Background
Venous thromboembolism (VTE) (including deep vein thrombosis [DVT] and pulmonary embolism [PE]) is a common clinical problem that occurs in up to 20% of patients with cancer over the course of their disease.1,2 Given that cancer-associated thrombosis (CAT) is the second leading cause of death for patients with cancer,3 it is critical that clinicians are familiar with the latest data to optimally manage this condition. Numerous evidence-based guidelines on this topic are available.4–7 Yet, many patients receive anticoagulant care that is discordant with the guidelines.8,9
This review covers the latest updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease.4 Specifically, this concise review is intended to help clinicians select an appropriate long-term outpatient anticoagulant for lower-extremity DVT and PE, the most common sites of CAT.10 Although the general principles of anticoagulant selection discussed herein may apply in a variety of situations, topics on the acute management of CAT (initial anticoagulation and the options of systemic or catheter-directed thrombolysis or embolectomy), catheter-associated venous thrombosis, thrombosis of unusual sites (eg, splanchnic vein thrombosis), inferior vena cava filters, and anticoagulation failure are beyond the scope of this review. We encourage interested readers to reference the current NCCN Guidelines4 and others that cover these topics.11,12
General Anticoagulant Characteristics
Anticoagulants recommended in current CAT treatment guidelines include low-molecular-weight heparin (LMWH), warfarin, and in recent years, the direct oral anticoagulants (DOACs).4 Fondaparinux is also occasionally used in outpatient CAT management. The anticoagulants approved for the treatment of VTE and their characteristics are outlined in Table 1.
Characteristics of Anticoagulants Used in the Management of CAT
Low-Molecular-Weight Heparin
LMWHs available in the United States include dalteparin and enoxaparin. Dalteparin has the highest level of evidence and is the only anticoagulant with FDA labeling for the extended treatment of VTE to reduce recurrence risk in patients with cancer.5,13 However, enoxaparin is often used in the United States,14 potentially because of ease of dose calculations or related to insurance coverage. This is despite limited trial data supporting enoxaparin for CAT. LMWHs are dosed based on weight, and therefore weight changes need to be considered. Dosing is often based on actual body weight,15 but concerns have been raised regarding toxicity in obese patients, given lower drug distribution into adipose tissue.16 Clearance of LMWH is predominantly renal, and renal function may require monitoring. LMWH should be used with caution in the setting of renal dysfunction, and modifications may be needed for patients with creatinine clearance (CrCl) <30 mL/min. Routine anti-Xa monitoring is controversial.4,17,18 The American Society of Hematology guidelines advise against anti-Xa monitoring for renal dysfunction and obesity for these patients.15 They note very low certainty in this recommendation, whereas monitoring is a consideration in the American College of Chest Physicians guidelines.19
Although dalteparin is administered daily, enoxaparin allows for once- or twice-daily dosing. Retrospective comparative data are limited but may favor a twice-daily regimen for LMWH.4,14,20 Pharmacokinetically, higher peak levels of LMWH will be encountered with once-daily dosing, and these patients will spend a lower proportion of time in the therapeutic range.14 Practically, patients weighing ≥120 kg often require 2 injections, regardless of the regimen selected, and end up on twice-daily dosing based on the commercially available syringe sizes.14 The NCCN Guidelines advocate twice-daily, weight-based dosing with consideration of daily dosing after a month.4 LMWHs have nonhemorrhagic toxicities, including a risk for heparin-induced thrombocytopenia (HIT) and osteoporosis.19 Accordingly, appropriate platelet count and bone health monitoring for long-term management are important.4 LMWH use is acceptable during pregnancy and breastfeeding.20
Warfarin
Warfarin is a vitamin K antagonist that requires initial overlap with a parenteral anticoagulant (LMWH, fondaparinux, or unfractionated heparin) until an international normalized ratio (INR) target of 2 to 3 is achieved. Warfarin requires routine monitoring given its pharmacokinetic/pharmacodynamic profile with altered metabolism based on genetics, drug interactions, and dietary/environmental factors.21 Nonhemorrhagic toxicities can include skin necrosis and limb gangrene in select cases.21 Caution is needed with concomitant inhibitors and inducers of CYP2C9, CYP1A2, or CYP3A4.4 Warfarin may be preferred in the setting of advanced chronic kidney disease, antiphospholipid syndrome, nonadherence (longer half-life), altered gastrointestinal anatomy, or advanced liver disease. It is typically the lowest-cost anticoagulant and is not recommended for pregnancy use.20 Warfarin use is considered acceptable during breastfeeding.20
Despite evidence, warfarin is the most commonly used anticoagulant for CAT.8 The 2 largest studies to date, the CLOT and CATCH trials, compared dalteparin versus vitamin K antagonist therapy.22,23 Both studies showed lower rates of symptomatic recurrent DVT or PE with dalteparin compared with warfarin. However, it is worth noting that the time in warfarin therapeutic range was only 46% in CLOT and 47% in CATCH. As such, clinical outcomes with warfarin may be better than reported in centers with close monitoring of INR that achieve higher time in therapeutic range.
Fondaparinux
Fondaparinux is FDA approved for the initial treatment of VTE in conjunction with warfarin, but has also been used off-label for the long-term treatment of VTE, especially for management of HIT or anticoagulation failure.4,24–26 It is a synthetic sulfated pentasaccharide that works through antithrombin to inhibit factor Xa.25 It is contraindicated for patients with a CrCl <30 mL/min and should be used with caution in older patients, patients weighing <50 kg, or with moderate renal insufficiency (CrCl 30–50 mL/min).4 It has not been extensively studied in patients with cancer.27 The long half-life of this agent can be a concern.
Direct Oral Anticoagulants
DOACs used for CAT include the direct thrombin inhibitor (dabigatran) and the factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban). These drugs are orally administered, taken once or twice daily, have a rapid onset of action (within hours), similar half-lives (5–17 hours), and do not require routine monitoring due to generally predictable pharmacokinetics. Dabigatran and edoxaban are administered after at least 5 days of parenteral anticoagulation with LMWH or unfractionated heparin. Quantitative tests for DOAC concentrations are available (in limited laboratories) and can be compared with expected peak/trough levels.28 However, drug levels have not been well studied in relation to clinical outcomes, and the utility of testing remains uncertain.29 Although routine monitoring of the DOACs is not required, monitoring of organ function may be necessary; this is especially true for patients receiving nephrotoxic or hepatotoxic antineoplastic therapies.4 DOACs are contraindicated during pregnancy and breastfeeding.20
DOAC Trial Characteristics
Within the past decade, 4 pivotal randomized controlled trials have compared the use of DOACs versus LMWHs in the acute treatment of CAT.30–33 The characteristics of these trials are detailed in Table 2.
Characteristics of Recent Clinical Trials of the DOACs for CAT
All 4 trials enrolled adult patients with cancer who have had lower-extremity proximal DVT and/or PE. The ADAM-VTE trial also included atypical VTE (upper-extremity DVT, splanchnic and cerebral vein thrombosis).32 Similarly, all 4 trials enrolled patients with any type of cancer (other than basal-cell or squamous cell carcinoma of the skin) but there were slight differences in the definition of cancer. ADAM-VTE32 and Hokusai VTE Cancer31 did not exclude any other type of cancer, whereas SELECT-D excluded patients with primary esophageal or gastroesophageal cancer during the study on the advice of the data safety monitoring board.30 Caravaggio33 excluded patients with primary or metastatic brain tumors and acute leukemia. All 4 trials excluded patients with a creatinine clearance <30 mL/min and liver disease.
Overall, the clinical characteristics of participating patients were similar across all 4 trials. Metastatic disease at presentation was comparable: 58% in SELECT‐D, 52.5% in HOKUSAI VTE Cancer, 65.3% in ADAM-VTE, and 67.5% in Caravaggio. Concurrent chemotherapy use was similar (69%, 71.6%, 73.5%, and 60.8%, respectively). Tumor types were also similar for each trial, with only a small proportion of patients with hematologic malignancies (<10%). Notably, even though ADAM-VTE and Caravaggio did not explicitly exclude patients with upper gastrointestinal cancer, the proportion of patients with upper gastrointestinal cancer in these 2 trials was low, likely reflecting concerns regarding the risk of increased upper gastrointestinal major bleeding in patients with gastrointestinal cancer.
Both SELECT-D and Caravaggio looked at VTE recurrence as the primary endpoint, ADAM-VTE used major bleeding, whereas Hokusai VTE Cancer used a composite endpoint of both VTE recurrence and major bleeding. All patients were followed for at least 6 months and all pertinent clinical outcomes (recurrence of VTE, major bleeding, and clinically relevant nonmajor bleeding) at 6 months for each trial were reported (data shown in Table 3).
Clinical Outcomes at 6 Months of Clinical Trials Comparing DOACs With LMWH
Comparative Efficacy and Safety
Multiple meta-analyses of these 4 trials consistently showed a statistically significant reduction in recurrent VTE at 6 months with DOACs compared with LMWH, with an approximate relative risk (RR) of 0.62 (differences in pooled RRs ranging from 0 to 0.08).34 However, given that the ADAM-VTE trial included atypical VTE, which was excluded in the 3 other trials, there are limitations to the conclusions derived from these meta-analyses, as atypical VTE may have different recurrence risk than typical VTE.
Pooled safety analysis from these 4 trials found an increased risk of major bleeding at 6 months, but this was not statistically significant (RR, 1.31; 95% CI, 0.83–2.08).35 This increased risk of major bleeding was predominantly seen in patients with gastrointestinal malignancies taking edoxaban and rivaroxaban compared with dalteparin. In contrast, both ADAM-VTE and Caravaggio found that apixaban was not associated with an increased risk of major bleeding compared with dalteparin. Notably, pooled analysis of the risk of clinically relevant nonmajor bleeding (CRNMB) was statistically higher with DOACs compared with LMWH (RR, 1.65; 95% CI, 1.19–2.28).35
Overall, DOACs are as effective as LMWH for the treatment of cancer-associated VTE. However, the increased rate of CRNMB warrants caution, especially in patients with gastrointestinal malignancies.
Trial Limitations
As all 4 trials had similar exclusion criteria, a knowledge gap remains on the generalizability of DOAC use in other comorbid conditions seen in patients with cancer. It is unclear whether apixaban can be used for patients with severe renal impairment (CrCl <30 mL/min) or on hemodialysis, given that these patients were excluded from the trials. Similar concerns apply for patients with liver cirrhosis who were also excluded. Because the trials also excluded patients with severe thrombocytopenia (platelet count <50,000/µL), more data are needed, especially to help guide management of anticoagulation in patients with hematologic malignancies and thrombocytopenia. There are also insufficient data to guide choice of anticoagulation in patients with primary or metastatic brain tumors. Lastly, it is unclear whether DOACs can be used for patients who present with life-threatening VTE requiring thrombolytic intervention.
Selecting an Outpatient Anticoagulant for CAT
There are several general considerations when selecting an outpatient anticoagulant for the management of CAT. NCCN Guidelines suggest considering organ function, FDA approval, cost, patient preference, ease of administration, monitoring, bleeding risk assessment, and ability to reverse anticoagulation when making this selection.4 Anticoagulant decisions ultimately must be individualized and shared between patients/providers. Availability of anticoagulant reversal agents may vary depending on regions and hospitals, and are not addressed here.
Contraindications to Anticoagulation
Bleeding is a risk with any anticoagulant, and patients with cancer have an increased risk of bleeding. Absolute and relative contraindications to therapeutic anticoagulation are listed in eTable 1.4 Other considerations are malignant hypertension, intracranial or intraspinal lesions at risk for bleeding, active gastrointestinal ulceration, and recent intracranial bleeding.5 Inferior vena cava filter placement may be appropriate for some patients with CAT unable to receive anticoagulation.4 In addition, some patients derive uncertain benefit from anticoagulation, including those on hospice/near the end of life and those who are asymptomatic from their CAT who have a high bleeding risk.5
Drug Interactions, Access, and Ease of Administration
One of the first steps of anticoagulant selection is to consult with a pharmacist or use an appropriate drug reference to assess for possible drug interactions, being sure to include any cancer-directed therapies or supportive care. Clinically relevant drug interactions can guide further anticoagulant decision-making.
Cost also influences anticoagulant selection, and providers should ensure patients can access their prescribed anticoagulant, especially when 2 equal therapeutic options are available.4,5 Generally, patients pay the highest costs in the United States with LMWHs followed by DOACs, and then warfarin.5,8 Prices vary based on region, negotiated discounts, rebates, insurance coverage, pharmacy, and associated monitoring costs. Efforts should be made to mitigate cost as a barrier to optimal anticoagulant selection, and financial counseling should be offered when appropriate.
Studies indicate that physicians underestimate patients’ willingness to accept injection therapies like LMWH36 and, qualitatively, patients have valued anticoagulant efficacy and safety (low recurrence rates, low bleeding) over convenience (oral formulations of drugs).37 Patients also prefer that their anticoagulation not interfere with or delay their cancer treatment, and strongly value their doctor’s recommendation.37 Ultimately, it is important that providers are adequately trained on anticoagulant options to provide informed recommendations when engaging in shared decision-making.
Warfarin adherence can be assessed through INR monitoring. There have been concerns about adherence with LMWH given that it is subcutaneously administered. Studies suggest that LWMH adherence is similar to that of DOACs.38 However, patients are less likely to stay on LMWH as long as oral anticoagulants.38,39 LMWH administration may be technically challenging for some patients, especially those with physical limitations, and oral agents may be preferred. For patients with adherence concerns, once-daily DOAC options40 (rivaroxaban or edoxaban) may be preferred. Some patients may benefit from the longer half-life of warfarin, because missed doses may not result in as much time spent at subtherapeutic levels of anticoagulation. However, the need for monitoring may be a concern in this setting. In addition, warfarin therapy is complicated by many drug interactions, and the time in the therapeutic range is often low in patients with cancer.41
Assessing a Patient for a DOAC and Special Populations
If there are no significant drug interactions, no significant renal or hepatic dysfunction, and no gastric or gastroesophageal lesions, DOACs can be considered. Genitourinary or gastrointestinal lesions such as ulcers, or instrumentation such as nephrostomy tubes should be considered a relative contraindication to DOACs because they have been associated with increased bleeding in these situations.4,42 Aside from these particular scenarios, DOACs likely have a better safety profile than LMWH.43–47
When selecting between DOACs, considerations include clinical trial data (see earlier discussion, minimal data for dabigatran; the largest studies focused on apixaban and edoxaban; some subgroups and high-risk clots were excluded from trials), the ability of the patient to take the medication with food (rivaroxaban), twice-daily regimens (apixaban, dabigatran) versus once-daily (edoxaban, rivaroxaban), the need to overlap with a parenteral anticoagulant (dabigatran, edoxaban), and cost. Dabigatran is unique in that the capsules contain tartaric acid to enhance pH-dependent absorption. It must be stored in the original bottle or blister package and is associated with dyspepsia. Apixaban has the least renal clearance, whereas dabigatran has the highest (Table 1). Although not fully covered in this review, access to reversal agents, including idarucizumab (for dabigatran), andexanet alfa (for rivaroxaban or apixaban), and prothrombin complex concentrate, may occasionally influence anticoagulant decisions.
Some commonly encountered clinical scenarios and anticoagulant considerations are detailed in the following sections and in Table 4.
Clinical Scenario and Anticoagulant Considerations for CAT When Pursuing Anticoagulation
Significant Renal Failure and Patients on Hemodialysis
LMWH should be used with caution in patients with renal impairment and generally avoided for those on hemodialysis. DOACs should generally be avoided. Based on pharmacokinetic and pharmacodynamic data, the prescribing information for apixaban does not suggest a dosing adjustment for patients with end-stage renal disease on dialysis. However, there are insufficient data to support apixaban for routine clinical use in this population and we generally avoid it.4 Warfarin may be preferred for this population. For patients with renal impairment but a CrCl >30 mL/min, apixaban may be preferred among the DOACs, given that it has the least renal clearance. Of note, edoxaban is not recommended in patients with nonvalvular atrial fibrillation and a CrCl >95 mL/min.48 However, the same concerns have not been evident for CAT so far.
Liver Disease
DOACs are to be avoided in active, and clinically significant liver disease.4 LMWH is preferred with warfarin as an alternative anticoagulant option. Although large retrospective studies and meta-analyses have not shown clear safety concerns with DOACs,49 there are significant limitations in the available data, especially with defining liver disease. It may be premature to use DOACs in patients with advanced liver disease in clinical practice. Hemostatic changes in liver disease, including acquired antithrombin deficiency with the potential for heparin resistance, are complex, and accordingly anticoagulation must be carefully considered for this patient population.
Extremes of Weight
DOACs have not been well studied in extremes of weight. Although there is no strong safety signal, DOACs should be used with caution with patients >120 kg and/or a body mass index >40 kg/m2.5,50,51 DOACs have also not been well studied in patients <50 kg,52 and edoxaban requires a dose reduction for weight <60 kg. Ultimately, anticoagulation choice should be individualized for extremes of weight.
Altered Gastrointestinal Anatomy or Feeding Tubes
The DOACs are absorbed at various locations in the gastrointestinal tract, largely in the stomach and small intestine, except for apixaban, which is also absorbed in the distal small bowel and ascending colon. For patients with a history of bariatric surgery or bowel resections, absorption can be a concern.53–55 LMWH may be preferred for some patients, with warfarin as an alternative option. Dabigatran and edoxaban are not recommended for administration by enteral tubes. Rivaroxaban and apixaban can be administered via nasogastric feeding tubes (rivaroxaban cannot be administered distal to the stomach).56
Conclusions
CAT management is complex and distinct from VTE management in other populations. Decisions must consider numerous factors. Clinicians should use guidelines,18 knowledge of their patient, consideration of costs, and anticoagulant pharmacology to engage their patients in deciding on an appropriate drug.
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