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
Authors: Cohen Alexander , Gallus Alexander S. , Agnelli Giancarlo , Buller Harry R , Pak Raphael , Porcari Anthony R. , Raskob Gary E. , Weitz Jeffrey I. , Yamabe Takaharu 
Published: October 2019

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.