Rapping about new anticoagulants for CAT at ICTHIC 2018

Rapping about new anticoagulants for CAT at ICTHIC 2018

 

Cancer patients are four or five times as likely to develop venous thromboembolism (VTE): not only does the disease increase the incidence but so do treatments such as chemotherapy and radiation. Drugs which can treat it and prevent recurrences are therefore an important part of oncology strategies. 

For many years the choice has been between low molecular weight heparins (LMWH) and vitamin K antagonists (VKAs) such as warfarin. While both can be effective, there are difficult problems with each approach. VKAs may interact with other drugs and food, have a narrow therapeutic range and require frequent monitoring and possibly dosage adjustments. They also have a slow onset of action which is a problem if rapid anticoagulation is needed.

The main problem with LMWH is that it requires injection and can be uncomfortable to administer. For metastatic cancer patients who require prolonged treatment, this can be major concern. Injection fatigue is associated with non-compliance and patients usually prefer oral therapy. The costs and complexity of needle management are other factor s as are longer offset times for LMWH.

The arrival of a new class of drugs, known as non-vitamin K antagonist oral anticoagulants (NOACs), was seen as a welcome alternative. The VKAs prevent coagulation by suppressing the synthesis of vitamin K-dependent factors. The new anticoagulants directly inhibit factor IIa and Xa proteases which is why they are also known as DOACs (direct oral anticoagulants). The first DOAC was the IIa inhibitor dabigatran (Pradaxa) which was approved in the European Union in 2008 and by the FDA in the US in 2010. Since then three anti-Xa drugs have been added: rivaroxaban (Xarelto), apixaban (Eliquis) and edoxaban (Lixiana).

New is not always better, but, in the case of the DOACs for cancer associated thrombosis (CAT), there are some evident advantages. They have more rapid onset and offset times, fewer interactions with other drugs and are more predictable. However, the main disadvantage with the DOACs in treating CAT is increased bleeding.

Results of two clinical studies presented at the 59th American Society of Hematology (ASH) meeting in December 2017, appeared to confirm that DOACs are more effective but also highlighted the increased bleeding risk. In one, the Select-d Trial, rivaroxaban was compared with the LMWH dalteparin. After 6 months of treatment, the VTE recurrence rate was 4% for those treated with rivaroxaban and 11% for dalteparin. While the incidence of major bleeds was similar in both trial arms, rivaroxaban patients had more than three times the number of total bleeding events. In the other study, the Hokusai VTE Trial, patients treated with the DOAC edoxaban had a 12.8% recurrence rate compared to 13.5% for those on dalteparin. However, the major bleeding rate was 6.3% with edoxaban compared with 3.2% with dalteparin.

The main question about the DOACs for treatment of CAT is, therefore, whether the benefits outweigh the risk of the increased bleeding risk. This was one of the issues considered during a debate at the 9th ICTHIC in Bergamo in April. Simon Noble, Clinical Professor in Palliative Medicine at Cardiff University, engaged in an entertaining verbal (and musical) tussle with Harry Büller, Professor of Internal Medicine at the Academic Medicine Center in Amsterdam. The aim of the discussion was to decide whether DOACs are a safe and reasonable alternative to LMWH in CAT treatment.

They intermingled light-hearted jibes and jokes with some very serious points about the risks and benefits of the two options. Büller identified the three main issues as the effects on the skin of frequent injections, the risk of recurrent VTE and the risk of serious bleeding. His conclusions were that new anticoagulants are definitely better for the skin, and data shows them to be more effective at preventing recurrences than LMWH . Although there are more episodes of major bleeding, the new anticoagulants are reasonably safe and appropriate when only severe bleeding is considered.

Noble put the emphasis on the lack of clear evidence that the new anticoagulants are safer and better than LMWH which have a longer track record. He suggested: “DOACs are only as safe as the stupidest person allowed to prescribe them”. In other words, there are too many unknowns and too little guidance in areas such as dosing for different types of cancer patients to be sure that the new anticoagulants are routinely safe and effective.  

Noble had the final say in the debate. He used it to perform an energetic rap during which he poked some more fun at his opponent and reinforced his message about the lack of information about the new anticoagulants. It is quite possible that his musical ability more than his message were the deciding factor in the vote which saw him emerge as the triumphant winner.

In reality, Noble and Büller are in almost complete agreement about the new oral anticoagulants. The debate was more of a staged event than an attempt to come to a definitive decision. The participants said afterward it was organised to draw attention to the possible advantages that DOACs will bring to treatment and prevention of VTE but also emphasize the need for more research and advice for doctors who prescribe them. It certainly achieved its aim in a most entertaining and compelling way.

 

We later interviewed Dr. Noble and Dr. Büller. Watch the video!

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