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

Author

Chi G, Januzzi JL, Korjian S, Daaboul Y, Goldhaber SZ, Hernandez AF, Hull RD, Gold A, Cohen AT, Harrington RA, and Gibson CM

Subjects
Acute Disease, Aged, Aged, 80 and over, Female, Heart Failure drug therapy, Hospitalization, Humans, Male, Risk Assessment, Venous Thrombosis, Benzamides administration & dosage, Enoxaparin administration & dosage, Heart Failure complications, Natriuretic Peptide, Brain blood, Peptide Fragments blood, Pyridines administration & dosage, Stroke diagnosis
Abstract

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 (P int  = 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.

Published
2017
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2. Competing risk analysis in a large cardiovascular clinical trial: An APEX substudy.

Author

Arbetter DF, Jain P, Yee MK, Michalak N, Hernandez AF, Hull RD, Goldhaber SZ, Harrington RA, Gold A, Cohen AT, and Gibson CM

Subjects
Aged, Delayed-Action Preparations, Double-Blind Method, Factor Xa Inhibitors administration & dosage, Humans, Kaplan-Meier Estimate, Models, Statistical, Proportional Hazards Models, Pulmonary Embolism prevention & control, Research Design, Risk, Risk Assessment methods, Venous Thrombosis prevention & control, Anticoagulants administration & dosage, Benzamides administration & dosage, Enoxaparin administration & dosage, Pyridines administration & dosage, Venous Thromboembolism prevention & control
Abstract

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., (Copyright © 2017 John Wiley & Sons, Ltd.)

Published
2017
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3. Comparison of Fatal or Irreversible Events With Extended-Duration Betrixaban Versus Standard Dose Enoxaparin in Acutely Ill Medical Patients: An APEX Trial Substudy.

Author

Gibson CM, Korjian S, Chi G, Daaboul Y, Jain P, Arbetter D, Goldhaber SZ, Hull R, Hernandez AF, Lopes RD, Gold A, Cohen AT, and Harrington RA

Subjects
Acute Disease, Adult, Aged, Anticoagulants administration & dosage, Benzamides administration & dosage, Cardiovascular Diseases diagnosis, Cardiovascular Diseases mortality, Double-Blind Method, Enoxaparin administration & dosage, Factor Xa Inhibitors administration & dosage, Female, Hemorrhage diagnosis, Hemorrhage mortality, Humans, Inpatients, Intracranial Hemorrhages chemically induced, Intracranial Hemorrhages mortality, Kaplan-Meier Estimate, Male, Middle Aged, Proportional Hazards Models, Pyridines administration & dosage, Risk Factors, Time Factors, Treatment Outcome, Venous Thromboembolism complications, Venous Thromboembolism diagnosis, Venous Thromboembolism mortality, Anticoagulants adverse effects, Benzamides adverse effects, Cardiovascular Diseases etiology, Enoxaparin adverse effects, Factor Xa Inhibitors adverse effects, Hemorrhage chemically induced, Pyridines adverse effects, Venous Thromboembolism prevention & control
Abstract

Background: Extended-duration betrixaban showed a significant reduction in venous thromboembolism in the APEX trial (Acute Medically Ill VTE Prevention With Extended Duration Betrixaban Study). Given the variable clinical impact of different efficacy and safety events, one approach to assess net clinical outcomes is to include only those events that are either fatal or cause irreversible harm., Methods and Results: This was a post hoc analysis of the APEX trial-a multicenter, double-blind, randomized controlled trial comparing extended-duration betrixaban versus standard-of-care enoxaparin. A composite of all fatal or irreversible safety (fatal bleeding or intracranial hemorrhage) and efficacy events (cardiopulmonary death, myocardial infarction, pulmonary embolism, and ischemic stroke) was evaluated in a time-to-first event analysis. In patients with positive D-dimer results, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.80% versus 3.54%; hazard ratio, 0.73; absolute risk reduction, 1.26%; number needed to treat, 79 [ P =0.033]) and at study end at 77 days (6.27% versus 4.36%; hazard ratio, 0.70; absolute risk reduction, 1.91%; number needed to treat, 52 [ P =0.005]) versus enoxaparin. In all patients, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.08% versus 2.90%; hazard ratio, 0.71; absolute risk reduction, 1.18%; number needed to treat, 86 [ P =0.006]) and 77 days (5.17% versus 3.64%; hazard ratio, 0.70; absolute risk reduction, 1.53%; number needed to treat, 65 [ P =0.002])., Conclusions: Among hospitalized medically ill patients, extended-duration betrixaban demonstrated an ≈30% reduction in fatal or irreversible ischemic or bleeding events compared with standard-duration enoxaparin. A total of 65 patients would require treatment with betrixaban to prevent 1 fatal or irreversible event versus enoxaparin., Clinical Trial Registration: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01583218., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Published
2017
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4. The safety and efficacy of full- versus reduced-dose betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention With Extended-Duration Betrixaban (APEX) trial.

Author

Gibson CM, Halaby R, Korjian S, Daaboul Y, Arbetter DF, Yee MK, Goldhaber SZ, Hull R, Hernandez AF, Lu SP, Bandman O, Leeds JM, Gold A, Harrington RA, and Cohen AT

Subjects
Aged, Aged, 80 and over, Anticoagulants therapeutic use, Double-Blind Method, Enoxaparin therapeutic use, Female, Hemorrhage chemically induced, Hospitalization, Humans, Male, Benzamides administration & dosage, Factor Xa Inhibitors administration & dosage, Pulmonary Embolism prevention & control, Pyridines administration & dosage, Venous Thromboembolism prevention & control, Venous Thrombosis prevention & control
Abstract

Background: The APEX trial assessed the safety and efficacy of extended-duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among hospitalized, acutely ill medical patients. The 80-mg betrixaban dose was halved to 40 mg among subjects with severe renal insufficiency and those receiving a concomitant strong P-glycoprotein inhibitor., Methods: This analysis assessed the pharmacokinetics, efficacy, and safety of full- (80 mg) and reduced-dose (40 mg) betrixaban relative to enoxaparin in the APEX trial., Results: The median concentration of betrixaban among subjects administered the 80-mg dose was higher than that of the 40-mg dose (19 ng/mL vs 11 ng/mL, P<.001). In the primary analysis cohort 1 (d-dimer ≥2× upper limit of normal), the primary efficacy outcome (asymptomatic proximal deep vein thrombosis, symptomatic proximal or distal deep vein thrombosis, symptomatic nonfatal pulmonary embolism, or venous thromboembolism-related death) was significantly reduced among subjects treated with 80 mg of extended-duration betrixaban versus enoxaparin (6.27% [95/1516] vs 8.39% [130/1549], relative risk reduction=0.26 [0.04-0.42], P=.023), and similarly in the entire primary efficacy outcome population (4.87% [122/2506] vs 7.06% [181/2562], relative risk reduction=0.30 [0.13-0.44], P=.001). There was no difference in the primary outcome for subjects treated with 40 mg betrixaban vs enoxaparin across cohorts. In addition, there was no excess of major bleeding associated with either betrixaban dose compared with enoxaparin., Conclusions: The 80-mg betrixaban dose achieves higher plasma concentrations than the 40-mg dose and, in contrast to the 40-mg dose, is associated with improved efficacy across all cohorts relative to standard-dose enoxaparin without an excess risk of major bleeding in the management of medically ill subjects., (Copyright © 2016. Published by Elsevier Inc.)

Published
2017
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5. Extended-Duration Betrixaban Reduces the Risk of Stroke Versus Standard-Dose Enoxaparin Among Hospitalized Medically Ill Patients: An APEX Trial Substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban).

Author

Gibson CM, Chi G, Halaby R, Korjian S, Daaboul Y, Jain P, Arbetter D, Goldhaber SZ, Hull R, Hernandez AF, Gold A, Bandman O, Harrington RA, and Cohen AT

Subjects
Aged, Anticoagulants administration & dosage, Benzamides administration & dosage, Enoxaparin administration & dosage, Female, Humans, Male, Pyridines administration & dosage, Venous Thromboembolism, Anticoagulants therapeutic use, Benzamides therapeutic use, Enoxaparin therapeutic use, Pyridines therapeutic use, Stroke drug therapy
Abstract

Background: Stroke is a morbid and potentially mortal complication among patients hospitalized with acute medical illness. The potential of extended-duration thromboprophylaxis with the factor Xa inhibitor betrixaban to reduce the risk of stroke compared with standard-dose enoxaparin in this population was assessed in this retrospective APEX trial substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban)., Methods: Hospitalized acutely medically ill subjects (n=7513) 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. Stroke events were adjudicated by an independent, blinded event adjudication committee., Results: The mean age of study participants was 76 years; 45% were male; 13% had had a stroke; and 45% had congestive heart failure. There were fewer all-cause strokes (0.54% versus 0.97%; relative risk [RR]=0.56; 95% confidence interval, 0.32-0.96; P =0.032; adjusted RR=0.43%; number needed to treat=233) and ischemic strokes (0.48% versus 0.91%; RR=0.53; 95% confidence interval, 0.30-0.94; P =0.026; adjusted RR=0.43%; number needed to treat=233) among patients treated with betrixaban versus enoxaparin through 77 days of follow-up. Among high-risk subjects, those with congestive heart failure or ischemic stroke as their index event, betrixaban reduced the risk of all-cause stroke (0.72% versus 1.48%; RR=0.49; 95% confidence interval, 0.26-0.90; P =0.019; adjusted RR=0.76%; number needed to treat=132) and ischemic stroke (0.63% versus 1.38%; RR=0.45; 95% confidence interval, 0.24-0.87; P =0.014; adjusted RR=0.75%; number needed to treat=134) compared with enoxaparin., Conclusions: Among hospitalized medically ill patients, extended-duration betrixaban significantly reduced all-cause stroke and ischemic stroke through 77 days of follow-up CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01583218., (© 2016 American Heart Association, Inc.)

Published
2017
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6. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients.

Author

Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, and Gibson CM

Subjects
Acute Disease, Adult, Aged, Benzamides adverse effects, Double-Blind Method, Drug Administration Schedule, Factor Xa Inhibitors adverse effects, Female, Fibrin Fibrinogen Degradation Products analysis, Hemorrhage chemically induced, Hospitalization, Humans, Male, Middle Aged, Pulmonary Embolism prevention & control, Pyridines adverse effects, Risk Factors, Ultrasonography, Venous Thrombosis diagnostic imaging, Venous Thrombosis prevention & control, Benzamides administration & dosage, Factor Xa Inhibitors administration & dosage, Pyridines administration & dosage, Venous Thromboembolism prevention & control
Abstract

Background: Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown., Methods: Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding., Results: A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55)., Conclusions: Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218.).

Published
2016
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7. Recognition of biomarker identified high-risk patients in the acute medically ill venous thromboembolism prevention with extended duration betrixaban study resulting in a protocol amendment.

Author

Cohen AT, Harrington R, Goldhaber SZ, Hull R, Gibson CM, Hernandez AF, and Gold A

Subjects
Humans, Anticoagulants administration & dosage, Benzamides administration & dosage, Enoxaparin administration & dosage, Factor Xa Inhibitors, Pyridines administration & dosage, Venous Thromboembolism prevention & control
Published
2015
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8. Extended-Duration Betrixaban Reduces the Risk of Stroke Versus Standard-Dose Enoxaparin Among Hospitalized Medically Ill Patients

Author

Legkonogov, O., Ramacciotti, E., Mikhailova, E., Koryk, V., Adzerikho, I., Schoenerr, H., Mathies, R., Konig, J., Huber, K., Rubinfeld, A., Finfer, S., Manenti, E., Bott, M., Blessing, E., Beyer-Westendorf, J., Coughlin, P., Baker, R., Poy, C., Dengler, T., Parody, M., Oliva, M., Macin, S., Jure, H., Ferrari, A. E., Dziewas, R., Genth-Zotz, S., Hamann, F., Horacek, T., Klimpe, S., Mitkovskaya, N., Kroning, R., Lapp, H., Lawall, H., Licka, M., Rizos, T., Tiefenbacher, C., Weimar, C., Alkonyi, B., Falukozy, J., Futo, L., Katona, A., Berrouschot, J., Kirschner, R., Amann, B., Paposhvili, K., Pagava, Z., Kristof, P., Lakatos, F., Laszlo, Z., Freire, A., Lupkovics, G., Megreladze, I., Kobulia, B., Khintibidze, I., Khabeishvili, G., Datikashvili-David, I., Simoneau, G., Merkely, B., Andras, C. Nagy, Nemeth, L., Papp, A., Soltesz, P., Fiss, E., Schmidt, J., Roy, P-M., Quere, I., Proust, A., Pottier, P., Pernod, G., Payot, L., Bizzacchi, J. Annichino, Lienart, F., Paleiron, N., Montaclair, K., Mismetti, P., Messas, E., Lacroix, P., Grange, C., Falvo, N., El Kouri, D., Decoulx, E., Debourdeau, P., De Geeter, G., Brisot, D., Belhassane, A., Aquilanti, S., Agraou, B., Vikman, S., Tatlisumak, T., Saarinen, J., Kaaja, R., Honkaniemi, J., Airaksinen, J., Uuetoa, T., Lember, M., Urhammer, S., Tuxen, C., Storgaard, M., Lassen, M., Christensen, H., Vyhnanek, M., Vejvoda, J., Spacek, R., Reiterer, P., Podpera, I., Mikulova, J., Lang, P., Jajtner, P., Hubac, J., Horny, I., Holaj, R., Herold, M., Havelka, J., Francek, L., Dusek, J., Dunaj, M., Cizek, V., Chochola, J., Chlumsky, J., Cermak, O., Skerk, V., Vagic, J. Sikic, Marusic, S., Knezevic, A., Kalinic-Grgorinic, H., Jakopovic, M., Francetic, I., Ciglenecki, N., Car, S., Butkovic-Soldo, S., Cardenas, S. Potthoff, Lazcano, M. Opazo, Alarcon, M. Arias, Verreault, S., Provencher, S., Pearce, M., Le Gal, G., Douketis, J., Dhar, A., Tokmakova, M., Todorov, G., Syulemzova, S., Raymuno, S., Rocha, A., Dimov, B., Grigorov, M., Kalpachki, R., Kamenova, Z., Bello, F., Harrington, Robert A., Bandman, Olga, Kostadinova, M., Milanova, M., Dive, A., Pencheva, G., Sudar, Z., Szabo, G., Szegedi, N., Timar, G., Valco, J., Delforge, M., Vertes, A., Efrati, S., Elias, M., Gafter, A., Nazliel, BİJEN, Hayek, T., Hussein, O., Lishner, M., Lugassy, G., Cerveri, I., D'Angelo, A., De Pellegrin, A., Imberti, D., Landolfi, R., Runev, N., Lembo, G., Lodigiani, C., Moia, M., Molteni, M., Mumoli, N., Novo, S., Orlandini, F., Stoeva, N., Parisi, R., Pizzini, A., Pomero, F., Salvi, A., Schenone, A., Gold, Alex, Visona, A., Martinova, V., Pontaga, N., Rozitis, V., Stukena, I., Alekniene, B., Basijokiene, V., Butkiene, Z., Griskeviciene, V., Naudziunas, A., Stoyanov, M., Norvaisiene, R., Norviliene, R., Petrauskiene, R., Poskiene, R., Susinskiene, D., Valavicius, A., Castillo Leon, R., Pimanov, S., Polonetsy, L., Pereyra, R. Cotrina, Karlo, L. Farjardo, Horna, M., Soroka, N., Salas, M., Yanez, L. Toche, Fryze, W., Gaciong, Z., Gniot, J., Gorecka, D., Gruenpeter, P., Grzelakowski, P., Jastrzebski, D., Kucharski, L., Mirek-Bryniarska, E., Pulkowski, G., Sobkowicz, B., Sulik, P., Walasek, L., Blockmans, D., Waldemar, K., Wrzesinski, K., Balogh, Z. E., Bojinca, M., Marin, I., Musetescu, R., Podoleanu, C., Popescu, M., Stamate, S., Stanciulescu, G., Vida-Simiti, L., Abashev, A., Andreev, D., Apartsin, K., Arkhipov, M., Averkov, O., Barbarash, O., Belskaya, G., Bogdanov, E., Boldueva, S., Chefranova, Z., Dovgalevskiy, Y., Ershova, O., Goloshchekin, B., Khachatryan, N., Klein, G., Kobalava, Z., Kosmacheva, E., Kostenko, V., Malygin, A., Martynenko, T., Martynenko, V., Maslova, N., Mordovin, V., Nikolaev, K., Nilk, R., Popov, D., Privalova, E., Reshetko, O., Shapovalova, Y., Shpagina, L., Shvarts, Y., Simanenkov, V., Solovyov, O., Vishneva, E., Vishnevskiy, A., Apostolovic, S., Celic, V., Ilic, S., Kovacevic-Kuzmanovic, A., Miloradovic, V., Bodikova, S., Cervenakova, A., Dvorak, M., Herman, O., Hrubon, A., Kokles, M., Krastev, G., Payer, J., Prokop, D., Spisakova, M., Adler, D., Basson, M., Breedt, J., Engelbrecht, J., Mitha, I., Van Dyk, C., Alvarez Sala, L. A., Barbagelata Lopez, C., Bisbe, J., Castro Guardiola, A., Cepeda, J. M., Cereto, F., Diaz Santos, E., Ferrer, R., Gomez Cerezo, J., Hernandez, Adrian F., Gonzales-Porras, J. R., Grandes, J., Cohen, Alexander T., Gibson, C. Michael, Chi, Gerald, Halaby, Rim, Korjian, Serge, Daaboul, Yazan, Jain, Purva, Arbetter, Douglas, Goldhaber, Samuel Z., Hull, Russel, Jimenez, D., Mellibovsky, L., Richart, C., Riera, A., Trujillo, J., Vargas Nunez, J. A., Villalta, J., Akgul, O., Guneri, S., Kilichesmez, K., Kirma, C., Kutluk, H., Okumus, G., Tigen, K., Topcuoglu, M., Tuncay, E., Abrahamovych, O., Batushkin, V., Brozhyk, J., Burmak, I., Godlevska, O., Goloborodko, A., Goloborodko, B., Goncharova, Y., Gryb, V., Karpenko, O., Kopytsya, M., Zakai, N., Yousef, K., Wichman, T., Whitman, B., Welker, J., Welch, M., Warner, A., Updegrove, J., Tuck, M., Stoltz, S., Sokol, S., Sharma, S., Shammas, N., Saba, F., Rodriguez, W., Rees, C., Rastogi, P., Rajan, R., Quintana, O., Pullman, J., Pratt, R., Pineda, L., Pearl, R., Parthiban, K., Overcash, J., Ortel, T., Ohaju, V., Nadar, V., Mittal, M., Milling, T., McLaren, G., Margolis, B., Mahal, S., Macchiavelli, A., Lopez, J., Lerner, R., Kung, M., Kouras, F., Kazimir, M., Kao, C-K., Kabler, H., Ioachimescu, O., Hazelrigg, M., Hamad, A., Haidar, A., Hahn, B., Goytia-Leos, D., Gaggin, H., Fulmer, J., Koshlia, V., Fraiz, J., Krakhmalova, O., Fermann, G., Farley, B., Doshi, A., Dhingra, R., Cornell, J., Concha, M., Clark, C., Chang, H., Carman, T., Bidair, M., Bercz, P., Bastani, A., Barney, J., Baker, S., Anderson, C., Amin, M., Almasri, E., Natarajan, I., McCollum, C., MacCallum, P., Davis, M., Body, R., Yagensky, A., Voronkov, L., Vishnivestsky, I., Vakaliuk, I., Ursol, G., Tseluyko, V., Kyrychenko, I., Svyshchenko, Y., Svyridova, I., Ryabichenko, T., Rudenko, L., Reshotko, D., Perepeliuk, M., Parkhomenko, O., Nikonov, V., Maslovaskyi, V., Malynovsky, Y., Sergeeva, E., and Kolman, P.

Subjects
Male, medicine.medical_specialty, Pyridines, Intracranial Hemorrhages, 030204 cardiovascular system & hematology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Medical illness, Physiology (medical), medicine, Humans, 030212 general & internal medicine, Enoxaparin, Intensive care medicine, Stroke, Aged, business.industry, Anticoagulants, Venous Thromboembolism, medicine.disease, Thrombosis, chemistry, Betrixaban, Benzamides, Emergency medicine, Female, Cardiology and Cardiovascular Medicine, business, Complication, Venous thromboembolism
Abstract

Background: Stroke is a morbid and potentially mortal complication among patients hospitalized with acute medical illness. The potential of extended-duration thromboprophylaxis with the factor Xa inhibitor betrixaban to reduce the risk of stroke compared with standard-dose enoxaparin in this population was assessed in this retrospective APEX trial substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban). Methods: Hospitalized acutely medically ill subjects (n=7513) 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. Stroke events were adjudicated by an independent, blinded event adjudication committee. Results: The mean age of study participants was 76 years; 45% were male; 13% had had a stroke; and 45% had congestive heart failure. There were fewer all-cause strokes (0.54% versus 0.97%; relative risk [RR]=0.56; 95% confidence interval, 0.32–0.96; P =0.032; adjusted RR=0.43%; number needed to treat=233) and ischemic strokes (0.48% versus 0.91%; RR=0.53; 95% confidence interval, 0.30–0.94; P =0.026; adjusted RR=0.43%; number needed to treat=233) among patients treated with betrixaban versus enoxaparin through 77 days of follow-up. Among high-risk subjects, those with congestive heart failure or ischemic stroke as their index event, betrixaban reduced the risk of all-cause stroke (0.72% versus 1.48%; RR=0.49; 95% confidence interval, 0.26–0.90; P =0.019; adjusted RR=0.76%; number needed to treat=132) and ischemic stroke (0.63% versus 1.38%; RR=0.45; 95% confidence interval, 0.24–0.87; P =0.014; adjusted RR=0.75%; number needed to treat=134) compared with enoxaparin. Conclusions: Among hospitalized medically ill patients, extended-duration betrixaban significantly reduced all-cause stroke and ischemic stroke through 77 days of follow-up Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01583218.

Published
2017

9. The safety and efficacy of full- versus reduced-dose betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention With Extended-Duration Betrixaban (APEX) trial

Author

Raymuno, S., Ramacciotti, E., Manenti, E., Freire, A., Fiss, E., Bizzacchi, J. Annichino, Lienart, F., Dive, A., Delforge, M., Blockmans, D., Soroka, N., Kamenova, Z., Kostadinova, M., Milanova, M., Pencheva, G., Runev, N., Stoeva, N., Stoyanov, M., Syulemzova, S., Todorov, G., Polonetsy, L., Pimanov, S., Mitkovskaya, N., Tokmakova, M., Dhar, A., Mikhailova, E., Koryk, V., Adzerikho, I., Schoenerr, H., Mathies, R., Douketis, J., Konig, J., Le Gal, G., Pearce, M., Provencher, S., Verreault, S., Alarcon, M. Arias, Lazcano, M. Opazo, Cardenas, S. Potthoff, Butkovic-Soldo, S., Car, S., Ciglenecki, N., Francetic, I., Jakopovic, M., Kalinic-Grgorinic, H., Knezevic, A., Marusic, S., Vagic, J. Sikic, Skerk, V., Cermak, O., Gibson, C. Michael, Halaby, Rim, Korjian, Serge, Daaboul, Yazan, Arbetter, Douglas F., Yee, Megan K., Chlumsky, J., Chochola, J., Cizek, V., Goldhaber, Samuel Z., Hull, Russel, Hernandez, Adrian F., Huber, K., Lu, Shiao-ping, Dunaj, M., Dusek, J., Francek, L., Havelka, J., Herold, M., Holaj, R., Nazliel, BİJEN, Bandman, Olga, Leeds, Janet M., Gold, Alex, Harrington, Robert A., Bello, F., Ferrari, A. E., Jure, H., Macin, S., Oliva, M., Parody, M., Horny, I., Hubac, J., Jajtner, P., Kolman, P., Poy, C., Baker, R., Lang, P., Mikulova, J., Podpera, I., Reiterer, P., Spacek, R., Vejvoda, J., Vyhnanek, M., Christensen, H., Lassen, M., Storgaard, M., Tuxen, C., Urhammer, S., Lember, M., Uuetoa, T., Airaksinen, J., Honkaniemi, J., Kaaja, R., Saarinen, J., Tatlisumak, T., Vikman, S., Agraou, B., Aquilanti, S., Belhassane, A., Brisot, D., De Geeter, G., Coughlin, P., Finfer, S., Debourdeau, P., Decoulx, E., El Kouri, D., Falvo, N., Grange, C., Rubinfeld, A., Lacroix, P., Messas, E., Mismetti, P., Montaclair, K., Paleiron, N., Payot, L., Zakai, N., Yousef, K., Wichman, T., Whitman, B., Welker, J., Welch, M., Warner, A., Updegrove, J., Tuck, M., Stoltz, S., Sokol, S., Sharma, S., Shammas, N., Saba, F., Rodriguez, W., Rastogi, P., Rajan, R., Quintana, O., Pullman, J., Pratt, R., Pineda, L., Pernod, G., Pearl, R., Parthiban, K., Ortel, T., Ohaju, V., Pottier, P., Proust, A., Quere, I., Roy, P-M., Schmidt, J., Simoneau, G., Datikashvili-David, I., Khabeishvili, G., Khintibidze, I., Nadar, V., Mittal, M., Milling, T., McLaren, G., Margolis, B., Mahal, S., Macchiavelli, A., Lopez, J., Lerner, R., Kung, M., Kouras, F., Kazimir, M., Kao, C-K., Kabler, H., Ioachimescu, O., Hazelrigg, M., Hamad, A., Haidar, A., Hahn, B., Goytia-Leos, D., Gaggin, H., Fulmer, J., Fraiz, J., Fermann, G., Farley, B., Doshi, A., Dhingra, R., Cornell, J., Concha, M., Clark, C., Chang, H., Carman, T., Bidair, M., Bercz, P., Bastani, A., Barney, J., Baker, S., Anderson, C., Amin, M., Almasri, E., Natarajan, I., McCollum, C., MacCallum, P., Davis, M., Body, R., Yagensky, A., Voronkov, L., Vishnivestsky, I., Vakaliuk, I., Ursol, G., Tseluyko, V., Svyshchenko, Y., Svyridova, I., Ryabichenko, T., Rudenko, L., Reshotko, D., Perepeliuk, M., Parkhomenko, O., Nikonov, V., Maslovaskyi, V., Malynovsky, Y., Legkonogov, O., Kyrychenko, I., Krakhmalova, O., Koshlia, V., Kopytsya, M., Karpenko, O., Gryb, V., Goncharova, Y., Goloborodko, B., Goloborodko, A., Godlevska, O., Burmak, I., Brozhyk, J., Batushkin, V., Abrahamovych, O., Tuncay, E., Topcuoglu, M., Tigen, K., Okumus, G., Kutluk, H., Kirma, C., Kilichesmez, K., Guneri, S., Akgul, O., Villalta, J., Vargas Nunez, J. A., Trujillo, J., Riera, A., Richart, C., Mellibovsky, L., Jimenez, D., Grandes, J., Gonzales-Porras, J. R., Gomez Cerezo, J., Ferrer, R., Diaz Santos, E., Cereto, F., Cepeda, J. M., Castro Guardiola, A., Bisbe, J., Barbagelata Lopez, C., Alvarez Sala, L. A., Van Dyk, C., Mitha, I., Engelbrecht, J., Breedt, J., Basson, M., Adler, D., Spisakova, M., Payer, J., Krastev, G., Kokles, M., Hrubon, A., Herman, O., Dvorak, M., Cervenakova, A., Bodikova, S., Miloradovic, V., Kovacevic-Kuzmanovic, A., Ilic, S., Celic, V., Apostolovic, S., Vishnevskiy, A., Vishneva, E., Solovyov, O., Simanenkov, V., Shvarts, Y., Shpagina, L., Shapovalova, Y., Sergeeva, E., Reshetko, O., Privalova, E., Popov, D., Nilk, R., Nikolaev, K., Mordovin, V., Maslova, N., Martynenko, V., Martynenko, T., Malygin, A., Kostenko, V., Kosmacheva, E., Kobalava, Z., Klein, G., Khachatryan, N., Ershova, O., Dovgalevskiy, Y., Chefranova, Z., Boldueva, S., Bogdanov, E., Belskaya, G., Barbarash, O., Averkov, O., Arkhipov, M., Apartsin, K., Andreev, D., Abashev, A., Vida-Simiti, L., Stanciulescu, G., Stamate, S., Kobulia, B., Megreladze, I., Pagava, Z., Paposhvili, K., Amann, B., Beyer-Westendorf, J., Blessing, E., Bott, M., Dengler, T., Dziewas, R., Genth-Zotz, S., Hamann, F., Horacek, T., Klimpe, S., Kroning, R., Lapp, H., Lawall, H., Licka, M., Rizos, T., Tiefenbacher, C., Weimar, C., Alkonyi, B., Falukozy, J., Futo, L., Katona, A., Kirschner, R., Kristof, P., Lakatos, F., Lupkovics, G., Merkely, B., Andras, C. Nagy, Nemeth, L., Papp, A., Soltesz, P., Sudar, Z., Szabo, G., Szegedi, N., Timar, G., Valco, J., Vertes, A., Efrati, S., Elias, M., Gafter, A., Hayek, T., Hussein, O., Lishner, M., Lugassy, G., Cerveri, I., D'Angelo, A., De Pellegrin, A., Imberti, D., Landolfi, R., Lembo, G., Lodigiani, C., Moia, M., Molteni, M., Mumoli, N., Novo, S., Orlandini, F., Parisi, R., Pizzini, A., Pomero, F., Salvi, A., Schenone, A., Visona, A., Martinova, V., Pontaga, N., Rozitis, V., Stukena, I., Alekniene, B., Basijokiene, V., Butkiene, Z., Griskeviciene, V., Naudziunas, A., Norvaisiene, R., Norviliene, R., Petrauskiene, R., Poskiene, R., Susinskiene, D., Valavicius, A., Castillo Leon, R., Pereyra, R. Cotrina, Karlo, L. Farjardo, Horna, M., Salas, M., Yanez, L. Toche, Fryze, W., Gaciong, Z., Gniot, J., Gorecka, D., Gruenpeter, P., Grzelakowski, P., Jastrzebski, D., Kucharski, L., Mirek-Bryniarska, E., Pulkowski, G., Sobkowicz, B., Sulik, P., Walasek, L., Waldemar, K., Wrzesinski, K., Balogh, Z. E., Bojinca, M., Marin, I., Musetescu, R., Podoleanu, C., Popescu, M., Kalpachki, R., Grigorov, M., Dimov, B., Rocha, A., Goloshchekin, B., Berrouschot, J., Laszlo, Z., Rees, C., Overcash, J., Prokop, D., and Cohen, Alexander T.

Subjects
Relative risk reduction, Male, Pyridines, Population, Hemorrhage, 030204 cardiovascular system & hematology, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pharmacokinetics, Randomized controlled trial, Double-Blind Method, law, Medicine, Humans, 030212 general & internal medicine, Dosing, Enoxaparin, education, Aged, Aged, 80 and over, Venous Thrombosis, education.field_of_study, business.industry, Absolute risk reduction, Anticoagulants, Venous Thromboembolism, Hospitalization, chemistry, Concomitant, Betrixaban, Anesthesia, Benzamides, Female, Cardiology and Cardiovascular Medicine, business, Pulmonary Embolism, Factor Xa Inhibitors
Abstract

The APEX trial assessed the safety and efficacy of extended-duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among hospitalized, acutely ill medical patients. The 80-mg betrixaban dose was halved to 40 mg among subjects with severe renal insufficiency and those receiving a concomitant strong P-glycoprotein inhibitor.This analysis assessed the pharmacokinetics, efficacy, and safety of full- (80 mg) and reduced-dose (40 mg) betrixaban relative to enoxaparin in the APEX trial.The median concentration of betrixaban among subjects administered the 80-mg dose was higher than that of the 40-mg dose (19 ng/mL vs 11 ng/mL, P.001). In the primary analysis cohort 1 (d-dimer ≥2× upper limit of normal), the primary efficacy outcome (asymptomatic proximal deep vein thrombosis, symptomatic proximal or distal deep vein thrombosis, symptomatic nonfatal pulmonary embolism, or venous thromboembolism-related death) was significantly reduced among subjects treated with 80 mg of extended-duration betrixaban versus enoxaparin (6.27% [95/1516] vs 8.39% [130/1549], relative risk reduction=0.26 [0.04-0.42], P=.023), and similarly in the entire primary efficacy outcome population (4.87% [122/2506] vs 7.06% [181/2562], relative risk reduction=0.30 [0.13-0.44], P=.001). There was no difference in the primary outcome for subjects treated with 40 mg betrixaban vs enoxaparin across cohorts. In addition, there was no excess of major bleeding associated with either betrixaban dose compared with enoxaparin.The 80-mg betrixaban dose achieves higher plasma concentrations than the 40-mg dose and, in contrast to the 40-mg dose, is associated with improved efficacy across all cohorts relative to standard-dose enoxaparin without an excess risk of major bleeding in the management of medically ill subjects.

Published
2016

10. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients

Author

Engelbrecht, J., Finfer, S., Van Dyk, C., Cohen, Alexander, Grandes, J., Cepeda, J. M., NAZLIEL, BİJEN, Cohen, Alexander T., Efrati, S., Zakai, N., Yousef, K., Wichman, T., Whitman, B., Welker, J., Welch, M., Warner, A., Updegrove, J., Tuck, M., Stoltz, S., Sokol, S., Sharma, S., Shammas, N., Saba, F., Rodriguez, W., Rees, C., Rastogi, P., Rajan, R., Quintana, O., Pullman, J., Pratt, R., Pineda, L., Pearl, R., Parthiban, K., Overcash, J., Ortel, T., Ohaju, V., Nadar, V., Mittal, M., Milling, T., McLaren, G., Margolis, B., Mahal, S., Macchiavelli, A., Lopez, J., Lerner, R., Kung, M., Kouras, F., Kazimir, M., Kao, C-K., Kabler, H., Ioachimescu, O., Hazelrigg, M., Hamad, A., Haidar, A., Hahn, B., Goytia-Leos, D., Gaggin, H., Fulmer, J., Fraiz, J., Fermann, G., Farley, B., Doshi, A., Dhingra, R., Cornell, J., Concha, M., Clark, C., Chang, H., Carman, T., Bidair, M., Bercz, P., Bastani, A., Barney, J., Baker, S., Anderson, C., Amin, M., Almasri, E., Natarajan, I., McCollum, C., MacCallum, P., Davis, M., Body, R., Yagensky, A., Voronkov, L., Vishnivestsky, I., Vakaliuk, I., Ursol, G., Tseluyko, V., Svyshchenko, Y., Svyridova, I., Ryabichenko, T., Rudenko, L., Alekniene, B., Reshotko, D., Perepeliuk, M., Parkhomenko, O., Nikonov, V., Maslovaskyi, V., Malynovsky, Y., Legkonogov, O., Kyrychenko, I., Krakhmalova, O., Koshlia, V., Kopytsya, M., Karpenko, O., Gryb, V., Goncharova, Y., Goloborodko, B., Goloborodko, A., Godlevska, O., Burmak, I., Brozhyk, J., Batushkin, V., Abrahamovych, O., Tuncay, E., Topcuoglu, M., Tigen, K., Okumus, G., Kutluk, H., Kirma, C., Kilichesmez, K., Guneri, S., Akgul, O., Villalta, J., Vargas Nunez, J. A., Trujillo, J., Riera, A., Richart, C., Mellibovsky, L., Jimenez, D., Gonzales-Porras, J. R., Gomez Cerezo, J., Ferrer, R., Diaz Santos, E., Cereto, F., Castro Guardiola, A., Bisbe, J., Barbagelata Lopez, C., Alvarez Sala, L. A., Mitha, I., Breedt, J., Basson, M., Adler, D., Spisakova, M., Prokop, D., Payer, J., Krastev, G., Kokles, M., Hrubon, A., Herman, O., Dvorak, M., Cervenakova, A., Bodikova, S., Miloradovic, V., Kovacevic-Kuzmanovic, A., Ilic, S., Celic, V., Apostolovic, S., Vishnevskiy, A., Vishneva, E., Solovyov, O., Simanenkov, V., Shvarts, Y., Shpagina, L., Shapovalova, Y., Sergeeva, E., Reshetko, O., Privalova, E., Popov, D., Nilk, R., Nikolaev, K., Mordovin, V., Maslova, N., Martynenko, V., Martynenko, T., Malygin, A., Kostenko, V., Kosmacheva, E., Kobalava, Z., Klein, G., Khachatryan, N., Goloshchekin, B., Ershova, O., Dovgalevskiy, Y., Chefranova, Z., Boldueva, S., Bogdanov, E., Belskaya, G., Barbarash, O., Averkov, O., Arkhipov, M., Apartsin, K., Andreev, D., Abashev, A., Vida-Simiti, L., Stanciulescu, G., Stamate, S., Harrington, Robert A., Goldhaber, Samuel Z., Hull, Russell D., Popescu, M., Wiens, Brian L., Gold, Alex, Hernandez, Adrian F., Gibson, C. Michael, Harrington, Robert, Hull, Russell, Goldhaber, Samuel, Hernandez, Adrian, Ceresetto, Jose Manuel, Colquhoun, David, Pilger, Ernst, Polonetsky, Leonid, Podoleanu, C., Musetescu, R., Marin, I., Bojinca, M., Motte, Serge, Saraiva, Jose Francisco, Balogh, Z. E., Wrzesinski, K., Waldemar, K., Walasek, L., Raev, Dimitar, Mincheva, Valentina, Kahn, Susan, Sulik, P., Canon, Claudia Olivares, Malojcic, Branko, Mayer, Otto, Husted, Steen, Marandi, Toomas, Lassila, Riitta, Mottier, Dominique, Shaburishvili, Tamaz, Bauersachs, Rupert, Zeymer, Uwe, Hajko, Erik, Sobkowicz, B., Zeltser, David, Ageno, Walter, Krievins, Dainis, Bagdonas, Alfredas, Osores, Juan Lema, Tomkowski, Witold, Mot, Stefan, Panchenko, Elizaveta, Tan, Ru San, Gaspar, Ludovit, Jacobson, Barry, Monreal, Manuel, Ongen, Gul, Parkhomenko, Alexander, Uprichard, James, Pulkowski, G., Mirek-Bryniarska, E., Kucharski, L., Jastrzebski, D., Yusen, Roger, Grzelakowski, P., Merli, Geno, Gruenpeter, P., Gorecka, D., Gniot, J., Gaciong, Z., Fryze, W., Peacock, Frank, Schellong, Sebastian, Januzzi, James, Piovella, Franco, Cochet, Madeleine, Michalak, Nathan, Stepanchak, Maria, Spielman, Kathryn, Neal, Brandon, Florea, Ana, Chi, Gerald, Szlosek, Donald, Jain, Purva, Popma, Christopher, Korjian, Serge, Daaboul, Yazan, Halaby, Rim, Yanez, L. Toche, Lemor, Alejandro, Zacarkim, Marcelo, Romero, Gonzalo, Hernandez Elenes, Jesus Rosario, Alvarado, Alonso, Susheela, Ammu, Leitao, Meghan, Salas, M., Bandman, Olga, Horna, M., Strumph, Peter, Vinh, Nancy, Visona, A., Kostadinova, M., Vance, Annemarie, Moia, M., Wiens, Brian, Orlandini, F., Parisi, R., Pontaga, N., Smoak, Carey, Storgaard, M., Molteni, M., Castelino, Rennie, Goodman, Shelly, Stukena, I., Leeds, Janet, al-Khalidi, Hussein, Milanova, M., Karlo, L. Farjardo, Leimberger, Jeffrey, Phillips, Thomas, Rizos, T., Pencheva, G., Pomero, F., Francis, Charles, Novo, S., Pereyra, R. Cotrina, Tiefenbacher, C., Buller, Harry, Roberts, Robin, Prins, Martin, Weimar, C., Tuxen, C., Urhammer, S., Lember, M., Runev, N., Uuetoa, T., Spyropoulos, Alex, Carrier, Marc, Alkonyi, B., Lopes, Renato D., Horacek, T., Airaksinen, J., Honkaniemi, J., Pottier, P., Falukozy, J., Kaaja, R., Stoeva, N., Saarinen, J., Stoyanov, M., Pizzini, A., Devor, Adam, Tatlisumak, T., Kolls, Bradley, Dedrick, Joseph, Todd, Jamie, Jones, William Schuyler, Vikman, S., Agraou, B., Futo, L., Castillo Leon, R., Eapen, Zubin, Katona, A., Proust, A., Quere, I., Kirschner, R., Syulemzova, S., Valavicius, A., Todorov, G., Tokmakova, M., Dhar, A., Klimpe, S., Ahmad, Tariq, Brenna, J. Matthew, Douketis, J., Le Gal, G., Pearce, M., Susinskiene, D., Brito, Flavio, Provencher, S., Rozitis, V., Roy, P-M., Kroning, R., Gulack, Brian, Schmidt, J., Meza, James, Parikh, Kishan, Cooper, Lauren, Poskiene, R., Aquilanti, S., Lapp, H., Kristof, P., Lakatos, F., Laszlo, Z., Belhassane, A., Petrauskiene, R., Pagidipati, Neha, Simoneau, G., Verreault, S., Guimaraes, Patricia, Brisot, D., Perkins, Lynn M., De Geeter, G., Debourdeau, P., Alarcon, M. Arias, Lupkovics, G., Norviliene, R., Wilson, Matthew, Merkely, B., Lazcano, M. Opazo, Collier, Jeannie, Andras, C. Nagy, Cardenas, S. Potthoff, Butkovic-Soldo, S., Norvaisiene, R., Decoulx, E., Hayden, Nikieia, El Kouri, D., Car, S., Nemeth, L., Leizorovicz, Alain, Ciglenecki, N., Naudziunas, A., Datikashvili-David, I., Francetic, I., Jakopovic, M., Becker, Francois, Jennings, Lisa, Khabeishvili, G., Bello, F., Ferrari, A. E., Jure, H., Macin, S., Griskeviciene, V., Kalinic-Grgorinic, H., Falvo, N., Khintibidze, I., Grange, C., Kobulia, B., Knezevic, A., Megreladze, I., Marusic, S., Papp, A., Pagava, Z., Lawall, H., Oliva, M., Paposhvili, K., Parody, M., Amann, B., Soltesz, P., Sudar, Z., Butkiene, Z., Szabo, G., Vagic, J. Sikic, Szegedi, N., Poy, C., Timar, G., Skerk, V., Cermak, O., Valco, J., Baker, R., Coughlin, P., Vertes, A., Rubinfeld, A., Elias, M., Berrouschot, J., Gafter, A., Hayek, T., Chlumsky, J., Lacroix, P., Messas, E., Chochola, J., Cizek, V., Basijokiene, V., Hussein, O., Dunaj, M., Dusek, J., Huber, K., Lishner, M., Lugassy, G., Cerveri, I., D'Angelo, A., De Pellegrin, A., Francek, L., Havelka, J., Konig, J., Beyer-Westendorf, J., Herold, M., Holaj, R., Imberti, D., Landolfi, R., Blessing, E., Mathies, R., Schoenerr, H., Adzerikho, I., Koryk, V., Licka, M., Martinova, V., Horny, I., Mikhailova, E., Mitkovskaya, N., Pimanov, S., Polonetsy, L., Soroka, N., Blockmans, D., Delforge, M., Dive, A., Lienart, F., Bizzacchi, J. Annichino, Fiss, E., Mismetti, P., Freire, A., Hubac, J., Jajtner, P., Manenti, E., Ramacciotti, E., Lembo, G., Raymuno, S., Rocha, A., Kolman, P., Lang, P., Bott, M., Dengler, T., Mikulova, J., Dimov, B., Podpera, I., Reiterer, P., Dziewas, R., Montaclair, K., Genth-Zotz, S., Hamann, F., Paleiron, N., Spacek, R., Payot, L., Vejvoda, J., Vyhnanek, M., Christensen, H., Salvi, A., Lodigiani, C., Pernod, G., Grigorov, M., Lassen, M., Mumoli, N., Kalpachki, R., Kamenova, Z., Schenone, A., Guy's and St Thomas' Hospital [London], Stanford Medicine, Stanford University, Brigham and Women's Hospital [Boston], Thrombosis Research Unit, University of Calgary, Portola Pharmaceuticals (Portola), PORTOLA PHARMACEUTICALS, Division of Cardiology, Duke University Medical Center, Duke Clinical Research Institute (DCRI - DURHAM), Duke University [Durham], Beth Israel Deaconess Medical Center [Boston, USA], Harvard Medical School [Boston] (HMS), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Université de Brest (UBO)

Subjects
Male, Pyridines, Medizin, 030204 cardiovascular system & hematology, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, Risk Factors, law, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, Ultrasonography, Venous Thrombosis, Factors de risc en les malalties, Medicine (all), Acute Disease, Adult, Aged, Benzamides, Double-Blind Method, Drug Administration Schedule, Factor Xa Inhibitors, Female, Fibrin Fibrinogen Degradation Products, Hemorrhage, Hospitalization, Humans, Middle Aged, Pulmonary Embolism, Venous Thromboembolism, General Medicine, 3. Good health, Pulmonary embolism, Venous thrombosis, Cohort, medicine.medical_specialty, Patients, Risk factors in diseases, Placebo, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Thromboembolism, medicine, Pacients, Betrixaban, Thromboprophylaxis, Acutely Ill Medical Patients, Tromboembolisme, business.industry, Settore MED/09 - MEDICINA INTERNA, ta3121, Population cohort, medicine.disease, Surgery, chemistry, Once daily, business
Abstract

Background\ud Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown.\ud \ud Methods\ud Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding.\ud \ud Results\ud A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55).\ud \ud Conclusions\ud Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218. opens in new tab.)

Published
2016

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