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
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.017 | 0.018 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.003 | 0.005 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".