Use of Prestudy Heparin Did Not Influence the Efficacy and Safety of Rivaroxaban in Patients Treated for Symptomatic Venous Thromboem‐bolism in the EINSTEIN DVT and EINSTEIN PE Studies

Abstract

ObjectivesIn the EINSTEIN DVT and EINSTEIN PE studies, the majority of patients received heparins to bridge the period during venous thromboembolism (VTE) diagnosis confirmation and the start of the study. In contrast to vitamin K antagonists (VKAs), rivaroxaban may not require initial heparin treatment.MethodsTo evaluate the effect of prestudy heparin on the efficacy and safety of rivaroxaban relative to enoxaparin/VKA, the 3‐month incidence of recurrent VTE, and the 14‐day incidence of major and nonmajor clinically relevant bleeding were compared in patients who did and did not receive prestudy heparin.ResultsOf the 8,281 patients randomized, 6,937 (83.8%) received prestudy heparin (mean ± SD duration = rivaroxaban: 1.04 [± 0.74] days; enoxaparin 1.03 [± 0.42] days), and 1,344 (16.2%) did not. In patients who did not receive prestudy heparin, the incidences of recurrent VTE were similar in rivaroxaban (15 of 649, 2.3%) and enoxaparin/VKA (13 of 695, 1.9%) patients (adjusted hazard ratio [HR] = 1.11; 95% confidence interval [CI] = 0.52 to 2.37). The incidences of recurrent VTE were also similar in rivaroxaban (54 of 3,501, 1.5%) and enoxaparin/VKA (69 of 3,436, 2.0%) patients who did receive prestudy heparin (adjusted HR = 0.74; 95% CI = 0.52 to 1.06; pinteraction = 0.32). The incidences of major or nonmajor clinically relevant bleeding with rivaroxaban were not significantly different from those with enoxaparin/VKA, either with (105 of 3,485, 3.0% vs. 104 of 3,428, 3.0%; adjusted HR = 0.98; 95% CI = 0.75 to 1.29) or without (24 of 645, 3.7% vs. 30 of 688, 4.4%; adjusted HR = 0.81; 95% CI = 0.46 to 1.40; pinteraction = 0.68) prestudy heparin.ConclusionsAlthough the majority of patients in the EINSTEIN studies received prestudy heparin, there were no notable differences in treatment effect of rivaroxaban versus enoxaparin/VKA in those who did and did not receive it.

Risk–Benefit Profile of Direct-Acting Oral Anticoagulants in Established Therapeutic Indications: An Overview of Systematic Reviews and Observational Studies

“…there is no need for initial acute-phase treatment with LMWHs, but they do require a dose change between initial and maintenance phases). Notably, in a phase III trial of rivaroxaban, the majority of patients (84 %) received prestudy heparins for a mean duration of 1 day before starting rivaroxaban, although no remarkable differences emerged in patients not receiving this bridge therapy [89]. It is still uncertain whether one approach has a clinical advantage over another.…”

British Thoracic Society Guideline for the initial outpatient management of pulmonary embolism (PE)

“…In the RE-COVER (dabigatran) 62 and Hokusai-VTE (edoxaban) 65 studies, LMWH was also administered for at least 5 days. In the EINSTEIN DVT and PE studies, a cohort of 649 patients received rivaroxaban without prior treatment with heparin 70 . A retrospective post-hoc analysis, comparing this cohort to those who did receive heparin (n=3501), concluded that the use of prestudy heparin did not influence the efficacy and safety of rivaroxaban in patients treated for symptomatic VTE as there were no differences in terms of recurrent VTE or major bleeding.…”

Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department With Suspected Acute Venous Thromboembolic Disease

“…For this critical question, 3 Class II studies 87-89 and 8 Class III studies [90][91][92][93][94][95][96][97] were identified comparing the efficacy and safety of NOACs with standard therapy in the treatment of acute VTE. All 3 of the Class II studies 87-89 and 3 of the Class III studies 90,91,94 specifically examined outcomes in patients receiving a diagnosis of isolated DVT, whereas the remaining 5 Class III studies 92,93,[95][96][97] examined cohorts that included patients with DVT and PE.…”

“…The number of deaths, acute coronary syndromes, and abnormal liver function test results were also similar between the 2 groups. The effect of prestudy heparin on the efficacy and safety of rivaroxaban relative to standard therapy and the incidence of bleeding compared with that of patients who did not receive prestudy heparin was evaluated in a Class III study by Prandoni et al 93 This retrospective, post hoc analysis of the EINSTEIN-DVT 87 and EINSTEIN-PE 98 studies found that the majority of patients (84%) enrolled in the EINSTEIN-DVT and PE studies received prestudy heparin but with most (70%) receiving prestudy heparin for 1 day or less. There was no difference observed in the incidence of recurrent VTE or bleeding between the groups.…”