Fahad AlKhalfan

Symptomatic Event Reduction with Extended-Duration Betrixaban in Acute Medically Ill Hospitalized Patients

Background: Approximately 15%‐30% of patients in trials of medical thromboprophylaxis will have missing compression ultrasound (CUS) data. The goal of the present analysis was to perform analyses to minimize missing data. Methods: The APEX trial randomized 7,513 acutely medically ill hospitalized patients to thromboprophylaxis with either betrixaban for 35‐42 days or enoxaparin for 6‐14 days. A modified intent‐to‐treat (mITT) analysis was performed and included all subjects administered study drug, irrespective of CUS performance, and an analysis of symptomatic events which do not require performance of a CUS (symptomatic deep vein thrombosis, nonfatal pulmonary embolism, and venous thromboembolism (VTE)–related mortality). Results: In the mITT population, betrixaban significantly reduced the primary end point (which included both symptomatic and CUS events) (165 [4.4%] vs 223 [6.0%]; relative risk = 0.75; 95% CI 0.61‐0.91; P = .003; absolute risk reduction [ARR] = 1.6%; number needed to treat [NNT] = 63). Betrixaban also reduced symptomatic VTE through day 42 (35 [1.28%] vs 54 [1.88%], hazard ratio [HR] = 0.65; 95% CI 0.42‐0.99; P = .044; ARR = 0.6%; NNT=167) as well as through day 77 (37 [1.02%] vs 67 [1.89%]; HR= 0.55; 95% CI 0.37‐0.83; P = .003; ARR = 0.87%; NNT=115) as well as the individual end point of nonfatal pulmonary embolism (9 [0.25%] vs 20 [0.55%]; HR= 0.45; 95% CI 0.21‐0.99; P = .041; ARR = 0.30%; NNT=334). On an “as‐treated” basis, 80 mg of betrixaban reduced VTE‐related mortality through day 77 (10 [0.34%] vs. 22 [0.79%]; HR=0.46; 95% CI 0.22‐0.96; P = .035; ARR = 0.45%; NNT=223). Conclusion: In an mITT analysis of all patients administered study drug, extended‐duration betrixaban reduced the primary end point as well as symptomatic events. In an as‐treated analysis, 80 mg of betrixaban reduced VTE‐related death.

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 10u2009±u20094 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, pu2009<u20090.001]. 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, pu2009=u20090.006, 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, pu2009=u20090.042, ARR 1.0%, NNT 100] (interaction pu2009>u20090.05). 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, pu2009=u20090.045] and through the end of study [38 vs. 71, HR 0.54, 95% CI 0.36–0.81, pu2009=u20090.004]. 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

Effect of Procedure and Coronary Lesion Characteristics on Clinical Outcomes Among Atrial Fibrillation Patients Undergoing Percutaneous Coronary Intervention: Insights From the PIONEER AF-PCI Trial

OBJECTIVESnThis study sought to assess whether there were significant interactions of procedural access strategies and lesion characteristics with bleeding and ischemic events among atrial fibrillation (AF) patients anticoagulated with rivaroxaban or warfarin following a percutaneous coronary intervention.nnnBACKGROUNDnAmong stented AF patients, the impact of procedural access strategies or lesion characteristics on antithrombotic safety and efficacy outcomes is unclear.nnnMETHODSnIn the PIONEER AF-PCI (An Open-label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention) trial, 2,124 patients were randomized to 3 groups and followed for 12 months: 1) rivaroxaban 15 mg once daily plus a P2Y12 inhibitor (nxa0= 709); 2) rivaroxaban 2.5 mg twice a day plus dual antiplatelet therapy (DAPT) (nxa0= 709); and 3) dose-adjusted warfarin plus DAPT (nxa0= 706). Kaplan-Meier rates of clinically significant bleeding and major adverse cardiovascular events were compared between treatments stratified by subgroups of procedure type and lesion characteristics.nnnRESULTSnCompared with warfarin, both rivaroxaban regimens consistently reduced clinically significant bleeding across subgroups of radial versus femoral arterial access and by vascular closure device use. Treatment effect of rivaroxaban on major adverse cardiovascular events did not vary when stratified by ischemia-driven revascularization, urgency of revascularization, location of culprit artery, presence of bifurcation lesion, presence of thrombus, type, and length of stent or number of stents (interaction p > 0.05 for all subgroups).nnnCONCLUSIONSnAmong stented AF patients requiring long-term oral anticoagulation, there was no effect modification by procedure or lesion characteristics of either clinically significant bleeding or major adverse cardiovascular events. Rivaroxaban-based therapy was superior to warfarin plus DAPT in bleeding outcomes regardless of the type of stent or arterial access during the index coronary revascularization. (A Study Exploring Two Strategies of Rivaroxaban [JNJ39039039; BAY-59-7939] and One of Oral Vitamin K Antagonist in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention [PIONEER AF-PCI]; NCT01830543).

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

BACKGROUNDnAnemia 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.nnnMETHODSnIn 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: 12.5-17.0xa0g/dL for males and 11.0-15.5xa0g/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.nnnRESULTSnLow hemoglobin at baseline was associated with a greater risk of symptomatic venous thromboembolism (relative risk [RR]xa01.94 [95% confidence interval, 1.27-2.98]; Pxa0=xa0.002), symptomatic deep vein thrombosis (RRxa02.29 [1.12-4.68]; Pxa0=xa0.019), and nonfatal pulmonary embolism (RRxa02.63 [1.22-5.65]; Pxa0=xa0.010) but not venous thromboembolism-related mortality (RRxa01.47 [0.71-3.04]; Pxa0=xa0.30). 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 ratioxa01.71 [95% confidence interval, 1.09-2.69]; Pxa0=xa0.020). Low hemoglobin also improved risk discrimination and reclassification after inclusion in the IMPROVE model.nnnCONCLUSIONSnAnemia 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.

Association of D-dimer Levels with Clinical Event Rates and the Efficacy of Betrixaban versus Enoxaparin in the APEX Trial

Background u2003Elevated D-dimer concentrations are associated with an increased risk of venous thromboembolism (VTE). However, they may also provide prognostic value. The present analysis sought to study the association of D-dimer levels with VTE event rates and the efficacy of betrixaban versus enoxaparin in the APEX trial. Methods u2003Hospitalized acutely medically ill subjects ( n u2009=u20097,513) were randomized in a double-dummy double-blind fashion to either extended-duration oral betrixaban (80u2009mg once daily for 35–42 days) or standard dose subcutaneous enoxaparin (40u2009mg once daily for 10u2009±u20094 days) for venous thromboprophylaxis. D-dimer was assessed using a central core laboratory measurement. Results u2003For every 0.25 µg/mL increase in D-dimer concentration, there was a 2% increase in the relative risk of experiencing the primary efficacy endpoint (asymptomatic deep vein thrombosis [DVT], symptomatic DVT, nonfatal pulmonary embolism, or VTE-related death) in both the betrixaban ( p u2009<u20090.001) and enoxaparin ( p u2009<u20090.001) treatment arms. Among D-dimer-positive (≥ 2u2009×u2009upper limit of normal; corresponding to ≥ 1.00 µg/mL) subjects, extended-duration betrixaban reduced the risk of experiencing the primary efficacy outcome (5.4% [ n u2009=u2009124] vs. 7.6% [ n u2009=u2009170]; odds ratiou2009=u20090.69; 95% confidence interval: 0.55–0.88; absolute risk reductionu2009=u20092.2%, number needed to treatu2009=u200946, p u2009=u20090.003). There was no interaction between D-dimer and the treatment effect ( p int u2009=u20090.53). Conclusion u2003Extended-duration betrixaban was superior to standard-duration enoxaparin, irrespective of D-dimer level at baseline. To prevent one VTE event, 46 D-dimer-positive patients would need to be treated with betrixaban.

Total bleeding with rivaroxaban versus warfarin in patients with atrial fibrillation receiving antiplatelet therapy after percutaneous coronary intervention

Among atrial fibrillation (AF) patients undergoing percutaneous coronary intervention (PCI), rivaroxaban with background antiplatelet therapy significantly reduced the first occurrence of bleeding compared to triple therapy with warfarin. This study hypothesized that total bleeding events, including those beyond the first event, would be reduced with rivaroxaban-based regimens. In the PIONEER AF-PCI trial, 2099 patients in the modified intention-to-treat population were randomized to three groups and followed for 12xa0months: (1) rivaroxaban 15xa0mg once daily plus a P2Y12 inhibitor (Nu2009=u2009696); (2) rivaroxaban 2.5xa0mg twice daily plus dual antiplatelet therapy (DAPT) (Nu2009=u2009706); and (3) dose-adjusted warfarin plus DAPT (Nu2009=u2009697). Descriptive statistics for the number of subjects who experienced one or more bleeding events were calculated. The total number of bleeding events was compared across treatment groups using the Wei, Lin, and Weissfeld method. A total of 514 and 439 events of clinically significant bleeding and bleeding requiring medical attention occurred throughout the study. Compared to triple therapy with warfarin, rivaroxaban-based regimen was associated with a reduction in total events of clinically significant bleeding (Group 1 vs. Group 3: HR 0.64 [95% CI 0.49–0.85], pu2009<u20090.001, NNTu2009=u200911; Group 2 vs. Group 3: HR 0.62 [95% CI 0.48–0.80], pu2009<u20090.001, NNTu2009=u200910). Similarly, rivaroxaban reduced the total bleeding events requiring medical attention (Group 1 vs. Group 3: HR 0.66 [95% CI 0.49–0.89], pu2009<u20090.001, NNTu2009=u200914; Group 2 vs. Group 3: HR 0.64 [95% CI 0.48–0.85], pu2009=u20090.002, NNTu2009=u200913). Rivaroxaban-based regimen reduced the total bleeding events compared with VKA-based triple therapy in stented AF patients. One clinically significant bleeding event could be prevented with rivaroxaban use for every 10–11 patients treated, and one bleeding requiring medical attention could be prevented with rivaroxaban for every 13–14 patients treated. These data provide evidence that total bleeding events, including those beyond the first event, are reduced with rivaroxaban-based antithrombotic regimens. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01830543 (PIONEER AF-PCI)

Betrixaban for first-line venous thromboembolism prevention in acute medically ill patients with risk factors for venous thromboembolism

ABSTRACT Introduction: Compared to other direct oral anticoagulants, betrixaban has a longer half-life, smaller peak-trough variance, minimal renal clearance, and minimal hepatic Cytochrome P (CYP) metabolism. The Acute Medically Ill VTE Prevention with Extended Duration Betrixaban (APEX) trial evaluated the efficacy and safety of extended duration betrixaban compared to standard duration enoxaparin in acutely ill hospitalized patients. Areas covered: This article describes the role of betrixaban in the prevention of venous thromboembolism (VTE) in acutely ill medical patients. This article provides a consolidated summary of the primary APEX study findings as well as prespecified and exploratory substudies. This article also provides a review of the results of studies in which other direct factor Xa inhibitors have been evaluated in an extended duration regimen in this patient population. Expert commentary: While previous agents have demonstrated that extended duration VTE prophylaxis can be efficacious, betrixaban is the first agent to demonstrate efficacy without an increase in major bleeding. The totality of the data from the APEX trial supports extended duration betrixaban for VTE prophylaxis in the acute medically ill patient population. As such, betrixaban has been approved in the USA for extended VTE prophylaxis in at-risk acute medically ill patients.

D-Dimer Levels and Effect of Rivaroxaban on Those Levels and Outcomes in Patients With Acute Coronary Syndrome (An ATLAS ACS-TIMI 46 Trial Substudy)

D-dimer has been used as both a diagnostic and prognostic biomarker in the assessment of patients with venous thromboembolism, but its prognostic value in the setting of arterial acute coronary syndromes (ACS) and the ability of pharmacotherapy to reduce D-dimer in ACS is less well characterized. It was hypothesized that elevated baseline D-dimer would be associated with poor clinical outcomes in ACS, and that Factor Xa inhibition with Rivaroxaban would reduce D-dimer acutely and chronically. The ATLAS ACS TIMI-46 trial assessed the safety and efficacy of rivaroxaban compared with placebo in ACS patients. A subset of subjects had a D-dimer measured at baseline (n = 1,834, 52.5%). A univariate and multivariable logistic regression assessed the relation between baseline D-dimer and a composite end point of cardiovascular death, myocardial infarction, or stroke through 6 months. The Wilcoxon rank sum test was used to compare change in D-dimer level between the treatment groups from baseline. Baseline D-dimer was associated with the composite efficacy outcome in a univariate logistic regression (odds ratio 1.15, 95% confidence interval 1.03 to 1.29, pu202f=u202f0.015) and a multivariable logistic regression (odds ratio 1.13, 95% confidence interval 1.00 to 1.28, pu202f=u202f0.048). Rivaroxaban administration lowered D-dimer levels compared wth placebo after administration of the first dose of study drug (pu202f=u202f0.026), at day 30 (p < 0.001) and day 180 (p < 0.001). In conclusion, elevated baseline D-dimer was associated with an increased risk of the composite outcome within 6 months of the ACS event and administration of the Factor Xa inhibitor rivaroxaban was associated with lower D-dimer levels compared with placebo after the first dose, at day 30 and day 180.