External validation of the ADA score for predicting thrombosis among acutely ill hospitalized medical patients from the APEX Trial.

The ADA (Age-D-dimer-Albumin) score was developed to identify hospitalized patients at an increased risk for thrombosis in the coronavirus infectious disease-19 (COVID-19) setting. The study aimed to validate the ADA score for predicting thrombosis in a non-COVID-19 medically ill population from the APEX trial. The APEX trial was a multinational, randomized trial that evaluated the efficacy and safety of betrixaban vs. enoxaparin among acutely ill hospitalized patients at risk for venous thromboembolism. The study endpoints included the composite of arterial or venous thrombosis and its components. Metrics of model calibration and discrimination were computed for assessing the performance of the ADA score as compared to the IMPROVE score, a well-validated VTE risk assessment model. Among 7,119 medical inpatients, 209 (2.9%) had a thrombosis event up to 77 days of follow-up. The ADA score demonstrated good calibration for both arterial and venous thrombosis, whereas the IMPROVE score had adequate calibration for venous thrombosis (p > 0.05 from the Hosmer-Lemeshow test). For discriminating arterial and venous thrombosis, there was no significant difference between the ADA vs. IMPROVE score (c statistic = 0.620 [95% CI: 0.582 to 0.657] vs. 0.590 [95% CI: 0.556 to 0.624]; ∆ c statistic = 0.030 [95% CI: -0.022 to 0.081]; p = 0.255). Similarly, for discriminating arterial thrombosis, there was no significant difference between the ADA vs. IMPROVE score (c statistic = 0.582 [95% CI: 0.534 to 0.629] vs. 0.609 [95% CI: 0.564 to 0.653]; ∆ c statistic = -0.027 [95% CI: -0.091 to 0.036]; p = 0.397). For discriminating venous thrombosis, the ADA score was modestly superior to the IMPROVE score (c statistic = 0.664 [95% CI: 0.607 to 0.722] vs. 0.573 [95% CI: 0.521 to 0.624]; ∆ c statistic = 0.091 [95% CI: 0.011 to 0.172]; p = 0.026). The ADA score had a higher sensitivity (0.579 [95% CI: 0.512 to 0.646]; vs. 0.440 [95% CI: 0.373 to 0.507]) but lower specificity (0.625 [95% CI: 0.614 to 0.637] vs. 0.747 [95% CI: 0.737 to 0.758]) than the IMPROVE score for predicting thrombosis. Among acutely ill hospitalized medical patients enrolled in the APEX trial, the ADA score demonstrated good calibration but suboptimal discrimination for predicting thrombosis. The findings support the use of either the ADA or IMPROVE score for thrombosis risk assessment. The applicability of the ADA score to non-COVID-19 populations warrants further research.Clinical Trial Registration: http://www.clinicaltrials.gov . Unique identifier: NCT01583218.

Inverse relationship between body mass index and risk of venous thromboembolism among medically ill hospitalized patients: Observations from the APEX trial.

Obesity is associated with cardiovascular complications such as diabetes and hypertension. However, obesity and high body mass index (BMI) can also be linked to improved clinical outcomes in certain patient populations. This counterintuitive observation is called the "obesity paradox." The effect of BMI on the risk of developing venous thromboembolism (VTE) in acutely ill medical patients remains unclear. In the Acute Medically Ill VTE Prevention with Extended Duration Betrixaban (APEX) trial, acutely ill hospitalized medical patients were randomized to receive either extended-duration betrixaban or shorter-duration enoxaparin and followed for 77 days. A total of 7372 patients with evaluable VTE endpoints had BMI measured at baseline. The association between BMI and VTE risk was assessed after adjusting for potential confounders. The multivariable adjusted ORs of VTE risk associated with BMI levels referencing the median BMI value (15, 18.5, 28.3 [reference], 35, 40, 45) were: 2.82 (95% CI, 1.32-6.04, [change from 28.3 to 15]), 1.85 (95% CI, 1.14-2.99, [change from 28.3 to 18.5]), 1.30 (95% CI, 1.04-1.63, [change from 28.3 to 35]), 1.13 (95% CI, 0.84-1.52, [change from 28.3 to 40]), and 0.91 (95% CI, 0.57-1.47, [change from 28.3 to 45]), respectively (p = 0.022). In conclusion, acutely ill hospitalized patients with lower BMI had a higher VTE risk through 77 days, which appears to be a manifestation of the BMI paradox.

Machine learning to predict venous thrombosis in acutely ill medical patients.

BACKGROUND: The identification of acutely ill patients at high risk for venous thromboembolism (VTE) may be determined clinically or by use of integer-based scoring systems. These scores demonstrated modest performance in external data sets. OBJECTIVES: To evaluate the performance of machine learning models compared to the IMPROVE score. METHODS: The APEX trial randomized 7513 acutely medically ill patients to extended duration betrixaban vs. enoxaparin. Including 68 variables, a super learner model (ML) was built to predict VTE by combining estimates from 5 families of candidate models. A "reduced" model (rML) was also developed using 16 variables that were thought, a priori, to be associated with VTE. The IMPROVE score was calculated for each patient. Model performance was assessed by discrimination and calibration to predict a composite VTE end point. The frequency of predicted risks of VTE were plotted and divided into tertiles. VTE risks were compared across tertiles. RESULTS: The ML and rML algorithms outperformed the IMPROVE score in predicting VTE (c-statistic: 0.69, 0.68 and 0.59, respectively). The Hosmer-Lemeshow goodness-of-fit P-value was 0.06 for ML, 0.44 for rML, and <0.001 for the IMPROVE score. The observed event rate in the lowest tertile was 2.5%, 4.8% in tertile 2, and 11.4% in the highest tertile. Patients in the highest tertile of VTE risk had a 5-fold increase in odds of VTE compared to the lowest tertile. CONCLUSION: The super learner algorithms improved discrimination and calibration compared to the IMPROVE score for predicting VTE in acute medically ill patients.

Extended prophylaxis of venous thromboembolism with betrixaban in acutely ill medical patients with and without cancer: insights from the APEX trial.

Acutely ill medical patients with cancer are at increased risk of venous thromboembolism (VTE). Thromboprophylaxis is recommended in the presence of cancer, but its safety is not known. The aim of this study was to assess the efficacy and safety of extended prophylaxis with betrixaban in cancer patients enrolled in the APEX trial. APEX was a randomized, double-blind trial comparing oral betrixaban 80 mg qd administered for 35-42 days with subcutaneous enoxaparin 40 mg qd administered for 10 ± 4 days. Patients with acute medical illness and a history of cancer or active cancer were eligible for inclusion. Primary efficacy outcome was VTE (composite of symptomatic VTE and asymptomatic proximal deep vein thrombosis); primary safety outcome was major bleeding. Of 7513 patients enrolled in the APEX trial, 959 patients (12.8%), 499 randomized to betrixaban and 460 to enoxaparin, had cancer. The primary efficacy outcome occurred in 5.7% of cancer patients treated with betrixaban and in 6.2% treated with enoxaparin (p = 0.95). No significant interaction according to the presence or absence of cancer was observed (p = 0.36). Major bleeding events occurred in 0.8% of patients in the betrixaban group and in 0% in the enoxaparin group (p = 0.13), with no significant interaction (p = 0.07). The composite of major and clinically relevant non-major bleeds was similar between the two groups (2.9% and 2.0%, respectively, RR 1.43, 95% CI 0.63-3.27). Betrixaban was similarly effective in the reduction of VTE among subjects with and without cancer. The incidence of major bleeding was similarly low.

Estimation of Acutely Ill Medical Patients at Venous Thromboembolism Risk Eligible for Extended Thromboprophylaxis Using APEX Criteria in US Hospitals.

Major medical illnesses place patients at risk of venous thromboembolism (VTE). Some risk factors including age ≥75 years or history of cancer place them at increased risk of VTE that extends for at least 5 to 6 weeks following hospital admission. Betrixaban thromboprophylaxis is now approved in the United States for this indication. We estimated the annual number of acutely ill medical patients at extended risk of VTE discharged from US hospital. Major medical illnesses (stroke, respiratory failure/chronic obstructive pulmonary disease, heart failure, pneumonia, other infections, and rheumatologic disorders) and 2 common risk factors for extended VTE risk, namely, age ≥75 years and history of cancer (active or past) were examined in 2014 US hospital discharges using the first 3 discharge diagnosis codes in the National Inpatient Sample (database of acute-care hospital discharges from the US Agency for Health Care Quality and Research). In 2014, there were 20.8 million discharges with potentially at risk of nonsurgical-related VTE. Overall, 7.2 million (35%) discharges corresponded to major medical illness that warranted thromboprophylaxis according to 2012 American College of Chest Physicians (ACCP) guideline. Among them, 2.79 million were aged ≥75 years and 1.36 million had a history of cancer (aged 40-74 years). Overall, 3.48 million discharges were at extended risk of VTE. Many medical inpatients at risk of VTE according to 2012 ACCP guideline might benefit from the awareness of continuing risk and some of these patients might benefit from extended thromboprophylaxis, depending on the risk of bleeding and comorbidities.

Net-clinical benefit of extended prophylaxis of venous thromboembolism with betrixaban in medically ill patients aged 80 or more.

BACKGROUND: Extended-duration thromboprophylaxis with betrixaban reduces the risk of venous thromboembolism (VTE) without increasing major bleeding rates in acutely ill medical patients as compared to standard duration enoxaparin. We aimed to assess the risk-benefit of betrixaban in patients aged ≥ 80 years enrolled in the APEX trial. METHODS: APEX was a randomized, double-blind trial in which patients hospitalized for acute medical illnesses received enoxaparin 40 mg qd for 10 ± 4 days or oral betrixaban 80 mg qd for 35 to 42 days. The primary efficacy outcome was VTE, the principal safety outcome was major bleeding. Net clinical benefit (NCB) was defined by the occurrence of VTE or major bleeding. RESULTS: Of 7513 patients enrolled in the APEX trial, 2781 (37%) were aged ≥ 80 years. In this subgroup, VTE or major bleeding occurred in 7.0% of betrixaban patients and in 8.4% of enoxaparin patients, for a relative risk in the NCB of 0.82 (95% confidence interval 0.62-1.10). The relative risk reduction obtained with betrixaban was similar between those aged ≥ 80 years and patients younger than 80 years (5.0% and 6.7%, respectively, NCB 0.75, 0.58-0.96, P = .024), with no significant interaction across age groups (P = .33). CONCLUSIONS: Event rates were higher in medically ill patients aged ≥ 80 years enrolled in the APEX study than in patients younger than 80 years. The predefined NCB was reduced with extended betrixaban therapy in both groups with no signs of age-related interactions. However, the primary efficacy endpoint was not achieved with betrixaban for patients 80 years of age or older.

Characterization of Major and Clinically Relevant Non-Major Bleeds in the APEX Trial.

Background Among medically ill patients treated with thromboprophylaxis, betrixaban was not associated with an increase in major bleeding compared with enoxaparin, but an increase in clinically relevant non-major (CRNM) bleeding was observed. The aim of this analysis is to describe the severity and clinical consequences of major and CRNM bleeding in the APEX trial. Methods The APEX trial randomized 7,513 hospitalized acutely ill medical patients to receive either enoxaparin for 6 to 14 days or betrixaban for 35 to 42 days. Subjects receiving a concomitant strong p-glycoprotein inhibitor or with creatinine clearance <30 mL/min were administered a reduced dose of study drug. Results A total of 25 (0.7%) and 21 (0.6%) major bleeds occurred in the betrixaban and enoxaparin arms, respectively ( p = NS) and a total of 91 (2.5%) and 38 (1.0%) CRNM bleeds occurred in the betrixaban and enoxaparin arm ( p < 0.001), respectively. Most major bleeds were considered moderate or severe and most CRNM bleeds were considered mild and moderate ( p = NS). One fatal major bleed occurred in each treatment arm. Rates of major or CRNM bleeds resulting in new or prolonged hospitalization (major: 44.0 vs. 28.6%; CRNM: 12.1 vs. 21.1%) or study treatment interruption or cessation (major: 72.0 vs. 71.4%; CRNM: 71.3 vs. 68.4%) were similar between treatment arms ( p = NS). Conclusions In the APEX trial, CRNM bleeds were mild or moderate in nature and had less of a clinical impact than major bleeds. The severity and clinical sequela of bleeds in the betrixaban arm were comparable to those in the enoxaparin arm. Clinical Trial Registration URL: http://www.clinicaltrials.gov .; Unique identifier: NCT01583218.

Evaluation of unmet clinical needs in prophylaxis and treatment of venous thromboembolism in high-risk patient groups: cancer and critically ill.

BACKGROUND: Clinical practice shows that venous thromboembolism (VTE) presents a substantial burden in medical patients, and awareness and advocacy for its primary and secondary prevention remains inadequate. Specific patient populations, such as those with cancer and the critically ill, show elevated risk for VTE, bleeding or both, and significant gaps in VTE prophylaxis and treatment exist in these groups. OBJECTIVE: To present novel insights and consolidated evidence collected from experts, clinical practice guidelines and original studies on the unmet needs in thromboprophylaxis, and on the treatment of VTE in two high-risk patient groups: patients with cancer and the critically ill. METHODOLOGY: To identify specific unmet needs in the management of VTE, a methodology was designed and implemented that assessed gaps in prophylaxis and treatment of VTE through interviews with 44 experts in the field of thrombosis and haemostasis, and through a review of current guidelines and seminal studies to substantiate the insights provided by the experts. The research findings were then analysed, discussed and consolidated by a multidisciplinary group of experts. RESULTS: The gap analysis methodology identified shortcomings in the VTE risk assessment tools, patient stratification approaches for prophylaxis, and the suboptimal use of anticoagulants for primary prophylaxis and treatment. CONCLUSIONS: Specifically, patients with cancer need better VTE risk assessment tools to tailor primary thromboprophylaxis to tumour types and disease stages, and the potential for drug-drug interactions needs to be considered. In critically ill patients, unfractionated heparin is not advised as a first-line treatment option, and the strength of evidence is increasing for direct oral anticoagulants as a treatment option over low-molecular-weight heparins.

Extended-duration betrixaban versus shorter-duration enoxaparin for venous thromboembolism prophylaxis in critically ill medical patients: an APEX trial substudy.

PURPOSE: To assess the efficacy and safety of betrixaban for venous thromboembolism (VTE) prophylaxis among critically ill patients. METHODS: The APEX trial randomized 7513 acutely ill hospitalized patients to betrixaban for 35-42 days or enoxaparin for 10 ± 4 days. Among those, 703 critically ill patients admitted to the intensive care unit were included in the analysis, and 547 patients who had no severe renal insufficiency or P-glycoprotein inhibitor use were included in the full-dose stratum. The risk of VTE, bleeding, net clinical benefit (composite of VTE and major bleeding), and mortality was compared at 35-42 days and at 77 days. RESULTS: At 35-42 days, extended betrixaban reduced the risk of VTE (4.27% vs 7.95%, P = 0.042) without causing excess major bleeding (1.14% vs 3.13%, P = 0.07). Both VTE (3.32% vs 8.33%, P = 0.013) and major bleeding (0.00% vs 3.26%, P = 0.003) were decreased in the full-dose stratum. Patients who received betrixaban had more non-major bleeding than enoxaparin (overall population: 2.56% vs 0.28%, P = 0.011; full-dose stratum: 3.32% vs 0.36%, P = 0.010). Mortality was similar at the end of study (overall population: 13.39% vs 16.19%, P = 0.30; full-dose stratum: 13.65% vs 16.30%, P = 0.39). CONCLUSIONS: Compared with shorter-duration enoxaparin, critically ill medical patients who received extended-duration betrixaban had fewer VTE without more major bleeding events. The benefit of betrixaban was driven by preventing asymptomatic thrombosis and offset by an elevated risk of non-major bleeding. The APEX trial did not stratify by intensive care unit admission and the present study included a highly selected population of critically ill patients. These hypothesis-generating findings need to be validated in future studies. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov . Unique identifier: NCT01583218.

Evaluation of unmet clinical needs in prophylaxis and treatment of venous thromboembolism in at-risk patient groups: pregnancy, elderly and obese patients.

BACKGROUND: Venous thromboembolism (VTE) accounts for an estimated 900,000 cases per year in the US alone and constitutes a considerable burden on healthcare systems across the globe. OBJECTIVE: To understand why the burden is so high, qualitative and quantitative research was carried out to gain insights from experts, guidelines and published studies on the unmet clinical needs and therapeutic strategies in VTE prevention and treatment in three populations identified as being at increased risk of VTE and in whom VTE prevention and treatment were regarded as suboptimal: pregnant women, the elderly and obese patients. METHODOLOGY: A gap analysis methodology was created to highlight unmet needs in VTE management and to discover the patient populations considered most at risk. A questionnaire was devised to guide qualitative interviews with 44 thrombosis and haemostasis experts, and a review of the literature on VTE in the specific patient groups from 2015 to 2017 was completed. This was followed by a Think Tank meeting where the results from the research were discussed. RESULTS: This review highlights the insights gained and examines in detail the unmet needs with regard to VTE risk-assessment tools, biomarkers, patient stratification methods, and anticoagulant and dosing regimens in pregnant women, the elderly and obese patients. CONCLUSIONS: Specifically, in pregnant women at high risk of VTE, low-molecular-weight heparin (LMWH) is the therapy of choice, but it remains unclear how to use anticoagulants when VTE risk is intermediate. In elderly patients, evaluation of the benefit of VTE prophylaxis against the bleeding risk is particularly important, and a head-to-head comparison of efficacy and safety of LMWH versus direct oral anticoagulants is needed. Finally, in obese patients, lack of guidance on anticoagulant dose adjustment to body weight has emerged as a major obstacle in effective prophylaxis and treatment of VTE.

Inverse relationship of serum albumin to the risk of venous thromboembolism among acutely ill hospitalized patients: Analysis from the APEX trial.

Hypoalbuminemia is a common finding and independent predictor for unfavorable prognosis. The prognostic value of albumin measurement for short-term VTE prediction in hospitalized patients remains unclear. In the APEX trial (ClinicalTrials.gov identifier: NCT01583218), medical inpatients were randomized to receive either extended-duration betrixaban or shorter-duration enoxaparin and followed for 77 days. Baseline albumin concentrations were obtained in 7266 subjects with evaluable VTE endpoints. The association of baseline albumin to VTE was assessed, with adjustment for patient characteristics, thromboprophylaxis, and biomarkers for fibrinolysis and inflammation (ie, D-dimer and C-reactive protein [CRP]). VTE risk refinement was evaluated by incorporation of albumin to well-validated risk assessment models. A stepwise increase in the risk of VTE (P < .0001) was observed with lower levels of albumin. Patients at the bottom albumin quartile (<35 g/L) had a two-fold greater odds for developing VTE compared with the top quartile (≥42 g/L) (OR = 2.119 [95% CI, 1.592-2.820]; adjusted OR = 2.079 [1.485-2.911]). The odds for VTE increased by 1.368 (95% CI, 1.240-1.509) times per SD decrement of albumin (5.24 g/L). Compared with the propensity score-matched pairs of patients with albumin ≥35 g/L, patients with albumin <35 g/L had a greater risk of VTE (OR = 1.623 [1.260-2.090]; adjusted OR = 1.658 [1.209-2.272]). Albumin measurement also refined VTE risk discrimination and reclassification after inclusion in the risk assessment models. In conclusion, acutely ill hospitalized patients with low serum albumin had an increased VTE risk through 77 days. VTE risk assessment models for medical inpatients should consider incorporation of baseline albumin measurement.

Asymptomatic Deep Vein Thrombosis is Associated with an Increased Risk of Death: Insights from the APEX Trial.

AIM: Asymptomatic deep vein thrombosis (DVT) diagnosed with compression ultrasound (CUS) is a common endpoint in trials assessing the efficacy of anticoagulants to prevent venous thromboembolism (VTE), but the relationship of asymptomatic thrombus to mortality remains uncertain. METHODS: In the APEX trial (ClinicalTrials.gov: NCT01583218), 7,513 acutely ill hospitalized medical patients were randomly assigned to extended-duration betrixaban (35-42 days) or enoxaparin (10 ± 4 days). Asymptomatic DVT was assessed once with CUS between day 32 and 47, and mortality was assessed through 77 days. RESULTS: A total of 309 asymptomatic DVTs were detected through CUS. Of these, 133 (4.27%) subjects were in the betrixaban group, and 176 (5.55%) subjects were in the enoxaparin group (relative risk = 0.77, 95% confidence interval [CI] = 0.62-0.97, p = 0.025, number needed to treat = 79). With respect to all-cause mortality due to cardiovascular diseases, non-cardiovascular diseases and unknown causes, the number of the deaths was 5 (1.67%), 4 (1.34%) and 1 (0.33%) in the asymptomatic DVT group and 25 (0.42%), 33 (0.56%) and 11 (0.19%) in the no DVT group, respectively. Subjects with an asymptomatic DVT had an almost threefold increase in the risk of all-cause mortality compared with subjects without DVT (hazard ratio = 2.87, 95% CI = 1.48-5.57, p = 0.001). A positive linear trend was observed between greater thrombus burden and mortality during the follow-up (p = 0.019). CONCLUSION: Asymptomatic DVT was associated with approximately threefold increased risk of short-term all-cause mortality in patients hospitalized with an acute medical illness within the prior 77 days. A positive linear trend was observed between greater thrombus burden and mortality during the follow-up.

Association of Anemia with Venous Thromboembolism in Acutely Ill Hospitalized Patients: An APEX Trial Substudy.

BACKGROUND: Anemia is a common finding and independent predictor for adverse outcomes in hospitalized patients with medical illness. It remains unclear whether anemia is a risk factor for venous thromboembolism and whether the presence of anemia can refine risk assessment for prediction of venous thromboembolism, thereby adding incremental utility to a validated model. METHODS: In the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban trial (APEX), 7513 hospitalized medical patients were randomized to receive either betrixaban or standard-of-care enoxaparin for thromboprophylaxis. Baseline hemoglobin concentrations were obtained in 6861 patients, with a follow-up of 77 days. Symptomatic venous thromboembolism events, including symptomatic deep vein thrombosis, pulmonary embolism, and venous thromboembolism-related mortality, were compared between low-hemoglobin and normal-hemoglobin groups (normal range: 12.5-17.0 g/dL for males and 11.0-15.5 g/dL for females). The relationship between anemia and venous thromboembolism events was assessed by fitting a univariable and multivariable logistic regression model composed of thromboprophylaxis and risk factors. Venous thromboembolism risk refinement by hemoglobin measurement was evaluated in the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) risk assessment model. RESULTS: Low hemoglobin at baseline was associated with a greater risk of symptomatic venous thromboembolism (relative risk [RR] 1.94 [95% confidence interval, 1.27-2.98]; P = .002), symptomatic deep vein thrombosis (RR 2.29 [1.12-4.68]; P = .019), and nonfatal pulmonary embolism (RR 2.63 [1.22-5.65]; P = .010) but not venous thromboembolism-related mortality (RR 1.47 [0.71-3.04]; P = .30). After adjusting for thromboprophylaxis, history of previous venous thromboembolism, intensive or coronary unit admission, and D-dimer, low hemoglobin (as a categorical or continuous variable) remained associated with an increased likelihood of venous thromboembolism (adjusted odds ratio 1.71 [95% confidence interval, 1.09-2.69]; P = .020). Low hemoglobin also improved risk discrimination and reclassification after inclusion in the IMPROVE model. CONCLUSIONS: Anemia was independently associated with a greater risk of symptomatic venous thromboembolism among acutely ill medical patients despite the provision of thromboprophylaxis. Hemoglobin measurement also improved risk stratification by the IMPROVE venous thromboembolism risk score.

Increased benefit of betrixaban among patients with a history of venous thromboembolism: a post-hoc analysis of the APEX trial.

Hospitalized acute medically ill patients with a history of venous thromboembolism (VTE) are at increased risk for recurrent VTE. We characterized the efficacy and safety of betrixaban for prevention of recurrent VTE in these high risk patients. The APEX trial randomized 7513 acutely ill hospitalized medical patients at risk for developing VTE to receive either betrixaban for 35-42 days or enoxaparin for 10 ± 4 days to prevent VTE. This exploratory post-hoc analysis assessed the efficacy and safety of betrixaban versus enoxaparin among subjects with and without prior VTE. Time-to-multiple symptomatic VTE events was also calculated. Approximately 8% of subjects in both arms had prior VTE, which was associated with a fourfold increase in adjusted risk of VTE [MV OR 4.03, 95% CI 3.06-5.30, p < 0.001]. Betrixaban reduced VTE compared with enoxaparin among subjects with prior VTE [32 (10.4%) vs. 55 (18.9%), RR 0.57, 95% CI 0.38-0.86, p = 0.006, ARR 8.5%, NNT 12] and without prior VTE [133 (3.9%) vs. 168 (4.9%), RR 0.79, 95% CI 0.64-0.99, p = 0.042, ARR 1.0%, NNT 100] (interaction p > 0.05). Additionally, four subjects in the enoxaparin arm and one subject in the betrixaban arm experienced a recurrent VTE. Compared with enoxaparin, betrixaban use was associated with reduction of recurrent VTE events through the active treatment period [36 vs. 57, HR 0.63, 95% CI 0.41-0.97, p = 0.045] and through the end of study [38 vs. 71, HR 0.54, 95% CI 0.36-0.81, p = 0.004]. Prior VTE is associated with a fourfold increase in the risk of VTE among hospitalized medically ill patients. Only 12 such patients would need to be treated with betrixaban versus enoxaparin to prevent an additional VTE endpoint. Betrixaban reduced not only the first but also all recurrent VTE events in a time-to-any-event analysis. TRIAL REGISTRATION: http://www.clinicaltrials.gov , Unique identifier: NCT01583218.

Thrombus Burden of Deep Vein Thrombosis and Its Association with Thromboprophylaxis and D-Dimer Measurement: Insights from the APEX Trial.

Background The aim of this study was to evaluate the effect of betrixaban on the occurrence of deep vein thrombosis (DVT) and also the extent of thrombus and to assess the association of baseline D-dimer with subsequent thrombus burden. Methods In the APEX trial (ClinicalTrials.gov: NCT01583218), 7,513 acutely ill hospitalized medical patients were randomly assigned to extended-duration betrixaban (35­42 days) or enoxaparin (10 ± 4 days). D-dimer concentration was measured at baseline, and mandatory lower-extremity compression ultrasonography (CUS) was performed at 35 to 42 days. The thrombus burden of DVT was assessed by the number of non-compressible vascular segments in six target proximal veins and compared between treatment groups and D-dimer categories (≥2 × upper limit of normal [ULN] versus <2 × ULN). Results Compared with enoxaparin, extended-duration betrixaban reduced the DVT risk at 35 to 42 days (any-dose: relative risk [RR] = 0.76 [95% confidence interval: 0.61­0.94]; p = 0.013; full-dose: RR = 0.70 [0.55­0.90]; p = 0.005). Patients who received betrixaban were more likely to have a lower thrombus burden (p = 0.012 for any-dose and p = 0.001 for full-dose). Elevated D-dimer at baseline was independently associated with a 2.12-fold increased risk of developing DVT (p < 0.001). A greater thrombus burden was also observed in those with D-dimer ≥ 2 × ULN compared with <2 × ULN (p < 0.0001). Conclusion Extended-duration betrixaban reduced the number of venous segments with thrombosis at 35 to 42 days compared with enoxaparin. A positive D-dimer was associated with a greater extent of thrombus burden among acutely ill medical patients who developed DVT despite receiving thromboprophylaxis.

N-terminal pro-B-type natriuretic peptide and the risk of stroke among patients hospitalized with acute heart failure: an APEX trial substudy.

BACKGROUND: Among patients hospitalized with acute heart failure (HF), the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in short-term stroke prediction remains unclear. METHODS: In the APEX trial, 7513 patients hospitalized for an acute medical illness were randomized to receive either extended-duration betrixaban (80 mg once daily for 35-42 days) or standard-of-care enoxaparin (40 mg once daily for 10 ± 4 days) for venous thromboprophylaxis. Baseline NT-proBNP concentrations were obtained in 3261 patients admitted for HF. Stroke events were adjudicated by an independent clinical events committee blinded to thromboprophylaxis allocation. The association of NT-proBNP level and other risk factors and biomarkers with stroke was assessed at 77 days after randomization. RESULTS: In univariate analysis, the risk of stroke at 77 days was associated with baseline NT-proBNP (HR 3.63 [95% CI 1.47-8.99]; P = 0.005), D-dimer (HR 2.73 [95% CI 1.03-7.20]; P = 0.043), and hsCRP (HR 3.03 [95% CI 1.36-6.75]; P = 0.007). In multivariable analysis adjusting for hsCRP and thromboprophylaxis, NT-proBNP was associated with the risk of stroke (adjusted HR 3.64 [95% CI 1.35-9.83]; P = 0.011). The interaction of NT-proBNP with the treatment effect was not significant (Pint = 0.30). CONCLUSIONS: Baseline NT-proBNP concentration was associated with short-term stroke among patients hospitalized with acute HF. Stroke risk assessment models should consider incorporation of NT-proBNP measurement.

Competing risk analysis in a large cardiovascular clinical trial: An APEX substudy.

Competing risk methods are time-to-event analyses that account for fatal and/or nonfatal events that may potentially alter or prevent a subject from experiencing the primary endpoint. Competing risk methods may provide a more accurate and less biased estimate of the incidence of an outcome but are rarely applied in cardiology trials. APEX investigated the efficacy of extended-duration betrixaban versus standard-duration enoxaparin to prevent a composite of symptomatic deep-vein thrombosis (proximal or distal), nonfatal pulmonary embolism, or venous thromboembolism (VTE)-related death in acute medically ill patients (n = 7513). The aim of the current analysis was to determine the efficacy of betrixaban vs standard-duration enoxaparin accounting for non-VTE-related deaths using the Fine and Gray method for competing risks. The proportion of non-VTE-related death was similar in both the betrixaban (133, 3.6%) and enoxaparin (136, 3.7%) arms, P = .85. Both the traditional Kaplan-Meier method and the Fine and Gray method accounting for non-VTE-related death as a competing risk showed equal reduction of VTE events when comparing betrixaban to enoxaparin (HR/SHR = 0.65, 95% 0.42-0.99, P = 0.046). Due to the similar proportion of non-VTE-related deaths in both treatment arms and the use of a univariate model, the Fine and Gray method provided identical results to the traditional Cox model. Using the Fine and Gray method in addition to the traditional Cox proportional hazards method can indicate whether the presence of a competing risk, which is dependent of the outcome, altered the risk estimate.