Tarek Nafee

Andexanet alfa for the reversal of anticoagulant activity in patients treated with direct and indirect factor Xa inhibitors

ABSTRACT Introduction: Andexanet alfa is a recombinant factor Xa decoy molecule that inhibits direct and indirect factor Xa inhibitors to allow the normal coagulation process to resume. Its development arises in a space where novel oral anticoagulants are receiving expanded indications yet their use is limited by the lack of an effective reversal agent. Areas covered: This article reviews the biochemical properties, mechanism of action and the preclinical and clinical trials on andexanet alfa. It additionally aims to provide expert commentary and future perspectives on the efficacy, safety and challenges facing andexanet alfa as a universal antidote for direct and indirect factor Xa inhibitors. Expert commentary: Andexanet alfa shows promise to become a highly effective, novel antidote for factor Xa anticoagulation. Its biochemical profile and mechanism of action are immediately more attractive than other drugs on the market and under development due to its inert nature within the normal coagulation cascade, with minimal intrinsic procoagulant or anticoagulant properties. The anticoagulant antidote space will continue to develop as more specific and universal options become available for reversal of the effect of DOACs. Preliminary results of a pivotal phase 3b/4 trial demonstrate a favorable efficacy and safety profile in patients with acute hemorrhage.

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 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

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

Background  Elevated 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  Hospitalized acutely medically ill subjects ( n  = 7,513) were randomized in a double-dummy double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35–42 days) or standard dose subcutaneous enoxaparin (40 mg once daily for 10 ± 4 days) for venous thromboprophylaxis. D-dimer was assessed using a central core laboratory measurement. Results  For 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  < 0.001) and enoxaparin ( p  < 0.001) treatment arms. Among D-dimer-positive (≥ 2 × upper 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  = 124] vs. 7.6% [ n  = 170]; odds ratio = 0.69; 95% confidence interval: 0.55–0.88; absolute risk reduction = 2.2%, number needed to treat = 46, p  = 0.003). There was no interaction between D-dimer and the treatment effect ( p int  = 0.53). Conclusion  Extended-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.

Anticoagulation in Acute Coronary Syndrome-State of the Art

Early intravenous anticoagulation is the corner stone treatment of patients admitted with an acute coronary syndrome: it antagonizes the ongoing coronary thrombosis and facilitates the percutaneous coronary intervention, hence a reduction of mortality and acute stent thrombosis. Unfractionated heparin, enoxaparin, bivalirudin and fondaparinux have been extensively studied in large randomized control trials and meta-analyses with the same objective: reducing the ischemic burden without hiking hemorrhagic events. This conundrum is evolving along the generalization of the radial-artery access, the use of potent P2Y12 and the trend towards a tailored approach regarding the ischemic and bleeding balance. In this systematic review, we aimed at presenting the evidence based data and strategies for each anticoagulant in the setting of acute coronary syndrome with and without ST-segment elevation.

Conundrum of Using Real-World Observational Data to Inform Real-World Conclusions About Safety and Efficacy

SEE PAGE 1790 T he higher-risk atrial fibrillation (AF) patient is optimally treated with an anticoagulant, such as a vitamin K antagonist (VKA), and the stented patient with dual antiplatelet therapy (DAPT), and when these 2 conditions coexist, these 3 drugs have been combined as “triple therapy.” Triple therapy, which is administered to reduce both the risk of stroke and myocardial infarction in stented patients with AF, has unfortunately been associated with an excess risk of bleeding (1). Two randomized controlled trials (RCTs), PIONEER AF-PCI (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) and REDUAL-PCI (Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting), recently demonstrated that, among AF patients undergoing stenting, direct oral anticoagulant (DOAC)-based therapies were associated with a reduced rate of bleeding and a similar risk of a major

Silent Myocardial Infarction: Listen to the Evidence

I t has been 30 years since the first report from the Framingham study demonstrated that silent or unrecognized myocardial infarction (MI), defined as evidence of MI on electrocardiography (ECG) in the absence of a history of MI, is associated with a greater risk of all-cause death, heart failure, and fatal MI (1). Despite this finding, silent MIs are rarely included as a component of clinical endpoints in randomized controlled trials. Clinical endpoints should be clinically meaningful (2). MI presents in a wide variety of ways across a broad spectrum of clinical settings. The severity of MI can range from silent to life threatening, and can occur in a wide variety of clinical settings such as stent thrombosis–related or procedural-related MI (3). As a result, there are different classification schemes, and thresholds to define MI (3). Silent MI is no exception to the rule. The definition depends on the methods used to identify the MI: ECG characteristics based on the Minnesota Classification (appearance of a Q-wave, abnormalities of the ST-segment or T-wave), stress echocardiography, dipyridamole scintigraphy, or cardiac magnetic resonance (4). Silent MI has variably been included as a component of composite endpoints in clinical trials to this point. (5).

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, p = 0.015) and a multivariable logistic regression (odds ratio 1.13, 95% confidence interval 1.00 to 1.28, p = 0.048). Rivaroxaban administration lowered D-dimer levels compared wth placebo after administration of the first dose of study drug (p = 0.026), 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.

ASSERT trial – How to assess the safety and efficacy of a high frequency rTMS in postpartum depression ? A multicenter, double blinded, randomized, placebo-controlled clinical trial

Background Postpartum Depression affects a considerable number of women worldwide. This condition inflicts severe consequences to mother and child health. Thus far, available treatments have low response and high relapse rates. We designed this trial to evaluate a safe and more efficacious innovative therapy. Aims To report a feasible and ethical study design to assess the safety and efficacy of a high frequency repetitive Transcranial Magnetic Stimulation 10 Hz (rTMS) compared to sham rTMS in women with moderate to severe Post-Partum Depression using standard treatment (sertraline). To conduct an ancillary, exploratory, randomized, active controlled, double blind study with a hypothesis to assess the safety and efficacy of 10 Hz rTMS compared to sertraline. Methods A multicenter, parallel arm, randomized, placebo-controlled, double-blind design to assess safety and efficacy of 10 Hz rTMS compared to sham. An ancillary study will be conducted with parallel arm, randomized, active controlled and double dummy design to assess safety and efficacy of 10 Hz rTMS compared to sertraline.