Horizon Scanning Centre September 2014

Betrixaban for the prevention of venous thromboembolism – first line

SUMMARY NIHR HSC ID: 4239

Betrixaban is intended to be used for the first-line prevention of venous thromboembolism (VTE) in acute medically ill patients (including one of the following: congestive heart failure, acute respiratory failure, acute infection without septic shock, acute rheumatic disorders or acute ischemic with lower extremity hemiparesis or hemi paralysis) in the in-hospital and post- discharge settings. If licensed, betrixaban will offer an oral treatment to prevent VTE, in a patient group who do not currently have a licensed factor Xa inhibitor available, and that extends into the post This briefing is discharge period. Betrixaban is a small molecule factor Xa inhibitor which based on acts as an anticoagulant to prevent thrombosis. Factor Xa is a key information component of the coagulation pathway, directly converts prothrombin to available at the time (factor IIa), via the prothrombinase complex, which in turn converts of research and a fibrinogen to fibrin to form clots. An excess tendency to form clots is an limited literature important contributor to VTE. Betrixaban does not currently have a Marketing search. It is not Authorisation in the EU for any indication. intended to be a definitive statement VTE is a common condition which encompasses pulmonary embolism (PE) on the safety, and deep vein thrombosis (DVT). VTE has an annual incidence of efficacy or approximately 2 in 1,000 population. However, the risk of VTE varies effectiveness of the substantially with age; for people aged under 40 years incidence of VTE is 1 health technology per 10,000 population, whereas for those over 80 years, the incidence rises covered and should to 1 per 100 population. Data indicate that over half of VTE events in not be used for hospitalised medical patients occur after discharge. In 2012-13, there were commercial 23,578 admissions for PE and 18,714 for DVT in England, resulting in purposes or 202,305 and 69,280 bed-days and 45,626 and 25,165 finished consultant commissioning episodes respectively. In 2012, in England and Wales there were 2,075 without additional deaths recorded due to PE and 2,903 due to DVT, however this is likely to be information. an underestimate and could be as high as 25,000 deaths .

VTE prophylaxis in patients hospitalised for medical conditions involves assessing the patient’s risk of VTE and applying appropriate prophylactic inventions. These include either pharmacological VTE prophylaxis usually in the form of anticoagulant drugs for those assessed as being at high risk of VTE and low risk of bleeding or mechanical VTE prophylaxis in those where the risk of bleeding is higher than the risk of VTE. Betrixaban is currently in phase III clinical trials comparing its effect on the number of VTE (DVT and/or PE) occurrences and VTE deaths against treatment with enoxaparin. This trial is expected to complete in September 2015.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre

TARGET GROUP

• Prevention of venous thromboembolism (VTE): in acute medically ill patients (one of: congestive heart failure, acute respiratory failure, acute infection without septic shock, acute rheumatic disorders or acute ischemic stroke with lower extremity hemiparesis or hemi paralysis) in hospitalised and post-discharge patients - first line.

TECHNOLOGY

DESCRIPTION

Betrixaban (MK-448; MLN-004; PRT054021) is a small molecule factor Xa inhibitor which acts as an anticoagulant to prevent thrombosis. Factor Xa, a key component of the coagulation pathway, directly converts prothrombin to thrombin (factor IIa), via the prothrombinase complex, which in turn converts fibrinogen to fibrin to form clots1. An excess tendency to form clots is an important contributor to venous thromboembolism (VTE). Betrixaban is intended to be used for the first-line prevention of VTE in acute medically ill patients (including one of the following: congestive heart failure, acute respiratory failure, acute infection without septic shock, acute rheumatic disorders or acute ischemic stroke with lower extremity hemiparesis or hemi paralysis) in both the in-hospital and post-discharge settings. In the phase III , betrixaban is administered orally at 80mg once daily for up to 35 days in hospital and post-discharge.

Betrixaban does not currently have a Marketing Authorisation in the EU for any indication.

Betrixaban is also in phase II clinical trials for stroke prevention in patients with .

INNOVATION and/or ADVANTAGES

If licensed, betrixaban will offer an oral anticoagulant treatment to prevent VTE, in a patient group for whom there is currently no licensed factor Xa inhibitor available, and that extends into the post discharge period.

DEVELOPER

Portola Pharmaceuticals.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

VTE, which typically arises from a deep vein thrombosis (DVT) and leads to pulmonary embolism (PE), is a leading cause of morbidity and mortality in hospitalised patients2, the treatment of which creates a considerable cost to the health service3. In DVT a thrombus forms in one of the deep veins, usually of the lower limbs4. Following a DVT, dislodged

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thrombi may travel to the lungs causing a PE4. PE has the potential to cause sudden death, and those who survive may require intensive care with a recovery that can take several weeks or months. DVT can itself also cause long-term morbidity, such as the development of post-thrombotic syndrome, a chronic disorder which may include pain, heaviness, swelling, cramps, itching, increased skin pigmentation and ulceration of the affected limb4. A number of risk factors, including hereditary factors, can predispose patients to VTE, however hospital-acquired VTE is associated with immobilisation, acute medical illness, surgery, cancer and cancer therapy, trauma, central venous catheters, previous history of VTE, older age and obesity2. The majority of patients hospitalised for medical conditions will have at least one VTE risk factor, and approximately 40% will have three or more risk factors2; prophylactic treatment for VTE is therefore recommended in such patients.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • NHS Commissioning Board. Commissioning for quality and innovation (CQUIN): 2013/14 guidance.

CLINICAL NEED and BURDEN OF DISEASE

The annual incidence of VTE is approximately 2 per 1,000 population and the annual incidence of diagnosed PE in the UK has been reported as 7-8 per 10,000 population5. The risk varies substantially with age; for people under 40 years the annual incidence of VTE is 1 per 10,000, whereas for people aged over 80 years, the incidence rises to 1 in 1002. Data indicate that patients are at particular risk up to 19 days after hospital admission and over half (57%) of VTE events in hospitalised medical patients occur after discharge (US data)6. In addition, people who have had an episode of VTE have a risk of recurrence within 8 years of approximately 30%2. However, the risk of recurrence decreases substantially with time and may vary according to the treatment received2.

In 2012-13 there were 23,578 admissions for PE (ICD10 I26.0-I26.9) and 18,714 for DVT (ICD10 I80.1-I80.3) in England, resulting in 202,305 and 69,280 bed-days and 45,626 and 25,165 finished consultant episodes, respectively7. In 2012, in England and Wales there were 2,075 deaths recorded as due to PE (ICD10 I26.0-I26.9) and 2,903 due to DVT (ICD10 I80.1-I80.3)8, however the actual number of those dying from these conditions is likely to be higher due to misdiagnosis and the failure to recognise VTE as the underlying cause9. A report from the House of Commons Health Committee published in 2005 estimated that 25,000 people in the UK die from preventable hospital-acquired VTE each year, including patients admitted to hospital for medical care and surgery10. In 2013, in England there were over 11.4 million prescription items for oral dispensed in the community at a 11 net ingredient cost of almost £43.5 million . Approximately 434,000 prescriptions for parenteral anticoagulants were made in England in 2013 at a net ingredient cost of around £50.3 million11.

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PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. tosylate for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism (ID662). Expected date of issue October 2015. • NICE technology appraisal in development. for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism (ID726). Expected date of issue June 2015. • NICE technology appraisal in development. etexilate for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism (ID483). Expected date of issue October 2014. • NICE technology appraisal. for treating pulmonary embolism and preventing recurrent venous thromboembolism (TA287). June 2013. • NICE technology appraisal. Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism (TA261). July 2012.

• NICE clinical guideline. Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing (CG144). June 2012. • NICE clinical guideline. Venous thromboembolism: reducing the risk: Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital (CG92). January 2010. • NICE quality standard. Quality standard for diagnosis and management of venous thromboembolic diseases (QS29). March 2013. • NICE quality standard. Venous thromboembolism prevention quality standard (QS3). June 2010. • NICE Medical Technology Guidance. The geko device for reducing the risk of venous thromboembolism (MTG19). June 2014.

Other Guidance

• SIGN. : indications and management. 201312. • The Finnish Medical Society Duodecim. Prevention of venous thromboembolism. 201313. • The Cochrane Collaboration. Interventions for implementation of thromboprophylaxis in hospitalized medical and surgical patients at risk for venous thromboembolism (Review). 20132. • therapy and prevention of thrombosis, 9th Ed: American College of Chest physicians evidence-based clinical practice guidelines. 201214. • British Committee for Standards in Haematology. Care Guideline. Guidelines on oral anticoagulation with - fourth edition. 201115. • Department of Health. Risk assessment for venous thromboembolism (VTE). 201016. • SIGN. Prevention and management of venous thromboembolism. 201017. • The Intensive Care Society. Venous thromboprophylaxis in critical care. Standards and Guidelines. 200818.

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CURRENT TREATMENT OPTIONS

Reducing the risk of VTE in patients hospitalised for medical conditions involves assessing the patient’s risk of VTE and applying appropriate prophylactic inventions, of which a range are available10,19.

• Pharmacological VTE prophylaxis – usually in the form of anticoagulant drugs for those assessed as being at high risk of VTE and low risk of bleeding. Options include: o Low molecular weight (LMWH) including dalteparin and enoxaparin. o Unfractionated heparin (for patients with renal failure). o Rivaroxaban (not specifically licensed for prophylaxis in medically hospitalised patients). o Dabigatran etexilate . o Apixaban (not specifically licensed for prophylaxis in medically hospitalised patients). o (not specifically licensed for prophylaxis in medically hospitalised patients).

• Mechanical VTE prophylaxis – a number of non-pharmacological mechanical methods are available to reduce the risk of VTE in those where the risk of bleeding is higher than the risk of VTE10,19. Options include: o Anti-embolism stockings. o Foot impulse devices. o Intermittent pneumatic compression devices. o Geko device – recommended for those at high risk of VTE and for whom other mechanical and pharmacological prophylaxis methods are impractical or contraindicated20.

EFFICACY and SAFETY

Trial APEX, NCT01583218, EudraCT No. 2012-000255-13, 11-019; betrixaban or enoxaparin vs placebo; phase III. Sponsor . Status Ongoing. Source of Trial registry21, company website22. information Location EU (incl UK), USA, Canada and other countries. Design Randomised, active-controlled. Participants n=6,850 (planned); aged ≥40 years; patients anticipated to be severely immobilised for ≥24 hrs; hospitalised with one of following: congestive heart failure; acute respiratory failure; acute infection without septic shock; acute rheumatic disorders; acute ischemic stroke with lower extremity hemiparesis or hemi paralysis.

Patients excluded if: condition requires prolonged anticoagulation or anti-platelet therapy; active bleeding or at high risk of bleeding; other contraindication to anticoagulant therapy. Schedule Randomised to betrixaban 80mg administered orally (OR) once daily for 35 days with enoxaparin placebo administered subcutaneously (SC) once daily for 6-14 days; or enoxaparin 40mg SC for 10 days with betrixaban placebo OR once daily for 35 days. Follow-up Active treatment for 35 days, follow-up at 35 days. Primary Number of VTE (DVT and/or PE) occurrences and VTE deaths. outcome/s Secondary Number of patients with symptomatic VTE. outcome/s No quality of life measurement included in trial outcomes.

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Expected Estimated study completion date reported as Sept 2015. reporting date

ESTIMATED COST and IMPACT

COST

The cost of betrixaban is not yet known. The costs of other selected oral anticoagulants for use in patients hospitalised for medical conditions are as follows:

Drug Dose23 Unit cost23 Unfractionated Thromboprophylaxis in medical Heparin sodium (1,000 units/mL): heparin. patients 5,000 units SC every 8–12 1mL ampule - £1.49 hrs. 5mL ampule - £3.75

Heparin sodium (5,000 units/mL): 1mL ampule - £2.90 5mL ampule - £7.58

Fondaparinux Prophylaxis of VTE - 2.5mg SC once 2.5mg prefilled syringe costs £6.28. sodium (Arixtra). daily. Enoxaparin Prophylaxis of DVT in medical patients 100mg/mL: (Clexane). – 40mg SC every 24 hrs. 20mg (0.2mL) syringe - £2.27 40mg (0.4mL) syringe - £3.03 Dalteparin Prophylaxis of DVT in medical patients 2,500units/mL: (Fragmin). – 5,000 units SC every 24 hrs. 4mL (10,000-unit) ampule - £5.12.

10,000unit/mL: 1mL (10,000-unit) ampule - £5.12.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other:  No impact identified

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs:

 Other: uncertain unit cost compared to  None identified existing treatments

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Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 Mueck W, Stampfuss J, Kubitza D, and Becka M. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clinical 2014; 53:1-16. 2 Kahn SR, Morrison DR, Cohen JM et al. Interventions for implementation of thromboprophylaxis in hospitalized medical and surgical patients at risk for venous thromboembolism (Review). Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD008201. DOI:10.1002/14651858.CD008201.pub2. 3 House of Commons Health Committee. The prevention of venous thromboembolism in hospitalised patients. London: The Stationery Office Limited 2005. 4 National Institute of Health and Care Excellence. Apixaban for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism; Final scope. London: NICE; August 2014. 5 National Institute of Health and Clinical Excellence. Final scope for the appraisal of Rivaroxaban for the treatment of pulmonary embolism and the prevention of recurrent venous thromboembolism. London: NICE; November 2012. 6 Amin AN, Varker H, Princic N, et al. Duration of venous thromboembolism risk across a continuum in medically ill hospitalized patients. Journal of Hospital Medicine 2012;7(3):231-238. 7 Health & Social Care Information Centre. Hospital episode statistics, admitted patient care, England – 2012-13: Diagnosis. www.hscic.gov.uk 8 Office for National Statistics. Mortality statistics: Deaths registered in England and Wales (Series DR), 2012. www.ons.gov.uk 9 Patient.co.uk. Deep Vein Thrombosis: Epidemiology. www.patient.co.uk/doctor/deep-vein- thrombosis-pro Accessed 5 September 2014. 10 National Institute of Health and Clinical Excellence. Venous thromboembolism: reducing the risk: Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital. NICE clinical guideline CG92. London: NICE; January 2010. 11 Health & Social Care Information Centre. Prescription cost analysis, England - 2013. www.ons.gov.uk 12 Scottish Intercollegiate Guidelines Network. Antithrombotics: indications and management: A national clinical guideline. SIGN 129. Edinburgh: SIGN; June 2013. 13 Finnish Medical Society Duodecim. Prevention of venous thromboembolism: EBM Guidelines. December 2013. 14 Kearon C, Akl EA Comerota AJ et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines. Chest 2012;141(2 suppl):e419S-94S. 15 Keeling D, Baglin T, Tait C et al. British Committee for Standards in Haematology: Guidelines on oral anticoagulation with warfarin - fourth edition. British Journal of Haematology 2011;154(3):311-324. 16 Department of Health. Risk assessment for venous thromboembolism (VTE). London: DOH; March 2010. 17 Scottish Intercollegiate Guidelines Network. Prevention and management of venous thromboembolism: A national clinical guideline. SIGN.122. Edinburgh: SIGN; December 2010. 18 The Intensive Care Society. Venous thromboprophylaxis in critical care. Standards and Guidelines. Guys and St Thomas’ NHS Trust. London. 2008. 19 National Institute of Health and Care Excellence. Reducing the risk of venous thromboembolism in hospital patients. NICE Pathways. London: NICE; June 2014. 20 National Institute of Health and Care Excellence. The geko device for reducing the risk of venous thromboembolism. NICE Medical Technology Guidance MTG19. London: NICE; June 2014. 21 ClinicalTrial.gov. Acute medically Ill VTE prevention with extended duration betrixaban study (The APEX Study). www.clinicaltrials.gov/ct2/show/study/NCT01583218 Accessed 4th September 2014.

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22 Portola.com. Clinical Trials: Betrixaban. www.portola.com/clinical-development/clinical-trials/ Accessed 4th September 2014. 23 bnf.org. British National Formulary (BNF) – September 2014. www.bnf.org Accessed 8 September 2014.

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