Christine Clark PhD FRPharmS FCPP(Hon)
Traditional vitamin K antagonists are difficult to use in practice for a number of reasons, according to Reinhold Kreuz (Acting Director, Institute for Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin, Berlin, Germany). They have the advantage of once-daily oral administration but they have a slow onset and offset of action and suffer from variable metabolism as a result of interactions with other drugs and with food. Genetic polymorphisms (in metabolising enzymes) account for further inter-individual variability in response, he added. They have a very poor dose–response relationship and unpredictable anticoagulant effects, which make monitoring of international normalised ratio (INR) and dosage adjustment obligatory.
Intensive research has been devoted to the development of selective anticoagulants. A good example of the success of this approach is the pentasaccharide fondaparinux, a selective Factor Xa inhibitor that works indirectly through antithrombin.
However, fondaparinux has to be injected.
Three of the new oral anticoagulants (NOACs) – rivaroxaban, apixaban and edoxaban – are inhibitors of Factor Xa, while dabigatran etexilate is an inhibitor of Factor IIa (thrombin). These drugs bind directly and reversibly to their targets. Peak plasma levels are reached (for all four) in two-to-four hours and there is a good relationship between dose and plasma level. “They are fundamentally different from the vitamin K antagonists (VKAs)”, said Professor Kreuz.
Dabigatran is a prodrug that is rapidly converted to the active compound by hydrolysis and this is not a rate-limiting step. Dabigatran has a bioavailability of about 6%, whereas the bioavailability for the Factor Xa inhibitors is higher, and exceeds 80% for rivaroxaban.
All the NOACs are substrates of cytochrome p450 3A4 (CYP3A4) and/or P-glycoprotein (P-Gp) and herein lies the potential for drug interactions. Drugs that are strong inhibitors of both CYP3A4 and P-Gp, such as the azoles and protease inhibitors, are contra-indicated with Factor Xa inhibitors; concomitant administration raises the levels of the Factor Xa inhibitor. Dabigatran is a substrate of P-Gp but not of CYP3A4. It should be noted that dabigatran etexilate, but not the active drug, is a substrate of P-Gp, so inhibitors influence the absorption of dabigatran. After dabigatran etexilate has been absorbed from the intestine, it is pumped back into the intestinal lumen by P-Gp. If a P-Gp inhibitor is given, then this cannot occur and bioavailability of the dabigatran is increased. Concomitant administration of the P-Gp inhibitors verapamil and amiodarone can increase the bioavailability of dabigatran.
Renal clearance for all the Factor Xa inhibitors is between 25 and 30% – a sharp contrast with dabigatran, 95% of which is eliminated by the kidneys. Dosage reduction is required for dabigatran when the creatinine clearance is 30–50ml/min. About two thirds of the dose of rivaroxaban is metabolised by the liver and the remainder is renally excreted. Patients with severe renal failure (creatinine clearance below 30ml/min) have been excluded from trials, noted Professor Kreuz.
Current and future regimens
Giancarlo Agnelli (Professor of Internal Medicine, University of Perugia, Italy) reviewed the published data for the four current indications for the NOACs rivaroxaban, apixaban and dabigatran. These are: prevention of venous thromboembolism (VTE) in major orthopaedic surgery and in internal medicine, prevention of stroke in atrial fibrillation (AF), treatment of VTE and secondary prevention of acute coronary syndrome (ACS). “These are all clinical situations where we have data about efficacy and safety”, he said.
The prevention of VTE in major orthopaedic surgery (total knee replacement and total hip replacement) has been examined in three studies using dabigatran, RENOVATE, REMODEL and REMOBILISE, all of which used enoxaparin as the comparator. All demonstrated non-inferiority of dabigatran and a good safety profile. The four RECORD studies of rivaroxaban in hip and knee replacement all demonstrated superiority over enoxaparin. One study showed a minor increase in bleeding, although none of the studies reported a significant increase in bleeding, said Professor Agnelli.
The three ADVANCE studies were concerned with the effects of apixaban in major orthopaedic surgery. Two of these showed superiority over enoxaparin and a good safety profile.
The prevention of VTE in medical patients was examined in two studies. The MAGELLAN study showed that 30 days’ prophylaxis with rivaroxaban was similar in efficacy to 7–10 days treatment with enoxaparin. There was an excess of bleeding in patients treated with rivaroxaban in the first phase. The ADOPT study, which compared apixaban and enoxaparin in a similar design to MAGELLAN, showed a similar increase in efficacy at the cost of a small increase in bleeding. Overall, the results in this indication were less dramatic than those seen in major orthopaedic surgery but the reason for this was unclear, commented Professor Agnelli.
Stroke prevention in AF
The prevention of stroke in patients with AF was the objective of the RELY study. Two different dose levels of dabigatran were compared with warfarin. The higher dose of dabigatran was more effective than warfarin but the lower dose was no different. There was also less intracranial bleeding in the dabigatran groups. This was the first clinical demonstration that it was possible to replace warfarin for this indication, said Professor Agnelli. A trial of rivaroxaban in AF (ROCKET AF) also showed non-inferiority and a reduction in intracranial bleeding.
The AVERROES study compared apixaban and aspirin in AF patients who could not be given warfarin. Apixaban was more effective than aspirin and there was no increase in bleeding. The fact that a NOAC compared with an antiplatelet agent showed no excess bleeding was a very promising result, noted Professor Agnelli. The ARISTOTLE trial, in which apixaban was compared with warfarin in patients with AF, also showed non-inferiority and less intracranial bleeding. Thus, there are now three studies showing that these compounds (Factor Xa inhibitors) reduce the rate of intracranial bleeding, he added.
The RECOVER 1 trial compared warfarin with dabigatran in the treatment of VTE, both deep vein thrombosis (DVT) and pulmonary embolism (PE). The results showed that dabigatran was non-inferior and had a good profile regarding bleeding.
The EINSTEIN trial compared rivaroxaban with enoxaparin plus warfarin but, unlike the RECOVER trial, no low molecular weight heparin was given before the rivaroxaban was started. This trial tested the hypothesis that a single agent could be given from the outset for treatment of DVT. Non-inferiority was demonstrated and there was a reduction in major bleeding. Further information could be expected when the results of the EINSTEIN-PE trial, comparing rivaroxaban and warfarin in the treatment of PE, are published in the near future, said Professor Agnelli.
Secondary prevention of ACS
The ATLAS-2 study compared rivaroxaban with placebo in addition to standard treatment (for example, aspirin, clopidogrel) for secondary prevention of ACS. There was a risk reduction of 16% (absolute risk reduction (ARR) of 1.7%). This corresponds to a number needed to treat (NNT) of 56, which is a good result in cardiology, commented Professor Agnelli.
In order to define future indications for NOACs, additional data will be required. In particular, data are needed on specific populations, such as those in renal failure, patients with prosthetic heart valves and patients with cancer – some 20% of VTE patients have cancer, said Professor Agnelli.
During the discussion, it was noted that, in comparisons with warfarin, the ‘time in therapeutic range’ (TTR) is critical. If the TTR is good, as is often the case in Sweden and Norway, then NOACs offer little advantage.
Health economics of the new oral anticoagulants
The economic burden of thromboembolic diseases is considerable, Gianluca Furneri (Independent Health Economics and Pharmaceutical Market Access Consultant, Charta Foundation, Milan, Italy) told the audience. In the UK, it is estimated that there are 32,000 deaths each year from VTE in hospitalised patients. The estimated cost of DVT in Europe is €3500 and, for PE, about €6000. Stroke is the third leading cause of death in Italy, with about 200,000 cases annually. The EcLIPSE (Economic Longitudinal Incidence-based Project for Stroke Evaluation) study showed that the mean social costs in the first six months alone were €12,000.
One analysis of the use of rivaroxaban, dabigatran and enoxaparin in major orthopaedic surgery showed that costs are broadly similar. An analysis by the National Institute for Health and Clinical Excellence in the UK concluded that rivaroxaban reduced costs and improved benefits. In Italy, stroke prevention treatment in AF patients is poor and many are not treated at all. Treatment of 1000 non-treated AF patients for two years would save €1.16million (in stroke treatment avoided) at a cost of €1.46million – an 80% return on investment. Other factors to be taken into account are that the costs of NOACs might fall in future and treatment of AF patients who are not candidates for warfarin would be possible.
The Bayer satellite symposium ‘The new oral anticoagulants: mechanisms, evidence and day-to-day decisions’ was held at the European Association of Hospital Pharmacists Congress in Milan, Italy on 21 March 2012.