Annotated EINSTEIN PE NEJM manuscript

Transcription

1 Annotated EINSTEIN PE NEJM manuscript

2 9 Predefined measures ensured that the study was conducted to a high standard and avoided potential bias of the open-label design: 1 Nearly half a million cases of PE are estimated to occur in Europe each year1 PE is associated with significant morbidity and mortality; one in 10 hospital deaths is potentially related to PE and the case-fatality rate from recurrent PE is 4 9% An independent data and safety monitoring board The hospitalization costs associated with the index PE and recurrent events are high.5 Long-term complications, such as chronic thromboembolic pulmonary hypertension and post-thrombotic syndrome, add to this burden6,7 3 Random assignment via voice-response system 9 Central adjudication committee unaware of the treatment assignments Patients were ineligible if they had been administered parenteral heparin/ fondaparinux for more than 48 hours 6 2 The conventional dual-drug approach for treatment is complex (overlapping therapy with subcutaneous LMWH injections and VKA) 3 11 Patients were ineligible if they had received thrombectomy or fibrinolysis for their current episode of PE 7 8 The unique singledrug approach with rivaroxaban represents a new era in anticoagulation and will offer simple, effective treatment of PE 12 4 Oral rivaroxaban showed consistently improved outcomes in a broad range of venous and arterial diseases as proven convincingly in RECORD1 4, EINSTEIN DVT, EINSTEIN EXT, ROCKET AF and ATLAS ACS 2 TIMI Minimizing the potential for bias (see call-out 9) 8 Patients with PE could have concurrent DVT 5 The EINSTEIN programme is unique in that it is the first time an oral anticoagulant has been studied separately for the treatment of acute DVT (EINSTEIN DVT) and acute PE (EINSTEIN PE) EINSTEIN EXT investigated continued treatment of DVT and PE compared with placebo In clinical practice, approximately 50% of patients with PE also have DVT8 6 The single-drug solution with rivaroxaban has already proved effective with reassuring safety for the treatment of acute DVT without symptomatic PE 7 EINSTEIN PE was an open-label study Note: EINSTEIN DVT was open label and EINSTEIN EXT was double blind References 1. Cohen AT et al. Thromb Haemost 2007;98: ; 2. Sandler DA, Martin JF. J R Soc Med 1989;82: ; 3. Torbicki A et al. Eur Heart J 2008;29: ; 4. Douketis JD et al. Ann Intern Med 2007;147: ; 5. Spyropoulos AC, Lin J. J Manag Care Pharm 2007;13: ; 6. Guanella R et al. J Thromb Haemost 2011;9: ; 7. Kirson NY et al. Appl Health Econ Health Policy 2011;9: ; 8. Jiménez D et al. Am J Respir Crit Care Med 2010;181:

3 13 The single-drug solution with rivaroxaban: 15 mg twice daily for the first 3 weeks followed by 20 mg once daily for 3, 6 or 12 months Importantly, the intensified twice-daily regimen covers the first 3 weeks, when patients are at highest risk of recurrence1, Primary efficacy outcome: symptomatic recurrent VTE (composite of DVT, non-fatal PE or fatal PE) Principal safety outcome: major plus non-major clinically relevant bleeding References 1. The van Gogh Investigators. N Engl J Med 2007;357: ; 2. Fiessinger JN et al. JAMA 2005;293:

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5 16 Approximately 92% of patients received pretreatment with LMWH/heparin or fondaparinux for 1 or 2 days, reflecting current real-life clinical practice There was no difference in outcomes irrespective of whether patients received pretreatment with LMWH/heparin or fondaparinux or not. However, because rivaroxaban has a fast onset of action,1,2 similar to LMWH, and is effective from the first dose of treatment, heparin injections are not needed 17 Discontinuation rates were similar in both study arms 18 Predefined secondary outcomes included vascular events and net clinical benefit (the composite of the primary efficacy outcome and major bleeding) EINSTEIN PE was a non-inferiority, eventdriven study EINSTEIN PE used a non-inferiority margin of 2.0 Note: in RE-COVER a less rigorous non-inferiority margin of 2.75 was used, meaning that noninferiority was easier to demonstrate References 1. Kubitza D et al. Eur J Clin Pharmacol 2005;61: ; 2. Kubitza D et al. Clin Pharmacol Ther 2005;78:

6 21 EINSTEIN DVT: rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily EINSTEIN PE: a doseconfirmation stage in 400 patients showed that this rivaroxaban dosing regimen was effective for the treatment of PE 22 Rivaroxaban was non-inferior to standard therapy 23 Major bleeding was significantly lower in the rivaroxaban arm 24 Rates of critical site bleeding were lower in the rivaroxaban arm

7 EINSTEIN PE: multinational, multicentre study in PE treatment 26 In the standard therapy group, the median duration of enoxaparin treatment was 8 days, as it was in EINSTEIN DVT Note: in the RE-COVER study it was 9 days

8 27 The percentage time that the INR was within the therapeutic range varied from 57.8% (month 1) to 72.7% (month 11) and compared favourably with other contemporary studies Note: the percentage time in therapeutic range was slightly higher than in EINSTEIN DVT; possibly a reflection of the fact that PE is considered more serious than DVT 28 The single-drug solution with rivaroxaban was as effective as the dual-drug approach with enoxaparin/vka 29 Rivaroxaban was as effective as enoxaparin/ VKA from the first day of treatment 32 Net clinical benefit outcomes were numerically lower with rivaroxaban than with standard therapy (3.4% vs 4.0%; see Table 3) Efficacy and safety were consistent across the prespecified subgroups, which was also the case in the EINSTEIN DVT and EINSTEIN EXT studies Importantly, major bleeding was significantly reduced in fragile patients in the rivaroxaban treatment arm Note: see supplementary appendix Vascular events occurred at a low and similar rate in both treatment arms 30 Patients with the full spectrum of PE severities were included in EINSTEIN PE All severities of PE contributed to the overall efficacy Note: in EINSTEIN DVT, rivaroxaban had a superior net clinical benefit compared with standard therapy 31 Note: patients treated with fibrinolysis or thrombectomy for their PE were excluded 31 Safety: rivaroxaban demonstrated a favourable and reassuring safety profile compared with standard therapy for the principal safety outcome (10.3% vs 11.4%) Importantly, rivaroxaban significantly reduced major bleeding compared with standard therapy (1.1% vs 2.2%; p=0.003) References 1. The van Gogh Investigators. N Engl J Med 2007;357: ; 2. The EINSTEIN Investigators. N Engl J Med 2010;363: ; 3. Fiessinger JN et al. JAMA 2005;293: There were no signs of liver toxicity 36 The simple, singledrug approach proved to be as effective as standard therapy with reassuring similar low rates of bleeding compared with enoxaparin/vka. Major bleeding was significantly lower with rivaroxaban than enoxaparin/vka (p=0.003)

9 37 The reductions in major bleeding seen with rivaroxaban occurred early on and continued over the entire treatment course 37

10 43 The intensified 3-week rivaroxaban regimen maintained efficacy and still decreased the risk of major bleeding 38 EINSTEIN PE is unique because it is the only large study of a single-drug approach with an oral compound for the successful treatment of PE. With almost 5000 patients enrolled, EINSTEIN PE is the largest trial of its kind 39 The patients enrolled in EINSTEIN PE were representative of those seen in clinical practice Note: given the severity of PE, patients with a subtherapeutic INR are more likely to receive additional parenteral anticoagulation on top of VKA treatment; this action, undertaken to prevent recurrence, may also account for the higher rates of major bleeding Approximately onequarter had extensive disease and one-quarter had concomitant symptomatic DVT 40 The convenience and built-in simplicity of rivaroxaban may contribute to the high adherence observed Subgroup analyses of the EINSTEIN PE data support no requirement for dose adjustment with rivaroxaban An initial 3-week intensified rivaroxaban regimen was used because: Inadequate initial therapy has been associated with unacceptably high recurrence rates (as seen in the van Gogh and THRIVE trials)1,2 Rivaroxaban phase II studies supported the use of a twice-daily regimen in the initial phase of treatment References 1. The van Gogh Investigators. N Engl J Med 2007;357: ; 2. Fiessinger JN et al. JAMA 2005;293: Importantly, the rates of critical site bleeding, including intracranial bleeding, were lower with rivaroxaban than with enoxaparin/vka 45 Although nearly all patients received LMWH before randomization, exposure was usually for 1 day or less Rivaroxaban was effective regardless of whether patients received prerandomization LMWH or not The open-label design of the EINSTEIN PE study did not produce a bias in favour of rivaroxaban; this was ensured by: The blinded adjudication committee An independent data and safety monitoring board Random assignment via voice-response system 47 The fast-acting, oral, single-drug solution with rivaroxaban proved to be as effective for the treatment of PE as the complex dualdrug approach of subcutaneous LMWH and VKA Importantly, rivaroxaban proved again its reassuring safety profile. This is consistent with the excellent findings of EINSTEIN DVT and EINSTEIN EXT, but also ROCKET AF, ATLAS ACS 2 TIMI 51 and RECORD1 4

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