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DOAC as a convenient alternative to LMWH in cancer-associated VTE

Dr. Herman Sung-Yu Liu
Specialist in Haematology & Haematological Oncology
Hong Kong
09 Jun 2020

History and presentation

A 65-year-old Chinese woman with metastatic lung carcinoma and brain secondaries presented in early 2019 with dyspnoea, palpitation, angina, and unilateral swollen and tender lower limb. She developed venous thromboembolism (VTE, which includes deep vein thrombosis [DVT] and pulmonary embolism) and required hospitalization.

Treatment and response

The patient received an injectable low molecular weight heparin (LMWH), enoxaparin (subcutaneous [SC] injection, 1 mg/kg, BID), and initially responded well to the treatment. However, she subsequently experienced bruising at multiple injection sites and developed a skin rash (approximately 2–3 months after treatment). The patient, who is a frequent traveller, eventually became noncompliant with treatment due to her dislike of injections and the difficulties she faced when travelling outside of Hong Kong with LMWH.

The patient received a direct oral anticoagulant (DOAC), edoxaban (60 mg tablet, QD), in May 2019, as an alternative to SC LMWH. She responded well to edoxaban, as her VTE symptoms improved and no venous blood clots were detected soon after treatment. (Figure) 

HK-DAI-135md

The patient did not experience any bleeding or thrombotic episodes during edoxaban treatment, and no drug-drug interactions (DDIs) were predicted or observed between edoxaban and the targeted therapy for her metastatic lung carcinoma. As of May 2020, the patient continues to receive edoxaban to help to control and prevent the recurrence of VTE symptoms.

Discussion

Risk factors known to be associated with the development of VTE include age, cancer, surgery, immobility, and long-distance air travel.1 Malignancy is considered one of the most common causes of VTE, with about half of the VTE patients having an active or a past history of cancer.2 Tumour cells activate coagulation, while a tumour mass can compress veins, causing stasis.1 In addition, hospitalization, surgery and chemotherapy all increase cancer patients’ risk of VTE.1

Injectable LMWH has been the standard of care for managing VTE in cancer patients, but the injections are painful and inconvenient, having a negative impact on patients’ quality of life, and are more expensive compared with DOACs.

Recent evidence from randomized clinical trials and meta-analyses show that oral DOACs are as effective and safe as injectable LMWH for VTE in cancer patients without gastrointestinal (GI) lesions (known to increase bleeding risk). These results led to updates by both the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) to recommend DOACs as the alternative treatment option to injectable LMWH for managing and preventing the recurrence of VTE in non-GI cancer patients.3,4

In Hong Kong, there is growing practice among haematologists and oncologists to prescribe DOACs instead of injectable LMWH for patients with cancer-associated VTE who do not have conditions that may increase the risk of bleeding (eg, severe renal impairment or GI cancer), if there are no potential DDIs predicted between the prescribed DOACs and anticancer agents.5 Based on our experience, only trivial bleeding events (eg, bruises, epistaxis, gum bleeding), but no major bleeding episodes, have been observed in cancer patients receiving DOACs for VTE.

Edoxaban is a direct factor Xa inhibitor and the first DOAC to receive category 1 recommendation (ie, supported by high-level evidence and uniform NCCN consensus) as part of a regimen for managing VTE in non-GI cancer patients.6 The recommendation was based on results of the open-label, noninferiority Hokusai VTE Cancer trial, which showed that edoxaban (60 mg QD, given for at least 6 months and up to 12 months following ≥5 days of lead-in LMWH) was noninferior to SC single-agent LMWH, dalteparin, in the composite outcome of recurrent VTE or major bleeding during 12 months after randomization, regardless of treatment duration.7

The primary outcome event rate was 12.8 percent vs 13.5 percent in the edoxaban vs dalteparin group (hazard ratio [HR], 0.97; 95 percent confidence interval [CI], 0.70 to 1.36; p=0.006 for noninferiority; p=0.87 for superiority).7 The results also showed a trend of lower recurrent VTE rate in cancer patients receiving edoxaban vs dalteparin (7.9 percent vs 11.3 percent; HR, 0.71; 95 percent CI, 0.48 to 1.06; p=0.09).7  

Subanalyses of the Hokusai VTE Cancer study showed that careful risk-benefit assessment is required for edoxaban use in GI cancer patients, who were the only group with an increased risk of major bleeding (albeit a lower risk of recurrent VTE) following edoxaban treatment.8,9

Among currently available DOACs, long-term use of edoxaban in cancer patients is supported by the largest body of clinical evidence, with the Hokusai VTE Cancer trial demonstrating edoxaban’s safety and efficacy over 12 months of follow-up – the longest for DOACs in the treatment of cancer-associated VTE.3

Compared with other DOACs, including direct factor Xa or thrombin inhibitors (orally, BID), edoxaban has a favourable dosing schedule (orally, QD).

In addition, edoxaban’s efficacy and safety in managing acute VTE had been demonstrated in both cancer and non-cancer patients from East Asia (including Japan, China, Korea and Taiwan), lending relevance to its use in local patients.10

Importantly, unlike for other DOACs, data are available for an adjusted dose of edoxaban for the treatment of cancer-associated VTE, which does not compromise its efficacy. A once-daily oral dose of 30 mg is recommended for mitigation of bleeding risk in patients with body weight (BW) ≤60 kg, renal impairment (creatinine clearance, 15–50 mL/min, or those on P-glycoprotein inhibitor(s).11 Notably, BW ≤60 kg and creatinine clearance of 30-50 mL/min  were more prevalent among East Asian vs non-East Asian patients in the Hokusai VTE trial.,9 This adjusted dose of edoxaban could also be considered in elderly patients who often have lower BW and/or other criteria, such as comorbidities, a higher incidence of falls or the use of polypharmacy, that may increase their risk of bleeding.12-16

Among currently available direct factor Xa inhibitors, edoxaban has the fewest anticipated DDIs with commonly prescribed cancer therapies due to its minimal competition for the CYP3A4 enzyme, for which many cancer therapies represent a substrate. As a result, edoxaban’s plasma concentration and bleeding risk remain more stable vs some other DOACs when used concomitantly with various cancer therapies.17,18 In spite of its advantages, it is worth noting that caution should be exercised when considering using edoxaban in patients with a known allergy towards other direct factor Xa inhibitors or a history of bleeding.

This case illustrates edoxaban as a viable treatment option for cancer-associated VTE in an elderly patient with metastatic lung carcinoma, who had previously received and eventually became noncompliant with injectable LMWH due to its inconvenient administration and negative impact on lifestyle. Edoxaban proved effective in controlling symptoms and preventing recurrence of VTE in our patient, without causing any bleeding or other side effects. The patient continues to receive edoxaban, remains symptom-free and is able to maintain her usual lifestyle, without the burden of daily injections and frequent clinic visits associated with LMWH treatment.    

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Most Read Articles
14 Feb 2020
The phase III CASTOR and POLLUX studies previously demonstrated benefit of daratumumab plus bortezomib and dexamethasone (DVd) or lenalidomide and dexamethasone (DRd) vs standard-of-care (SoC) Vd or Rd regimen in relapsed or refractory multiple myeloma (R/R MM). The latest efficacy and safety results after 4 years of follow-up from CASTOR and POLLUX were presented at the American Society of Hematology (ASH) 61st Meeting & Exposition 2019 held in Orlando, Florida, US.  
Dr. Roy Herbst, Dr. David Spigel, 6 days ago
The third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) osimertinib is a standard of care in patients with EGFR-positive advanced non-small-cell lung cancer (NSCLC). Results of the ADAURA study, presented at the American Society of Clinical Oncology 2020 Virtual Scientific Programme (ASCO 2020), support earlier use of osimertinib in the adjuvant setting, with superior disease-free survival (DFS) in patients who underwent complete resection of stage IB/II/IIIA EGFR-positive NSCLC. 
Prof. Mark Shackleton, 01 Apr 2020
In recent years, the focus on immuno-oncology has generated a wealth of compelling evidence supporting the use of immune checkpoint inhibitors – in particular those targeting the programmed death-ligand 1 (PD-L1) or PD-1 pathway. At the 8th Oncology Summit organized by the Hong Kong Society of Clinical Oncology, Professor Mark Shackleton of Alfred Health and Monash University, Australia, discussed recent advances in immunotherapy for the management of metastatic Merkel cell carcinoma (MCC) with a focus on the role of the PD-L1 inhibitor avelumab.  
Dr. Jason Butler, 01 Apr 2020
Proteasome inhibitors have become a cornerstone of therapy for multiple myeloma (MM). At the Hong Kong Society of Myeloma Annual Scientific Meeting 2019, Dr Jason Butler of the Icon Cancer Care & Royal Brisbane and Women’s Hospital, Brisbane, Australia, reviewed current evidence for the use of proteasome inhibitors in the management of relapsed/refractory MM (R/R MM), with a focus on the efficacy and safety profile of carfilzomib.