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Published on 25 January 2010

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ESCP symposium Geneva: new developments in anticoagulant therapy

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Dabigatran and rivaroxaban reduce the risk of thromboembolic events and are easier and safer to use than classical anticoagulants

Christine Clark
BSc MSc PhD FRPharmS FCPP(Hon)
Editor
HPE

Speaking at a therapeutic update session at the ESCP symposium on clinical pharmacy, Ismail Elalamy (professor of haematology, Tenon Hospital, Paris, France) described the antithrombotic pipeline as being “heavy with novel agents”. These include agents such as rivaroxaban, dabigatran and prasugrel that have already reached the market, others such apixaban, otamixaban and cangrelor that are in a late stage of development and many more in the early stages.

Classical anticoagulants, both heparins and vitamin K antagonists have multiple targets of action and this gives rise to a number of practical problems. The vitamin K antagonists (VKAs) have been the only oral anticoagulants. They have a delayed action and so are only suitable for the chronic phase of treatment but they are limited by a narrow therapeutic index, numerous food and drug interactions and the need for frequent monitoring and dosage adjustment. In France, accidental haemorrhages with VKAs account for more than 17,000 hospital admissions and costs of more than 760 million Euros per year. The heparins have a rapid onset of action and are suitable antithrombotic agents for acute phase treatment. However, they are of biological origin, have heterogeneous compositions and a complex mode of action. They bind to a number of plasma proteins, can be neutralised by platelet factor 4 and carry a risk of heparin induced thrombocytopaenia (HIT) of 0.1-2.0%.

In contrast, the ideal anticoagulant would be suitable for once-daily oral administration, have a predictable dose response relationship and be effective with a low rate of bleeding. It would have no interactions with other drugs or food and require no monitoring or dosage adjustment. In addition, it would be cost-effective in use.

Antithrombotic prophylaxis in orthopaedic surgery has steadily improved over recent years. At first warfarin was used, followed in turn by unfractionated heparin, low molecular weight heparin and finally the indirect factor Xa inhibitor fondaparinux. As a result the incidence of asymptomatic deep vein thrombosis (DVT) has been progressively reduced to 12.5%. Dosage reduction is required when using fondaparinux in fragile patients, that is those with low body weight, poor renal function or aged over 75 years, said Professor Elalamy.

Selective, direct, oral, reversible factor Xa inhibition is now possible with rivaroxaban (Xarelto). The molecular structure of rivaroxaban is such that it binds directly to factor Xa, inhibiting its action and thereby preventing thrombin generation. In the normal course of events molecule of factor Xa generates 1000 molecules of thrombin, making it a critical element of the coagulation cascade, said Prof Elalamy.

A key feature of rivaroxaban is that it inhibits both free and bound factor Xa whereas heparins and fondaparinux only act on factor Xa in plasma.

Compared to apixaban, a similar product, the only major difference is in clearance, rivaroxaban is cleared one third by liver and two thirds by kidneys whereas apixaban undergoes (75%) biliary clearance.

Rivaroxaban does not interact with antacids, aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), digoxin or amiodarone. However, it can accumulate if given together with strong inhibitors of CYP3A4 such as ketoconazole or ritonavir or if given to patients who are very old, or who have severe renal or hepatic failure. The absorption of rivaroxaban is increased in the presence of food. It has a wide therapeutic window and a 10mg dose is suitable for a wide range of body weights, ages and renal functions.

Two studies have demonstrated the efficacy of rivaroxaban for prophylaxis of venous thromboembolism (VTE) in orthopaedic surgery. The RECORD study, which compared rivaroxaban and enoxaparin in knee replacement surgery, reported a relative risk reduction of 49% in thromboembolic episodes. The RECORD study, which compared rivaroxaban and enoxaparin in hip replacement surgery, reported a relative risk reduction of 70% in thromboembolic episodes. There was no increase in major bleeding in either study.

Thrombin inhibitors
Thrombin (factor IIa) is the target for heparins, hirudins, argatroban and dabigatran. Dabigatran etexilate is a prodrug that is cleaved by esterases to release dabigatran in the body. The drug has a bioavailability of 6% when taken orally and a half-life of 14–17 hours. Unlike its predecessor, ximelagatran, it exhibits no hepatic toxicity.

Three double blind, randomised studies in orthopaedic surgery (Re-mobilise, Re-model and Re-novate) compared 220mg and 150mg of dabigatran etexilate, once-daily following a half-dose on the day of surgery, to enoxaparin. Enoxaparin was given in a dose of 40mg once-daily in the two European studies, and 30mg twice daily in the North American study. Treatment was given for 6–15 days after knee replacement and 28–35 days after hip replacement. Definitive diagnostic testing was required for all suspected symptomatic VTE events. Bilateral venography was performed at the end of the treatment period.

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The pooled results showed that dabigatran was non-inferior to enoxaparin and did not cause hepatotoxicity.

Dabigatran has also been compared to warfarin in the management of atrial fibrillation (the RE-LY study). The results showed that the frequency of stroke was reduced with dabigatran and the rate of intracranial haemorrhage, the primary safety endpoint, was also reduced. Further trials of direct thrombin inhibitors and factor Xa inhibitors in atrial fibrillation are in progress, said Professor Elalamy (See Table 1).

Both rivaroxaban and dabigatran represent a new type of anti-thrombotic drug. They need no monitoring and produce a predictable response. Oral administration makes them simple to use and the fact that treatment does not need to be started until after surgery is an advantage. A number of studies are now in progress to examine the efficacy of rivaroxaban and dabigatran in other conditions including VTE prevention in medical patients, VTE treatment, stroke prevention in atrial fibrillation and secondary prevention in acute coronary syndromes.

In future it should be possible to use targeted therapy to tailor treatment to individual needs. Clinicians must select the treatments that best balance the thrombotic risk, concluded Professor Elalamy.



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