by Floris T.M. Bosch and Pieter W. Kamphuisen
Since the publication of the SELECT-D trial1 and the Hokusai-VTE Cancer study2, there has been a shift in the treatment of cancer-associated thrombosis (CAT). Whereas low-molecular weight heparin (LMWH) has been the gold standard and the only well-validated treatment option in recent years, rivaroxaban and edoxaban are now also valid choices in treating CAT. With studies using apixaban upcoming3, more evidence regarding the efficacy and safety of direct oral anticoagulants (DOACs) in CAT is expected soon. Based on these studies, treatment options for CAT have increased, and patients are no longer only dependent on burdensome daily LMWH injections. However, certain points need to be considered when treating a cancer patient with thrombosis.
Primarily, the risk of bleeding is a point of concern when choosing a DOAC or LMWH. Although guidelines, such as those issued by the ISTH, now recommend the use of edoxaban or rivaroxaban in CAT, there are no clear recommendations on when to use DOACs and when to avoid them.
Carrier et al. presented a well-constructed and simple algorithm for the treatment of CAT based on recent literature4. This algorithm chooses between a DOAC and LMWH based on three clear and simple characteristics: the risk of bleeding, the type of cancer and possible drug–drug interactions with DOACs.
The first step is to assess the risk of bleeding via the presence of certain risk factors. Risk factors for bleeding in cancer patients are gastrointestinal (GI) morbidity, previous GI bleeding, treatment associated with GI toxicity, thrombocytopenia (<50,000 platelets/µL), renal impairment (GFR 30–50 mL/min), recent life-threatening bleeding, intracranial lesions and use of antiplatelet agents. In the Hokusai-VTE Cancer data, combination of three or more of these factors was correlated with a significant increase in bleeding risk in patients using edoxaban. Therefore, LMWH might be a safer option for these patients.
The next step is the assessment of the type of cancer. According to the algorithm, patients with GI and urothelial tumors should preferably use LMWH. This is based on data showing that patients with GI and urothelial tumors were more likely to have bleeding. In the SELECT-D trial, patients with esophageal or other GI tumors were excluded after an intermediate safety analysis that showed a non-significant increase in major bleeding in the rivaroxaban arm.
In the Hokusai-VTE Cancer trial, of all the patients who used edoxaban and had any form of GI tumor (n=165), 21 patients had major bleeding (12.7%) compared to 5 out of 140 (3.6%) in the dalteparin group. The mechanism responsible for the increased risk of bleeding in patients with GI tumors remains unclear. The increased risk of bleeding in patients with urothelial cancer is based on the intention-to-treat analysis of the Hokusai data, with 5 major bleeds out of 31 in the edoxaban group (13.2%) compared to 0 out of 31 in the dalteparin group.
However, there are two points that need to be addressed. The first point is the difference in the severity of major bleeding. In the ISTH criteria, major bleeding is defined as clinically overt bleeding associated with a decrease in hemoglobin of 2 g/dL or more, requiring transfusion of two or more units of blood, occurring in a critical site or fatal bleeding. This is a broad definition, and there is considerable variability in the severity of presentation and clinical course within the major bleeding events. Kraaijpoel et al. presented an overview of the clinical presentation and course of bleeding in the Hokusai-VTE Cancer study and divided the clinical course into four different categories5.
- Category 1: treatment only of discomfort, no transfusions;
- Category 2: requiring only transfusions, and straightforward interventions;
- Category 3: life-threatening bleeding events; and
- Category 4: bleeding events where death was unavoidable.
Of the 32 major bleeding events in the edoxaban group, 3 (9.4%) were life-threatening major bleeds. Of the 16 major bleeding events in the dalteparin group, 4 (25%) were life-threatening, and there was 1 (6.3%) event in Category 4. There was no significant difference in the interruption of cancer treatment because of major bleeding in the two groups (28.1% versus 25% in the edoxaban and dalteparin groups, respectively).
The second point that needs to be addressed is that the intention-to-treat analysis of the Hokusai data is different from the on-treatment safety analysis, which is usually used for evaluation of safety, according to Kraaijpoel et al. In the on-treatment safety analysis of the 65 patients with genitourinary tumors, 3 had major bleeding, 2 of these being patients with urothelial tumors. This compares to 1 patient with a renal tumor out of 71 patients with genitourinary tumors in the dalteparin group. This analysis suggests no increased risk in patients with urothelial cancer.
The last step in the algorithm is to assess possible drug–drug interactions. All DOACs are P-glycoprotein (P-gp) substrates, and apixaban and rivaroxaban are also substrates of CYP3A4. Many drugs inhibit these proteins, which can then increase the plasma concentrations of substrates, and thereby enhance the bleeding risk. Conversely, P-gp or CYP3A4 inducers may increase the excretion of DOACs, and thereby reduce bioavailability. The authors make an important point in listing the drugs that are known to have a potential P-gp or CYP3A4 effect (inducers or inhibitors). It is of note that there is a difference in the interaction between these drugs. For example, erythromcyin can increase edoxaban plasma levels by up to 90%, while the plasma levels of rivaroxaban only increase by 34%6,7.
Furthermore, not all interactions have been directly tested. Tamoxifen is a known P-gp inhibitor, but it is unclear by how much the plasma levels of DOACs increase and whether this has clinical significance. In 2018 the European Heart Rhythm Association (EHRA) published a practical guideline with respect to the known interactions between DOACs and different cancer treatments8. There is some clinical and pharmacological data, but many of the recommendations are based only on expert opinion. This needs to be considered when choosing a therapy. More studies are required to adequately assess the effect of these treatments on the plasma levels of DOACs.
The treatment algorithm is a very simple, clear and helpful tool for choosing the type of treatment in CAT. However, within the decision process not all points carry the same weight. All options and the risks and benefits of both treatments should be discussed with patients, and patient preference should play an important role in the treatment choice.
- Young, A. M. et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J. Clin. Oncol. 36, 2017–2023 (2018).
- Raskob, G. E. et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N. Engl. J. Med. 378, 615–624 (2018).
- Agnelli, G. et al. Apixaban versus dalteparin for the treatment of acute venous thromboembolism in patients with cancer: The Caravaggio study. Thromb. Haemost. 118, 1668–1678 (2018).
- Carrier, M. et al. Treatment algorithm in cancer-associated thrombosis: Canadian expert consensus. Curr. Oncol. 25, 329–337 (2018).
- Kraaijpoel, N. et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: Results from the Hokusai VTE Cancer study. Thromb. Haemost. 118, 1439–1449 (2018).
- Parasrampuria, D. A. et al. Edoxaban drug–drug interactions with ketoconazole, erythromycin, and cyclosporine. Br. J. Clin. Pharmacol. 82, 1591–1600 (2016).
- Mueck, W., Kubitza, D. & Becka, M. Co-administration of rivaroxaban with drugs that share its elimination pathways: Pharmacokinetic effects in healthy subjects. Br. J. Clin. Pharmacol. 76, 455–466 (2013).
- Steffel, J. et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur. Heart J. 39, 1330-1393 (2018).