237
Novel or Non–Vitamin K Antagonist Oral Anticoagulants and the Treatment of Cancer-Associated Thrombosis Agnes Y. Y. Lee, MD, MSc, FRCPC2,3
1 Division of Hematology, Department of Medicine, University of
Alberta, Edmonton, Alberta, Canada 2 Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada 3 Thrombosis Program, Vancouver Coastal Health Authority, Vancouver, British Columbia, Canada
Address for correspondence Cynthia Wu, MD, FRCPC, Division of Hematology, Department of Medicine, University of Alberta, 4-112 Clinical Sciences Building, 11350-83rd Avenue, Edmonton, AB T6G 2G3, Canada (e-mail: [email protected]).
Semin Thromb Hemost 2015;41:237–243.
Abstract
Keywords
► cancer ► venous thromboembolism ► novel oral anticoagulants
Cancer-associated thrombosis remains a common and challenging clinical presentation. Despite advances in therapy using low-molecular-weight heparins, both venous thromboembolic recurrence and clinically relevant bleeding while on therapeutic anticoagulation occur at high rates. Multiple novel (or non–vitamin K antagonist) oral anticoagulants have recently been developed for the treatment and prevention of venous thromboembolism. There are many attractive features of these agents including convenience and simplicity of administration. Unfortunately, there are also several limitations such as dependency on gastrointestinal absorption, renal clearance, and some significant drug–drug interactions. The use of these newer oral agents in cancer patients is not recommended, as their safety and efficacy are not yet established and the complexity of these patients warrants further cancer-specific clinical trials.
Venous thromboembolism (VTE), composed of deep vein thrombosis (DVT) and pulmonary embolism (PE), occurs at an annual incidence of 117 per 100,000 in the general population.1 It is associated with significant morbidity and mortality as well as a risk of recurrent events.2,3 In those afflicted with cancer, the incidence and consequences of VTE are even greater. Cancer and its treatment contribute significantly to the pathophysiology of VTE through mechanisms described as Virchow’s triad: venous stasis, endothelial injury, and hypercoagulability.4 As a result, cancer patients have a 4.1- to 6.5-fold increased risk of VTE, with an estimated annual incidence of 1 in 200,5 and a higher rate of VTE recurrence and anticoagulant failure compared with noncancer patients.6–9 Those with VTE also have a poorer prognosis and a threefold increase in mortality compared with their peers without thrombosis.10 Behind cancer progression, VTE is the second leading cause of death in cancer patients.11
published online February 15, 2015
Issue Theme Anticoagulant Therapy: Present and Future; Guest Editor: Job Harenberg, MD.
Goals of Venous Thromboembolism Therapy in Cancer Patients While the overall goals of treatment, including symptom control, preventing clot progression and embolization, and decreasing VTE recurrence and long-term complications such as post thrombotic syndrome and pulmonary hypertension, are similar to goals in noncancer patients, anticoagulant therapy in those with cancer is fraught with unique challenges. The inherent complexity of cancer and its treatment increases the chances of organ failure and thrombocytopenia, which in turn increase the risk of bleeding. The typical on and off cyclical nature of chemotherapy and its associated arsenal of supportive care therapies make drug–drug interactions more difficult to manage. The prognosis and intensity of cancer treatment also change over time, which may influence anticoagulant of choice and alter the risk–benefit ratio of anticoagulation with each phase of cancer treatment.
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0035-1544160. ISSN 0094-6176.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Cynthia Wu, MD, FRCPC1
NOACs and Cancer
Wu, Lee
Current Standard of Treatment: Low-Molecular-Weight Heparin Several studies have established low-molecular-weight heparin (LMWH) as the current standard of care in the treatment of cancer-associated thrombosis (CT). The Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) trial12 demonstrated significant superiority of dalteparin over warfarin with equivalent safety outcomes (8 vs. 16% recurrent VTE, respectively; 6% major bleeding). The Longterm Innovations in TreatmEnt (LITE) trial13 (a cancer subgroup analysis of the Main-LITE trial14) was underpowered but demonstrated a similar trend in efficacy and safety for tinzaparin versus warfarin (7 vs. 16% recurrent VTE, respectively; 7% major bleeding). Data for enoxaparin versus warfarin (Secondary Prevention Trials of Venous Thrombosis with Enoxaparin: CANTHANOX15 and ONCENOX16) were equivocal, as both trials were stopped early and were underpowered to demonstrate statistical difference, though a trend in favor of enoxaparin was noted in the ONCENOX trial (6 vs. 10% recurrent VTE). Although the CLOT trial redefined the standard of care for CT, the rates of recurrent VTE and major bleeding are both still several-fold higher compared with noncancer patients on anticoagulation for VTE.12,17 Improving the safety and efficacy of CT treatment remains a high priority.
Novel Oral Anticoagulants Several new direct (or non–vitamin K antagonist) oral anticoagulants (NOACs) have been recently developed. Four of these have been compared against warfarin in completed phase III randomized control trials for the treatment of DVT and PE. Three are direct factor Xa inhibitors: apixaban (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy, AMPLIFY trial18), edoxaban (Hokusai-VTE trial19), and rivaroxaban (EINSTEIN DVT20 and EINSTEIN PE21 trials). The fourth is a direct thrombin inhibitor: dabigatran (RECOVER trial22). All of these trials showed that NOACs are at least as safe and as effective as warfarin for the acute treatment of VTE in the general population.
Comparing LMWH with NOACs: Similarities and Cautions There are several pharmacologic properties that are shared between the LMWHs and NOACs that make these agents more favorable over warfarin. Compared with warfarin, both LMWHs and NOACs have an immediate onset of action, a shorter half-life, a more stable and predictable anticoagulant effect that generally obviates the need for laboratory monitoring, and no food interactions.23,24 Unfortunately, there are some significant differences that are more relevant to cancer patients. When dealing with a population of patients that have multiple reasons for compromised gastrointestinal function (site of cancer, cancer-associated cachexia, poor oral intake, treatment-related Seminars in Thrombosis & Hemostasis
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nausea, vomiting, and mucositis), oral agents are less reliable compared with parenteral agents. In particular, rivaroxaban requires concurrent intake of food to enhance absorption at its therapeutic doses and dabigatran requires a more acidic environment for effective absorption.24 In addition, while LMWHs and NOACs are designed to not require laboratory monitoring, the availability of anti-Xa measurement for LMWH is advantageous in certain clinical circumstances. One common situation is severe renal impairment. Although anti-Xa levels do not strongly correlate with efficacy and safety of LMWH use, there is clinical experience and familiarity with this test, and measuring trough levels to check for LMWH accumulation can be useful.25 At this time, there are no clinically validated methods to measure the anticoagulant activity of NOACs and therapeutic levels of these agents have not been established. Another frequent challenge in cancer patients is the higher rate of anticoagulant failure as well as the increased risk of bleeding from factors such as thrombocytopenia. While no evidencebased guidelines exist, considerable experience has accumulated to help guide titration of the LMWH dose to balance the thrombotic and hemorrhagic risks.26–28 NOACs have far fewer dosing options than LMWH and experience is lacking in potentially titrating the dose in complex scenarios. Importantly, although there are fewer drug–drug interactions for NOACs compared with warfarin, there are virtually none for LMWHs. All the NOACs rely on p-glycoprotein for drug absorption and some are dependent on CYP3A4 for metabolism.24 Drugs that inhibit these enzymes (such as tamoxifen, tyrosine kinase inhibitors, cyclosporine) may significantly increase the anticoagulant effect and drugs that induce these enzymes (such as dexamethasone, doxorubicin, vinblastine, St John’s Wort) may significantly decrease the anticoagulant effect.27 The net effect of inhibition and induction would be difficult to estimate in multidrug chemotherapeutic regimens. There remain many undefined, though suspected, drug interactions as well as an increased exposure in cancer patients to new anticancer drugs which have unknown drug–drug interactions. Finally, the lack of an antidote to rapidly reverse the anticoagulant activity remains worrisome to clinicians and patients. All these limitations give pause to the use of NOACs for CT and further cancer-specific data are required. ►Table 1 summarizes the key differences between NOACs and LMWHs.
Reviewing the Existing Evidence for NOACS in CT While robust cancer-specific NOAC trials have not been performed, several subgroup analyses of existing trials have been presented or published recently.
Prevention of VTE in Cancer Patients Given the higher rate of VTE in the cancer population as well as the difficulties treating VTE when it does occur, a sensible approach would be primary prevention.
Medical Inpatients DVT prophylaxis is recommended for most patients admitted to hospital for medical illnesses, including those with cancer,
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Table 1 Comparison of novel oral anticoagulants and low-molecular-weight heparins Low-molecular-weight heparins
$c
$$$c
Route of administration
Oral
Subcutaneous
Gastrointestinal absorption
Yes
No
Onset of action
Rapid
Half-life
5–14 h
Rapid a
2–5 h
Renal dependence
Yes
Yes
Need for monitoring levels
No
No
Ability to monitor levels
Nob
Anti-Xa assay
Reversal agents
No
Protamine (partial reversal)
Drug interactions
P-glycoprotein/CYP3A4
None
Flexible dose adjustments
No
Yes
Highest available evidence in cancer-associated thrombosis
Subgroup analyses of non–cancer-specific trials suggest noninferiority to warfarin
Randomized controlled cancer-specific trials show superiority to warfarin
a
Half-life increases for older patients or those with renal impairment. Drug assays may be available in select centers but are not validated for clinical use. c Cost of each agent may vary but overall cost of low-molecular-weight-heparin is significantly higher than of novel oral anticoagulants. b
as multiple VTE risk factors are present.29–32 Existing data on LMWH or fondaparinux prophylaxis in cancer patients are limited to small post hoc, subgroup analyses. A recent metaanalysis of all published data showed no significant VTE reduction with either LMWH or fondaparinux prophylaxis (relative risk, 0.91; 95% confidence interval [CI], 0.21–4.0).33 This is very different from the 50% risk reduction observed in the overall patient population in these DVT prophylaxis trials. As expected, cancer patients represented only 6% of the study population in these studies, so their results are masked by the main results derived largely from noncancer patients.33–35 For NOACs, there are two placebo-controlled randomized trials examining DVT prophylaxis in medical inpatients. The Apixaban Dosing to Optimize Protection from Thrombosis (ADOPT) study has not published any data from the 211 cancer patients randomized to either 30 days of apixaban 2.5 mg twice daily or 6 to 14 days of enoxaparin 40 mg daily.36 In the overall study population (n ¼ 6,528), 3.2% had active cancer (defined as having received cancer treatment within the last year). There was no difference in the primary composite outcome of VTE-related death, fatal or nonfatal PE, symptomatic DVT, and asymptomatic proximal DVT detected on screening bilateral leg ultrasound (2.71% apixaban vs. 3.06% enoxaparin), but there was a significantly higher rate of major bleeding with apixaban than with enoxaparin (0.47 vs. 0.19%, respectively; relative risk, 2.58; p ¼ 0.04) at the end of the 30-day follow-up period. More importantly, the trend to higher major bleeding rates was still evident when analysis was restricted to the initial in-hospital phase of therapy (0.25% apixaban vs. 0.12% enoxaparin; relative risk, 2.06; p ¼ 0.23). The MAGELLAN (Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the
Prevention of Venous Thromboembolism in Hospitalized Acutely Ill Medical Patients Comparing Rivaroxaban with Enoxaparin) study37 included 8,101 patients, 7.3% of whom had active cancer (defined as admitted for chemotherapy or active cancer complications). A total of 296 cancer patients received 35 days of rivaroxaban 10 mg daily and an additional 296 cancer patients received 10 days of enoxaparin 40 mg daily. In the cancer subgroup at 35 days of follow-up, there was no statistical difference in the primary composite outcome of asymptomatic proximal or symptomatic VTE and VTE-related death (7.4% rivaroxaban vs. 9.9% enoxaparin; p ¼ 0.074), but there was a dramatic increase in the composite rate of major bleeding and clinically relevant nonmajor bleeding in the rivaroxaban group (5.4 vs. 1.7%; p < 0.05). Trends were similar when looking at the first 10 days of treatment only. Rates of clinically relevant bleeding (major bleeding and clinically relevant nonmajor bleeding) were higher in the rivaroxaban group (2.8 vs. 1.2%; p ¼ 0.02).37,38 Overall, the results of available cancer subgroup analyses in trials using NOACs for DVT prophylaxis in hospitalized medical patients demonstrate a higher rate of clinically relevant and major bleeding compared with LMWH, and NOACs should be avoided until more cancer-specific DVT prophylaxis trials are available.
Ambulatory Patient The majority of cancer treatment is delivered to nonhospitalized patients who still carry a high risk of VTE.39 The role of outpatient DVT prophylaxis and appropriate patient selection remains an area of research. Two double-blind randomized trials have studied the use of low-dose LMWH in high-risk ambulatory cancer patients receiving chemotherapy. The PROphylaxis of ThromboEmbolism During CHemoTherapy Seminars in Thrombosis & Hemostasis
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Cost
Novel oral anticoagulants
NOACs and Cancer
Wu, Lee
(PROTECHT) trial compared nadroparin 3,800 units daily with placebo in chemotherapy patients with metastatic cancer or locally advanced lung, gastrointestinal, pancreatic, breast, ovarian, or head and neck cancer (n ¼ 1,150).40 VTE occurred less frequently in the nadroparin group (2.0 vs. 3.9%, p ¼ 0.02) with no significant increase in major bleeding (0.7 vs. 0%, p ¼ 0.18). In the SAVE-ONCO trial, semuloparin 20 mg daily was compared with placebo in patients planned for chemotherapy in the setting of metastatic or locally advanced lung, pancreatic, stomach, colon, rectal, bladder, or ovarian cancer (n ¼ 3,212).41 VTE occurred less frequently in the semuloparin group (1.2 vs. 3.4%, p < 0.001) with no significant increase in major bleeding (1.2 vs. 1.1%). For NOACs, one phase II trial has randomized patients with advanced or metastatic cancer (but no baseline VTE) to placebo versus apixaban 5 mg once daily, 10 mg once daily, or 20 mg once daily for 12 weeks.42 It was ultimately underpowered due to poor accrual and it was terminated after 125 patients were enrolled. Results were encouraging with apixaban groups having a 2.2% rate of major bleeding (mostly in the 20 mg group), no symptomatic lower extremity DVT or PE (compared with three patients (10.3%) in placebo group) and one case of catheter-related DVT (also 1 case in the placebo group). Future clinical trials are highly anticipated.
Surgical Inpatients There are no existing trials using NOACs for postoperative DVT prophylaxis in cancer patients both during hospital admission and postdischarge. Whether future trials will be available is unknown. In the early postoperative setting, the advantage of an oral agent over parenteral agent is less evident, as many surgical patients are unable to take oral medications immediately after surgery. There is certainly a potential role for NOACs for extended prophylaxis beyond the hospital-stay period, as 4 weeks of LMWH prophylaxis has been shown to significantly reduce VTE in patients undergoing abdominal or pelvic surgery for cancer.43–45 An oral agent in this setting would definitely be welcomed, as shown by the rapid practice change to adopt NOACs for postoperative prophylaxis in the major joint replacement setting.46
Summary on DVT Prophylaxis with NOACs in Cancer Patients While high priority should be placed on preventing VTE whenever possible in high-risk patients, the available trials have not established a role for NOACs in DVT prophylaxis for cancer patients yet. There are some safety concerns with an increased rate of bleeding at least with extended use of NOACs for medical inpatient prophylaxis. For the time being, NOAC use for VTE prevention in cancer patients should be limited to clinical trials.
Treatment of VTE in Cancer Patients There are no CT treatment trials prospectively and specifically evaluating the use of NOACs. The four main phase III trials comparing NOACs to warfarin in VTE have all published or presented their cancer subgroup data. Recent meta-analyses of these data reported no statistically significant differences Seminars in Thrombosis & Hemostasis
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in the rates of recurrent VTE or major bleeding when comparing NOACs to warfarin in cancer subgroups.47–49 They also highlighted the methodological limitations of these subgroup analyses and recommended future trials comparing NOAC with LMWH. A comparison of NOAC and LMWH trials which reported data on recurrent VTE and major bleeding in cancer patients is summarized in ►Table 2. Of the 5,395 patients randomized in the AMPLIFY study, 169 (3.1%) had active cancer. These patients were diagnosed with or treated for cancer within the past 6 months, had recurrent cancer or metastatic cancer, but patients were excluded if longterm LMWH treatment was planned.50 Recurrent VTE occurred in 3/81 (3.7%) on apixaban and 5/78 (6.4%) on warfarin. Major bleeding occurred in 2/87 (2.3%) on apixaban and 4/80 (5.0%) on warfarin. A total of 8,292 patients were randomized in the HokusaiVTE study.51 Those with cancer in whom LMWH use was anticipated were excluded from the study. Among the cancer patients enrolled, 563 had a history of cancer and 208 had active cancer, defined according to the local investigators’ discretion. Of these, VTE recurrence occurred in 4/109 (3.7%) patients on edoxaban and 7/99 (7.1%) patients on warfarin. Major bleeding occurred in 5/109 (4.6%) patients on edoxaban and 3/99 (3.0%) patients on warfarin. These risk reductions were consistent with the overall results of the entire study cohort. A recent meta-analysis pooled the results of the cancer patients enrolled in the EINSTEIN-DVT20 and EINSTEIN-PE21 trials.52 Of the 8,282 patients randomized in these studies, 655 (7.9%) had active cancer at baseline or were diagnosed with cancer during the study period.52 The definition of cancer was not prespecified in the original EINSTEIN studies, but in the post hoc pooled analysis, it was disclosed that patients were reclassified according to their active cancer status, defined post hoc as having active cancer if cancer was diagnosed or treated within 6 months, or recurrent/metastatic. This included 14 patients with basal-cell or squamous-cell carcinoma in the active cancer group. VTE recurred in 16/354 (4.5%) on rivaroxaban and 20/301 (6.6%) on warfarin. Major bleeding occurred in 8/353 (2.3%) on rivaroxaban and 15/298 (5.0%) on warfarin. These results also included patients who had occult cancer and were diagnosed with the cancer during the study period. If limited to only those with active cancer at baseline, VTE recurred in 6/258 (2.3%) on rivaroxaban and 8/204 (3.9%) on warfarin, and major bleeding occurred in 5/238 (2.1%) on rivaroxaban and 8/204 (3.9%) on warfarin. Finally, the RECOVER study enrolled 121 patients with cancer excluding basal-cell or squamous-cell carcinoma of the skin, who received their cancer diagnosis within 5 years, any cancer treatment within 5 years, or had recurrent/ metastatic cancer out of a total of 2,539 patients.22 VTE recurrence occurred in 2/64 (3.1%) patients on dabigatran and 3/57 (5.3%) patients on warfarin. Major bleeding occurred in 5/62 (7.8%) patients on dabigatran and 3/57 (5.3%) patients on warfarin.53 It should be noted that compared with the noncancer patients randomized in all the NOAC trials, both the rates
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241
Table 2 Recurrent venous thromboembolism and major bleeding in cancer patients with acute venous thromboembolism treated with novel oral anticoagulants, low-molecular-weight heparins, or warfarin
Low-molecular-weight heparin
Anticoagulant CLOT12 13
Major bleeding
n (%)
n (%)
Dalteparin
27/336 (8.0)
19/338 (5.6)
Warfarin
53/336 (15.8)
12/335 (3.6)
LITE (subgroup)
Tinzaparin
6/100 (6.0)
7/100 (7.0)
Warfarin
10/100 (10.0)
7/100 (7.0)
CANTHANOX15
Enoxaparin
2/71 (2.8)
5/71 (7.0)
Warfarin
3/75 (4.0)
12/75 (16.0)
Enoxaparin
4/61 (6.6)
6/67 (9.0)
Warfarin
3/30 (10.0)
1/34 (2.9)
AMPLIFY (subgroup)
Apixaban
3/81 (3.7)
2/87 (2.3)
Warfarin
5/78 (6.4)
4/80 (5.0)
Hokusai-VTE51 (subgroup)
Edoxaban
4/109 (3.7)
5/109 (4.6)
Warfarin
7/99 (7.1)
3/99 (3.0)
ONCENOX16 Novel oral anticoagulants
Recurrent VTE
50
52
EINSTEIN (subgroup)a
Rivaroxaban
6/258 (2.3)
5/238 (2.1)
Warfarin
8/204 (3.9)
8/204 (3.9)
RECOVER53 (subgroup)
Dabigatran
2/64 (3.1)
6/159 (7.8)
Warfarin
3/57 (5.3)
3/57 (5.3)
Abbreviations: CLOT trial, Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer trial; LITE trial, Long-term Innovations in TreatmEnt trial; CANTHANOX and ONCENOX trials, Secondary Prevention Trials of Venous Thrombosis with Enoxaparin; AMPLIFY trial, Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy. a Numbers in table represent only the patients who had active cancer at the time of enrolment.
of recurrent VTE (ranging from 1.8 to 3.5% in noncancer subgroups vs. 1.8 to 7.4% in cancer subgroups) and major bleeding and clinically relevant nonmajor bleeding (ranging from 3.7 to 11.5% in noncancer subgroups vs. 9.3 to 25.3% in cancer subgroups) were higher in cancer patients.47
Limitations in the Existing NOAC Data in Cancer Patients While the available subgroup analyses have not raised critical red flags for NOACs in CT, the data are still inadequate to support their use in the typical patient with active cancer. First, only small numbers of cancer patients were included in each of the trials. Second, the definition of active cancer varied widely between studies, was often quite vague and usually did not match up with the definition used in the CLOT trial (diagnosis of cancer other than basal-cell or squamouscell carcinoma of the skin within 6 months, any treatment for cancer within the previous 6 months, or recurrent or metastatic cancer).12 Third, all treatment trials compared NOACs to warfarin and not to LMWH, which is the current standard of care and already proven to be superior to warfarin. Fourth, each NOAC treatment trial is accompanied by a long list of exclusion criteria (found in their associated online supplemental appendices) which include items such as life expectancy
Novel or Non–Vitamin K Antagonist Oral Anticoagulants and the Treatment of Cancer-Associated Thrombosis Agnes Y. Y. Lee, MD, MSc, FRCPC2,3
1 Division of Hematology, Department of Medicine, University of
Alberta, Edmonton, Alberta, Canada 2 Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada 3 Thrombosis Program, Vancouver Coastal Health Authority, Vancouver, British Columbia, Canada
Address for correspondence Cynthia Wu, MD, FRCPC, Division of Hematology, Department of Medicine, University of Alberta, 4-112 Clinical Sciences Building, 11350-83rd Avenue, Edmonton, AB T6G 2G3, Canada (e-mail: [email protected]).
Semin Thromb Hemost 2015;41:237–243.
Abstract
Keywords
► cancer ► venous thromboembolism ► novel oral anticoagulants
Cancer-associated thrombosis remains a common and challenging clinical presentation. Despite advances in therapy using low-molecular-weight heparins, both venous thromboembolic recurrence and clinically relevant bleeding while on therapeutic anticoagulation occur at high rates. Multiple novel (or non–vitamin K antagonist) oral anticoagulants have recently been developed for the treatment and prevention of venous thromboembolism. There are many attractive features of these agents including convenience and simplicity of administration. Unfortunately, there are also several limitations such as dependency on gastrointestinal absorption, renal clearance, and some significant drug–drug interactions. The use of these newer oral agents in cancer patients is not recommended, as their safety and efficacy are not yet established and the complexity of these patients warrants further cancer-specific clinical trials.
Venous thromboembolism (VTE), composed of deep vein thrombosis (DVT) and pulmonary embolism (PE), occurs at an annual incidence of 117 per 100,000 in the general population.1 It is associated with significant morbidity and mortality as well as a risk of recurrent events.2,3 In those afflicted with cancer, the incidence and consequences of VTE are even greater. Cancer and its treatment contribute significantly to the pathophysiology of VTE through mechanisms described as Virchow’s triad: venous stasis, endothelial injury, and hypercoagulability.4 As a result, cancer patients have a 4.1- to 6.5-fold increased risk of VTE, with an estimated annual incidence of 1 in 200,5 and a higher rate of VTE recurrence and anticoagulant failure compared with noncancer patients.6–9 Those with VTE also have a poorer prognosis and a threefold increase in mortality compared with their peers without thrombosis.10 Behind cancer progression, VTE is the second leading cause of death in cancer patients.11
published online February 15, 2015
Issue Theme Anticoagulant Therapy: Present and Future; Guest Editor: Job Harenberg, MD.
Goals of Venous Thromboembolism Therapy in Cancer Patients While the overall goals of treatment, including symptom control, preventing clot progression and embolization, and decreasing VTE recurrence and long-term complications such as post thrombotic syndrome and pulmonary hypertension, are similar to goals in noncancer patients, anticoagulant therapy in those with cancer is fraught with unique challenges. The inherent complexity of cancer and its treatment increases the chances of organ failure and thrombocytopenia, which in turn increase the risk of bleeding. The typical on and off cyclical nature of chemotherapy and its associated arsenal of supportive care therapies make drug–drug interactions more difficult to manage. The prognosis and intensity of cancer treatment also change over time, which may influence anticoagulant of choice and alter the risk–benefit ratio of anticoagulation with each phase of cancer treatment.
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0035-1544160. ISSN 0094-6176.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Cynthia Wu, MD, FRCPC1
NOACs and Cancer
Wu, Lee
Current Standard of Treatment: Low-Molecular-Weight Heparin Several studies have established low-molecular-weight heparin (LMWH) as the current standard of care in the treatment of cancer-associated thrombosis (CT). The Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) trial12 demonstrated significant superiority of dalteparin over warfarin with equivalent safety outcomes (8 vs. 16% recurrent VTE, respectively; 6% major bleeding). The Longterm Innovations in TreatmEnt (LITE) trial13 (a cancer subgroup analysis of the Main-LITE trial14) was underpowered but demonstrated a similar trend in efficacy and safety for tinzaparin versus warfarin (7 vs. 16% recurrent VTE, respectively; 7% major bleeding). Data for enoxaparin versus warfarin (Secondary Prevention Trials of Venous Thrombosis with Enoxaparin: CANTHANOX15 and ONCENOX16) were equivocal, as both trials were stopped early and were underpowered to demonstrate statistical difference, though a trend in favor of enoxaparin was noted in the ONCENOX trial (6 vs. 10% recurrent VTE). Although the CLOT trial redefined the standard of care for CT, the rates of recurrent VTE and major bleeding are both still several-fold higher compared with noncancer patients on anticoagulation for VTE.12,17 Improving the safety and efficacy of CT treatment remains a high priority.
Novel Oral Anticoagulants Several new direct (or non–vitamin K antagonist) oral anticoagulants (NOACs) have been recently developed. Four of these have been compared against warfarin in completed phase III randomized control trials for the treatment of DVT and PE. Three are direct factor Xa inhibitors: apixaban (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy, AMPLIFY trial18), edoxaban (Hokusai-VTE trial19), and rivaroxaban (EINSTEIN DVT20 and EINSTEIN PE21 trials). The fourth is a direct thrombin inhibitor: dabigatran (RECOVER trial22). All of these trials showed that NOACs are at least as safe and as effective as warfarin for the acute treatment of VTE in the general population.
Comparing LMWH with NOACs: Similarities and Cautions There are several pharmacologic properties that are shared between the LMWHs and NOACs that make these agents more favorable over warfarin. Compared with warfarin, both LMWHs and NOACs have an immediate onset of action, a shorter half-life, a more stable and predictable anticoagulant effect that generally obviates the need for laboratory monitoring, and no food interactions.23,24 Unfortunately, there are some significant differences that are more relevant to cancer patients. When dealing with a population of patients that have multiple reasons for compromised gastrointestinal function (site of cancer, cancer-associated cachexia, poor oral intake, treatment-related Seminars in Thrombosis & Hemostasis
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No. 2/2015
nausea, vomiting, and mucositis), oral agents are less reliable compared with parenteral agents. In particular, rivaroxaban requires concurrent intake of food to enhance absorption at its therapeutic doses and dabigatran requires a more acidic environment for effective absorption.24 In addition, while LMWHs and NOACs are designed to not require laboratory monitoring, the availability of anti-Xa measurement for LMWH is advantageous in certain clinical circumstances. One common situation is severe renal impairment. Although anti-Xa levels do not strongly correlate with efficacy and safety of LMWH use, there is clinical experience and familiarity with this test, and measuring trough levels to check for LMWH accumulation can be useful.25 At this time, there are no clinically validated methods to measure the anticoagulant activity of NOACs and therapeutic levels of these agents have not been established. Another frequent challenge in cancer patients is the higher rate of anticoagulant failure as well as the increased risk of bleeding from factors such as thrombocytopenia. While no evidencebased guidelines exist, considerable experience has accumulated to help guide titration of the LMWH dose to balance the thrombotic and hemorrhagic risks.26–28 NOACs have far fewer dosing options than LMWH and experience is lacking in potentially titrating the dose in complex scenarios. Importantly, although there are fewer drug–drug interactions for NOACs compared with warfarin, there are virtually none for LMWHs. All the NOACs rely on p-glycoprotein for drug absorption and some are dependent on CYP3A4 for metabolism.24 Drugs that inhibit these enzymes (such as tamoxifen, tyrosine kinase inhibitors, cyclosporine) may significantly increase the anticoagulant effect and drugs that induce these enzymes (such as dexamethasone, doxorubicin, vinblastine, St John’s Wort) may significantly decrease the anticoagulant effect.27 The net effect of inhibition and induction would be difficult to estimate in multidrug chemotherapeutic regimens. There remain many undefined, though suspected, drug interactions as well as an increased exposure in cancer patients to new anticancer drugs which have unknown drug–drug interactions. Finally, the lack of an antidote to rapidly reverse the anticoagulant activity remains worrisome to clinicians and patients. All these limitations give pause to the use of NOACs for CT and further cancer-specific data are required. ►Table 1 summarizes the key differences between NOACs and LMWHs.
Reviewing the Existing Evidence for NOACS in CT While robust cancer-specific NOAC trials have not been performed, several subgroup analyses of existing trials have been presented or published recently.
Prevention of VTE in Cancer Patients Given the higher rate of VTE in the cancer population as well as the difficulties treating VTE when it does occur, a sensible approach would be primary prevention.
Medical Inpatients DVT prophylaxis is recommended for most patients admitted to hospital for medical illnesses, including those with cancer,
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Table 1 Comparison of novel oral anticoagulants and low-molecular-weight heparins Low-molecular-weight heparins
$c
$$$c
Route of administration
Oral
Subcutaneous
Gastrointestinal absorption
Yes
No
Onset of action
Rapid
Half-life
5–14 h
Rapid a
2–5 h
Renal dependence
Yes
Yes
Need for monitoring levels
No
No
Ability to monitor levels
Nob
Anti-Xa assay
Reversal agents
No
Protamine (partial reversal)
Drug interactions
P-glycoprotein/CYP3A4
None
Flexible dose adjustments
No
Yes
Highest available evidence in cancer-associated thrombosis
Subgroup analyses of non–cancer-specific trials suggest noninferiority to warfarin
Randomized controlled cancer-specific trials show superiority to warfarin
a
Half-life increases for older patients or those with renal impairment. Drug assays may be available in select centers but are not validated for clinical use. c Cost of each agent may vary but overall cost of low-molecular-weight-heparin is significantly higher than of novel oral anticoagulants. b
as multiple VTE risk factors are present.29–32 Existing data on LMWH or fondaparinux prophylaxis in cancer patients are limited to small post hoc, subgroup analyses. A recent metaanalysis of all published data showed no significant VTE reduction with either LMWH or fondaparinux prophylaxis (relative risk, 0.91; 95% confidence interval [CI], 0.21–4.0).33 This is very different from the 50% risk reduction observed in the overall patient population in these DVT prophylaxis trials. As expected, cancer patients represented only 6% of the study population in these studies, so their results are masked by the main results derived largely from noncancer patients.33–35 For NOACs, there are two placebo-controlled randomized trials examining DVT prophylaxis in medical inpatients. The Apixaban Dosing to Optimize Protection from Thrombosis (ADOPT) study has not published any data from the 211 cancer patients randomized to either 30 days of apixaban 2.5 mg twice daily or 6 to 14 days of enoxaparin 40 mg daily.36 In the overall study population (n ¼ 6,528), 3.2% had active cancer (defined as having received cancer treatment within the last year). There was no difference in the primary composite outcome of VTE-related death, fatal or nonfatal PE, symptomatic DVT, and asymptomatic proximal DVT detected on screening bilateral leg ultrasound (2.71% apixaban vs. 3.06% enoxaparin), but there was a significantly higher rate of major bleeding with apixaban than with enoxaparin (0.47 vs. 0.19%, respectively; relative risk, 2.58; p ¼ 0.04) at the end of the 30-day follow-up period. More importantly, the trend to higher major bleeding rates was still evident when analysis was restricted to the initial in-hospital phase of therapy (0.25% apixaban vs. 0.12% enoxaparin; relative risk, 2.06; p ¼ 0.23). The MAGELLAN (Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the
Prevention of Venous Thromboembolism in Hospitalized Acutely Ill Medical Patients Comparing Rivaroxaban with Enoxaparin) study37 included 8,101 patients, 7.3% of whom had active cancer (defined as admitted for chemotherapy or active cancer complications). A total of 296 cancer patients received 35 days of rivaroxaban 10 mg daily and an additional 296 cancer patients received 10 days of enoxaparin 40 mg daily. In the cancer subgroup at 35 days of follow-up, there was no statistical difference in the primary composite outcome of asymptomatic proximal or symptomatic VTE and VTE-related death (7.4% rivaroxaban vs. 9.9% enoxaparin; p ¼ 0.074), but there was a dramatic increase in the composite rate of major bleeding and clinically relevant nonmajor bleeding in the rivaroxaban group (5.4 vs. 1.7%; p < 0.05). Trends were similar when looking at the first 10 days of treatment only. Rates of clinically relevant bleeding (major bleeding and clinically relevant nonmajor bleeding) were higher in the rivaroxaban group (2.8 vs. 1.2%; p ¼ 0.02).37,38 Overall, the results of available cancer subgroup analyses in trials using NOACs for DVT prophylaxis in hospitalized medical patients demonstrate a higher rate of clinically relevant and major bleeding compared with LMWH, and NOACs should be avoided until more cancer-specific DVT prophylaxis trials are available.
Ambulatory Patient The majority of cancer treatment is delivered to nonhospitalized patients who still carry a high risk of VTE.39 The role of outpatient DVT prophylaxis and appropriate patient selection remains an area of research. Two double-blind randomized trials have studied the use of low-dose LMWH in high-risk ambulatory cancer patients receiving chemotherapy. The PROphylaxis of ThromboEmbolism During CHemoTherapy Seminars in Thrombosis & Hemostasis
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Cost
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Wu, Lee
(PROTECHT) trial compared nadroparin 3,800 units daily with placebo in chemotherapy patients with metastatic cancer or locally advanced lung, gastrointestinal, pancreatic, breast, ovarian, or head and neck cancer (n ¼ 1,150).40 VTE occurred less frequently in the nadroparin group (2.0 vs. 3.9%, p ¼ 0.02) with no significant increase in major bleeding (0.7 vs. 0%, p ¼ 0.18). In the SAVE-ONCO trial, semuloparin 20 mg daily was compared with placebo in patients planned for chemotherapy in the setting of metastatic or locally advanced lung, pancreatic, stomach, colon, rectal, bladder, or ovarian cancer (n ¼ 3,212).41 VTE occurred less frequently in the semuloparin group (1.2 vs. 3.4%, p < 0.001) with no significant increase in major bleeding (1.2 vs. 1.1%). For NOACs, one phase II trial has randomized patients with advanced or metastatic cancer (but no baseline VTE) to placebo versus apixaban 5 mg once daily, 10 mg once daily, or 20 mg once daily for 12 weeks.42 It was ultimately underpowered due to poor accrual and it was terminated after 125 patients were enrolled. Results were encouraging with apixaban groups having a 2.2% rate of major bleeding (mostly in the 20 mg group), no symptomatic lower extremity DVT or PE (compared with three patients (10.3%) in placebo group) and one case of catheter-related DVT (also 1 case in the placebo group). Future clinical trials are highly anticipated.
Surgical Inpatients There are no existing trials using NOACs for postoperative DVT prophylaxis in cancer patients both during hospital admission and postdischarge. Whether future trials will be available is unknown. In the early postoperative setting, the advantage of an oral agent over parenteral agent is less evident, as many surgical patients are unable to take oral medications immediately after surgery. There is certainly a potential role for NOACs for extended prophylaxis beyond the hospital-stay period, as 4 weeks of LMWH prophylaxis has been shown to significantly reduce VTE in patients undergoing abdominal or pelvic surgery for cancer.43–45 An oral agent in this setting would definitely be welcomed, as shown by the rapid practice change to adopt NOACs for postoperative prophylaxis in the major joint replacement setting.46
Summary on DVT Prophylaxis with NOACs in Cancer Patients While high priority should be placed on preventing VTE whenever possible in high-risk patients, the available trials have not established a role for NOACs in DVT prophylaxis for cancer patients yet. There are some safety concerns with an increased rate of bleeding at least with extended use of NOACs for medical inpatient prophylaxis. For the time being, NOAC use for VTE prevention in cancer patients should be limited to clinical trials.
Treatment of VTE in Cancer Patients There are no CT treatment trials prospectively and specifically evaluating the use of NOACs. The four main phase III trials comparing NOACs to warfarin in VTE have all published or presented their cancer subgroup data. Recent meta-analyses of these data reported no statistically significant differences Seminars in Thrombosis & Hemostasis
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in the rates of recurrent VTE or major bleeding when comparing NOACs to warfarin in cancer subgroups.47–49 They also highlighted the methodological limitations of these subgroup analyses and recommended future trials comparing NOAC with LMWH. A comparison of NOAC and LMWH trials which reported data on recurrent VTE and major bleeding in cancer patients is summarized in ►Table 2. Of the 5,395 patients randomized in the AMPLIFY study, 169 (3.1%) had active cancer. These patients were diagnosed with or treated for cancer within the past 6 months, had recurrent cancer or metastatic cancer, but patients were excluded if longterm LMWH treatment was planned.50 Recurrent VTE occurred in 3/81 (3.7%) on apixaban and 5/78 (6.4%) on warfarin. Major bleeding occurred in 2/87 (2.3%) on apixaban and 4/80 (5.0%) on warfarin. A total of 8,292 patients were randomized in the HokusaiVTE study.51 Those with cancer in whom LMWH use was anticipated were excluded from the study. Among the cancer patients enrolled, 563 had a history of cancer and 208 had active cancer, defined according to the local investigators’ discretion. Of these, VTE recurrence occurred in 4/109 (3.7%) patients on edoxaban and 7/99 (7.1%) patients on warfarin. Major bleeding occurred in 5/109 (4.6%) patients on edoxaban and 3/99 (3.0%) patients on warfarin. These risk reductions were consistent with the overall results of the entire study cohort. A recent meta-analysis pooled the results of the cancer patients enrolled in the EINSTEIN-DVT20 and EINSTEIN-PE21 trials.52 Of the 8,282 patients randomized in these studies, 655 (7.9%) had active cancer at baseline or were diagnosed with cancer during the study period.52 The definition of cancer was not prespecified in the original EINSTEIN studies, but in the post hoc pooled analysis, it was disclosed that patients were reclassified according to their active cancer status, defined post hoc as having active cancer if cancer was diagnosed or treated within 6 months, or recurrent/metastatic. This included 14 patients with basal-cell or squamous-cell carcinoma in the active cancer group. VTE recurred in 16/354 (4.5%) on rivaroxaban and 20/301 (6.6%) on warfarin. Major bleeding occurred in 8/353 (2.3%) on rivaroxaban and 15/298 (5.0%) on warfarin. These results also included patients who had occult cancer and were diagnosed with the cancer during the study period. If limited to only those with active cancer at baseline, VTE recurred in 6/258 (2.3%) on rivaroxaban and 8/204 (3.9%) on warfarin, and major bleeding occurred in 5/238 (2.1%) on rivaroxaban and 8/204 (3.9%) on warfarin. Finally, the RECOVER study enrolled 121 patients with cancer excluding basal-cell or squamous-cell carcinoma of the skin, who received their cancer diagnosis within 5 years, any cancer treatment within 5 years, or had recurrent/ metastatic cancer out of a total of 2,539 patients.22 VTE recurrence occurred in 2/64 (3.1%) patients on dabigatran and 3/57 (5.3%) patients on warfarin. Major bleeding occurred in 5/62 (7.8%) patients on dabigatran and 3/57 (5.3%) patients on warfarin.53 It should be noted that compared with the noncancer patients randomized in all the NOAC trials, both the rates
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Table 2 Recurrent venous thromboembolism and major bleeding in cancer patients with acute venous thromboembolism treated with novel oral anticoagulants, low-molecular-weight heparins, or warfarin
Low-molecular-weight heparin
Anticoagulant CLOT12 13
Major bleeding
n (%)
n (%)
Dalteparin
27/336 (8.0)
19/338 (5.6)
Warfarin
53/336 (15.8)
12/335 (3.6)
LITE (subgroup)
Tinzaparin
6/100 (6.0)
7/100 (7.0)
Warfarin
10/100 (10.0)
7/100 (7.0)
CANTHANOX15
Enoxaparin
2/71 (2.8)
5/71 (7.0)
Warfarin
3/75 (4.0)
12/75 (16.0)
Enoxaparin
4/61 (6.6)
6/67 (9.0)
Warfarin
3/30 (10.0)
1/34 (2.9)
AMPLIFY (subgroup)
Apixaban
3/81 (3.7)
2/87 (2.3)
Warfarin
5/78 (6.4)
4/80 (5.0)
Hokusai-VTE51 (subgroup)
Edoxaban
4/109 (3.7)
5/109 (4.6)
Warfarin
7/99 (7.1)
3/99 (3.0)
ONCENOX16 Novel oral anticoagulants
Recurrent VTE
50
52
EINSTEIN (subgroup)a
Rivaroxaban
6/258 (2.3)
5/238 (2.1)
Warfarin
8/204 (3.9)
8/204 (3.9)
RECOVER53 (subgroup)
Dabigatran
2/64 (3.1)
6/159 (7.8)
Warfarin
3/57 (5.3)
3/57 (5.3)
Abbreviations: CLOT trial, Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer trial; LITE trial, Long-term Innovations in TreatmEnt trial; CANTHANOX and ONCENOX trials, Secondary Prevention Trials of Venous Thrombosis with Enoxaparin; AMPLIFY trial, Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy. a Numbers in table represent only the patients who had active cancer at the time of enrolment.
of recurrent VTE (ranging from 1.8 to 3.5% in noncancer subgroups vs. 1.8 to 7.4% in cancer subgroups) and major bleeding and clinically relevant nonmajor bleeding (ranging from 3.7 to 11.5% in noncancer subgroups vs. 9.3 to 25.3% in cancer subgroups) were higher in cancer patients.47
Limitations in the Existing NOAC Data in Cancer Patients While the available subgroup analyses have not raised critical red flags for NOACs in CT, the data are still inadequate to support their use in the typical patient with active cancer. First, only small numbers of cancer patients were included in each of the trials. Second, the definition of active cancer varied widely between studies, was often quite vague and usually did not match up with the definition used in the CLOT trial (diagnosis of cancer other than basal-cell or squamouscell carcinoma of the skin within 6 months, any treatment for cancer within the previous 6 months, or recurrent or metastatic cancer).12 Third, all treatment trials compared NOACs to warfarin and not to LMWH, which is the current standard of care and already proven to be superior to warfarin. Fourth, each NOAC treatment trial is accompanied by a long list of exclusion criteria (found in their associated online supplemental appendices) which include items such as life expectancy
