7 March 2018

The compelling case for DOACs

Clinical Drugs Patients

Three drugs are available on the PBS in Australia for the prevention of stroke and systemic embolisation in atrial fibrillation. The drugs are apixaban (Eliquis), dabigatran (Pradaxa) and rivaroxaban (Xarelto).

The need for treatment is usually decided by the use of a risk score such as CHADS or CHADS-VASc. These scores are freely available as phone apps or on websites. A CHADS score of one or greater is an indication to treat, and aspirin is no longer recommended in any patient population.

There is extensive clinical trial data involving tens of thousands of patients showing that the new agents are at least as effective as warfarin and have half the risk of intracranial haemorrhage. Patient populations within the trials varied, so direct comparison of agents is difficult, and no head-to-head data exists at present.

Real-world data from patient registries supports the results of the clinical trials.

Apixaban and rivaroxaban are also available on the PBS for treatment and prevention of venous thromboembolism (DVT and PE). Again, large clinical trials support their use.

How do they work?

All these drugs are based on the inhibition of factor II (prothrombin) or factor X. This is nothing new. Heparins act by the same mechanism, with low molecular weight heparins (e.g. enoxaparin and dalteparin) having more anti-Xa activity and pentasaccharides (fondaparinux) having almost exclusively anti-Xa effects. Heparins are however limited by the need for parenteral administration.

The DOACs can all be given orally. The dosing is either once daily (rivaroxaban) or twice daily (apixaban and dabigatran). The half-life of the drugs range from 5 to 17 hours depending on age and renal function and the route of elimination varies between drugs which may be a consideration when choosing one.

Renal function is important to some extent with all agents, and they are generally contraindicated when the creatinine clearance is less than 25-30 mL/min.

Bleeding risk 

There has been much concern that these agents do not have a reversal agent and that bleeding is problematic. Heparins and antiplatelet drugs do not have a specific reversal agent either, but are still well accepted in to standard practice. Most bleeding is minor and not clinically significant.

The data from clinical trials show that the rate of major bleeding (requiring blood transfusion or bleeding into a critical organ e.g. brain) is around 1-3% per year and mortality from an intracranial bleed is at least 30%. Similar rates of major bleeding were seen with all agents compared with warfarin, but the rates of intracranial haemorrhage were all up to 50% lower.

Mortality following a major bleed has been shown to be lower with DOACs than with warfarin, which probably reflects the longer half-life of warfarin and poor therapeutic attempts at reversal. Real world data supports the clinical trial findings.

Reversal of DOACs 

Dabigatran is the only drug with a currently available reversal agent (idarucizumab, Praxbind©). It is a humanised monoclonal antibody fragment that binds the drug, resulting in immediate correction of coagulopathy.

Andexanet, a factor X mimetic reversal agent, is currently in clinical trials and is likely to be available for use in Australia for reversing apixaban and rivaroxaban over the next few years, and in the US and Europe within the next year.

Most bleeding events on DOACs are minor and merely require temporary cessation of the drug for one to two doses.

In patients presenting with intracranial haemorrhage or other major bleeding events, reversal is possible with prothrombin complex concentrates (PCCs) (Prothrombinex –VF CSL Behring, Australia) which are available in most hospitals with blood banks.

The product is a plasma-derived, heat treated and nanofiltered factor concentrate containing clotting factors II, IX and X. Each vial of lyophilised product contains 500 IU of the above factors and can be stored at 2o to 8oC for up to six months.

A typical dose for the reversal of factor Xa inhibitors would be 25-50 IU/kg bodyweight or five vials for a 100kg patients.

There is animal data in a porcine model showing reduced blood loss and mortality with use of a PCC to reverse rivaroxaban.

Laboratory data in normal volunteers shows correction of coagulopathy following administration of a PCC. Clinical case series support their efficacy in patients presenting with major haemorrhage while treated with Xa inhibitors.

There is a small risk of thrombosis (<5%) with the use of PCCs.

Managing patients on DOACs

1. DOACs are essentially oral heparins

2. Choose a drug based on renal and hepatic function, choice of once versus twice daily dosing and familiarity of use

3. Monitoring of drug level or effect is not necessary, but monitoring of renal function and LFT every 3-6 months is important

4. The onset (2-4hrs) and offset of action is rapid. Stopping the drug for a few doses is usually sufficient for minor bleeding, but remember underlying pathology may be highlighted by anticoagulation

5. Major bleeding is rare (2% per year) but has a better outcome than with warfarin. Reversal agents are available

6. There is half the risk of intracranial bleeding on a DOAC compared to warfarin

Peter Wood is Associate Professor at the University of Queensland School of Medicine and works as a specialist haematologist at the Princess Alexandra Hospital. He has had an integral involvement in the development of local and state-wide guidelines for anticoagulant drugs.

 Disclosure: Associate Professor Wood has served on advisory boards for Bayer, Bristol-Myer-Squibb/Pfizer and Boehringer Ingelheim who manufacture these drugs. He has received sponsorship to attend clinical meetings by these companies and given paid lectures on their behalf.

The opinions in the above article are those of Associate Professor Wood and do not necessarily represent Bayer’s.

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2 Comments on "The compelling case for DOACs"

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4 months 13 days ago

Found this article interesting until disclaimer at end. Then my interest just evaporated. This article is NOT independent. Need independent information, are info from the clexane and coumadin/marevan companies. So disappointing – that was not flagged as from medical companies

4 months 13 days ago

When find out he is on the boards for the 3 companies my interest in article evaporated. There is conflict here. Would like some independent opinion, or maybe someone also speaking for warfarin and heparin. Where do get independent information.