Time in Therapeutic Range (TTR) and Relative Efficacy and Safety of Treatment with Apixaban or Enoxaparin/Warfarin for Acute Symptomatic Venous Thromboembolism: An Analysis of the Amplify Trial Data
Notice bibliographique
Résumé
Abstract Introduction: The AMPLIFY trial showed that apixaban is as effective as conventional treatment with enoxaparin followed by warfarin for treatment of venous thromboembolism (VTE) and causes less bleeding (1). There is a perception that the advantages of the new oral anticoagulants over warfarin are lost if warfarin is well managed. To examine this possibility, we analyzed the efficacy and safety of apixaban versus enoxaparin/warfarin according to the center time in therapeutic range (cTTR) for warfarin-treated patients in the AMPLIFY trial. Methods: A total of 5,395 symptomatic VTE patients were randomized to a 6-month course of apixaban (10 mg BID for 7 days followed by 5 mg BID) or conventional treatment consisting of enoxaparin (1 mg/kg BID for at least 5 days) and dose-adjusted warfarin (target INR, 2-3) thereafter. Using the linear interpolation method of Rosendaal (2), TTR was assessed from international normalised ratios (INRs) recorded after day 15 of study therapy and excluding periods of planned warfarin interruption. To address whether high or low TTR across study centers exerts a treatment interaction effect, we divided cTTR values into quartiles and performed an interaction test on primary efficacy and bleeding outcome events, based on logistic model using Wald's chi-square test. Results: The overall time the INR was 2.0-3.0 (TTR) in the AMPLIFY study was 61%; and the INR was <2.0 and > 3.0 for 23% and 16% of the time, respectively. Quartiles of cTTR were <51.5% (Q1), 51.5 – 59.0% (Q2), >59.0 – 68.0% (Q3) and >68.0% (Q4). The percentages of time (%) INR was <2.0, INR = 2.0-3.0 (TTR), or INR >3.0 for each quartile are as follows: Q1: 34.0, 43.4, 22.6; Q2: 26.4, 55.7, 17.9; Q3: 20.8, 63.8, 15.4; and Q4: 15.0, 73.9, 11.0, respectively. Table 1 shows the efficacy and safety results for cTTR with interaction testing. The risk reductions (RR) with apixaban ranged from 0.75 to 1.00 for efficacy (VTE/VTE-related death) and from 0.15 to 0.50 for major bleeding across cTTR quartiles, and was not influenced by cTTR as evidenced by p-values for interactions of 0.96 and 0.65, respectively. Table 1. Center TTR (%) Apixaban Warfarin Nos. of Event/N Event Rate (%) Nos. of Event/N Event Rate (%) RR (95% CI) P-value for interaction Primary efficacy – VTE/VTE-related death. <51.5% 8/388 2.1 8/387 2.1 1.00 (0.38, 2.63) 0.96 51.5 – 59.0% 18/679 2.7 21/692 3.0 0.87 (0.47, 1.62) 59.1 – 68.0% 17/948 1.8 23/960 2.4 0.75 (0.41, 1.40) >68.0% 13/574 2.3 17/593 2.9 0.79 (0.39, 1.61) Primary safety - major bleeding. <51.5% 4/403 1.0 8/405 2.0 0.50 (0.15, 1.63) 0.65 51.5 – 59.0% 2/699 0.3 14/711 2.0 0.15 (0.03, 0.64) 59.1 – 68.0% 6/962 0.6 18/971 1.9 0.33 (0.13, 0.83) >68.0% 3/588 0.5 9/598 1.5 0.34 (0.09, 1.25) Conclusion: The results of the primary efficacy and safety outcomes within each quartile of cTTR demonstrate consistent findings across the quartiles with no evidence of a treatment by cTTR interaction. Even in centres with the best cTTR, apixaban has similar efficacy to conventional treatment and is associated with less major bleeding. References: (1) Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799-808. (2) Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69:236-9. Disclosures Cohen: Pfizer, Inc.: Consultancy. Gallus:Pfizer, Inc.: Consultancy, Honoraria. Agnelli:Pfizer, Inc.: Consultancy, Honoraria. Buller:Pfizer, Inc.: Consultancy, Honoraria. Pak:Pfizer, Inc.: Employment. Porcari:Pfizer, Inc.: Employment. Raskob:ISIS Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Bayer Healthcare: Consultancy, Honoraria. Weitz:Pfizer, Inc.: Consultancy, Honoraria. Yamabe:Pfizer, Inc.: Employment.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,017 | 0,018 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,003 | 0,005 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».