EINSTEIN-PE Trial Research Articles

The Effects of Rivaroxaban Exposure and Clinical Risk Factors on Efficacy and Safety Outcomes in Patients Treated for Venous Thromboembolism

Introduction: The oral factor Xa inhibitor rivaroxaban has previously demonstrated a predictable pharmacokinetic (PK) and pharmacodynamic profile, and has been developed for fixed dose administration without the need for routine coagulation or therapeutic drug monitoring (TDM). The objectives of this study were to investigate the relationship between rivaroxaban exposure and efficacy/safety outcomes, and to evaluate the relative influence of relevant clinical risk factors in patients receiving rivaroxaban for treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE) to assess whether TDM might further improve the benefit-risk profile of rivaroxaban in this population.Methods: An exposure-response analysis was conducted using data from patients receiving rivaroxaban (15 mg twice daily [BID] for 21 days followed by 20 mg once daily [OD] for up to 12 months) in the phase 3 EINSTEIN-DVT (NCT00440193) and EINSTEIN-PE (NCT00439777) trials (BID period, N = 4130; OD period, N = 3953). Due to a lack of measured PK data in the phase 3 trials, individual rivaroxaban exposure metrics (area under the concentration-time curve, maximum concentration [Cmax] and trough concentration [Ctrough]) were estimated using an integrated population PK model based on clinical risk factors, regimen and (where available) PT measurements. Exposure estimates were improved by application of an adjustment function based on a linear relationship between PK and prothrombin time measurements (measured centrally using a rivaroxaban-sensitive thromboplastin reagent) obtained in phase 2/3 rivaroxaban studies. Composite efficacy outcomes were: (1) objectively-documented recurrent DVT, or fatal or non-fatal PE; and (2) recurrent DVT, fatal or non-fatal PE, or death from any cause. Safety outcomes were major bleeding, and a composite of major and non-major clinically relevant (NMCR) bleeding. Relationships between exposure/clinical risk factors and outcomes were evaluated using logistic regression for the 21-day BID dosing period and Cox regression for the subsequent OD dosing period.Results: Of the estimated exposure parameters, Ctrough displayed the strongest associations for efficacy and safety during both dosing periods. The first and second composite efficacy outcomes occurred in 1.0% and 1.1% of patients, respectively, in the BID period, and 1.0% and 1.6% of patients, respectively, in the OD period. Individual predicted Ctrough was significantly associated with the first efficacy outcome in both dosing periods (Table 1), and with recurrent DVT, fatal or non-fatal PE, or death from any cause in the BID period only (Figure 1, Table 1). Patients with reduced creatinine clearance (CrCL; < 50 mL/min) were more likely than patients with CrCL > 80 mL/min to develop one of the composite efficacy outcomes during the BID and OD dosing periods (Figure 1, Table 1). Active malignancy at randomization was significant for the second efficacy endpoint in the OD period (hazard ratio 5.31 [95% CI: 2.97-9.51]). Major bleeding and major and NMCR bleeding occurred in 0.4% and 4.3% of patients, respectively, in the BID period and in 0.6% and 6.0% of patients, respectively, in the OD period. None of the investigated exposure metrics was a significant predictor of major bleeding or major and NMCR bleeding in either dosing period. Clinical variables including a history of bleeding, low baseline hemoglobin and non-steroidal anti-inflammatory drug use were, however, significant predictors of bleeding events (Table 2). CrCL was not a significant predictor of bleeding events.Conclusions: Estimated rivaroxaban exposure was significantly associated with efficacy outcomes but not with bleeding outcomes in patients with DVT or PE enrolled in the EINSTEIN-DVT and EINSTEIN-PE trials. Clinical risk factors had a substantial impact on outcomes. Based on these findings, it is unlikely that TDM would further improve the benefit-risk profile of rivaroxaban treatment in patients with venous thromboembolism. [Display omitted] DisclosuresBerkowitz:Bayer US: Employment. Weitz:Daiichi-Sankyo: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria; Janssen Biotech, Inc.: Consultancy, Honoraria; Merck & Co., Inc.: Consultancy, Honoraria; Portola Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Ionis Pharmaceuticals: Consultancy, Honoraria; Pfizer, Inc.: Consultancy, Honoraria. Schmidt:Bayer HealthCare Pharmaceuticals: Consultancy. Fox:AstraZeneca: Research Funding; Janssen Biotech, Inc.: Consultancy, Honoraria; Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria. Garmann:Bayer AG: Employment. Kubitza:Bayer AG: Employment. Mueck:Bayer AG: Employment. Peters:Janssen Research & Development: Employment. Reinecke:Bayer AG: Employment; Bayer AB: Employment. Solms:Bayer AG: Employment. Spiro:Bayer US: Employment. Yan:Janssen Research & Development: Employment. Zhang:Janssen Research & Development: Employment. Willmann:Bayer AG: Employment.

Rivaroxaban and the EINSTEIN clinical trial programme.

Rivaroxaban, a direct oral anticoagulant, is widely used for the treatment of venous thromboembolism (VTE) in adult patients. The approval of rivaroxaban for the treatment of deep vein thrombosis and pulmonary embolism and the extended secondary prevention of recurrent VTE is based on the results of the EINSTEIN DVT and EINSTEIN PE trials, and the EINSTEIN EXT and EINSTEIN CHOICE trials, respectively. This review provides an updated overview of these completed EINSTEIN studies in adult patients, including results of subanalyses in patients at high risk of recurrent VTE, and discusses the emerging data from the EINSTEIN Junior programme, which is evaluating the use of rivaroxaban for the treatment of paediatric VTE. In the EINSTEIN DVT and EINSTEIN PE trials, rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily thereafter) was shown to be an effective and safe alternative to standard anticoagulation for the treatment of deep vein thrombosis and pulmonary embolism in a broad range of adult patients. These results are supported by increasing amounts of real-world data from patients treated with rivaroxaban in routine clinical practice worldwide. In the EINSTEIN EXT and EINSTEIN CHOICE trials, rivaroxaban was superior to placebo and acetylsalicylic acid, respectively, for the extended treatment of VTE – physicians can now choose between two doses of rivaroxaban (20 mg once daily or 10 mg once daily) for the extended prevention of recurrent VTE, based on a patient's risk of recurrence, bleeding and personal preferences.

Patient-Reported Treatment Experience with Oral Rivaroxaban: Results from the Noninterventional XALIA Study of Deep-Vein Thrombosis.

For venous thromboembolism (VTE) treatment, patient satisfaction was shown to improve with rivaroxaban versus standard anticoagulation in the phase III EINSTEIN DVT and EINSTEIN PE trials. This substudy of the prospective, noninterventional XALIA study of rivaroxaban for deep-vein thrombosis treatment assessed if this was also observed in routine clinical practice. Patients enrolled in XALIA who received rivaroxaban or standard anticoagulation treatment were eligible for inclusion in this substudy. Treatment decisions were at the physician's discretion. Patients completed the 17-item Anti-Clot Treatment Scale (ACTS, comprising a 12-item Burdens subscale, a 3-item Benefits subscale and one global item per subscale) during follow-up. The propensity score-matched set (PMS) was used for the main analysis; the adjusted safety analysis (ASAF) set was used for confirmatory purposes. Analyses by follow-up visit and subgroup, including age, sex, and previous VTE, were also conducted. The PMS-ACTS analysis included 458 rivaroxaban-treated and 434 standard anticoagulation-treated patients. Baseline demographic and clinical characteristics were generally similar across treatment arms. ACTS Burdens scores significantly improved with rivaroxaban versus standard anticoagulation (least-squares mean difference of 2.4 ± 0.4 points; p < 0.0001); ACTS Benefits scores were numerically higher with rivaroxaban (least-squares mean difference of 0.2 ± 0.1 points; p = 0.2). Similar findings occurred across follow-up visits and subgroups. Results were confirmed in the ASAF-ACTS analysis. Consistent with phase III analyses, rivaroxaban was associated with improved ACTS Burdens scores; ACTS Benefits scores numerically favored rivaroxaban, although without reaching statistical significance.

Treatment of venous thromboembolism with rivaroxaban in relation to body weight. A sub-analysis of the EINSTEIN DVT/PE studies.

The pharmacokinetics of oral rivaroxaban are highly predictable and only affected to a limited extent by bodyweight; therefore, dose adjustments for bodyweight are not required. However, this raises concerns among physicians for potential under- or overdosing. This substudy of the randomised EINSTEIN DVT and EINSTEIN PE trials, which compared rivaroxaban with enoxaparin/vitamin K antagonist (VKA) therapy, aimed to determine the incidence of major bleeding in patients with a low bodyweight and recurrent venous thromboembolism (VTE) in patients with a high bodyweight during rivaroxaban or enoxaparin/VKA therapy. More than 8,000 patients with objectively diagnosed deep-vein thrombosis or pulmonary embolism were included. Adjusted hazard ratios for recurrent VTE and bleeding were calculated using the Cox proportional hazards model. Analyses were performed for both the first 21 days of treatment and the whole treatment period. For rivaroxaban recipients, there was no association between bodyweight or body mass index (BMI) and risk of recurrent VTE (ptrend=0.87 and 0.62, respectively), major bleeding (ptrend=0.24 and 0.36, respectively) or clinically relevant bleeding (ptrend=0.17 and 0.63, respectively). Major bleeding events were numerically lower in rivaroxaban patients across all bodyweight and BMI categories. Hazard ratios for rivaroxaban vs enoxaparin/VKA were similar in all bodyweight and BMI categories, both during the first 21 days and the whole treatment period. The fixed-dose rivaroxaban regimen is not associated with an increased risk of major bleeding or recurrent VTE in patients with either a low or high bodyweight. A high BMI was not associated with an increased risk of recurrent VTE during anticoagulation.

Rivaroxaban: A Review of Its Use in the Treatment of Deep Vein Thrombosis or Pulmonary Embolism and the Prevention of Recurrent Venous Thromboembolism

Rivaroxaban (Xarelto(®)), an oral direct factor Xa inhibitor, is approved for the initial treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as the prevention of recurrent DVT and PE. It is administered at a fixed oral dose and does not require routine coagulation monitoring. In the EINSTEIN-DVT and EINSTEIN-PE trials, in over 8,000 patients with DVT and/or PE, a single-drug approach with rivaroxaban was shown to be noninferior to standard therapy consisting of subcutaneous enoxaparin sodium overlapping with and followed by an oral dose-adjusted vitamin K antagonist (enoxaparin-VKA) with regard to the incidence of symptomatic recurrent venous thromboembolism (VTE) after 3, 6 or 12 months of treatment. Rivaroxaban was generally well tolerated in patients with DVT or PE, with no significant between-group differences in clinically relevant bleeding between the rivaroxaban and enoxaparin-VKA groups. Notably, rivaroxaban was associated with a significantly lower rate of major bleeding compared with enoxaparin-VKA when EINSTEIN-DVT and EINSTEIN-PE data were pooled. Pharmacoeconomic analyses indicated that rivaroxaban may be a cost-effective alternative to enoxaparin-VKA for the treatment of DVT or PE and prevention of recurrent VTE. Extended prophylaxis with rivaroxaban reduced the incidence of symptomatic recurrent VTE to a greater extent than placebo in the EINSTEIN-Extension trial, but was associated with a non-significant increase in the risk of clinically relevant bleeding compared with placebo. In conclusion, rivaroxaban is a reasonable alternative to standard therapy for the treatment of DVT and PE, and as extended thromboprophylaxis.

Pulmonary embolism hotline 2012

SummaryManagement of acute pulmonary embolism (PE) has advanced considerably in the past year, and progress is expected to continue in 2013. To help determine the optimal management strategy for normotensive patients with intermediate-risk PE, the Pulmonary Embolism Thrombolysis (PEITHO) study completed enrolment of 1006 patients with evidence of right ventricular dysfunction (by echocardiography or computed tomography) plus a positive troponin test. Patients have been randomised to thrombolytic treatment with tenecteplase versus placebo, and the effects on clinical end points (death or haemodynamic collapse) assessed at 7 and 30 days. The results are expected in spring 2013; long-term follow-up is also being performed. The results of a randomised trial on ultrasound- enhanced low-dose catheter-delivered thrombolysis will also become available soon. While optimisation of treatment with vitamin K antagonists incorporating pharmacogenetic testing is still being pursued, new oral anticoagulants are entering the field of PE treatment and secondary prophylaxis. Following the successful use of rivaroxaban as single oral drug therapy in the EINSTEIN-PE trial, the approval of this drug has recently been extended to cover, apart from deep vein thrombosis, PE as well. The apixaban (AMPLIFY) and edoxaban (HOKUSAI) trials have finished recruitment of PE patients, and their results will become available shortly. In the meantime, the AMPLIFY-EXT trial showed that both the therapeutic (5 mg twice daily) and the prophylactic dose (2.5 mg twice daily) of apixaban are effective and safe for longterm secondary prophylaxis after PE. For the extended prophylaxis (after the reommended initial anticoagulation period) of the (few) patients who are unable to tolerate any form of anticoagulation, low-dose asprin may be a safe albeit moderately efficacious option, as indicated by two recent investigator-initiated trials with a total of 1224 patients.

Cost Effectiveness of Rivaroxaban Versus Warfarin for the Prevention of Recurrent Venous Thromboembolism.

AbstractAbstract 3177 Background:Rivaroxaban is an oral anticoagulant administered once daily that works by direct inhibition of factor Xa. It has been found to be noninferior to warfarin in the prevention of recurrent venous thromboembolism (VTE). Whether rivaroxaban is cost effective in the prevention of recurrent VTE, however, is not known. Methods:To assess the cost effectiveness of rivaroxaban compared with warfarin in the prevention of recurrent VTE, we built a Markov state transition model over a 10-year time horizon. The base case analysis consisted of a hypothetical cohort of 60-year-old patients who were diagnosed with their first VTE and received secondary prophylaxis with either rivaroxaban or warfarin for 6 months. Cost estimates were derived from the Healthcare and Utilization Project (HCUP) and other sources. Probabilities for VTE recurrence and mortality and for major and minor bleeding were based on the EINSTEIN PE trial (NEJM 2012; 366: 1287–97). Outcomes included costs in 2011 United States dollars, quality adjusted life years (QALYs), and incremental cost effectiveness ratios (ICERs) over 10 years from a societal perspective. Results:Base case results are shown in the Table, showing total medication and other medical costs associated with each strategy. Compared with warfarin, the rivaroxaban strategy cost less ($4057 vs $7004) and was more effective (9.30 QALYs vs 9.16 QALYs). Thus, warfarin was dominated by rivaroxaban. In sensitivity analyses, results were most sensitive to changes in the probability of major bleeding with rivaroxaban. As shown in the Figure, when major bleeding with rivaroxaban (base case 1.1%) was less than 4.5%, the ICRE was within the $100,000 per QALY gained acceptability threshold range. Results favoring rivaroxaban were robust to individual variation of other parameter values. Conclusion:Prophylactic anticoagulation with rivaroxaban appears to be a cost effective, and perhaps cost saving, alternative to warfarin for the prevention of recurrent VTE.TableAnticoagulation StrategyCostIncremental CostEffectiveness (QALY)Incremental Effectiveness (QALY)Incremental C/E Ratio (ICER)1) Rivaroxaban$4057-9.30--2) Warfarin$7004$29479.16−0.14Dominated [Display omitted] Disclosures:Off Label Use: Rivaroxaban - Prevention of recurrent venous thromboembolism.

Rivaroxaban

Rivaroxaban

EINSTEIN transforms anticoagulant therapy in acute PE

The EINSTEIN-PE trial showed that rivaroxaban has equal efficacy and a lower rate of bleeding than coumarins in the treatment of acute pulmonary embolism. We anticipate regulatory and consumer acceptance for rivaroxaban, representing the first new anticoagulant treatment for venous thromboembolism since the introduction of warfarin compounds 50 years ago.