A Pooled Analysis of Four Pivotal Studies of Rivaroxaban for the Prevention of Venous Thromboembolism after Orthopaedic Surgery: Effect on Symptomatic Venous Thromboembolism, Death, and Bleeding
Notice bibliographique
Résumé
Abstract Four multinational, randomized, double-blind, double-dummy phase III studies (RECORD1, 2, 3 and 4) investigated the oral, direct Factor Xa inhibitor rivaroxaban for the prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery. A total of 12,729 patients were randomized to receive oral rivaroxaban 10 mg once daily (od) starting 6–8 hours after surgery, or subcutaneous enoxaparin 40 mg od starting the evening before surgery (RECORD1–3), or 30 mg bid starting 12–24 hours after wound closure or adequate hemostasis (RECORD4). In both RECORD1 and 2, patients undergoing total hip replacement (THR) were given rivaroxaban for 31–39 days. Enoxaparin was given for 31–39 days in RECORD1 or 10–14 days in RECORD2. In RECORD3 and 4, patients undergoing total knee replacement (TKR) received prophylaxis for 10–14 days. All patients were followed up for 30–35 days after the last dose of study medication. All outcomes, including symptomatic outcomes, were adjudicated by the same independent, blinded committees for all four studies. In each of the studies, the rivaroxaban regimens tested significantly reduced the incidence of the primary efficacy outcome (total VTE; the composite of any deep vein thrombosis [DVT], non-fatal pulmonary embolism [PE], and all-cause mortality) compared with enoxaparin regimens tested, with similar rates of bleeding in both groups. The rivaroxaban regimens also consistently reduced the incidence of major VTE (the composite of proximal DVT, non-fatal PE, and VTE-related death) in all four trials compared with the enoxaparin regimens tested. This pre-specified pooled analysis was performed on all randomized patients who received at least one dose of double-blind study medication to evaluate the effect of rivaroxaban on the composite of symptomatic VTE (comprising DVT or PE) and death, and bleeding. These primary outcomes were analyzed at day 12±2 in the active treatment pool (i.e. during the enoxaparin-controlled period common to all studies, to allow for unbiased comparison with enoxaparin), and for the total study duration pool (planned treatment period and 30–35 days follow-up). The results are shown in the table. Rivaroxaban significantly reduced the incidence of symptomatic VTE and death compared with enoxaparin regimens at day 12±2 (0.47% vs 0.97%; p=0.001) and for the total study duration (0.81% vs 1.63%; p<0.001). Rivaroxaban was not associated with a statistically significant increased risk of major bleeding (Table). These data demonstrate that in the regimens tested, rivaroxaban reduced the composite of major clinical outcomes compared with enoxaparin regimens, with no significant increase in the risk of major bleeding in patients undergoing major orthopaedic surgery. Rivaroxaban n=6183 n (%) Enoxaparin n=6200 n (%) p-value *Total study duration pool: active study drug period and 30–35 days follow-up including the placebo phase in RECORD2. †Bleeding after initiation of study medication, regardless of onset after last dose of study medication. ‡Post hoc analysis. p-values refer to Cox regression with treatment and study as covariates (two-sided Wald-test). Symptomatic VTE and death (primary outcome) 29 (0.5) 60 (1.0) 0.001 Day 12±2 active treatment pool 50 (0.8) 101 (1.6) <0.001 Total study duration pool* Death 6 (0.1) 10 (0.2) 0.320 Day 12±2 active treatment pool 13 (0.2) 25 (0.4) 0.055 Total study duration pool* PE or death 12 (0.2) 24 (0.4) 0.049 Day 12±2 active treatment pool 29 (0.5) 47 (0.8) 0.039 Total study duration pool* Major bleeding 21 (0.3) 13 (0.2) 0.175 Day 12±2 active treatment pool 27 (0.4) 17 (0.3) 0.135 Total study duration pool† Any bleeding 409 (6.6) 384 (6.2) 0.376 Day 12±2 active treatment pool 452 (7.3) 415 (6.7) 0.207 Total study duration pool† Composite of major clinical outcomes (death, myocardial infarction, stroke, symptomatic VTE, and major bleeding)*‡ 96 (1.6) 139 (2.2) 0.004
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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 | 0,032 | 0,038 |
| Méta-épidémiologie (sens strict) | 0,003 | 0,001 |
| Méta-épidémiologie (sens large) | 0,011 | 0,025 |
| Bibliométrie | 0,003 | 0,003 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,003 | 0,001 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,002 | 0,001 |
| 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 ».