followed up for 12 months. Outcome data at 12 months was collected for all patients irrespective of treatment duration. This prespecified subgroup analysis focuses on the included patients with pulmonary embolism. The primary efficacy outcome was the incidence of adjudicated symptomatic recurrent venous thromboembolism defined as a composite of deep vein thrombosis or non-fatal or fatal pulmonary embolism at 12 months. Recurrence rates with edoxaban and warfarin were compared in patients with and without right ventricular dysfunction. In those with NT-proBNP concentrations of 500 pg/mL or higher, we compared baseline characteristics, duration of heparin treatment, and bleeding leading to study drug discontinuation in the edoxaban and warfarin groups. We also assessed quality of warfarin treatment. All analyses were done with the modified intention-to-treat population. The Hokusai-VTE trial is registered with ClinicalTrials.gov, number NCT00986154. Between Jan 28, 2010, and Oct 5, 2012, 8292 patients were enrolled from 439 centres, of whom 8240 received at least one dose of study drug. 3319 patients had pulmonary embolism. NT-proBNP was 500 pg/mL or higher in 465 (30%) of 1565 patients given edoxaban and in 507 (32%) of 1599 given warfarin. Recurrent venous thromboembolism occurred in 14 (3%) of 465 patients in the edoxaban group and 30 (6%) of 507 in the warfarin group (hazard ratio [HR] 0·50, 95% CI 0·26-0·94; p=0·033). The right to left ventricular diameter ratio was 0·9 or higher in 414 (44%) of 937 patients in the edoxaban group and 427 (45%) of 946 in the warfarin group. Recurrent venous thromboembolism occurred in 11 (3%) of 414 and 20 (5%) of 427 patients in the edoxaban and warfarin groups (HR 0·57, 95% CI 0·27-1·17; p=0·13). Baseline characteristics, duration of heparin treatment, and rates of bleeding leading to study drug discontinuation were similar in the edoxaban and warfarin groups and the quality of warfarin management was adequate for patients with NT-proBNP concentrations of 500 pg/mL or higher. Findings from our analysis suggest that edoxaban is more effective than warfarin in the treatment and prevention of recurrent venous thromboembolism in patients with pulmonary embolism and evidence of right ventricular dysfunction. Daiichi Sankyo.

Risk of Venous Thromboembolism in Patients With Rheumatoid Arthritis

ObjectiveRheumatoid arthritis (RA) is associated with cardiovascular disease (CVD), but little is known about its association with another form of vascular disorder, venous thromboembolism (VTE).MethodsA retrospective cohort study was conducted using US insurance claims. RA and non‐RA patients were matched on age, sex, and index date. Incidence rates (IRs) and rate ratios (RRs) of VTE, defined as the composite of deep vein thrombosis (DVT) or pulmonary embolism (PE), were calculated. Cox proportional hazards models compared VTE risks between RA and non‐RA patients, adjusting for VTE risk factors such as CVD, surgery, hospitalization, medications, and acute‐phase reactants.ResultsOver the mean followup of 2 years, the IR for VTE among RA patients was 6.1 per 1,000 person‐years, 2.4 times higher (95% confidence interval [95% CI] 2.1–2.8) than the rate of non‐RA patients. The IRs for both DVT (RR 2.2, 95% CI 1.9–2.6) and PE (RR 2.7, 95% CI 2.2–3.5) were higher in RA patients compared with non‐RA patients. After adjusting for risk factors of VTE, the VTE risk remained elevated in RA patients (hazard ratio 1.4, 95% CI 1.1–1.7) compared to non‐RA patients. The result was similar after further adjustment for elevated acute‐phase reactants (hazard ratio 1.5, 95% CI 0.3–6.5). One‐third of patients who developed VTE had at least 1 major VTE risk factor 90 days before and after the VTE event.ConclusionOur results showed an increased risk of developing VTE for RA patients compared with non‐RA patients. The risk was attenuated but remained elevated even after adjusting for various risk factors for VTE.

Low-Molecular-Weight Heparin for Prevention of Venous Thromboembolism After Varicose Vein Surgery in Moderate-Risk Patients: A Randomized, Controlled Trial

Deep vein thrombosis (DVT) after varicose vein surgery (VVS) is not well recognized. Observational studies have yielded variable estimates of the risk, but evidence from randomized trials is lacking. Our aim was to compare the use of thromboprophylaxis with and without low-molecular-weight heparin (LMWH). We prospectively randomized moderate-risk patients scheduled for VVS in two arms. The first group of patients received bemiparin for 10 days at a prophylactic dose, early ambulation, and compression therapy for 3 months; the second group received early ambulation and compression therapy alone. The primary efficacy outcome was the composite of DVT (symptomatic or asymptomatic detected by mandatory, bilateral duplex scan). Secondary efficacy and primary safety end points were superficial venous thrombosis, postoperative bleeding, and clinical pulmonary embolism (PE). We assessed transient and permanent risk factors for venous thromboembolism. Two-hundred sixty-two patients were eligible for evaluation. There were no cases of DVT. There were also no cases of clinical PE, death, or major bleeding. No significant differences were seen between groups in the rates of bleeding episodes. The data show no superiority of a short-term regimen of LMWH and early ambulation and compression therapy, as compared with early ambulation and compression therapy alone, in patients undergoing VVS in a moderate-risk population.

THU0075 The risk of venous thromboembolism in patients with rheumatoid arthritis compared to the general population: A very large cohort study

BackgroundSome data suggest that rheumatoid arthritis (RA) is associated with an increased risk of venous thromboembolism (VTE). Prior studies have been relatively small and used a very limited set of...

Rivaroxaban

Rivaroxaban (Xarelto®), an oral oxazolidinone-based anticoagulant, is a potent, selective, direct inhibitor of factor Xa that is used in the prevention of venous thromboembolism (VTE) in adult patients after total hip replacement (THR) or total knee replacement (TKR) surgery. In large, clinical trials, oral rivaroxaban 10 mg once daily was more effective than subcutaneous enoxaparin 40 mg once daily in preventing postoperative VTE in patients undergoing THR or TKR surgery. Rivaroxaban was associated with significantly lower incidences of the primary endpoint, total VTE (composite of deep vein thrombosis, non-fatal pulmonary embolism, or death from any cause) compared with enoxaparin regimens across all studies. For example, in the largest trial in patients undergoing THR, total VTE occurred in 1.1% of rivaroxaban recipients and 3.7% of enoxaparin recipients (absolute risk reduction 2.6% [95% CI 1.5, 3.7]) in the modified intent-to-treat population. Notably, the greater efficacy of rivaroxaban was achieved without a significant increase in the incidence of major bleeding episodes compared with enoxaparin; bleeding events were the most frequently reported adverse events across clinical trials. Pyrexia, vomiting, nausea, and constipation were the most frequently reported of the non-bleeding treatment-emergent adverse events in rivaroxaban recipients and occurred at a similar rate to that with enoxaparin treatment. In addition, preliminary pharmacoeconomic analyses in Canada and the US indicate that rivaroxaban is a cost-saving treatment strategy versus enoxaparin. Although the position of rivaroxaban relative to other therapies remains to be fully determined, it is an effective option for the prophylaxis of VTE following THR and TKR.

Extended prophylaxis with bemiparin for the prevention of venous thromboembolism after abdominal or pelvic surgery for cancer: the CANBESURE randomized study.

There is not enough clinical evidence to make a strong recommendation on the optimal duration of thromboprophylaxis using low-molecular weight heparins (LMWH) in patients undergoing major cancer surgery. CANBESURE is a randomized, double-blind study which enrolled patients admitted for abdominal or pelvic surgery for cancer. They received 3500 IU of bemiparin subcutaneously once daily for 8 days and were then randomized to receive either bemiparin or placebo for 20 additional days. Bilateral venography was performed after 20 days and evaluated blinded. The primary efficacy outcome was the composite of deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE) and all-cause mortality at the end of double-blind period. Major venous thromboembolism (proximal deep-vein thrombosis, non-fatal pulmonary embolism and venous thromboembolism-related deaths) was also evaluated. The primary safety outcome was major bleeding. Six hundred and twenty-five and 488 patients were included in the safety and main efficacy analyzes, respectively. The primary efficacy outcome occurred in 25 out of 248 patients (10.1%) in the bemiparin group and 32 out of 240 (13.3%) in the placebo group (relative risk reduction 24.4%; 95% CI: -23.7-53.8%; P = 0.26). At the end of double-blind period, major venous thromboembolism occurred in 2 (0.8%) and 11 (4.6%) patients, respectively (relative risk reduction 82.4%; 95% CI: 21.5-96.1%; P = 0.010). No significant difference was found in major bleedings. Four weeks compared with 1 week of prophylaxis with bemiparin after abdominal or pelvic cancer surgery did not significantly reduce the primary efficacy outcome, but decreased major venous thromboembolism (VTE) without increasing hemorrhagic complications.

Effects of Age, Weight, Gender and Renal Function in a Pooled Analysis of Four Phase III Studies of Rivaroxaban for Prevention of Venous Thromboembolism after Major Orthopedic Surgery

The RECORD program comprised four pivotal phase III trials comparing the oral direct Factor Xa inhibitor, rivaroxaban, with subcutaneous enoxaparin for the prevention of venous thromboembolism (VTE) after total hip and knee replacement (THR and TKR). A total of 12,729 patients were randomized to receive rivaroxaban 10 mg once daily (od) starting 6–8 hours after surgery, or enoxaparin 40 mg od (RECORD1–3) starting the evening before surgery, or 30 mg every 12 hours (RECORD4) starting 12–24 hours after surgery. In RECORD1, patients undergoing THR received extended prophylaxis for 31–39 days. In RECORD2, patients undergoing THR received rivaroxaban for 31–39 days, or enoxaparin for 12±2 days followed by placebo up to 35 days. Patients undergoing TKR in RECORD3 and 4 received prophylaxis for 12±2 days. In all four trials the rivaroxaban regimens showed superior efficacy to the enoxaparin regimens with no significant increase in bleeding. The RECORD1–4 pooled analysis showed that rivaroxaban was significantly superior to enoxaparin for the primary endpoint, symptomatic VTE and all-cause mortality (0.8% vs 1.6%, respectively; p<0.001), with similar bleeding rates in both groups. Pooled subgroup analyses were performed to determine the influence of age, weight, gender, or renal function (calculated creatinine clearance [CrCl] at baseline) on the studies primary and main secondary efficacy outcomes, and any adjudicated bleeding events in RECORD1–4. Treatment effect (rivaroxaban vs enoxaparin regimens) was expressed on the odds-ratio (OR) scale for total VTE (the composite of any deep vein thrombosis, non-fatal pulmonary embolism and all-cause mortality, modified-intention-to-treat [mITT] population) and major VTE (the composite of proximal deep vein thrombosis, non-fatal pulmonary embolism and VTE-related death, mITT population for major VTE) at the end of the planned medication period. For any bleeding (major and non-major bleeding after the start of study medication up to 2 days after the last dose, safety population) the hazard ratio (HR) was used. Separate analyses were done for each subgroup. These pooled analyses show consistently superior efficacy to enoxaparin, irrespective of patients' age (<65, 65–75, >75 yrs), weight (≤70, >70–90, >90kg), gender, or renal function (CrCl >80, 50–80, <50 ml/min). Interaction testing in logistic regression models provided no indication of treatment effect differences in these subgroups, except for total VTE and the CrCl subgroups, where treatment effect with rivaroxaban appeared to be larger for the >80 and <50 ml/min group compared with the 50–80 ml/min group. With respect to any bleeding, the risk on rivaroxaban relative to enoxaparin regimens was comparable across gender and the different age, body weight and renal function (>30 ml/min CrCl) groups studied. Similar trends were seen in the smaller subgroups of body weight extremes (>110 kg subgroup - total VTE: 5/100 [5.0%] vs 8/119 [6.7%], respectively; ≤50 kg subgroup - any bleeding: 12/147 [8.2%] vs 8/162 [4.9%], respectively).These results suggest that age, body weight, gender and renal function (>30 ml/min CrCl) have no clinically relevant effect on the efficacy or safety of rivaroxaban as thrombroprophylaxis following major orthopedic surgery.SubgroupTotal VTE Odds ratio (rivaroxaban vs enoxaparin regimens) (95% CIMajor VTE Odds ratio (rivaroxaban vs enoxaparin regimens) (95% CI)Any major or non-major bleeding Hazard ratio (rivaroxaban vs enoxaparin regimens) (95% CI)Age<65 years0.40 (0.28–0.55)0.22 (0.10–0.44)1.05 (0.86–1.29)65–75 years0.39 (0.29–0.52)0.18 (0.08–0.34)1.11 (0.90–1.38)>75 years0.54 (0.36–0.81)0.51 (0.21–1.15)1.10 (0.79–1.52)Weight≤70kg0.43 (0.31–0.60)0.25 (0.11–0.52)1.17 (0.91–1.51)>70–90kg0.45 (0.34–0.59)0.21 (0.11–0.39)0.95 (0.77–1.17)>90kg0.38 (0.25–0.57)0.32 (0.13–0.69)1.22 (0.95–1.58)GenderMale0.35 (0.25–0.48)0.21 (0.10–0.40)1.12 (0.93–1.36)Female0.47 (0.37–0.59)0.27 (0.16–0.45)1.06 (0.87–1.28)CrCl (ml/min)>800.35 (0.27–0.46)0.22 (0.12–0.38)1.12 (0.94–1.35)50–800.60 (0.45–0.81)0.30 (0.15–0.56)0.99 (0.79–1.24)<50*0.32 (0.15–0.64)0.23 (0.02–1.15)1.07 (0.64 – 1.79)*Because of study exclusion criteria, few patients had CrCl <30 ml/min, CI = confidence interval

Randomized Double-Blind Comparison of Apixaban with Enoxaparin for Thromboprophylaxis after Knee Replacement: The ADVANCE-1 Trial

Thromboprophylaxis with enoxaparin after total knee replacement is an evidence-based recommended standard of care. The ADVANCE-1 clinical trial was a phase III randomized double-blind multicenter study that evaluated the efficacy and safety of apixaban, an oral direct factor Xa inhibitor, 2.5 mg orally bid compared with enoxaparin 30 mg subcutaneously every 12 hours for preventing venous thromboembolism after total knee replacement. Apixaban (or oral placebo) and enoxaparin (or subcutaneous placebo) were begun 12 to 24 hours post-operatively (mean 20 hours) and continued until mandatory bilateral venography was completed at 12± 2 days. The primary efficacy outcome was the composite of deep-vein thrombosis (DVT) by venography; symptomatic, objectively confirmed DVT or pulmonary embolism (PE); or death from any cause during the treatment period. The secondary efficacy outcome was the composite of objectively confirmed proximal DVT or PE, or death. The primary safety outcome was bleeding, including major bleeding (defined by ISTH criteria), clinically relevant non-major bleeding, and minor bleeding. All outcome events were interpreted by a central independent adjudication committee without knowledge of treatment. The study hypothesis was that apixaban would be as effective as enoxaparin based on a pre-specified non-inferiority margin in which the upper limit of the two-sided 95% CI is < 1.25 for relative risk and < 5.6% for the absolute risk difference for the primary efficacy outcome. A total of 3195 patients from 129 sites in 14 countries were randomized. The primary efficacy outcome occurred in 104 of 1157 patients (8.99%) given apixaban and in 100 of 1130 (8.85%) given enoxaparin (relative risk 1.02, 95% CI 0.78 to 1.32, one-sided p= 0.064 for non-inferiority, statistical criteria not met). The secondary efficacy outcome occurred in 26 patients (2.05%) given apixaban and in 20 patients (1.64%) given enoxaparin. Symptomatic PE occurred in 16 patients (1.0%) who received apixaban (2 fatal) and in 7 patients (0.44%) given enoxaparin (0 fatal); the majority of the PE in apixaban patients occurred within 48 hours postoperatively. Major or clinically relevant non-major bleeding occurred in 46 of 1596 patients (2.88%) given apixaban, compared with 68 patients (4.28%) given enoxaparin (absolute difference 1.46%, two-sided p=0.034). Major bleeding occurred in 11patients (0.69%) who received apixaban and in 22 patients (1.39%) who received enoxaparin (two-sided p=0.053). Elevated levels of liver transaminase enzymes were uncommon (2% to 3%) in both groups; no patient given apixaban met Hy's criteria. Myocardial infarction or stroke occurred in only one patient who received apixaban (0.06%) and in 5 patients (0.31%) given enoxaparin. The lower-than-expected incidence of the primary efficacy outcome in the enoxaparin group resulted in an undersized study to meet the pre-defined statistical criteria for non-inferiority in spite of a similar incidence with the apixaban regimen. This is the first phase III trial to demonstrate a potential advantage of the new oral anticoagulants for bleeding. The apixaban regimen resulted in less clinically relevant bleeding than enoxaparin 30 mg given every 12 hours. Maintaining this advantage while optimizing efficacy with an altered dosing regimen, either by earlier postoperative dosing or by a slightly increased dose, would be an important advance in patient care.

Prevention of postoperative venous thromboembolism in Japanese patients undergoing total hip or knee arthroplasty: two randomized, double-blind, placebo-controlled studies with three dosage regimens of enoxaparin

BackgroundEnoxaparin is a low-molecular-weight heparin indicated in Europe and North America for the prevention of venous thromboembolism (VTE) in patients undergoing major orthopedic surgery. Registration trials of enoxaparin have been conducted primarily in Caucasian populations, and the efficacy and safety of enoxaparin in Japanese patients have not been demonstrated. We evaluated three dosage regimens of postoperative enoxaparin in Japanese patients undergoing elective total hip or knee arthroplasty. MethodsTwo multicenter, randomized, double-blind studies enrolled 436 and 396 Japanese adults undergoing total hip or knee arthroplasty, respectively. The dosage regimens of enoxaparin were 20 mg once daily (qd), 40 mg qd, 20 mg twice daily (bid), or placebo for 14 consecutive days. The primary efficacy endpoint was the incidence of VTE in the modified intention-to-treat (mITT) population up to 15 days after surgery. VTE was defined as a composite of deep vein thrombosis (determined by venography) and symptomatic pulmonary embolism (confirmed by appropriate objective methods). Patients were also followed up at 90 days for VTE events. The primary safety outcome was the incidence of any bleeding during treatment and the follow-up period. ResultsIn the mITT populations, the incidence of VTE was 41.9% and 60.8% in the placebo groups after hip or knee arthroplasty, respectively, 25.9% and 44.9% in the enoxaparin 20 mg qd groups, 33.8% and 35.1% in the enoxaparin 40 mg qd groups, and 20.0% and 29.8% in the enoxaparin 20 mg bid groups. Only enoxaparin 20 mg bid significantly lowered the risk of VTE relative to placebo (by 52.2% and 51.0% after hip and knee arthroplasty, respectively). At the 90-day follow-up, no further cases of VTE were reported. In both the hip and knee studies, the four treatment groups did not differ significantly regarding the incidence of patients with any bleeding. ConclusionsOur findings support the use of enoxaparin (20 mg bid daily, commencing 24–36 h postoperatively) in Japanese patients undergoing total hip or knee arthroplasty.

Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Hip Arthroplasty

This phase 3 trial compared the efficacy and safety of rivaroxaban, an oral direct inhibitor of factor Xa, with those of enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. In this randomized, double-blind study, we assigned 4541 patients to receive either 10 mg of oral rivaroxaban once daily, beginning after surgery, or 40 mg of enoxaparin subcutaneously once daily, beginning the evening before surgery, plus a placebo tablet or injection. The primary efficacy outcome was the composite of deep-vein thrombosis (either symptomatic or detected by bilateral venography if the patient was asymptomatic), nonfatal pulmonary embolism, or death from any cause at 36 days (range, 30 to 42). The main secondary efficacy outcome was major venous thromboembolism (proximal deep-vein thrombosis, nonfatal pulmonary embolism, or death from venous thromboembolism). The primary safety outcome was major bleeding. A total of 3153 patients were included in the superiority analysis (after 1388 exclusions), and 4433 were included in the safety analysis (after 108 exclusions). The primary efficacy outcome occurred in 18 of 1595 patients (1.1%) in the rivaroxaban group and in 58 of 1558 patients (3.7%) in the enoxaparin group (absolute risk reduction, 2.6%; 95% confidence interval [CI], 1.5 to 3.7; P<0.001). Major venous thromboembolism occurred in 4 of 1686 patients (0.2%) in the rivaroxaban group and in 33 of 1678 patients (2.0%) in the enoxaparin group (absolute risk reduction, 1.7%; 95% CI, 1.0 to 2.5; P<0.001). Major bleeding occurred in 6 of 2209 patients (0.3%) in the rivaroxaban group and in 2 of 2224 patients (0.1%) in the enoxaparin group (P=0.18). A once-daily, 10-mg oral dose of rivaroxaban was significantly more effective for extended thromboprophylaxis than a once-daily, 40-mg subcutaneous dose of enoxaparin in patients undergoing elective total hip arthroplasty. The two drugs had similar safety profiles. (ClinicalTrials.gov number, NCT00329628.)

Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial

The risk of venous thromboembolism is high after total hip arthroplasty and could persist after hospital discharge. Our aim was to compare the use of rivaroxaban for extended thromboprophylaxis with short-term thromboprophylaxis with enoxaparin. 2509 patients scheduled to undergo elective total hip arthroplasty were randomly assigned, stratified according to centre, with a computer-generated randomisation code, to receive oral rivaroxaban 10 mg once daily for 31-39 days (with placebo injection for 10-14 days; n=1252), or enoxaparin 40 mg once daily subcutaneously for 10-14 days (with placebo tablet for 31-39 days; n=1257). The primary efficacy outcome was the composite of deep-vein thrombosis (symptomatic or asymptomatic detected by mandatory, bilateral venography), non-fatal pulmonary embolism, and all-cause mortality up to day 30-42. Analyses were done in the modified intention-to-treat population, which consisted of all patients who had received at least one dose of study medication, had undergone planned surgery, and had adequate assessment of thromboembolism. This study is registered at ClinicalTrials.gov, number NCT00332020. The modified intention-to-treat population for the analysis of the primary efficacy outcome consisted of 864 patients in the rivaroxaban group and 869 in the enoxaparin group. The primary outcome occurred in 17 (2.0%) patients in the rivaroxaban group, compared with 81 (9.3%) in the enoxaparin group (absolute risk reduction 7.3%, 95% CI 5.2-9.4; p<0.0001). The incidence of any on-treatment bleeding was much the same in both groups (81 [6.6%] events in 1228 patients in the rivaroxaban safety population vs 68 [5.5%] of 1229 patients in the enoxaparin safety population; p=0.25). Extended thromboprophylaxis with rivaroxaban was significantly more effective than short-term enoxaparin plus placebo for the prevention of venous thromboembolism, including symptomatic events, in patients undergoing total hip arthroplasty.