Hello, I'm Stavros Konstantinides, and today we will discuss the management of Cancer-Associated Venous Thromboembolism.

Briefly showing my disclosures.

So our educational aims today are to discuss clinical practice guidelines on anticoagulation for VTE treatment in general. The association between VTE (venous thromboembolism) and cancer.The efficacy and safety of vitamin K antagonists and parenteral anticoagulant so far in cancer patients. And the clinical benefits, and also the caveats for direct oral anticoagulants or DOACs in patients with cancer. And finally, the evolution of guideline recommendations over the past three years.

So for the general population that 2019 European Society of Cardiology guidelines on the treatment of acute pulmonary embolism and venous thromboembolism in general say that when oral anticoagulation is started in a patient with acute PE or VTE who is eligible for a NOAC or DOAC such as apixaban, dabigatran, edoxaban or rivaroxaban. A NOAC is recommended in preference to a VKA (vitamin K antagonists). This is a very strong IA recommendation as a class of the NOACs or DOACs.

NOACs are not recommended in patients with severe renal impairment during pregnancy and lactation and in patients with the antiphospholipid antibody syndrome.

So, apart from the acute phase and the early phase of treatment with anticoagulation. We have also learned over the past few years that longer times of anticoagulation for secondary prophylaxis may be necessary because as you see in this slide, the recurrence rates after discontinuation of anticoagulation are quite high. They can be as high as 10 percent in the first year after discontinuation, then they drop a little, but they stabilize about 3% per year, which is quite a lot over the long term. So generally in most patients in the majority of patients, after acute VTE long-term, anticoagulation may have benefits.

And, in fact, the 2019 ESC Guidelines also recommend to consider indefinite anticoagulation in patients who have suffered a first episode of PE and by extension VTE without an identifiable risk factor for thrombosis, in patients, who have had a first episode of PE or VTE associated with a persistent risk factor such as an inflammatory chronic systemic condition and in patients who have suffered a first episode of PE or VTE and had a minor transient or reversible risk factors such as for example, long travel. So this covers, the majority of patients who have suffered acute PE or VTE. For these patients, long-term indefinite anticoagulation should at least be considered and discussed with these patients and in the majority of cases, we indeed continue anticoagulation.

Now, cancer and VTE have a very well-known association. One of five patients with cancer will suffer VTE once at least in their lives and vice versa. One of five patients with VTE is a cancer patient. Not all cancer types. Not all tumors, have the same thrombosis risk. You can see here that, for example, pancreas carcinoma and brain tumors and ovarian tumors are the most thrombogenic, but with regard to the prevalence of tumor types in patients with thrombosis, there of course, we meet the most common forms of cancer. So relatively the risk is not very high, but these are the large number of patients. So we have the patients with prostate cancer in men, with breast cancer in women, lung cancer, and colon cancer, and so on. So there is a very strong association.

And of course, VTE if it occurs in patients with cancer, it must be treated. This is clear. And for many years the treatment was as in the general population before the NOACs came or the DOACs, VKA is Vitamin K antagonist. But as you can see, compared to patients without cancer, those that were on VKAs had higher rates of recurrence of VTE on treatment, that means therapy failed, and they also had higher rates of bleeding, so less safety. So two major drawbacks for these drugs.

It was then found in studies that compared low molecular weight heparin treatment at least over the first six months in comparison to VKA that low molecular weight heparin, especially in the first study the CLOT study was performed with dalteparin and invented in the meta-analysis of all studies. That low molecular weight Heparins appear to be better more efficacious than vitamin K antagonists. So they reduced the recurrence rate by almost 50% compared to vitamin K antagonist. Although the safety was similar so they did not bleed more. But also they did not bleed less.

So low molecular weight Heparins have been recommended by guidelines for many years. As first line therapy of treatment for VTE in patients with cancer. What is the problem with this? Well, they are parenteral drugs. They have to be injected and one might think, okay, once or twice daily, subcutaneous injection is not a big deal, but for patients with cancer it is. And as you can see persistence on therapy in real life is not very good. So, even before the large trials came with the new oral anticoagulants. Patients did not tend to stay a long time on low molecular weight heparin, even if prescribed. You can see the median treatment duration in patients on low molecular weight heparin was just above three months but it was much longer in patients with NOACs even without a lot of data at that time. Even on Warfarin that we knew to be inferior. So we have to provide patients with something that is efficacious, but is also better tolerated by them. And this is what the NOAC studies since 2018 did. We had first the Hokusai-VTE cancer study with edoxaban, so patients with VTE and active cancer. There was a combined outcome of efficacy and safety. In which edoxaban compared to the standard of care which was dalteparin, that was the control arm was non-inferior.So that was good news.

And actually it was found that it tended to be better in terms of efficacy, better than low molecular weight heparin, which I remind you was much better than VKA, in previous studies. Although there was some, there was also a trend and actually a significant trend towards more, major bleeding. So there was better perhaps efficacy, marginally better efficacy, but there was also some more bleeding.

The results were very similar in a smaller study performed with rivaroxaban, which was officially a pilot study of 400 patients. In that study the signal was again similar. There was a trend which actually reached very high almost statistically significance. It was very close to that and this trend showed superior efficacy to vitamin K antagonists, but there was also a trend as I said towards more major bleeding.

So the 2019 ESC guidelines said that for patients with VTE, PE in that case and cancer weight adjusted, subcutaneous low molecular weight heparin should be considered for the first six months over VKAs but edoxaban or rivaroxaban available with data at that time should be considered as an alternative to the standard of care, low molecular weight heparin.

So that was already a major change. But then, after these guidelines, we had the Caravaggio trial also a large phase 3 open-label trial and patients with venous thromboembolism and cancer. More than 1100 patients randomized again to the standard of care, dalteparin treatment or to apixaban. And there, we had a very similar trend, we had this superior efficacy with regard or in comparison to dalteparin and we had in this case, also a very good safety profile. We did not have significantly more major bleeding compared to dalteparin. So again, very good data.

Based on this guidelines that have appeared since then and now have considered the data of all trials with the three drugs performed. That is apixaban, edoxaban, rivaroxaban. These are those of the American Society of Hematology, for which said that for patients with cancer and VTE the guideline panel of the American Society of hematology suggests that DOACs, apixaban or rivaroxaban should be used for initial treatment. Of course, low molecular weight heparin can also be used but now they are put in the first place with a caveat, a warning. They should be used carefully for patients with gastrointestinal cancers. I would add gastrointestinal luminal tumors because of the higher risk of GI bleeding in some of the studies. And that was for initial treatment. Because with these two drugs, we can start right from the beginning with the oral drug. For edoxaban, as you know, we cannot start right from the beginning with a drug. We have to have at least five days of low molecular weight heparin first. So there is a second recommendation to include this part as well saying for the short treatment of VTE. So after this initial phase of the first few days and over the first three to six months then for patients with active cancer the guidelines recommend a DOAC, apixaban, edoxaban or rivaroxaban, over low molecular weight heparin. So in this case, they are clearly first-line treatment again with a warning for gastrointestinal bleeding in patients with gastrointestinal cancers.

So over the past three years, we have had new data with the DOACs in cancer, and we have had an evolution of guidelines in which they have moved from first having entirely as the gold standard low molecular weight heparins over to the ESC Guidelines that said low molecular weight heparins remain that the gold standard. But DOACs are a very good alternative. And now to the ASH guidelines that say that the DOAC's are first-line treatment in patients with VTE and cancer.

So my take home messages would be; there is a close association between cancer thrombosis and VTE. We've known that for many years. Vitamin K antagonists are less efficacious and also less safe for VTE treatment in cancer patients compared to patients without cancer. Low molecular weight heparins have superior efficacy to VKAs and this has been shown in large studies, but persistence on therapy may be poor in patients with cancer in real life. And this always has to be taken into consideration. Direct oral anticoagulants have replaced the VKAs as first-line therapy for VTE in the general population and recently randomized controlled trials demonstrated the efficacy, and overall safety of DOACs in the treatment of VTE in cancer as well. So guidelines now as of 2022 recommend the DOACs, apixaban and rivaroxaban in the initial treatment and the DOACs, apixaban, edoxaban and rivaroxaban over the first three to six months after VTE. In cancer, there is a caveat for the risk of bleeding in patients with intraluminal gastrointestinal tumors or patients in whom pathology of the gastrointestinal, or the urogenital tract, may predispose to bleeding.

Thank you very much.

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