NCCN: Continuing Education
Target Audience: This activity is designed to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer.
Accreditation Statement NCCN
Physicians: National Comprehensive Cancer Network is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurses: National Comprehensive Cancer Network is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.
NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacists: National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: 0836-0000-18-011-H01-P
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the educational content; 2) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/84204; and 3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail email@example.com.
Release date: November 10, 2018; Expiration date: November 10, 2019
Upon completion of this activity, participants will be able to:
Integrate into professional practice the updates to the NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease
Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease
NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
Venous thromboembolism (VTE) is a common and life-threatening condition in patients with cancer.1,2 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease outline strategies to prevent and treat VTE in adult patients (≥18 years) either with a diagnosis of cancer or in whom cancer is clinically suspected. In the guidelines, VTE is broadly defined to include deep venous thrombosis (DVT), pulmonary embolism (PE), superficial vein thrombosis (SVT), and splanchnic vein thrombosis (SPVT).
Depending on the absence of contraindications and other patient- and case-specific factors, therapeutic anticoagulation is a key component of management of cancer-associated VTE. The specific contexts in which therapeutic anticoagulation is recommended for DVT, catheter-related DVT, PE, and acute SPVT are shown on DVT-2, DVT-3, PE-2,
Use of Anticoagulants in Patients With VTE and Cancer: Clinical Data
Therapeutic anticoagulation regimens include combination therapy regimens in which one agent is used initially (as “acute” treatment) and then switched to a different agent that is used for long-term or chronic treatment (eg, ≥3 months), and monotherapy regimens in which the same agent is used for both acute and chronic treatment. Since the duration of “acute” treatment varies across regimens, the NCCN Guidelines list complete therapeutic anticoagulation regimens, including initial and long-term dosing, timing for changes in agents or dosing, and considerations for determining appropriate duration of treatment (VTE-E, pages 1291–1294).
Low Molecular Weight Heparin Alone Versus With Vitamin K Antagonist
For many years low molecular weight heparin (LMWH) alone or in combination with warfarin was the standard anticoagulation treatment for
In the 4 trials that reported VTE recurrence data,4–7 rates with single-agent LMWH were lower than those for LMWH plus VKA, although these trends reached statistical significance in only 2 of the 4 trials (Table 1). Although there was no difference in recurrent VTE between treatment arms during the 12-week study period in the Main-LITE study, recurrent VTE was significantly lower at 12 months with single-agent LMWH (tinzaparin) compared with UFH plus warfarin (7% vs 16%; P=.044; relative risk, 0.44).6
Trends in rates of major bleeding were not consistent across trials (Table 1). CANTHANOX found that major bleeding was significantly less frequent with single-agent enoxaparin compared with enoxaparin plus warfarin.3 In contrast, major bleeding did not differ by treatment arm in the other 4 studies (Table 1). CANTHANOX also showed that single-agent enoxaparin was associated with less fatal bleeding compared with enoxaparin plus warfarin (0% vs 8% of patients; P=.03).3 Two studies (CLOT, ONCENOX) reported nonsignificant trends toward more major bleeding with single-agent LMWH.4,5
Taken together, results from these randomized trials show that in patients with cancer-associated VTE, LMWH is associated with a similar or lower risk of VTE and similar risk of major bleeding compared with LMWH/UFH plus VKA. In addition, no difference was seen in overall survival between LMWH and UFH/LMWH plus VKA, although the vast majority of study death was due to progressive cancer.3–7 There were no consistent trends regarding VTE- or bleeding-associated fatalities between treatment arms. Meta-analyses of randomized controlled trials have consistently shown that LMWH is superior
Because trials including patients with cancer have not compared LMWH with VKAs for a duration of >6 months, decisions regarding continued LMWH therapy beyond this time frame or transition to a VKA should be based on clinical judgment.
Combinations With Warfarin
Combining LMWH or UFH With Warfarin: Given that patients have great difficulty with long-term adherence to parenteral agents and the higher cost of LMWH, the NCCN Guidelines also include combinations of LMWH/UFH plus warfarin among the recommended options for treatment of cancer-associated VTE (see VTE-E 2 of 5, page 1292). The recommended LMWH dosing in these combination regimens reflects the regimens used in the comparator arms of the CLOT trial (for dalteparin) and ONCENOX trial (for enoxaparin) (Table 2).
Combining Fondaparinux With Warfarin: Fondaparinux is a specific indirect factor Xa inhibitor FDA-approved for the treatment of acute DVT or PE when administered in conjunction with warfarin.12 The prospective randomized MATISSE trials compared fondaparinux plus warfarin versus LMWH plus warfarin, or versus UFH plus warfarin, for treatment of DVT or PE, respectively13,14 (Tables 3 and 4). In patients
LMWH Versus Warfarin for Long-Term Treatment of VTE in Patients With Active Cancera: Data From Prospective Randomized Trials
Direct Oral Anticoagulants
Although the FDA approvals of the DOACs apixaban, dabigatran, edoxaban, and rivaroxaban for treatment of VTE were based on trials in which most patients did not have cancer,15–20 subanalyses of patients with cancer have now been published for the pivotal trials testing each of these agents,21–24 and results have now been reported from 2 randomized trials testing DOACs specifically in patients with cancer.25,26 Table 5 summarizes the VTE index event criteria, overall treatment scheme, and key results from patients with cancer in each of these prospective randomized trials. Table 6 provides details about the anticoagulation regimens used in these trials. The following sections describe the data and rationale supporting each of the DOAC-containing regimens included in the guidelines among the recommended options for anticoagulation treatment of cancer-associated VTE.
Apixaban: Apixaban is an orally administered direct factor Xa inhibitor that has been FDA-approved for the treatment of DVT and PE based on results from the AMPLIFY trial, which compared single-agent apixaban with combination enoxaparin plus warfarin in patients with acute symptomatic proximal DVT and/or acute symptomatic PE (supplemental eTable 1, available with this article at JNCCN.org).17,27 As shown in Table 5, the subanalysis of patients with
LMWH Versus Warfarin for Long-Term Treatment of VTE in Patients With Active Cancer: Study Treatment Dosing
Dabigatran: Dabigatran is an orally administered direct thrombin inhibitor FDA-approved for the treatment of DVT and PE in patients who have received parenteral anticoagulant for 5 to 10 days.28 This approved indication is based on results of the RE-COVER and RE-COVER II trials (supplemental eTable 1).20 As shown in Table 5, analysis of the subset of patients with cancer at baseline showed no treatment-dependent differences in the rates of VTE recurrence or major bleeding.22 Among patients with cancer, the mortality rates were not significantly different between treatment arms. Similar to the apixaban trials, the cancer subgroup in the dabigatran studies was substantially healthier than the CLOT trial population, as evidenced by the lower mortality (14% vs 39%).4,22 Based on results from this subgroup analysis, the NCCN Guidelines include LMWH/UFH plus dabigatran as potential treatment options for cancer-associated VTE (see VTE-E 3 of 5, page 1293). Because of the limitations of the RE-COVER trials (comparison with LMWH plus warfarin, healthier population of patients with cancer), the recommendation for LMWH/UFH plus dabigatran is limited to those who refuse or have compelling reasons to avoid long-term LMWH.
Fondaparinux for VTE in Patients With Active Cancera: Data From Prospective Randomized Trials
Edoxaban: Edoxaban is an orally administered direct factor Xa inhibitor that is FDA approved for the treatment of DVT or PE after 5 to 10 days of initial therapy with a parenteral anticoagulant.29 The FDA-approved indication is based on results from the Hokusai-VTE study, a prospective randomized trial that tested edoxaban in patients with acute lower extremity DVT and/or acute PE (supplemental eTable 1).18 Results from subgroup analyses showed that although there were no treatment-dependent differences in recurrent VTE rates among patients with no history of cancer and no active cancer while on study (3% vs 3% for edoxaban vs warfarin), there was a trend toward higher rates of recurrent VTE with warfarin in the subset of patients with active cancer at baseline (Table 5), which reached significance for the subgroup that included all patients with current or prior cancer at baseline (4% [14/378] vs 7% [28/293]; hazard ratio, 0.53; 95% CI, 0.28–1.00; P=.0007).23 Rates of major bleeding did not differ across treatment arms in any of the subgroups based on current/prior cancer status.18,23 Mortality was similar across treatment arms for all categories of patients with current or prior cancer.
Given that single-agent LMWH is the preferred option for the treatment of VTE in patients with cancer, a separate randomized trial specifically in patients with cancer (Hokusai VTE-Cancer) compared LMWH plus edoxaban combination therapy (initial short-term LMWH followed by longer-term edoxaban) with single-agent LMWH (dalteparin) for the treatment of acute lower extremity DVT or acute PE.25 As shown in Table 5, the rate of recurrent VTE was lower in those who received combination LMWH plus edoxaban versus single-agent dalteparin, although this trend did not reach significance and the rate of major bleeding was significantly higher in the edoxaban arm. Mortality was not significantly different between treatment arms, and the vast majority of deaths were cancer related. The numbers of VTE- or bleed-related deaths were too small to allow for meaningful comparisons across treatment arms. Based on these results, the NCCN Guidelines include combination treatment with LMWH followed by edoxaban as a category 1 option for anticoagulation of cancer-associated VTE and combination therapy with initial UFH followed by edoxaban as a category 2A option because it was not
Fondaparinux for VTE in Patients With Active Cancer: Study Treatment Dosinga
DOACs for Treatment of VTE in Patients With Active Cancera: Data From Prospective Randomized Trials
Rivaroxaban: Rivaroxaban is an orally administered direct factor Xa inhibitor approved by the FDA as a single-agent treatment for DVT and/or PE.30 FDA approval for this indication was based on the results of 2 phase 3 open-label noninferiority randomized trials comparing single-agent rivaroxaban versus initial short-term LMWH (enoxaparin) plus warfarin/acenocoumarol (started concurrently with LMWH and continued as single agent after LMWH discontinuation; See Table 6 for details on regimens tested, supplemental eTable 1 for results).15,16,31 As shown in Table 5, pooled analysis of the subset of patients with active cancer (at baseline or presenting during the study) in these trials yielded similar results as the larger pooled analysis, with no treatment-dependent
DOACs for Treatment of VTE in Patients With Active Cancer: Study Treatment Dosing
Given that single-agent LMWH is the preferred option for patients with cancer, the randomized open-label pilot Select-D trial compared single-agent rivaroxaban with single-agent LMWH (dalteparin) for the treatment of PE or symptomatic lower extremity DVT in patients with cancer.26 As shown in Table 5, the cumulative rate of VTE recurrence at 6 months was lower with rivaroxaban, but the cumulative major bleed rate was slightly higher with rivaroxaban.26 Overall survival at 6 months did not differ by treatment, and the numbers of deaths related to VTE or bleeds were too small to allow for meaningful comparison.
Based on these results, the NCCN Guidelines include single-agent rivaroxaban as an option for anticoagulation treatment of VTE in patients with cancer. Unlike single-agent apixaban, the recommendation for single-agent rivaroxaban is not limited to patients with compelling reasons to avoid LMWH, because the Select-D trial showed that rivaroxaban has similar or better efficacy than single-agent dalteparin in patients with cancer-associated VTE.26 The recommended dosing regimen for rivaroxaban matches that used in the EINSTEIN and Select-D trials (Table 6) and recommended in the FDA label.30
Selection Among Therapeutic Anticoagulation Options
Use of single-agent LMWH for treatment of cancer-associated VTE is challenging because LMWH is expensive and the injections are painful to administer; both factors negatively impact patient quality of life. Many studies of clinical practice patterns have shown that single-agent LMWH is underutilized in patients with cancer-associated VTE despite guideline recommendations that it is the preferred treatment option.32–46 Compared with oral anticoagulants, LMWH is associated with poorer persistence, shorter duration of treatment, and a higher likelihood of switching to a different anticoagulant.34,37,39,42,44,47–49 One prospective cohort study of patients with cancer-associated VTE found that 21% discontinued LMWH due to side effects, the most common being injection site pain, large local injection site hematomas, and allergic reactions.47 In the Hokusai VTE-Cancer trial, nearly 15% of patients in the dalteparin arm decided to discontinue study treatment due to inconvenience of dosing, whereas only 4% in the edoxaban arm discontinued for this reason.25
Although physicians may be reluctant to prescribe long-term LMWH based on the assumption that outpatients are much more likely to adhere to a prescribed oral dosing than to daily painful subcutaneous injections, it is unclear to what degree poor patient adherence is a barrier to sufficient anticoagulation for cancer-associated VTE. In prospective trials, adherence to long-term LMWH regimens was remarkably high among patients with cancer-associated VTE (supplemental eTable 2). In the 2 prospective randomized trials that compared single-agent LMWH to a DOAC-containing regimen for treatment of VTE in cancer patients (Hokusai VTE-Cancer and Select-D), results showed no significant difference between treatment arms in the level of adherence to the study protocol (supplemental eTable 2). One prospective observational study in patients prescribed long-term LMWH for cancer-associated VTE found that although the overall adherence to guidelines was only 55%, the mean duration of LMWH treatment was consistent with guidelines.50 This and other studies that surveyed patients with cancer-associated VTE found that most patients did not find the LMWH regimen to be difficult to use, distressing, or inconvenient, and that preference for oral medication versus injection was of moderate importance.35,50–52
Challenges to using DOACs to treat cancer-associated VTE are mostly related to safe administration of DOACs in patients with cancer. There is concern that the patient selection criteria used in the prospective randomized trials testing DOACs may have excluded a significant proportion of patients with cancer who need therapeutic anticoagulation in real world clinical settings. Supplemental eTable 3 summarizes exclusion criteria that may have impacted the eligibility of patients with cancer in these trials. Based on trial entry criteria, FDA prescribing information, and data on clinical/case-specific features that may increase the risk of adverse events, the NCCN Guidelines Panel developed a list of contraindications and warnings for each of the anticoagulants recommended for treatment of VTE in patients with cancer (see VTE-E 4 of 5, page 1294).
Some of the factors that could influence the efficacy and safety of DOACs include advanced age, weight/body mass index, gender, concomitant medications, kidney or liver function, chemotherapy-associated nausea/vomiting, and surgical resection of the proximal small bowel.53–72 The recommended agents differ in the extent to which these variables impact drug clearance/absorption, and in the quality and quantity of safety data in special populations available to support dose adjustments. Likewise, anticoagulants vary widely in terms of the extent of information available on recommended dose adjustments based on the previously mentioned patient-specific factors.73–75 There are ongoing debates among NCCN panel members and in the field on how to manage VTE patients with and without cancer in regards to drug–drug interactions, extremes of weight, compromised kidney and liver function, and previous small bowel resection. At present, it is recommended that alternative agents be considered in the event of major drug–drug interactions, severe renal or hepatic impairment, or small bowel resections until further data are developed to inform decision-making.
The NCCN Guidelines Panel discussed at length whether any subsets of patients with cancer are at particularly high risk of bleeding if treated with DOACs. Several studies have noted that patients with gastrointestinal (GI) and genitourinary (GU) cancers are increased risk for bleeding when treated with DOACs.25,26 Subgroup analyses in the Hokusai VTE-Cancer trial found that patients with Gl cancer at randomization had a significantly higher bleeding rate with LMWH plus edoxaban versus dalteparin monotherapy (13.2% [18/136] vs 2.4% [3/125]; P=.0224).25 In addition, in the overall population (all cancer types), the trend toward higher rates of major bleeding with edoxaban was largely due to increases in the rate of GI and urogenital bleeds (patients with GI/GU bleeds, 4.8% vs 1.1% for edoxaban vs dalteparin arms). In the Select-D trial, analysis of bleeding rate according to primary tumor type showed that patients with esophageal or gastroesophageal cancer tended to experience more bleeding with rivaroxaban versus dalteparin (36% [4/11] versus 11% [1/19]), and in the overall population (all cancer types) the trend toward increased rates of major bleeding with rivaroxaban was due to higher rates of bleeds located in the GI and GU tracts (patients with GI/GU bleeds, 4.4% vs 2.0% for rivaroxaban vs dalteparin).26 Hence the NCCN Guidelines list urinary or GI tract lesions, pathology, or instrumentation as relative contraindications to DOACs in patients with cancer.
For patients with cancer-associated VTE for whom anticoagulation is appropriate, the NCCN Guidelines provide a list of recommended regimens. In addition to single-agent LMWH, edoxaban and rivaroxaban are considered preferred regimens by many panel members. Selection among agents should be based on the clinical setting (inpatient/outpatient), cost, ease of administration, monitoring, bleeding risk assessment, ability to reverse anticoagulation, and assessment of patient- and case-specific factors such as renal/hepatic function, potential for drug–drug interactions, GI/GU malignancies or instrumentation, and previous small bowel surgery. The NCCN Guidelines provide an agent-specific list of contraindications and warnings that should be considered when selecting treatment, and baseline laboratory testing needed to inform treatment and dose selection. Careful review of the prescribing information for each agent is also important for safe administration of these agents. For treatment in the outpatient setting, selection of a parenteral versus orally administered agent should include a discussion with the patient and their caregiver to ensure adherence to and completion of the prescribed treatment regimen.
See JNCCN.org for supplemental online content.
PrinsMHLensingAWBrightonTA. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematol2014;1:e37–46.
ReillyPALehrTHaertterS. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol2014;63:321–328.