Otamixaban for non-ST-segment elevation

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

September 2011

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 . 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 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 .

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 1 • In development. for the treatment of ACS. Expected October 2011 . • and modified-release for the prevention of occlusive vascular events (review of TA90). 20102. • for the treatment of acute coronary syndromes with percutaneous coronary intervention. 20093. 4 • Drug-eluting stents for the treatment of coronary artery disease. 2008 . • Clopidogrel in the treatment of non-ST-segment-elevation acute coronary syndrome. 20045. 6 • Ischaemic heart disease – coronary artery stents (review). 2003 . 7 • Glycoprotein IIb/IIIa inhibitors in the treatment of coronary syndromes. 2002 .

NICE Clinical Guidelines • Unstable angina and NSTEMI: the early management of unstable angina and non- ST-segment-elevation myocardial infarction. 20108.

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• European Society of Cardiology. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. 20119. 10 • SIGN. Acute Coronary Syndromes. 2007 . • Bassand et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. 200711. • Acute Coronary syndrome Guidelines Working Group. Guidelines for the management of acute coronary syndrome. 200612. • University of Warwick, Joint Royal Colleges Ambulance Liaison Committee. Acute coronary syndrome. 200613.

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 plaques8. Left untreated, prognosis is poor and mortality is high, particularly in people who have myocardial damage11.

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 estimate11. The annual incidence of hospital admission for NSTE ACS is approximately 3 per 1,000 population in Europe11. 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 2009-10, 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 ACS15. In 2008, 29,330 deaths from acute MI (ICD10 I21) occurred in England and Wales16.

Existing comparators and treatments Current guidelines recommend four categories of treatment8,11: • Antiplatelet agents – , (eg. and clopidogrel), prasugrel (undergoing PCI), and/or glycoprotein IIb/IIIa inhibitors (eg. [undergoing PCI], and ). • Anti-ischaemic agents – reduce myocardial oxygen consumption and/or induce vasodilation: beta blockers, nitrates, calcium channel blockers. • – inhibit thrombin generation and/or activity, thereby reducing thrombus-related events: unfractionated (UFH), low molecular weight heparin, factor Xa inhibitors (eg. ), direct thrombin inhibitors (eg. , , ) and vitamin K antagonists. • Revascularisation – to relieve angina and ongoing myocardial ischaemia: , PCI angioplasty with or without stent placement, or coronary artery bypass grafting (CABG). Approach dependent on the extent and severity of lesions.

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Efficacy and safety

Trial NCT01076764, EFC6204; otamixaban vs UFH NCT00317395, DRI6624; and eptifibatide; phase III. otamixaban vs UFH and eptifibatide; phase II. Sponsor Sanofi. Sanofi. Status Ongoing. Completed. Source of Trial registry17. Manufacturer, trial registry18, information publication19. Location EU (inc UK), USA, Canada and other EU, USA, Canada and other countries. countries. Design Randomised, active-controlled. Randomised, active-controlled. Participants n=13,220 (planned); adults; NSTE ACS; n=3,241; adults; NSTE ACS; and schedule ischaemic symptoms at rest within 24 hrs of ischaemic symptoms at rest within trial entry; planned coronary angiography 24 hrs of trial entry; planned within 36 hrs; either new ST-segment coronary angiography within 36 hrs; depression/transient ST segment elevation on either new ST-segment ECG, or elevation of cardiac biomarkers. depression/transient ST segment elevation on ECG, or elevation of Randomised to otamixaban 0.08mg/kg bolus cardiac biomarkers. followed by infusion at one of 2 dose levels (0.10 or 0.14mg/kg/hr) until planned interim Randomised to otamixaban analysis, after which a single dose will be (0.08mg/kg IV bolus followed by 1 carried forward; or UFH 60 U/kg bolus of 5 infusion doses: 0.035mg/kg/h, (maximum 4,000U) followed by 12 U/kg/hr 0.070 mg/kg/h, 0.105 mg/kg/h, 0.140 infusion (maximum 1,000 U/hr) and mg/kg/h or 0.175mg/kg/h), and UFH eptifibatide 180µg/kg bolus (maximum matching placebo until PCI, day 4 or 22.6mg) administered prior to PCI initiation, hospital discharge, and eptifibatide followed by 2µg/kg/min infusion (decreased to matching placebo for up to 24 hrs 1 µg/kg if creatinine clearance <50ml/min) and post-PCI; or otamixaban matching second 180µg/kg bolus. placebo and UFH until PCI, day 4 or hospital discharge, and eptifibatide Otamixaban arm receive IV bolus and UFH for up to 24 hrs post-PCI. 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. Follow-up Active treatment period 7 days. Follow up Active treatment period 7 days. between 30 and 180 days. Follow up 30, 90 and 180 days. Primary Primary efficacy endpoint: all-cause death or Primary efficacy endpoint: outcomes MI until day 7; primary safety endpoint: composite of death, MI, urgent thrombolysis in MI (TIMI) significant bleeding revascularisation, or bailout until day 7. glycoprotein IIb/IIIa inhibitor use until day 7; primary safety endpoint: TIMI major or minor bleeding outcomes, not related to coronary- artery bypass grafting. Secondary All-cause death, stroke and MI until day 7; Individual components of composite outcomes prolonged hospital admission/readmission due endpoint at 7 days; composite to myocardial ischemia/MI until day 30; all- endpoint at 180 days; thrombotic cause death until day 30; thrombotic complications; stroke. procedural complications during PCI; safety. 4 September 2011

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 0.56-2.38), 4.6% (0.74, 0.45-1.21), 3.8% (0.61, 0.36- 1.02), 3.6% (0.58, 0.34-1.00), 4.3% (0.69, 0.42-1.15) (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=0.0001 for otamixaban vs control). Expected Sept 2012. - completion date

Trial NCT00133731, DRI6199; adults; otamixaban vs UFH; phase II. Sponsor Sanofi. Status Completed. Source of Manufacturer, trial registry20, publication21. information Location EU, USA, Canada and other countries. Design Randomised, active-controlled. Participants n=947; adults; NSTE ACS; due to undergo non-urgent PCI, planned treatment with and schedule 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 Follow up 30 days. Primary Change in thrombin fragments (F1+2) and anti-factor Xa activity. outcome Secondary TIMI bleeding at day 3 or hospital discharge; 30 day ischaemic events. outcomes Key results 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. Adverse 4 TIMI major bleeds were observed, 1 in each of the highest otamixaban groups and 2 effects 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 September 2011

Claimed or potential impact – speculative

Patients Reduced mortality or increased  Reduction in associated morbidity Quicker, earlier or more accurate length of survival or Improved quality of life for diagnosis or identification of patients and/or carers disease Other: None identified

Services  Increased use: IV administration. Service organisation Staff requirements

 Decreased use: no requirement Other: None identified for monitoring of anticoagulation. Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment 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 2011. 2 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 2010. 3 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 2009. 4 National Institute of Health and Clinical Excellence. Drug-eluting stents for the treatment of coronary artery disease. Technology appraisal TA152. London: NICE; July 2008. 5 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 2004. 6 National Institute of Health and Clinical Excellence. Ischaemic heart disease - coronary artery stents. Technology appraisal TA71. London: NICE; October 2003. 7 National Institute of Health and Clinical Excellence. Glycoprotein Ilb/llla inhibitors in the treatment of acute coronary syndromes. Technology appraisal TA47. London: NICE; September 2002. Reviewed July 2010. 8 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 2010. 9 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 2007. 11 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):1598-1660. 12 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-e157. 13 University of Warwick, Joint Royal Colleges Ambulance Liaison Committee. Acute coronary syndrome. Care guideline. JRCALC; October 2006. 14 NHS. Hospital episode statistics. NHS England. HES data 2009-10. www.hesonline.nhs.uk 15 British Cardiovascular Intervention Society. National Audit of Angioplasty Procesdures 2010. www.ic.nhs.uk 16 Office for National Statistics. Mortality statistics. Deaths registered in 2008; http://www.statistics.gov.uk/downloads/theme_health/DR2008/DR_08.pdf Accessed 26 July 2011. 6 September 2011

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). http://www.clinicaltrials.gov/ct2/show/study/NCT01076764 Accessed 27 July 2011. 18 ClinicalTrials.gov. Study of otamixaban versus unfractionated heparin (UFH) and eptifibatide in non-ST elevation acute coronary syndrome (SEPIA-ACS1). http://clinicaltrials.gov/ct2/show/NCT00317395 Accessed 27 July 2011. 19 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;374:787-95. 20 ClinicalTrials.gov. The SEPIA-PCI Trial: Otamixaban in comparison to heparin in subjects undergoing non- urgent percutaneous coronary intervention. http://clinicaltrials.gov/ct2/show/NCT00133731 Accessed 27 July 2011. 21 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;115:2642-2651.

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