Direct oral anticoagulants (DOACs) are coming to the fore as an increasingly prescribed therapy to treat and prevent venous thromboembolism (VTE), and primary care physicians should consider them for additional populations, including some cancer patients, according to the latest guidance.
These medications, the first of which was approved in 2010, provide an alternative to warfarin and low-molecular-weight heparin (LMWH) to treat or guard against deep venous thrombosis or pulmonary embolism. The two classes of DOACs include direct factor Xa inhibitors, such as apixaban (Eliquis) and rivaroxaban (Xarelto), and direct thrombin inhibitors, such as dabigatran (Pradaxa).
An updated American Society of Clinical Oncology (ASCO) guideline, published Feb. 10, 2020, in the Journal of Clinical Oncology, added DOACs to the medication options for VTE treatment and prevention, including a recommendation to start a DOAC or LMWH as a prophylactic measure prior to chemotherapy in patients assessed to be at high VTE risk. More recently, the American College of Chest Physicians (ACCP) updated its guidelines for antithrombotic therapy for VTE across all populations, outlining the role that DOACs can play in extended treatment to prevent recurrence.
The update, published December 2021 in CHEST, is the first since 2016 and incorporates both the ACCP's recommendations and the guidelines of other medical groups to offer physicians additional context, said Scott C. Woller, MD, FACP, chair of medicine at Intermountain Medical Center in Murray, Utah, Governor for ACP's Utah Chapter, and co-chair of the committee that developed the update. “It is difficult to manage patients with venous thromboembolism for the general internal medicine doctor, because of that balance between risk of bleeding and risk of thrombosis,” he said, noting that DOACs are increasingly a good option to consider.
Dr. Woller explained that DOACs appear to be as effective as warfarin for clot prevention at a lower overall bleeding risk. “I would say broadly speaking among patients with VTE we prefer DOACs over other anticoagulants, period,” he said, adding that there are case-by-case exceptions in certain populations.
A recent analysis of Medicare spending shows how DOAC prescribing has overtaken vitamin K antagonists, such as warfarin. Among Medicare beneficiaries taking an oral anticoagulant, 66.8% were prescribed a DOAC in 2019 compared with 7.4% in 2011, according to the findings, published July 23, 2021, in JAMA Health Forum.
Primary care physicians play a crucial role in ongoing anticoagulation management, including educating patients about the signs of VTE and the importance of not skipping even an occasional DOAC dose “because essentially you are losing its anticoagulation effect pretty much immediately,” said Daniel Dressler, MD, FACP, a professor of medicine at Emory University School of Medicine in Atlanta.
“This is the kind of condition where you can put yourself at a lot of risk by missing doses,” Dr. Dressler said. “And sometimes patients don't totally realize that unless we provide a strong explanation.”
The CHEST update focused on VTE treatment—prevention guidance is in the works, according to Dr. Woller—and recommended the use of DOACs over LMWH to treat cancer patients who develop thrombosis. (The three drugs specified are apixaban, edoxaban, and rivaroxaban.) But apixaban or LMWH may be preferred in patients with luminal gastrointestinal malignancies, the guidelines state.
That distinction stems from the latest research, which indicates that patients' bleeding risk with a DOAC may differ versus LMWH depending on which DOAC is prescribed, Dr. Woller said. In two large, randomized trials, both edoxaban (in the Hokusai-VTE study) and rivaroxaban (in the SELECT-D study) were found to be equally effective when compared to LMWH, he noted. But that effectiveness may be offset by a higher rate of bleeding, most notably GI bleeding. The more recent Caravaggio study, which compared apixaban to dalteparin and was published April 23, 2020, in the New England Journal of Medicine, did not find any elevated bleeding, including major GI bleeding.
Except for patients with GI cancers, Dr. Woller said, “The aggregate body of evidence does suggest that as a family DOACs are as good as low-molecular-weight heparin with an acceptable risk for bleeding when applied thoughtfully.”
For initial thrombosis treatment, the ASCO update preferred LWMH over IV unfractionated heparin for the first five to 10 days unless the patient has severe renal impairment, with a creatinine clearance of less than 30 mL/min. For long-term anticoagulation, the ASCO guideline recommends LMWH, edoxaban (Savaysa), or rivaroxaban for at least six months over vitamin K antagonists. But the authors also struck a cautionary note regarding GI bleeding risk, particularly in patients with gastrointestinal malignancies.
The ASCO update, initially published online in 2019, was finalized prior to the publication of the Caravaggio study's findings but align with them, said Alok Khorana, MD, FACP, a professor of medicine at the Cleveland Clinic in Ohio and a coauthor on the update. “There is always a bleeding risk with any anticoagulation, but there's not an excess bleeding risk outside of the GI cancer population,” he said. “DOACs are an option for acute VTE in cancer patients—I think that's the big headline.” Physicians may opt for another medication due to a patient's insurance coverage or underlying risk factors, such as severe renal impairment or potential drug interactions, he said.
But Dr. Khorana noted that he continues to see cancer patients newly diagnosed with VTE who are started on other drugs and could have been a candidate for a DOAC. LMWH is not only more troublesome for patients, requiring a self-injection, but also can be much pricier, he said, with the generic version of LMWH costing at least double the price of brand-name DOACs.
The ASCO update also recommends for the first time the use of preventive anticoagulation at the time of starting systemic chemotherapy in cancer patients at elevated risk of developing a clot, Dr. Khorana said. The recommended drugs include apixaban, rivaroxaban, and LMWH in patients who don't have a significant risk for bleeding or a potential interaction with another drug.
This guidance was based on two recent randomized studies, which found anticoagulation benefits for cancer patients who are at high risk for VTE, Dr. Khorana said. One of the studies, Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer Patients (AVERT), published Feb. 21, 2019, in the New England Journal of Medicine, found that 4.2% of the patients had developed VTE within six months compared with 10.2% in the placebo group. The reduction was largely driven by fewer cases of pulmonary embolism, the authors wrote. For every 17 patients treated, one VTE episode was prevented.
The ASCO update recommends that a patient's VTE risk be assessed based on the Khorana score, developed by Dr. Khorana, which assigns points to malignancies with the highest risk of a blood clot (such as stomach and pancreas), as well as other risk factors (such as the patient's prechemotherapy platelet count and body mass index). Other cancer patients undergoing chemotherapy should not be routinely offered prophylactic anticoagulation, according to the ASCO guideline. “We want to target people who are at high risk but not give it willy-nilly to everyone,” Dr. Khorana said.
Physicians also should consider more patients overall for ongoing VTE prevention after initial treatment, said Peter Gross, MD, MSc, an associate professor in the division of hematology and thromboembolism at McMaster University in Ontario, who has served on advisory boards for manufacturers and marketers of DOACs in Canada. Some may be candidates for a lower dose of a DOAC to reduce recurrence after acute treatment, including elderly patients, he said.
“If the VTE wasn't caused by a major reversible risk factor, such as a hip fracture or acute hospitalization or major surgery, then they should be considered for extension, especially if the bleeding risk is low,” said Dr. Gross.
The recent CHEST update, which recommends three months of anticoagulation for acute VTE, uses the terminology “major transient risk factor” to describe patients who don't need longer-term anticoagulation. According to categories established by the International Society on Thrombosis and Haemostasis, this would include someone whose clot can be linked to a recent major surgery or a hospitalization for a critical illness, Dr. Woller said. Following treatment, these patients are believed to have a recurrence risk approaching that of the general population, he said.
For all other patients, including those whose VTE is unprovoked with no discernible major cause, physicians should consider “indefinite-duration anticoagulation” with a reduced-dose DOAC, Dr. Woller said. Specifically, the CHEST guidelines suggest apixaban, 2.5 mg twice a day, or rivaroxaban, 10 mg once a day.
Patients should be reassessed periodically—the guidelines suggest at least annually—to determine relative individual risks and benefits of treatment, as well as patients' preferences, including those related to cost, Dr. Woller said. The CHEST update also notes that studies to date have not monitored extended use of these drugs for longer than two to four years.
Beyond the broad guidance by medical groups, primary care physicians will still need to tailor their recommendations to the individual patient, said ACP Member Vicky Tagalakis, MD, MSc, division director of general internal medicine at McGill University in Quebec, Canada, as well as a thrombosis researcher and specialist.
“Sometimes I continue the 5 mg [of apixaban] instead of decreasing to the 2.5-mg dose in patients who are at a particularly high risk of re-clotting,” she said. For instance, Dr. Tagalakis said that she may opt to continue the higher dose in patients with a strong family history of VTE, who are obese, or who have a history of recurrent thrombosis.
“There is a suggestion to decrease the dose to 2.5 mg of apixaban, but that's a suggestion,” she said. “The treating physician can continue with the 5 mg if benefits outweigh risks.”
Similarly, patients on extended-duration anticoagulation should be assessed periodically to update their medical history and determine if there are new risk factors for bleeding that must be considered, Dr. Tagalakis said. Changes in a patient's medical condition, whether worsening kidney function or newly prescribed aspirin in the wake of a heart attack, may alter the risk-benefit equation, she said, and necessitate a cessation of DOAC therapy.
But when Dr. Tagalakis discusses with patients at three months whether to continue taking a DOAC to reduce the risk of recurrence, she does not describe that treatment as continuing for just a year or two.
“I advise the patient that therapy is most likely indefinite,” she said. “I also inform the patient that we'll have annual assessments to review that decision based on acquired bleeding risk factors,” as well as any new research on extended prescribing.
Tailoring drug selection
A low-dose DOAC reduces risk for VTE recurrence by 90%, Dr. Gross noted. However, patients may decline ongoing DOAC treatment to prevent recurrence, particularly because of cost, Dr. Woller said. While research has shown that a reduced-dose DOAC is more effective than aspirin in reducing future clots—the CHEST guidelines noted that only rivaroxaban at that point had been compared with aspirin for prevention, and Dr. Dressler pointed out that aspirin may only reduce recurrence risk for about a year, based on results from the 2014 INSPIRE Study—aspirin remains an option, Dr. Woller said.
In short, taking an aspirin offers patients some anticoagulation benefits rather than going without entirely, Dr. Woller said. “It reduces your risk [of recurrence] by about one-third compared to if you take nothing at all.”
When talking to a patient about which DOAC to start, Dr. Gross explains the different daily dosing for each drug as well as other stipulations, such as which ones must be taken with food, to sort out the best fit with the patient's lifestyle. He also emphasizes the importance of not missing doses. If the patient is already taking warfarin and has done well for years, there is no reason to switch, he said.
DOACs should be avoided entirely in a few subgroups, per the CHEST guideline update. A vitamin K antagonist should be prescribed instead in patients with antiphospholipid syndrome (APS), especially if they are positive for lupus anticoagulant, anti-cardiolipin, and anti-β2-glycoprotein-I antibodies (i.e., “triple-positive”), and in those with arterial thrombosis, it noted.
Along with educating patients about their drug options, physicians also must describe warning signs of another VTE episode, including any breathing difficulties or noticing if one leg is more swollen than another, Dr. Khorana said.
This is particularly important for cancer patients, he stressed. “Cancer patients remain really woefully unaware that they are at high risk.”