NICE asks for more information on new drug to treat blood clots

NICE, the healthcare guidance body, is currently appraising rivaroxaban (Xarelto, Bayer) for the treatment of deep vein thrombosis (DVT) and preventing recurrent DVT and pulmonary embolism (PE) following an acute DVT in adults. In draft guidance issued today (13 March) for consultation NICE requests Bayer, the manufacturer of rivaroxaban, to provide further evidence relating to the drug's clinical and cost effectiveness.

Venous thromboembolism (VTE) is a term used to describe DVT and PE. DVT is the formation of a thrombus (clot) in a deep vein, usually of the lower limbs. If it comes loose it can be carried in the blood to another part of the body where it can cause problems. If the blood clot reaches the lungs (PE) it can cause sudden death. Other complications of DVT include post-thrombotic syndrome, a chronic disorder that may include symptoms such as pain, heaviness, swelling, cramps, itching or tingling, increased skin pigmentation and ulceration in the affected limb.

Risk factors for VTE include recent surgery, immobility, active cancer or cancer treatment, age over 60 years, obesity, hormone replacement therapy or oestrogen containing contraceptive therapy and the presence of co-morbidities such as heart disease. The annual incidence of DVT in the general population varies considerably with age, ranging from 1 in 10,000 for people under 40 years to 1 in 100 for people over 80 years. People with a previous episode of VTE have a high (30%) chance of suffering a recurrence within 8 years. It is estimated that there will be over 46,000 cases of acute DVT in England and Wales during 2012, rising to nearly 50,000 by 2016 due to growth and aging in the population.

Treatments for VTE include initiation with anticoagulant drugs, such as low-molecular weight heparin - for example enoxaparin (the most commonly used low-molecular weight heparin in the UK) - unfractionated heparin or fondaparinux sodium. Treatment is then overlapped with a vitamin-K antagonist (VKA), such as warfarin, until the oral blood thinner is effective and a proper dose is achieved.

Rivaroxaban is an orally administered drug that helps to prevent blood from clotting. It does this by stopping a substance called Factor Xa from working. Factor Xa is necessary in the formation of thrombin and fibrin, the key components in blood clot formation.

Meindert Boysen, Programme Director Technology Appraisals at NICE, said: “The Independent Appraisal Committee noted the evidence from patient experts which stated that many patients find taking warfarin to be a source of stress, because it requires regular monitoring with blood tests, dosing adjustments, and patients must be careful about their diet because of warfarin's interaction with certain foods, and that rivaroxaban may be a useful alternative.

"However, the Committee was unable to make a decision on the data presented by the manufacturer because it felt that the data failed to demonstrate the drug's clinical and cost effectiveness in the context of UK clinical practice. In particular the Committee was concerned that an analysis for patients who required treatment beyond 12 months was not presented, and noted the comments of clinical specialists to the effect that some people with DVT need to continue on anticoagulant therapy permanently. The Committee also noted subgroup analyses in the main clinical trial that suggested that there could be differences in the effectiveness of rivaroxaban between the groups that were assigned treatment durations of 3, 6 and 12 months that it would wish to explore further. The Committee has therefore requested further information from Bayer about the clinical and cost effectiveness of rivaroxaban used as a long-term treatment and has also asked for comment on the differences between the subgroups receiving different intended treatment-durations."

Consultees, including the manufacturer, healthcare professionals and members of the public are now able to comment on the preliminary recommendations which are available for public consultation. Comments received during this consultation will be considered by the Committee and following this meeting the next draft guidance will be issued. Until final guidance is issued to the NHS, NHS bodies should make decisions locally on the funding of specific treatments. Once NICE issues its final guidance on a technology, it replaces local recommendations across the country.


Notes to Editors

About the draft guidance

1. The EINSTEIN-DVT and EINSTEIN-Ext trials are the key trials supporting the clinical effectiveness of rivaroxaban in the manufacturer's submission.

2. The draft guidance requests the manufacturer provide the following information:

  • Comments on the differences between the populations that were assigned treatment durations of 3, 6 and 12 months, and further details of any clinical criteria or algorithm used by the treating physician for assigning patients to the three groups.
  • Consideration of the cost effectiveness of rivaroxaban compared with low molecular weight heparin (LMWH) and a vitamin K antagonist in patients in whom long-term anticoagulation is intended. Ideally this should be supported by a cost-effectiveness analysis of rivaroxaban as a lifelong treatment after the index event. This analysis should use data from the whole population of the EINSTEIN-DVT trial for estimating clinical effectiveness and should include sensitivity analyses that assume a less intensive INR monitoring program of 6 visits in the first 3 months, followed by 2 or 3 visits every 3 months thereafter in the comparator arm.

3. The Committee concluded that rivaroxaban was at least as effective as enoxaparin/vitamin K antagonist in preventing venous thromboembolism recurrences but noted that the main clinical trial (EINSTEIN-DVT) did not evaluate treatment beyond one year.

4. The Committee considered that there could be important clinical differences in patient characteristics in each intended duration group, and concluded that more information on patient characteristics is needed to decide whether or not the estimate of clinical effectiveness should be influenced by subgroup analyses based on treatment duration. The Committee requested comments on the patient characteristics of the patients in the treatment duration in order to further explore the biological plausibility of any differences there might be.

5. The Committee was aware that a proportion of patients require long-term anticoagulation because they have ongoing risk factors for recurrent DVT. The cost effectiveness analyses presented only considered treatment up to a maximum duration of 12 months. the Committee therefore requests the manufacturer to consider the cost effectiveness of longer durations, ideally by submitting a cost effectiveness analysis of rivaroxaban as a life-long treatment.

6. The Committee was unable to deliberate and decide on a most likely cost-effectiveness estimate given the limitations outlined in 5 and 6 above.

7. Rivaroxaban costs £2.10 per tablet. The cost of treatment is estimated to be £235.86, £427.61 and £811.13 for 3, 6 and 12 months of treatment respectively. Costs may vary in different settings because of negotiated procurement discounts.

8. The Scottish Medicines Consortium published guidance on the use of rivaroxaban for this indication in February 2012.

9. NICE has appraised rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults. NICE technology appraisal guidance 170 (2009).

About NICE

The National Institute for Health and Care Excellence (NICE) is the independent organisation responsible for providing national guidance and standards on the promotion of good health and the prevention and treatment of ill health

NICE produces guidance in three areas of health:

  • public health - guidance on the promotion of good health and the prevention of ill health for those working in the NHS, local authorities and the wider public and voluntary sector
  • health technologies - guidance on the use of new and existing medicines, treatments, medical technologies (including devices and diagnostics) and procedures within the NHS
  • clinical practice - guidance on the appropriate treatment and care of people with specific diseases and conditions within the NHS.

NICE produces standards for patient care:

  • quality standards - these reflect the very best in high quality patient care, to help healthcare practitioners and commissioners of care deliver excellent services
  • Quality and Outcomes Framework - NICE develops the clinical and health improvement indicators in the QOF, the Department of Health scheme which rewards GPs for how well they care for patients

NICE provides advice and support on putting NICE guidance and standards into practice through its implementation programme, and it collates and accredits high quality health guidance, research and information to help health professionals deliver the best patient care through NHS Evidence.

This page was last updated: 13 March 2012

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Copyright 2014 National Institute for Health and Care Excellence. All rights reserved.

Accessibility | Cymraeg | Freedom of information | Vision Impaired | Contact Us | Glossary | Data protection | Copyright | Disclaimer | Terms and conditions

Copyright 2014 National Institute for Health and Care Excellence. All rights reserved.