Thrombosis in patients with cancer may be a relatively common complication, but the treatment of venous thromboembolism (VTE) in this patient population is anything but simple. Patients with cancer have up to 6 times increased risk for recurrent VTE compared with patients without cancer, and they are also at higher risk for treatment-related side effects, such as bleeding. Furthermore, patients with cancer require longer-term use of anticoagulants, which raises concerns about quality of life and medication adherence.
At the 2021 Hematology/Oncology Pharmacy Association Annual Conference, 2 experts discussed the evidence and challenges regarding the use of anticoagulants in patients with cancer. They addressed issues related to low-molecular-weight heparin (LMWH) and direct oral anticoagulants (DOACs) and preferred DOACs for cancer-associated VTE. The American Society of Hematology recently published its updated guidelines for VTE thromboembolism in patients with cancer.1
DOACs versus LMWH
Multiple randomized controlled clinical trials have confirmed that DOACs are safe and effective for VTE in patients with cancer, but the choice between LMWH and DOACs in this patient population remains controversial.
According to Allison Schepers, PharmD, BCOP, Clinical Pharmacist Specialist, Inpatient Medical Oncology, University of Michigan Medicine, Ann Arbor, although LMWH is superior to warfarin, the use of LMWH has major disadvantages, including time within the therapeutic range.
In the CLOT and the CATCH clinical trials,2,3 according to Dr Schepers, patients were only able to achieve a therapeutic international normalized ratio (INR) approximately 45% of the time, even in a highly controlled and highly monitored clinical trial setting.
“I’m sure all of you have experienced how challenging it is to keep patients on their therapeutic INR due to loss of appetite, nausea, and vomiting, and having to hold anticoagulation for procedures or thrombocytopenia,” Dr Schepers said. “In addition, VTE recurrence rates on LMWH approach 10%, which simply isn’t good enough for patients.”
By contrast, a meta-analysis of 3 landmark studies with DOACs has demonstrated that treatment of VTE recurrence with DOACs is superior to treatment with LMWH. Although these data also showed an increased incidence of major bleeding with DOACs, said Dr Schepers, the difference between DOACs and LMWH was erased when all bleeding events were combined.
“All of the trials showed better outcomes with DOACs compared to LMWH. In 2 of the trials, the DOAC arm achieved noninferiority, and for both apixaban and rivaroxaban, the 2 most used DOACs, we saw superiority over LMWH, establishing DOACs as the agent of choice for cancer-associated VTE,” said Dr Schepers. “The days of LMWH as standard of care are numbered,” she predicted.
However, according to Victoria R. Nachar, PharmD, BCOP, Clinical Pharmacist Specialist-Ambulatory Hematology Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, the patients enrolled in these clinical trials do not necessarily resemble real-world settings. Dr Nachar discussed the patients who are typically enrolled in clinical trials of DOACs.
“A good percentage of patients did not have metastatic disease, or had no evidence of malignancy altogether. You could argue that patients with metastatic disease who were undergoing active treatment are the patients that we care most about,” Dr Nachar suggested.
She also underscored the higher risk or equivalent risk for major bleeding with DOACs, as well as the clinically relevant nonmajor bleeding associated with DOACs compared with the LMWH dalteparin.
The one DOAC outlier, Dr Nachar said, is apixaban, which has shown few associated major bleeding events.
DOACs: Improved Convenience, Quality of Life
Ultimately, the most convincing argument in favor of DOACs versus LMWH may be convenience.
“Neither warfarin nor LMWH is convenient for our patients,” said Dr Schepers. “No one likes to get their INR checked regularly, and no one likes to do daily, or even twice daily, injections. We really need to offer a better option for our patients.”
A formal quality-of-life assessment done in the ADAM-VTE clinical trial of apixaban and dalteparin showed that even in the first month of treatment, patients who received the LMWH dalteparin had excess stress, worry, irritation, and frustration compared with patients who received the DOAC apixaban.
“These are burdens that our patients experience at baseline due to their cancer diagnosis,” Dr Schepers said. “We certainly don’t want to be adding to those emotions with their anticoagulant.”
In addition, Dr Schepers reported that the rates of treatment discontinuation were 4 times greater with dalteparin than with apixaban.
“An anticoagulant cannot be effective if people are not taking it,” Dr Schepers emphasized. “I think that the quality of life and convenience argument clearly favor the DOACs as standard of care.”
Although the major anticoagulation guidelines now endorse DOACs for cancer-associated VTE “to some extent,” said Dr Schepers, they provide limited information about how to choose between an LMWH versus a DOAC. “It’s really up to us to take into account the patient factors, clot factors, and malignancy factors to make the best decision for our patients,” she said.
Apixaban and Rivaroxaban for Cancer-Related VTE
The cancer-related anticoagulation guidelines are also unclear about how to choose a preferred DOAC.1 According to Dr Schepers and Dr Nachar, apixaban is preferred from a safety and efficacy perspective, but rivaroxaban may be preferred in patients with strong objections to twice-daily dosing.
By contrast, edoxaban may be used if cyp3A4 drug–drug interactions preclude the use of rivaroxaban and apixaban. Dabigatran is not recommended in this setting because of lack of data and tolerability issues.
“There’s a role for both rivaroxaban and apixaban, depending on the clinical situation, but apixaban probably comes out on top more often,” said Dr Nachar. “Twice-a-day dosing is inconvenient, but if a patient does miss a dose, there’s less of a risk, and in the setting of renal dysfunction, you don’t have to worry about creatinine clearance. Apixaban also seems safer from a bleeding perspective,” she concluded.
- Lyman GH, Carrier M, Ay C, et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv. 2021;5:927-974.
- Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146-153.
- Lee AY, Kamphuisen PW, Meyer G, et al. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA. 2015;314:677-686.