Otamixaban for non-st-segment elevation acute coronary syndrome

Transcription

1 Otamixaban for non-st-segment elevation acute coronary syndrome September 2011 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research

2 Otamixaban for non-st-segment elevation acute coronary syndrome Target group Non-ST elevation acute coronary syndrome (NSTE ACS) patients undergoing planned invasive treatment. Technology description Otamixaban is a reversible, direct selective factor Xa inhibitor. The inhibition of factor Xa prevents the coagulation cascade through decreased generation and activity of thrombin. Otamixaban is administered by intravenous (IV) bolus followed by IV infusion. In phase III clinical trials otamixaban is administered as a 0.08mg/kg bolus, followed by continuous IV infusion at 0.1mg/kg/hr or 0.14mg/kg/hr continued until the end of percutaneous coronary intervention, up to day 4 or hospital discharge if medically indicated. The company report that the final dose regimen will be decided following an interim analysis of the ongoing phase III trial. Innovation and/or advantages If licensed, otamixaban would allow rapid anticoagulant treatment for patients with NSTE ACS who are planned to undergo invasive procedures without the need for either anticoagulation monitoring or dose adjustment in special patient groups (such as renal impairment or the elderly). Developer Sanofi. Availability, launch or marketing dates, and licensing plans In phase III clinical trials. NHS or Government priority area None identified Relevant guidance NICE Technology Appraisals In development. Ticagrelor for the treatment of ACS. Expected October Clopidogrel and modified-release dipyridamole for the prevention of occlusive 2 vascular events (review of TA90) Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary 3 intervention Drug-eluting stents for the treatment of coronary artery disease Clopidogrel in the treatment of non-st-segment-elevation acute coronary syndrome Ischaemic heart disease coronary artery stents (review) Glycoprotein IIb/IIIa inhibitors in the treatment of coronary syndromes NICE Clinical Guidelines Unstable angina and NSTEMI: the early management of unstable angina and non- ST-segment-elevation myocardial infarction

3 European Society of Cardiology. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation SIGN. Acute Coronary Syndromes Bassand et al. Guidelines for the diagnosis and treatment of non-st-segment 11 elevation acute coronary syndromes Acute Coronary syndrome Guidelines Working Group. Guidelines for the 12 management of acute coronary syndrome University of Warwick, Joint Royal Colleges Ambulance Liaison Committee. Acute coronary syndrome Clinical need and burden of disease ACS encompasses a spectrum of disease including unstable angina, NSTE myocardial infarction (MI) and ST elevation myocardial infarction (STEMI), usually caused by coronary atherosclerosis. In a large proportion of cases the episode of coronary occlusion arises from thrombus formation on atheromatous plaques 8. Left untreated, prognosis is poor and mortality is high, particularly in people who have myocardial damage 11. Lacking a unique ICD code, the diagnosis of NSTE ACS (which overlaps unstable angina and NSTE MI) is more difficult to establish than STEMI and therefore its prevalence is harder to estimate 11. The annual incidence of hospital admission for NSTE ACS is approximately 3 per 1,000 population in Europe 11. Hospital mortality is higher in patients with STEMI than among those with NSTE ACS (7% vs 5%, respectively), but at 6 months, the mortality rates are very similar in both conditions (12% vs 13%, respectively) 11. In , there were 75,088 admissions to hospital for angina pectoris (ICD10 I20) in England, of which 39,368 were specified as unstable angina (ICD10 I20.0) 14. In the same time period, there were 56,784 admissions for acute myocardial infarction (MI) (ICD10 I21) and 27,704 FCEs for subsequent MIs (ICD10 I22) 14. The number of percutaneous coronary interventions (PCI) for all indications has increased significantly in recent decades, with 83,130 PCI procedures being performed in 2009 with approximately 38% of these being undertaken for NSTE ACS 15. In 2008, 29,330 deaths from acute MI (ICD10 I21) occurred in England and Wales 16. Existing comparators and treatments Current guidelines recommend four categories of treatment 8,11 : Antiplatelet agents aspirin, thienopyridines (eg. ticlopidine and clopidogrel), prasugrel (undergoing PCI), and/or glycoprotein IIb/IIIa inhibitors (eg. abciximab [undergoing PCI], eptifibatide and tirofiban). Anti-ischaemic agents reduce myocardial oxygen consumption and/or induce vasodilation: beta blockers, nitrates, calcium channel blockers. Anticoagulants inhibit thrombin generation and/or activity, thereby reducing thrombus-related events: unfractionated heparin (UFH), low molecular weight heparin, factor Xa inhibitors (eg. fondaparinux), direct thrombin inhibitors (eg. hirudin, argatroban, bivalirudin) and vitamin K antagonists. Revascularisation to relieve angina and ongoing myocardial ischaemia: thrombolysis, PCI angioplasty with or without stent placement, or coronary artery bypass grafting (CABG). Approach dependent on the extent and severity of lesions. 3

4 Efficacy and safety Trial NCT , EFC6204; otamixaban vs UFH and eptifibatide; phase III. NCT , DRI6624; otamixaban vs UFH and eptifibatide; phase II. Sponsor Sanofi. Sanofi. Status Ongoing. Completed. Source of Trial registry 17. Manufacturer, trial registry, information publication 19. Location EU (inc UK), USA, Canada and other countries. EU, USA, Canada and other countries. Design Randomised, active-controlled. Randomised, active-controlled. Participants and schedule Follow-up Primary outcomes Secondary outcomes n=13,220 (planned); adults; NSTE ACS; ischaemic symptoms at rest within 24 hrs of trial entry; planned coronary angiography within 36 hrs; either new ST-segment depression/transient ST segment elevation on ECG, or elevation of cardiac biomarkers. Randomised to otamixaban 0.08mg/kg bolus followed by infusion at one of 2 dose levels (0.10 or 0.14mg/kg/hr) until planned interim analysis, after which a single dose will be carried forward; or UFH 60 U/kg bolus (maximum 4,000U) followed by 12 U/kg/hr infusion (maximum 1,000 U/hr) and eptifibatide 180µg/kg bolus (maximum 22.6mg) administered prior to PCI initiation, followed by 2µg/kg/min infusion (decreased to 1 µg/kg if creatinine clearance <50ml/min) and second 180µg/kg bolus. Otamixaban arm receive IV bolus and UFH matching placebo until PCI, day 4 or hospital discharge, and eptifibatide matching placebo up to 24 hrs post-pci. Active comparator group receive otamixaban matching placebo and UFH until PCI, day 4 or hospital discharge, and eptifibatide up to 24 hrs post- PCI. Active treatment period 7 days. Follow up between 30 and 180 days. Primary efficacy endpoint: all-cause death or MI until day 7; primary safety endpoint: thrombolysis in MI (TIMI) significant bleeding until day 7. All-cause death, stroke and MI until day 7; prolonged hospital admission/readmission due to myocardial ischemia/mi until day 30; allcause death until day 30; thrombotic procedural complications during PCI; safety. n=3,241; adults; NSTE ACS; ischaemic symptoms at rest within 24 hrs of trial entry; planned coronary angiography within 36 hrs; either new ST-segment depression/transient ST segment elevation on ECG, or elevation of cardiac biomarkers. Randomised to otamixaban (0.08mg/kg IV bolus followed by 1 of 5 infusion doses: 0.035mg/kg/h, mg/kg/h, mg/kg/h, mg/kg/h or 0.175mg/kg/h), and UFH matching placebo until PCI, day 4 or hospital discharge, and eptifibatide matching placebo for up to 24 hrs post-pci; or otamixaban matching placebo and UFH until PCI, day 4 or hospital discharge, and eptifibatide for up to 24 hrs post-pci. Active treatment period 7 days. Follow up 30, 90 and 180 days. Primary efficacy endpoint: composite of death, MI, urgent revascularisation, or bailout glycoprotein IIb/IIIa inhibitor use until day 7; primary safety endpoint: TIMI major or minor bleeding outcomes, not related to coronaryartery bypass grafting. Individual components of composite endpoint at 7 days; composite endpoint at 180 days; thrombotic complications; stroke. 4

5 Key results - For 0.035mg/kg/h, 0.070mg/kg/h, 0.105mg/kg/h, 0.140mg/kg/h and 0.175mg/kg/h otamixaban and control groups respectively: Primary efficacy endpoint, % (RR), 7.2% (1.6, 95% CI ), 4.6% (0.74, ), 3.8% (0.61, ), 3.6% (0.58, ), 4.3% (0.69, ) (p=0.34 for trend) and 6.2%. Primary safety endpoint, 1.6%, 1.6%, 3.1%, 3.4%, 5.4% and 2.7% (p= for otamixaban vs control). Expected completion date Sept Trial Sponsor Status Source of information Location Design Participants and schedule Follow-up Primary outcome Secondary outcomes Key results Adverse effects NCT , DRI6199; adults; otamixaban vs UFH; phase II. Sanofi. Completed. Manufacturer, trial registry 20, publication 21. EU, USA, Canada and other countries. Randomised, active-controlled. n=947; adults; NSTE ACS; due to undergo non-urgent PCI, planned treatment with aspirin and clopidogrel. Randomised before PCI to otamixaban and UFH placebo, or UFH and otamixaban placebo. Otamixaban group receive IV bolus followed by a 3 hr infusion at 1 of 5 dose levels: 0.025mg/kg and 0.035mg/kg/h, 0.045mg/kg and 0.065mg/kg/h, 0.080mg/kg and 0.120mg/kg/h or 0.140mg/kg and 0.200mg/kg/h. UFH group receive 50-70U/kg. Patients remained in hospital for at least 18 hrs following infusions. Follow up 30 days. Change in thrombin fragments (F1+2) and anti-factor Xa activity. TIMI bleeding at day 3 or hospital discharge; 30 day ischaemic events. Median change in F1+2 at end of infusion for highest otamixaban dose vs placebo, -0.3 vs -0.2ng/mL (p=0.008). Anti-factor Xa levels, 65, 155, 393, 571, and 691ng/mL in otamixaban doses 1 to 5 respectively. Significant TIMI bleeding (major or minor) occurred in 2.0%, 1.9%, 3.8%, 3.9%, and 2.6% of patients receiving otamixaban doses 1 to 5 respectively, and in 3.8% of patients receiving UFH. 4 TIMI major bleeds were observed, 1 in each of the highest otamixaban groups and 2 in UFH group. Ischaemic events occurred in 5.8%, 7.1%, 3.8%, 2.5%, and 5.1% of patients receiving otamixaban doses 1 to 5 respectively, and in 5.6% of patients receiving UFH. Estimated cost and cost impact The cost of otamixaban is not yet known. 5

6 Claimed or potential impact speculative Patients Reduced mortality or increased length of survival Other: Reduction in associated morbidity or Improved quality of life for patients and/or carers Quicker, earlier or more accurate diagnosis or identification of disease None identified Services Increased use: IV administration. Service organisation Staff requirements Costs Decreased use: no requirement for monitoring of anticoagulation. Increased unit cost compared to alternative Other: Increased costs: more patients coming for treatment None identified Increased costs: capital investment needed New costs: Savings: Other: unknown unit cost compared to alternative anticoagulant regimens. Other issues Clinical uncertainty or other research question identified: Expert suggests direct comparison with other factor Xa inhibitors needed to guide treatment decisions. References 1 National Institute for Health and Clinical Excellence. Ticagrelor for the treatment of acute coronary syndromes (ACS). Technology appraisal in development. Expected October National Institute for Health and Clinical Excellence. Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events. Technology appraisal TA210. London: NICE; December National Institute for Health and Clinical Excellence. Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention. Technology appraisal TA182. London: NICE; October National Institute of Health and Clinical Excellence. Drug-eluting stents for the treatment of coronary artery disease. Technology appraisal TA152. London: NICE; July National Institute for Health and Clinical Excellence. Clopidogrel in the treatment of non-st-segment elevation acute coronary syndrome. Technology appraisal TA80. London: NICE; July National Institute of Health and Clinical Excellence. Ischaemic heart disease - coronary artery stents. Technology appraisal TA71. London: NICE; October National Institute of Health and Clinical Excellence. Glycoprotein Ilb/llla inhibitors in the treatment of acute coronary syndromes. Technology appraisal TA47. London: NICE; September Reviewed July National Institute of Health and Clinical Excellence. Unstable angina and NSTEMI. The early management of unstable angina and non-st-segment-elevation myocardial infarction. Clinical guideline CG94. London: NICE; March Hamm CW, Bassand JP, Agewall S et al. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. European Heart Journal 2011;32(16). 10 Scottish Intercollegiate Guidelines Network. Acute coronary syndromes. Clinical guideline 93. Edinburgh: SIGN; February Bassand JP, Hamm CW and Ardissino D. Guidelines for the diagnosis and treatment of non-st-segment elevation acute coronary syndromes. European Heart Journal. 2007;28(13): Anderson JL, Adams CD and Antman EM. Guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology 2007;50:e1-e University of Warwick, Joint Royal Colleges Ambulance Liaison Committee. Acute coronary syndrome. Care guideline. JRCALC; October NHS. Hospital episode statistics. NHS England. HES data British Cardiovascular Intervention Society. National Audit of Angioplasty Procesdures Office for National Statistics. Mortality statistics. Deaths registered in 2008; Accessed 26 July

7 17 ClinicalTrials.gov. Effect of otamixaban versus unfractionated heparin and eptifibatide in patients with unstable angina/non ST elevation myocardial infarction undergoing early invasive strategy (TAO). Accessed 27 July ClinicalTrials.gov. Study of otamixaban versus unfractionated heparin (UFH) and eptifibatide in non-st elevation acute coronary syndrome (SEPIA-ACS1). Accessed 27 July Sabatine MS, Antman EM, Widimsky P et al. Otamixaban for the treatment of patients with non-st elevated acute coronary syndrome (SEPIA-ACS TIMI 42): a randomised, double-blind, active controlled phase II trial. Lancet 2009;374: ClinicalTrials.gov. The SEPIA-PCI Trial: Otamixaban in comparison to heparin in subjects undergoing nonurgent percutaneous coronary intervention. Accessed 27 July Cohen M, Bhatt DL, Alexander JH et al. Randomized, double-blind, dose-ranging study of otamixaban, a novel, parenteral, short-acting direct factor Xa inhibitor, in percutaneous coronary intervention, the sepia trial. Circulation 2007;115: The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B15 2SP, England Tel: +44 (0) Fax +44 (0)