CONTEXTE: La oral direct inhibiteur de la thrombine dabigatran a un effet anticoagulant prévisible et peut être une alternative thérapeutique à la warfarine chez les patients qui ont la maladie thromboembolique veineuse aiguë. MÉTHODES: Dans une étude randomisée, en double aveugle non-infériorité, des patients atteints de la maladie thromboembolique veineuse aiguë qui ont été initialement fournies traitement anticoagulant parentéral pendant une durée médiane de 9 jours (intervalle interquartile, 8-11), nous avons comparé le dabigatran par voie orale, administré à une dose de 150 mg deux fois par jour, avec la warfarine qui a été la dose ajustée pour atteindre un ratio international normalisé de 2,0 à 3,0. Le critère principal était l'incidence de 6 mois de récidive symptomatique, la maladie thromboembolique veineuse objectivement confirmés et de décès liés. Points d'extrémité de sécurité comprenaient des événements hémorragiques, syndromes coronariens aigus, d'autres événements indésirables, et les résultats des tests de fonction hépatique. Résultats: Un total de 30 des patients 1274 randomisés pour recevoir le dabigatran (2,4%), comparativement à 27 des 1265 patients randomisés à la warfarine (2,1%), a eu la maladie thromboembolique veineuse récidivante, la différence dans le risque était de 0,4 points de pourcentage (95% intervalle de confiance [IC], -0,8 à 1,5; P <0,001 pour les non-infériorité de la marge prédéfinie). Le hazard ratio était de 1,10 avec le dabigatran (IC à 95%, de 0,65 à 1,84). Épisodes hémorragiques majeurs sont survenus chez 20 patients assignés au dabigatran (1,6%) et chez 24 patients assignés à la warfarine (1,9%) (rapport de risque avec le dabigatran, 0,82, IC 95%, 0,45 à 1,48), et des épisodes de saignement ont été observés dans 205 patients assignés au dabigatran (16,1%) et 277 patients assignés à la warfarine (21,9%; hazard ratio avec le dabigatran, 0,71, IC 95%, 0,59 à 0,85). Les nombres de décès, les syndromes coronariens aigus, et des anomalies des fonctions hépatique étaient comparables dans les deux groupes. Les événements indésirables conduisant à l'arrêt du médicament à l'étude a eu lieu dans 9,0% des patients assignés au dabigatran et dans 6,8% des patients assignés à la warfarine (P = 0,05). CONCLUSIONS: Pour le traitement de la thromboembolie veineuse aiguë, une dose fixe de dabigatran est aussi efficace que la warfarine, a un profil d'innocuité semblable à celle de la warfarine, et ne nécessitent pas de surveillance en laboratoire. (Nombre ClinicalTrials.gov, NCT00291330.) Copyright 2009 Massachusetts Medical Society.
BACKGROUND: Extended treatment with warfarin is effective at prevent ing recurrent venous thromboembolism (VTE) but is associated with increased bleeding and is burdensome. METHODS: Patients with VTE who had initially received 3–12 months of anticoagulant therapy were randomized, using a double-blind design, to treatment with dabigatran 150 mg twice daily or with wafarin (to maintain an international normalized ratio of 2.0–3.0) for an additional period of 6–36 months. The primary efficacy outcome was the frequency of recurrent symptomatic VTE and related deaths at the end of the planned treatment period. Safety outcomes were bleeding events, acute coronary syndromes and other adverse events. RESULTS: Recurrent VTE occurred in 26 (1.8%) of 1430 patients treated with dabigatran and 18 (1.3%) of 1426 patients treated with war farin (hazard ratio [HR] 1.44; 95% confidence interval [CI], 0.78 2.64; P = 0.03 for the pre-specified non-inferiority margin). There were 13 major bleeds (0.9%) in patients on treatment with dabigatran and 25 (1.8%) in patients on treatment with warfarin (HR 0.52; 95% CI, 0.27–1.01). Any bleeding occurred in 277 patients (19%) on treat ment with dabigatran and in 373 patients (26%) on warfarin (HR 0.71; 95% CI, 0.61–0.83). Acute coronary syndromes were observed n 13 patients (0.9%) on treatment with dabigatran and in three patients (0.2%) on warfarin (P = 0.02). There were 17 deaths in the dabigatran group and 19 deaths in the warfarin group; other adverse events were also similar with the two treatments. CONCLUSIONS: Dabigatran was as effective as warfarin in the extended treatment of VTE. Dabigatran was associated with a reduced risk for bleeding but an increased incidence of acute coronary events. Disclosure of Interest: Anne Mathilde Kvamme and Janet Schnee are employees of Boehringer Ingelheim. All other authors have received honoraria from Boehringer Ingelheim for their work in the Steering Committee of studies on dabigatran in VTE.
BACKGROUND: In the RE-COVER and RE-COVER II trials, a fixed dose of dabigatran etexilate was as effective as warfarin for prevention of recurrent VTE and was associated with a lower risk of bleeding. It is not known whether this efficacy and difference in bleeding rates is maintained in older patients.
OBJECTIVES: Older patients may be at greater risk of bleeding and/or VTE. Therefore, we performed a subgroup analysis on the pooled RE-COVER and RE-COVER II trial results to investigate the efficacy and safety of dabigatran versus warfarin for the treatment of acute VTE according to age.
METHODS: Patients with acute VTE received parenteral anticoagulation and were randomized to the addition of warfarin or warfarin-placebo for at least 5 days until the international normalized ratio (INR) was ≥ 2 at two consecutive measurements. This was followed (on discontinuation of parenteral therapy) by continued warfarin (target INR range 2.0–3.0) or dabigatran 150 mg twice daily (double dummy; “oral only” treatment period) for 6 months. Outcomes were centrally adjudicated. The primary efficacy outcome was recurrent, symptomatic, objectively confirmed VTE or VTE-related death from randomization (i.e., start of parenteral therapy plus either warfarin or warfarin-placebo) up to the end of the prespecified post-treatment follow-up. Major bleeding events (MBEs), the composite of MBEs or clinically relevant non-major bleeding events (CRBEs), and any bleeds were counted from the start of the double-dummy period (treatment with oral dabigatran or warfarin alone) up to the end of the 6-month study period. Thus, the safety analysis excludes events associated with parenteral therapy either in combination with warfarin or with warfarin-placebo prior to commencing dabigatran treatment; it therefore compares dabigatran with warfarin at its full pharmacological potential.
RESULTS: Of 2553 patients randomized to dabigatran, 68 (2.7%) had recurrent VTE or VTE-related death compared with 62 (2.4%) of 2554 patients randomized to warfarin; hazard ratio (HR) 1.09 (95% CI 0.77, 1.54). The incidences of the primary efficacy outcome (dabigatran vs warfarin) by age group were 3.0% (53/1769) versus 2.4% (42/1748) for patients < 65, 2.3% (12/531) versus 2.5% (13/530) for patients 65–75, and 1.2% (3/253) versus 2.5% (7/276) for patients > 75 years; and in a second age-group comparison were 2.8% (67/2418) vs 2.3% (57/2429) for patients < 80 and 0.7% (1/135) versus 4.0% (5/125) for patients ≥ 80 years. Cox regression analysis showed no statistically significant interaction, indicating that there are similar treatment effects across age groups. MBEs were significantly less frequent with dabigatran than with warfarin overall (HR 0.60; 95% CI 0.36, 0.99). Incidences by age group are shown in the Table. MBE/CRBE incidence was also significantly lower with dabigatran versus warfarin overall (HR 0.56; 95% CI 0.45, 0.71). The Table shows event rates for each age group. Similarly, any bleeding events were significantly less frequent with dabigatran than with warfarin overall. There was no significant treatment-by-age interaction for MBEs or MBEs/CRBEs or any bleeds in either analysis.
CONCLUSIONS: No differences in recurrent VTE or efficacy were apparent across the age groups. Bleeding events increased with increasing age but numerically were similar or lower with dabigatran than with warfarin regardless of age. The results suggest there is no need for dose adjustment of dabigatran according to age for the treatment of VTE.
BACKGROUND: In two phase III trials, RE-COVER and RE-COVER II, dabigatran etexilate was as effective as warfarin for treatment of acute venous thromboembolism (VTE), with a lower risk of bleeding. Cancer and its treatments are risk factors for VTE and bleeding. OBJECTIVES: We performed a prespecified subgroup analysis on pooled data from RE-COVER and RE-COVER II to investigate the efficacy and safety of dabigatran versus warfarin in patients with and without active cancer at any time during the study. Active cancer was defined as: a diagnosis of cancer (other than basal-cell or squamous-cell carcinoma of the skin) within 5 years before enrolment; any treatment for cancer within 5 years before enrolment; or recurrent or metastatic cancer. METHODS: Patients with acute VTE received parenteral anticoagulation and were randomized to the addition of warfarin or warfarin-placebo for at least 5 days until the international normalized ratio (INR) was ≥ 2 at two consecutive measurements. This was followed (on discontinuation of parenteral therapy) by continued warfarin (target INR range 2.0–3.0) or dabigatran 150 mg twice daily (double dummy; “oral only” treatment period) for 6 months. Primary efficacy outcome : recurrent, symptomatic, objectively confirmed VTE or VTE-related death from randomization (i.e., start of parenteral therapy plus either warfarin or warfarin-placebo) up to the end of the prespecified post-treatment follow-up. Safety: major bleeding events (MBEs), the composite of MBEs or clinically relevant bleeding events (CRBEs), and any bleeds, measured from the start of the double-dummy period (treatment with oral dabigatran or warfarin alone) up to the end of the 6-month study period. Thus, the safety analysis excludes events associated with parenteral therapy either in combination with warfarin or with warfarin-placebo prior to commencing dabigatran treatment; it therefore compares dabigatran with warfarin at its full pharmacological potential. RESULTS Overall, recurrent VTE or VTE-related death occurred in 68/2553 patients (2.7%) randomized to dabigatran and 62/2554 (2.4%) randomized to warfarin; hazard ratio (HR) 1.09 (95% confidence interval [CI] 0.77, 1.54). The [Table][2] shows event rates for dabigatran versus warfarin in subgroups with and without active cancer at any time. Cox regression analysis showed that presence of cancer was associated with a statistically significant increase in the likelihood of VTE or VTE-related death. However, there was no significant interaction with treatment, indicating similar treatment effects regardless of the presence or absence of active cancer. Overall, MBEs were significantly less frequent with dabigatran than with warfarin during the oral treatment only (double dummy) period (HR 0.60; 95% CI 0.36, 0.99). Likewise, the MBE/CRBE incidence overall was significantly lower with dabigatran versus warfarin overall (HR 0.56; 95% CI 0.45, 0.71). Results according to cancer status are shown in the [Table][2]. Patients with cancer had significantly higher rates of MBEs and MBEs/CRBEs than those without. There was no significant treatment interaction by cancer status for MBEs, whereas the treatment interaction for MBEs/CRBEs was significant (p = 0.0257) with a lower rate of bleeding with dabigatran versus warfarin in patients without compared to with cancer. Any bleeding events were significantly less frequent with dabigatran than with warfarin overall, and showed no significant treatment interaction with cancer status. CONCLUSIONS: There was a significantly higher frequency of recurrent VTE or VTE-related mortality among patients who had cancer, but the efficacy of dabigatran versus warfarin was similar irrespective of cancer status. The incidence of bleeding events was similar or numerically lower with dabigatran than with warfarin across cancer subgroups. DISCLOSURES: Schulman: Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Bayer Healthcare: Consultancy, Honoraria, Research Funding.
BACKGROUND: Dabigatran and warfarin have been compared for the treatment of acute venous thromboembolism (VTE) in a previous trial. We undertook this study to extend those findings. METHODS AND RESULTS: In a randomized, double-blind, double-dummy trial of 2589 patients with acute VTE treated with low-molecular-weight or unfractionated heparin for 5 to 11 days, we compared dabigatran 150 mg twice daily with warfarin. The primary outcome, recurrent symptomatic, objectively confirmed VTE and related deaths during 6 months of treatment occurred in 30 of the 1279 dabigatran patients (2.3%) compared with 28 of the 1289 warfarin patients (2.2%; hazard ratio, 1.08; 95% confidence interval [CI], 0.64-1.80; absolute risk difference, 0.2%; 95% CI, -1.0 to 1.3; P<0.001 for the prespecified noninferiority margin for both criteria). The safety end point, major bleeding, occurred in 15 patients receiving dabigatran (1.2%) and in 22 receiving warfarin (1.7%; hazard ratio, 0.69; 95% CI, 0.36-1.32). Any bleeding occurred in 200 dabigatran (15.6%) and 285 warfarin (22.1%; hazard ratio, 0.67; 95% CI, 0.56-0.81) patients. Deaths, adverse events, and acute coronary syndromes were similar in both groups. Pooled analysis of this study RE-COVER II and the RE-COVER trial gave hazard ratios for recurrent VTE of 1.09 (95% CI, 0.76-1.57), for major bleeding of 0.73 (95% CI, 0.48-1.11), and for any bleeding of 0.70 (95% CI, 0.61-0.79). CONCLUSION: Dabigatran has similar effects on VTE recurrence and a lower risk of bleeding compared with warfarin for the treatment of acute VTE. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov. Unique identifiers: NCT00680186 and NCT00291330.
La oral direct inhibiteur de la thrombine dabigatran a un effet anticoagulant prévisible et peut être une alternative thérapeutique à la warfarine chez les patients qui ont la maladie thromboembolique veineuse aiguë.
MÉTHODES:
Dans une étude randomisée, en double aveugle non-infériorité, des patients atteints de la maladie thromboembolique veineuse aiguë qui ont été initialement fournies traitement anticoagulant parentéral pendant une durée médiane de 9 jours (intervalle interquartile, 8-11), nous avons comparé le dabigatran par voie orale, administré à une dose de 150 mg deux fois par jour, avec la warfarine qui a été la dose ajustée pour atteindre un ratio international normalisé de 2,0 à 3,0. Le critère principal était l'incidence de 6 mois de récidive symptomatique, la maladie thromboembolique veineuse objectivement confirmés et de décès liés. Points d'extrémité de sécurité comprenaient des événements hémorragiques, syndromes coronariens aigus, d'autres événements indésirables, et les résultats des tests de fonction hépatique. Résultats: Un total de 30 des patients 1274 randomisés pour recevoir le dabigatran (2,4%), comparativement à 27 des 1265 patients randomisés à la warfarine (2,1%), a eu la maladie thromboembolique veineuse récidivante, la différence dans le risque était de 0,4 points de pourcentage (95% intervalle de confiance [IC], -0,8 à 1,5; P <0,001 pour les non-infériorité de la marge prédéfinie). Le hazard ratio était de 1,10 avec le dabigatran (IC à 95%, de 0,65 à 1,84). Épisodes hémorragiques majeurs sont survenus chez 20 patients assignés au dabigatran (1,6%) et chez 24 patients assignés à la warfarine (1,9%) (rapport de risque avec le dabigatran, 0,82, IC 95%, 0,45 à 1,48), et des épisodes de saignement ont été observés dans 205 patients assignés au dabigatran (16,1%) et 277 patients assignés à la warfarine (21,9%; hazard ratio avec le dabigatran, 0,71, IC 95%, 0,59 à 0,85). Les nombres de décès, les syndromes coronariens aigus, et des anomalies des fonctions hépatique étaient comparables dans les deux groupes. Les événements indésirables conduisant à l'arrêt du médicament à l'étude a eu lieu dans 9,0% des patients assignés au dabigatran et dans 6,8% des patients assignés à la warfarine (P = 0,05).
CONCLUSIONS:
Pour le traitement de la thromboembolie veineuse aiguë, une dose fixe de dabigatran est aussi efficace que la warfarine, a un profil d'innocuité semblable à celle de la warfarine, et ne nécessitent pas de surveillance en laboratoire. (Nombre ClinicalTrials.gov, NCT00291330.) Copyright 2009 Massachusetts Medical Society.
