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New oral anticoagulants


Christine Clark PhD FRPharmS
Editor HPE

Numerous studies involving 
a growing number of new oral anticoagulants are providing steadily increasing amounts of information about potential applications for these products. Speaking at a satellite symposium sponsored by Bayer Healthcare at the 16th EAHP Congress held in Vienna in March 2011, Kurt Huber (Professor and Director of the Third Department of Medicine, Cardiology and Emergency Medicine Wilhelminenspital, Vienna, Austria) explained what is known about the currently available products and which new products are on the horizon.

The new oral anticoagulants include the Factor Xa inhibitors, rivaroxaban, apixaban, edoxaban, betrixaban, otomixaban and also dabigatran, a direct thrombin inhibitor. Of these, rivaroxaban and dabigatran currently have marketing authorisations and approval for apixaban is imminent. All three have been investigated for prevention of venous thromboembolism (VTE) after hip and knee surgery and are being investigated for other applications such as VTE prevention in atrial fibrillation (AF) and acute coronary syndrome (ACS) and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE).

Prevention is critical in the management of VTE but it is likely that 
as few as 20% are actually detected. The recent American College of Chest Physicians (ACCP) guidelines recommended prophylaxis with low molecular weight heparin, vitamin K antagonists (VKAs) or fondaparinux 
for all patient groups. They also recommended that neither aspirin nor low dose unfractionated heparin should be used alone. However, only 60% of surgical patients suitable for prophylactic treatment and only 40% of acutely ill medical patients receive the recommended treatment.

Turning to AF, Professor Huber said that the prevalence increases with age, the condition affects more men than women and that a stroke is more likely to be fatal in someone with pre-existing AF. Stroke survivors face persistent disability and the economic burden of stroke is considerable, according to studies conducted in the USA, Germany and the United Kingdom. The risk of stroke is predicted by the CHADS score, which takes into account congestive heart failure, hypertension, age, diabetes and previous stroke or transient ischaemic attack. The new CHA2DS2-VASc score, which also takes into account vascular disease and gender, is more sensitive and better able to predict the risk of stroke or thromboembolic event, he explained. Treatment – with aspirin or a VKA – can be selected according to the level of risk. Warfarin reduces the relative risk of stroke by 64%, whereas aspirin reduces the relative risk of stroke by only 22%. 
On the other hand, VKA therapy has limitations that make it difficult to use in practice, including unpredictable responses, the need for monitoring and the narrow therapeutic range. Moreover, studies show that up to 45% of eligible patients do not receive a VKA in spite of clear indications. Both rivaroxaban and dabigatran are effective in reducing the incidence of stroke although intracranial bleeding was a problem with dabigatran. Two further studies in this area will be of interest – AVERROES, which compares apixaban with aspirin, and ARISTOTLE, which compares apixaban with warfarin in patients with AF.

The next frontier will be treatment of ACS and a number of studies are currently in progress to evaluate the effects of the new oral anticoagulants in this condition.

Clinical development programme
Sebastian Schellong (Professor and Head of Medical Clinic II, Municipal Hospital, Dresden Friedrichstadt, Dresden, Germany) described the development programme for rivaroxaban, tracing its beginnings in the prevention of primary venous thromboembolic disease through secondary prevention in ACS to treatment of DVT and PE.

The earliest studies had involved major orthopaedic surgery – hip and 
knee surgery. This a common starting point because it represents a good human thrombosis model, noted Professor Schellong. Dose-finding studies had determined that a daily dose of rivaroxaban 10mg gave the best anticoagulant effect with the lowest rate of bleeding. Accordingly, this was the dose used in the four RECORD studies (REgulation of Coagulation in major Orthopaedic surgery reducing the Risk 
of DVT and PE).

The ROCKET–AF study (Rivaroxaban Once daily oral direct Factor Xa inhibition Compared with vitamin K antagonist for the prevention of stroke and Embolism Trial in AF) compared rivaroxaban with warfarin for the prevention of stroke in patients with atrial fibrillation. No dose-finding studies were performed and the dose (20mg daily) was based on the dose used in studies of treatment of DVT. Those with moderate renal impairment were given a reduced dose of 15mg daily. Patients recruited for the ROCKET-AF study had, in general, a higher risk of suffering a stroke than patients in comparable studies, commented Professor Schellong.

The MAGELLAN study (Multicenter, rAndomized, parallel Group Efficacy and safety study for the prevention of VTE in hospitalized medically iLL patients comparing rivaroxabAN with enoxaparin) compared rivaroxaban with enoxiparin in acutely ill medical patients.

Patients with ACS are almost always treated with aspirin and clopidogrel. The important question to answer is whether the addition of a Factor Xa inhibitor provides any additional benefit. The ATLAS studies (Anti-Xa Therapy to Lower cardiovascular events in addition to aspirin with/without thienopyridine therapy in subjects with Acute coronary Syndrome) were designed to answer this question. The second ATLAS study uses low doses of rivaroxaban (2.5mg or 5mg daily) for a long period, he said.

The EINSTEIN studies were designed to examine the effects of rivaroxaban in the treatment of DVT and PE. The current treatment for these patients during the acute phase is either heparin or fondaparinux. During the intermediate phase a prothrombotic state can develop, noted Professor Schellong. Most patients who have had a DVT or PE are then treated with a vitamin K antagonist for six months and some may need long-term anticoagulation to prevent recurrences. Patients in the rivaroxaban arm of the EINSTEIN DVT and PE studies receive immediate treatment with rivaroxaban instead of enoxaparin followed by a VKA. Each of the studies – EINSTEIN–DVT and EINSTEIN–PE – has recruited more than 3000 patients.

An extended version of the study will now compare the effects of rivaroxaban 20mg daily and placebo in patients who have completed six months of treatment with either rivaroxaban or a VKA.

Economic evaluation
Previous economic evaluations of warfarin therapy could have underestimated the true cost, according to Sam Schulman (Professor of Medicine, McMaster University, Hamilton, Canada). The costs of VKAs are low but the costs of laboratory monitoring and dosage adjustment can be considerable. However, many studies have been small, single-centre studies and have been incomplete in that they included only direct costs. Additional indirect costs such as the cost of taking time off work or sending a nurse to assist a patient should be included, he explained.

A three-month, prospective observational study was conducted involving both hospital- and community-based clinics. Both physician-managed clinics and pharmacist-managed clinics were included. The study took place over five Canadian provinces and involved 15 sites and 429 patients. In each site, patients were provided with a diary and asked to record all costs for warfarin medication, contacts with health professionals, travel to the clinic, assistance required and time lost from work including time lost by their care-giver. The costs of managing bleeding episodes were excluded from the analysis, although there were hardly any complications during the study period, said Professor Schulman.

From the Ministry of Health’s perspective, the cost of warfarin treatment ranged from $108–199 (Canadian) (€78–144) per three months, depending on the clinical setting. Costs for the patients were $40–80 (€29–58) for three months and the total costs to society were $188 (€136) for hospital doctor-led clinics, $198 (€143) for hospital pharmacist-led clinics and $244 (€177) when treatment was provided by a community-based doctor. If reimbursement for unemployed care-givers was also included, the total estimate increased to $308–503 
(€223–364) per three months. About a quarter of patients required assistance from a care-giver and about 65% were able to walk to the clinic, he noted. Overhead costs were lowest for clinics managed by hospital pharmacists, he added.

Professor Schulman concluded that the costs of managing warfarin therapy amount to at least 10–20 times the cost of the drug itself. Moreover, previous studies have underestimated the true costs. In addition, he emphasised that the first three months of treatment can be the most expensive.

Rivaroxaban in practice
The clinical pharmacy team at Southampton General Hospital sees about 80% of patients on admission and makes about 1000 interventions each week – a significant number of which relate to thromboprophylaxis, Sharron Millen (Head of Clinical Pharmacy, Southampton University NHS Hospital Trust, Southampton, UK) told the audience.

In Southampton General Hospital, extended thromboprophylaxis with low molecular weight heparin (LMWH) was introduced in 2008. Since 2009, oral anticoagulants have been provided to those who are unable to self-inject and rivaroxaban was introduced for elective hip and knee surgery in December 2009. A considerable amount of support work was needed to make these changes possible. This included careful planning, the preparation of guidelines and education of staff. “Previously patients who had had a DVT were discharged on LMWH together with sharps bins for disposal but tablets look less impressive,” commented Ms Millen. For this reason, education of patients is also important.

Comprehensive guidelines were prepared for the hospital and printed on an A1-sized poster for display in the hospital. The poster describes the care pathway that patients will follow and provides information on risk assessment and selection of appropriate thromboprophylaxis measures.

It was important to ensure that there was adequate financial support for the changes so that the changes in practice could be introduced without adding unnecessary risk, she emphasised.

When the changes were all implemented, an audit of extended prophylaxis with enoxaparin and rivaroxaban after hip and knee replacements was performed. The results showed that all patients adhered to their treatment regimens but the patients receiving rivaroxaban experienced fewer adverse effects. Less nursing time was required during their hospital stays and, after discharge, there were no sharps bins or clinical waste for disposal.

In the UK, a ‘Three Professions Group’ comprising the Royal Pharmaceutical Society, The Royal College of Nursing and the Academy of Royal Medical Colleges has been established. The objective of the group is to support staff to deliver the best possible patient care.

In conclusion, Ms Millen said that careful teamwork and planning are key 
to the successful introduction of new oral anticoagulants. In addition, having champions in key areas is crucial and measuring success and providing feedback to those involved helps to support change.

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