Anticoagulants in cancer
David Garcia, Division of Hematology/Oncology, University of New Mexico Cancer Center, 1201 Camino De Salud, Albuquerque, NM 87131, USA.
Tel.: +1 505 925 0404; fax: +1 505 925 0408.
Summary. Cancer patients are at high risk for venous thromboembolism (VTE), which results in substantial morbidity and mortality. In this narrative review, we present evidence for the use of anticoagulants in the treatment and prevention of VTE in cancer patients. The benefit of perioperative anticoagulant prophylaxis following cancer surgery is well established. However, the risk-benefit trade-offs in non-surgical hospitalized cancer patients and among outpatients receiving chemotherapy are more complex. Emerging evidence suggests that the use of low molecular weight heparin (LMWH) may confer a small survival benefit in cancer patients without VTE. However, specific patient populations that may derive the most benefit have yet to be defined. Guidelines endorse LMWH as the preferred treatment for acute VTE, on the basis of high-quality clinical trial data, but the optimal duration of treatment remains unclear, and practical issues may limit its use outside the clinical trial setting. Novel oral anticoagulants may provide additional treatment and prophylaxis options, but their efficacy and safety in this population have not been established. Despite the significant impact of VTE on the lives of cancer patients and the large body of existing literature regarding treatment and prevention, important unanswered clinical questions remain, emphasizing the need for additional high-quality clinical trial data.
The relationship between venous thromboembolism (VTE) and malignancy is well recognized, having been first suggested by Trousseau in 1865 . Since then, a bidirectional clinical association has emerged: patients with cancer have at least a six-fold to seven-fold increased risk of VTE [2,3]. Conversely, patients with idiopathic VTE have at a two-fold to four-fold increased risk of malignancy, especially in the first year after diagnosis [4–8].
The pathogenesis of hypercoagulability in malignancy involves a complex interplay between malignant cells, host cells, and the coagulation system, with activation of coagulation, production of cytokines, and interaction of malignant and host cells through adhesion molecules [9,10]. Tissue factor (TF), a procoagulant molecule normally expressed by vascular cells in response to inflammatory cytokines, is constitutively expressed in tumor cells, resulting in continuous activation of coagulation and increased thrombin generation [9–11]. Increased TF expression was traditionally thought to arise from microenvironmental stimuli, but oncogenic events associated with malignant transformation lead to upregulation of TF expression [12,13]. TF expression is closely related to the production of the proangiogenic cytokine vascular endothelial growth factor, which increases vascular permeability, allowing increased exposure to coagulation factors . Adenocarcinomas secrete mucins, which produce microthrombi through interactions with leukocyte and platelet selectins; this interaction may explain the higher risk of venous thrombosis in patients with adenocarcinoma than in those with squamous cell carcinoma of the lung [11,14,15].
Cancer patients are not a homogeneous population. The spectrum of VTE risk is influenced by primary site of cancer, extent of disease, patient age, medical comorbidities, inherited thrombophilia, thrombocytosis, and circulating tumor cells [3,16–23]. Heterogeneity in prothrombotic potential among different malignancies probably underlies the observed differences in the benefits and risks of anticoagulation in patients with a variety of different cancer types. The risk of VTE in cancer patients is further increased by certain interventions, including surgery, chemotherapy, antiangiogenic therapy, hormonal therapy, central venous catheters (CVCs), red blood cell and platelet transfusions, and erythropoiesis-stimulating agents [2,16,22–29].
VTE has a well-established detrimental impact on the survival of patients with a variety of malignancies [17,30–34]. However, the increased mortality is explained only partly by VTE, suggesting that increased tumor-associated coagulation activation may be a marker of more aggressive disease. VTE also results in significant morbidity affecting quality of life. Cancer patients with venous thrombosis experience higher rates of recurrence (21–27% vs. 7–9%) and more major anticoagulation-associated bleeding (12–13% vs. 2–5%) than do patients without cancer [35–37].
In this narrative report, we review the current evidence for anticoagulant prophylaxis and treatment of VTE in cancer patients, including emerging evidence.
Primary prophylaxis of VTE in cancer patients
Ambulatory cancer patients receiving chemotherapy
In cancer patients receiving active therapy, annual rates of VTE range from 0.5% to 20%, depending on patient-related and treatment-related factors, in addition to the timing and duration of follow-up in published studies [17,33,38]. Chemotherapy increases the risk of VTE 2.2 to 6.5-fold [2,18,28]. Currently, international guidelines do not recommend routine thromboprophylaxis in ambulatory cancer patients undergoing treatment with chemotherapy, except for those with multiple myeloma receiving thalidomide or lenalidomide in addition to chemotherapy or dexamethasone [39–41]. However, recent data suggest a possible benefit of anticoagulation, particularly with low molecular weight heparin (LMWH), as a primary prevention strategy.
The PROTECHT study was a large (n = 1150) randomized trial in which patients with metastatic or locally advanced lung, gastrointestinal, pancreatic, ovarian or head and neck cancer received nadroparin (3800 IU daily) or placebo during chemotherapy . Treatment with nadroparin reduced thromboembolic events (2.0% vs. 3.9%), with no difference in major bleeding (0.7% vs. 0%), as compared with placebo.
A recent Cochrane systematic review of nine randomized controlled trials (including PROTECHT) addressed the efficacy and safety of anticoagulants in ambulatory cancer patients without VTE and receiving chemotherapy . LMWH, but not warfarin, reduced symptomatic VTE (relative risk [RR] 0.62; 95% confidence interval [CI] 0.41–0.93; number needed to treat [NNT] 60), with a non-significant increase in major bleeding (RR 1.57; 95% CI 0.69–3.60), as compared with inactive control. In myeloma patients, LMWH decreased symptomatic VTE when compared with warfarin (RR 0.33; 95% CI 0.14–0.83).
Several recent clinical trials published since the Cochrane review have confirmed the hypothesis that LMWH can reduce the risk of a first VTE in ambulatory cancer patients receiving chemotherapy (Table 1). The SAVE-ONCO study evaluated the efficacy and safety of semuloparin (an ultra-low molecular weight heparin) compared to placebo for prevention of VTE in patients with metastatic or locally advanced solid tumors receiving chemotherapy . Semuloparin decreased the risk of symptomatic VTE or VTE-related death (1.2% vs. 3.4%; hazard ratio [HR] 0.36; 95% CI 0.21–0.60), with no difference in major bleeding (1.2% vs. 1.1%; HR 1.05; 95% CI 0.55–1.99) or rate of death (43.4% vs. 44.5%; HR 0.96; 95% CI 0.86–1.06). While the concept that anticoagulation can reduce the symptomatic VTE risk in cancer patients receiving chemotherapy has been proven, the subgroup of high-risk cancer patients in whom the net clinical benefit favors thromboprophylaxis remains to be identified. Clinical assessment tools will probably help to identify patients in whom the costs and burdens of primary prophylaxis may be justified [45,46].
Table 1. Published randomized trials of thromboprophylaxis in ambulatory cancer patients receiving chemotherapy
|Levine et al. ||Metastatic stage IV breast carcinoma||Warfarin (oral, 1 mg daily for 6 weeks, and then INR 1.3–1.9)||Placebo||Start of chemotherapy until 1 week after termination of chemotherapy, 181 days (median)||0.7||4.4||RR 0.15 (0.02–0.91)||0.7||1.3||RR 0.52 (0.07–3.96)|
|Altinbas et al. ||Small cell lung carcinoma||Dalteparin 5000 IU once daily||No dalteparin||18 weeks||0||2.4||–||0||0||–|
|FAMOUS, Kakkar et al. ||Advanced stage III or IV malignant disease of the breast, lung, gastrointestinal tract, pancreas, liver, genitourinary tract, ovary, or uterus||Dalteparin 5000 IU once daily||Placebo||12 months||2.1||2.7||RR 0.77 (0.23–2.63)||0.5||0.0||–|
|Sideras et al. ||Advanced breast, prostate, lung or colorectal cancer||Dalteparin 5000 IU once daily||Placebo||18 weeks||5.9*||3.8*||RR 1.52 (0.25–10.02)||2.9†||3.8†||RR 0.76 (0.10–5.75)|
|Standard clinical care||9.1*||RR 0.65 (0.19–2.27)||9.1†||RR 0.32 (0.07–1.46)|
|PROTECHT, Agnelli et al. ||Metastatic or locally advanced lung, gastrointestinal, pancreatic, breast, ovarian or head/neck cancer||Nadroparin 3800 IU once daily||Placebo||Duration of chemotherapy maximum 4 months||1.6||3.1||RR 0.49 (0.23–1.07)||0.7||0||–|
|PRODIGE, Perry et al. ‡||WHO grade 3 or 4 glioma||Dalteparin 5000 IU once daily||Placebo||6 months||9.1||14.9||HR 0.51 (0.19–1.4)||3.0||0||–|
|5.1§||1.2§||HR 4.2 (0.48–36)|
|Palumbo et al. ||Myeloma||Enoxaparin 40 mg once daily||Aspirin 100 mg once daily||6 months||2.7¶||5.4¶||RR 0.50 (0.19–1.31)||0||1.4||–|
|24.9 months (median)||4.6¶||7.3¶||RR 0.63 (0.29–1.35)||–||–||–|
|Warfarin 1.25 mg daily||6 months||2.7¶||8.2¶||RR 0.33 (0.14–0.83)||0||0||–|
|24.9 months (median)||4.6¶||9.5¶||RR 0.48 (0.23–0.99)||–||–||–|
|Maraveyas et al. ||Advanced pancreatic cancer||Dalteparin 200 IU kg−1 once daily for 4 weeks, and then 150 IU kg−1 for 8 weeks||Placebo||12 weeks||0**||17.0**||RR 0.05 (0.00–0.81)||3||3||RR 1.05 (0.19–5.81)|
|9.0††||22.0††||RR 0.39 (0.15–1.03)||–||–||–|
|Larocca et al. ||Myeloma||Enoxaparin 40 mg once daily||ASA 100 mg once daily||12 months||1.2||2.3||RR 0.53 (0.11–2.44)||0||0||–|
|SAVE-ONCO, Agnelli et al. ||Metastatic or locally advanced solid tumors||Semuloparin 20 mg once daily||Placebo||3.5 months (median)||1.2||3.4||HR 0.36 (0.21–0.60)||1.2||1.1||HR 1.05 (0.55–1.99)|
|TOPIC-I, TOPIC-II, Haas et al. ||Metastatic breast carcinoma||Certoparin 3000 IU once daily||Placebo||6 months||1.7||2.3||RR 0.76 (0.19–3.00)||1.7||0||–|
|Stage III/IV non-small cell lung carcinoma||Certoparin 3000 IU once daily||Placebo||6 months||1.9||3.8||RR 0.49 (0.18–1.36)||3.7||2.2||RR 1.67 (0.64–4.36)|
A recent pilot study examined the administration of the oral factor Xa inhibitor apixaban for primary thromboprophylaxis in patients receiving chemotherapy for advanced or metastatic cancers [41,47]. Treatment with apixaban (5 mg daily, 10 mg daily, and 20 mg daily) was associated with lower rates of VTE than placebo (0% vs. 10.3%). Major bleeding occurred only in patients receiving the highest dose (20 mg). However, this phase II study was small, and the efficacy of apixaban or other novel anticoagulants in preventing (or treating) cancer-associated VTE will have to be established by larger trials.
Current guidelines (American College of Chest Physicians [ACCP], European Society for Medical Oncology [ESMO], National Comprehensive Cancer Network [NCCN], and American Society of Clinical Oncologists [ASCO]) recommend against primary thromboprophylaxis for most ambulatory cancer patients [40,41,48,49]. These recommendations may change with the identification of a subgroup of cancer patients in whom the NNT to prevent one VTE event approaches 10–20 (rather than 50–100), or if the novel oral anticoagulants are proven to be effective and affordable treatments in this setting.
Cancer patients undergoing surgery
Cancer surgery is an established risk factor for VTE, and carries a higher VTE risk than surgery for benign disease [50–56]. Paradoxically, cancer patients undergoing surgery also have an increased risk of bleeding and increased transfusion requirements .
The benefit of prophylactic heparin in cancer surgery was established in a meta-analysis by Clagett and Reisch , showing that heparin use decreased perioperative VTE as compared with no treatment (13% vs. 30.6%). A recent Cochrane review found no difference in VTE risk or mortality between LMWH and unfractionated heparin (UFH) for perioperative VTE prophylaxis in cancer patients undergoing surgical interventions . However, unlike UFH, LMWH offers the possibility of once-daily administration, and it has more predictable pharmacokinetics and anticoagulant effects, while carrying a lower risk of heparin-induced thrombocytopenia. Standard fixed prophylactic doses of LMWH are effective and safe perioperatively. In a study of patients undergoing elective curative surgery for abdominal or pelvic cancer, dalteparin 5000 units daily as compared with 2500 units daily decreased the incidence of deep vein thrombosis (DVT) (8.5% vs. 14.9%), with no increased risk of bleeding . In comparison with fondaparinux, LMWH significantly decreased the risk of VTE (4.7% vs. 7.7%; relative risk reduction [RRR] 38.6%; 95% CI 6.7–59.6), with a similar risk of bleeding, in a subgroup analysis of patients undergoing high-risk abdominal surgery for cancer .
VTE risk persists following the immediate post-operative period [52,55]. Several randomized controlled trials have demonstrated an additional benefit of extended-duration VTE prophylaxis in cancer patients undergoing surgery. Bergqvist et al.  showed that, in patients with planned curative open surgery for abdominal or pelvic cancer, extended-duration VTE prophylaxis with enoxaparin 40 mg daily (21 days vs. 6–10 days) reduced the rate of VTE (4.8% vs. 12.0%), with a similar rate of bleeding. Similarly, dalteparin 5000 units daily administered for 28 days vs. 7 days decreased the rates of all VTE (7.3% vs. 16.3%; RRR 55%; NNT 12) and proximal VTE (1.8% vs. 8.0%), with no increase in major bleeding, in patients undergoing major abdominal surgery (cancer surgery > 50%) . In patients admitted for abdominal or pelvic cancer surgery, there was no difference in the primary outcome of DVT, non-fatal pulmonary embolism (PE) or death with extended-duration bemiparin (3500 units daily for 20 days vs. 8 days) . However, there was a significant decrease in ‘major’ VTE (a composite of proximal DVT, non-fatal PE, and VTE-related deaths) in patients receiving extended-duration treatment (0.8% vs. 4.6%; RRR 82.4%), with no difference in major bleeding. A systematic review concluded there is low-quality evidence that extended-duration prophylaxis with LMWH (range: 25 days to 4 weeks) reduced the risk of asymptomatic DVT as compared with limited-duration prophylaxis (up to 10 days postdischarge) in patients undergoing cancer surgery (RR 0.21; 95% CI 0.05–0.94) . The risk of major bleeding was not significantly different at 4 weeks following surgery (RR 2.94; 95% CI 0.12–71.85).
Hospitalized non-surgical cancer patients
There have been no clinical trials specifically addressing VTE prophylaxis in non-surgical hospitalized cancer patients. Randomized controlled trials are needed, because, in addition to a very high risk of VTE, cancer patients may have unique bleeding risks (thrombocytopenia, poor nutritional status, and requirement for procedures) that could impact on the ‘net clinical benefit’ of pharmacologic prophylaxis. There is moderate-quality evidence that mechanical strategies (e.g. sequential compression devices or elastic compression stockings) reduce the risk of VTE in unselected surgical patients, but their effectiveness for non-surgical cancer patients is unproven.
The major trials of pharmaceutical agents to prevent VTE in medical patients have included relatively few cancer patients. In these trials, the overall bleeding rates were low, but bleeding data were not presented for cancer subgroups. Furthermore, the primary endpoints of these trials were composites that included asymptomatic VTE. Although the results indicate that pharmacologic prophylaxis can reduce the risk of VTE, they provide little information regarding ‘patient-important’ events in patients with or without cancer.
The MEDENOX study was conducted in hospitalized medical patients, 14% of whom had former or current cancer . VTE prophylaxis with enoxaparin 40 mg daily significantly decreased VTE (5.5% vs. 14.9%; RR 0.37) as compared with placebo. In a subgroup analysis of patients with cancer, there was a non-significant reduction in VTE with enoxaparin 40 mg daily as compared with placebo (RR 0.50; 95% CI 0.14–1.72) [66,67]. In the PREVENT study, dalteparin 5000 units daily was effective at reducing VTE as compared with placebo (2.77% vs. 4.96%; RR 0.55) in hospitalized medical patients, 10.3% of whom had active cancer . Prophylaxis with dalteparin resulted in a reduction in VTE in the subgroup of patients with cancer as compared with placebo (3.08% vs. 8.33%; RR 0.37) . Fondaparinux 2.5 mg daily decreased VTE as compared with placebo (5.6% vs. 10.5%; RRR 46.7%) in the ARTEMIS trial of hospitalized medical patients, including 30.9% of patients with previous or current cancer . The LIFENOX study showed no difference in the primary outcome of all-cause mortality in hospitalized medical patients (7.6% of patients with cancer) receiving enoxaparin 40 mg daily plus elastic compression stockings (vs. placebo plus compression stockings) for VTE prophylaxis . Unfortunately, subgroup analyses of 777 cancer patients enrolled in the MEDENOX, ARTEMIS and LIFENOX trials have not been published.
Cancer patients with CVCs
CVCs increase the risk of thrombosis in cancer patients, probably because of a combination of endothelial injury during and after CVC insertion, indwelling catheter-related venous stasis, and hypercoagulability [2,72,73]. The incidence of symptomatic DVT ranges from 0.3% to 28.3%. Not only does CVC-associated VTE expose patients to the consequences of thrombosis, but it may also result in delays in cancer treatment.
The efficacy and safety of anticoagulants (UFH, LMWH, and vitamin K antagonists [VKAs]) for the prevention of CVC-associated VTE were evaluated in a meta-analysis of trials in cancer and non-cancer patients . Anticoagulant prophylaxis reduced the risk of all catheter-associated DVT (symptomatic and asymptomatic combined; RR 0.31; 95% CI 0.13–0.71), but not symptomatic VTE (RR 0.59; 95% CI 0.35–0.97) or PE (RR 1.96; 95% CI 0.52–7.45). The risk of major bleeding was not increased with the use of anticoagulant prophylaxis (RR 0.54; 95% CI 0.20–1.42).
A recent Cochrane systematic review examined the efficacy and safety of anticoagulant VTE prophylaxis in cancer patients with CVCs . In 12 randomized controlled trials, prophylaxis with UFH, LMWH or low-dose VKAs was associated with a trend towards a reduction in symptomatic DVT, with no effect on mortality or major bleeding. However, the power to detect differences in any of these clinically important endpoints was low because the number of events is small, even in the aforementioned pooled analysis. High-quality randomized controlled trials are needed to address the benefits and risks of prophylactic anticoagulants in patients with cancer and CVCs.
Treatment of VTE in cancer patients
Effective treatment of acute VTE prevents DVT extension, fatal PE, recurrent VTE and long-term complications such as post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension. Cancer patients have an annual risk of recurrent VTE of 21–27%, despite appropriate anticoagulation with VKAs, and are three to four times more likely to develop recurrent VTE than non-cancer patients [35–37]. Cancer patients are also more likely to experience bleeding complications while on anticoagulants, with an annual risk of 12–13%, representing a two-fold to six-fold risk increase over non-cancer patients [35,36,76,77].
Initial treatment of acute VTE
Standard initial treatment for acute VTE includes intravenous UFH (titrated to an activated partial thromboplastin time prolongation of 1.5–2.5 times normal), weight-adjusted LMWH (200 U of anti-FXa activity per kg body weight daily, or 100 U of anti-FXa activity per kg body weight twice daily) for 5–7 days, or fondaparinux 7.5 mg (5 mg in patients < 50 kg and 10 mg in patients > 100 kg) once daily or for at least 5 days and until an International Normalized Ratio (INR) of 2.0 has been achieved with a VKA [48,78]. A recent Cochrane review examined 16 randomized controlled trials of LMWH, UFH and fondaparinux as initial treatment in patients with cancer and acute VTE . Mortality at 3 months was significantly decreased with LMWH as compared with UFH (RR 0.71; 95% CI 0.52–0.98), with no difference in VTE recurrence. Although this difference is statistically significant, it seems biologically implausible that the mortality benefit could be attributable to the choice of anticoagulant during the first few days. There were no differences in death, recurrent VTE or major bleeding with heparin as compared with fondaparinux.
Long-term treatment of VTE
All major international guidelines (ACCP, ASCO, NCCN, and ESCO) favor LMWH for long-term anticoagulant management of acute VTE in cancer patients, not only because of the disturbingly high rates of major bleeding and recurrent thrombosis with warfarin, but also because at least three different randomized trials have shown LMWH monotherapy to be more effective [80–82]. The recent 2012 ACCP guidelines downgraded the recommendation for LMWH in this setting from 1A to 2B, recognizing the burden (financial and lifestyle) that daily injectable LMWH presents to patients .
There is no consensus regarding the optimal duration of anticoagulant therapy for secondary prevention of VTE in cancer patients, owing to a paucity of data. The 2012 ACCP guidelines recommend extended-duration anticoagulation beyond 3 months in patients with cancer, with annual reassessment of risks and benefits . The best-quality evidence for 6 months of treatment with LMWH is from the randomized controlled CLOT trial, in which patients with cancer and acute symptomatic VTE received dalteparin (200 IU kg−1 for 1 month, and then 175 IU kg−1 for 5 months) or warfarin for 6 months . Treatment with dalteparin significantly decreased recurrent VTE as compared with warfarin (HR 0.48; 9% vs. 17%), with no significant differences in major bleeding or mortality. Patients with cancer and acute symptomatic proximal DVT received tinzaparin (175 IU kg−1 daily) or UFH followed by warfarin for 3 months in the LITE trial . Recurrent VTE was significantly reduced at 12 months in patients receiving tinzaparin as compared with those receiving warfarin (RR 0.44; 7% vs. 16%), with no difference in major bleeding. In the pilot ONCENOX study, patients with active malignancy and acute VTE received enoxaparin alone or enoxaparin followed by warfarin for a total of 180 days . There was no difference in safety or efficacy between the enoxparin and warfarin groups. A Cochrane review of nine randomized controlled trials recently evaluated the efficacy and safety of treatments for symptomatic VTE in cancer patients . A reduction in recurrent VTE was seen with LMWH vs. VKAs (HR 0.47; 95% CI 0.32–0.71). There were no differences in mortality or major bleeding.
Treatment of VTE recurrence
Compared to patients without cancer, cancer patients have a three-fold increased risk of VTE recurrence despite appropriate anticoagulation . Even among patients treated with the current standard of care (LMWH), published studies suggest that the rate of recurrent VTE may be as high as 6–9% in the first 6 months [80–82].
For patients who experience a recurrence while receiving VKA therapy, LMWH is preferred over increasing the intensity of VKA therapy, owing to the superior efficacy of LMWH and concerns regarding potential increased bleeding risk with INR fluctuation around a higher target .
Dose escalation of LMWH appears to be safe and effective for patients with VTE recurrence while on LMWH. In a retrospective cohort study of cancer patients with symptomatic recurrent VTE receiving anticoagulant treatment, patients receiving VKAs were switched to therapeutic-dose LMWH, and those already receiving LMWH were treated with a 20–25% dose escalation . Six of 70 patients experienced a second VTE recurrence during 3 months of follow-up (annual event rate of 9.9%), and were treated with an increased dose (20–25%) of LMWH, with no further thrombotic events and few bleeding complications. Further studies are needed to assess the efficacy and safety of different management strategies for recurrent VTE. An approach to the management of symptomatic VTE recurrence was recently published .
Novel oral anticoagulants for treatment of VTE in cancer patients
Given the remarkable difference in efficacy between LMWH and VKAs in the treatment of cancer-associated thrombosis, novel oral anticoagulants (direct thrombin inhibitors and FXa inhibitors) will have to be specifically tested in this population. LMWH should be the comparator in any trial of the novel oral agents, because LMWH is the most effective available treatment for cancer-associated VTE. Existing data regarding the novel oral anticoagulants for malignancy-associated VTE are limited to several hundred cancer patients included in major acute VTE treatment trials (Table 2). The value of this evidence is limited, because these trials have, for the most part, compared the novel agents with VKAs (not LMWH), and the CIs for estimates of relative treatment effects are wide.
Table 2. Clinical trials of novel oral anticoagulants for the treatment or prevention of venous thromboembolism (VTE)
| RE-COVER, Schulman et al. ||VTE acute treatment||2564||121||150 mg twice daily||Warfarin (INR 2–3)||6 months||Symptomatic recurrent VTE and related death||2.4||2.1||HR 1.10 (0.65–1.84)|
| EINSTEIN, Bauersachs et al. ||DVT acute treatment||3449||207||15 mg twice daily for 3 weeks, and then 20 mg once daily||Enoxaparin 1 mg kg−1 twice daily, anf then VKA (INR 2–3)||3, 6 or 12 months||Symptomatic recurrent VTE||2.1||3.0||HR 0.68 (0.44–1.04)|
|DVT continued treatment||1197||54||20 mg once daily||Placebo||6 or 12 months||Symptomatic recurrent VTE||1.3||7.1||HR 0.18 (0.09–0.39)|
| EINSTEIN-PE, Buller et al. ||PE acute treatment||4832||223||15 mg twice daily for 3 weeks, and then 20 mg once daily||Enoxaparin 1 mg kg−1 twice daily, and then VKA (INR 2–3)||3, 6 or 12 months||Symptomatic recurrent VTE||2.1||1.8||HR 1.12 (0.75–1.68)|
| Agnelli et al. ||VTE acute treatment||613||16||10 mg twice daily||Enoxaparin 1 mg kg−1 twice daily, and then VKA (INR 2–3)||12 weeks||Symptomatic recurrent DVT, PE, or VTE-related death||1.9||0.9||RR 2.11 (0.28–16.00)|
|20 mg twice daily||2.0||RR 2.24 (0.29–16.96)|
|30 mg twice daily||1.8||RR 2.02 (0.27–15.29)|
|40 mg daily||2.6||RR 2.95 (0.43–20.42)|
| MAGELLAN, Cohen et al. ||VTE prophyaxis in acutely ill medical patients||8101||560†||10 mg once daily||Enoxaparin 40 mg once daily||Rivaroxaban 35 ± 4 days, enoxaparin 10 ± 4 days||Asymptomatic proximal DVT, symptomatic VTE||2.7‡||2.7‡||RR 0.97 (0.71–1.33)|
|4.4§||5.7§||HR 0.77 (0.62–0.96)|
| Levine et al. ¶||VTE prophylaxis in cancer patients receiving chemotherapy||125||125||5 mg once daily||Placebo||12 weeks||Symptomatic DVT and PE||0||10.3||–|
|10 mg once daily||0|
|20 mg once daily||0|
| ADOPT, Goldhaber et al. ||VTE prophylaxis in medically ill patients||6528||211||2.5 mg twice daily||Enoxaparin 40 mg once daily||Apixaban 30 days Enoxaparin 6–14 days||Total VTE or VTE-related death||2.7||3.1||RR 0.87 (0.62–1.23)|
The direct thrombin inhibitor dabigatran (150 mg twice daily) was compared with warfarin (target INR of 2–3) for the treatment of acute symptomatic VTE in the double-blind non-inferiority RECOVER trial . Dabigatran was non-inferior to warfarin with respect to risk of recurrent VTE (2.4% vs. 2.1%; HR 1.10; 95% CI 0.65–1.84). Rates of major bleeding were similar. A subgroup analysis of patients with active cancer (9.5% of the total study population) revealed no difference in the primary outcome between dabigatran and warfarin (3.1% vs. 5.3%).
In the open-label non-inferiority EINSTEIN DVT trial, patients with acute symptomatic proximal DVT received rivaroxaban (15 mg twice daily for 3 weeks, and then 20 mg daily) or enoxaparin (1 mg kg−1 twice daily) followed by VKAs . Rivaroxaban was non-inferior to enoxaparin/warfarin with regard to recurrent VTE (HR 0.68; 95% CI 0.44–1.04) and major bleeding (HR 0.65; 95% CI 0.33–1.30) in the acute DVT study. In the continued treatment study, additional treatment with rivaroxaban for 6–12 months reduced recurrent VTE (HR 0.18; 95% CI 0.09–0.39), with no increase in major bleeding as compared with placebo. A subgroup analysis of patients with malignancy at randomization (12% of the study population) showed no difference in efficacy (3.4% vs. 5.6%) or bleeding (14.4% vs. 15.9%) between rivaroxaban and exoxaparin/VKAs. With a similar trial design, patients with acute symptomatic PE were randomized to receive rivaroxaban (15 mg twice daily for 3 weeks, and then 20 mg daily) or enoxaparin (1 mg kg−1 twice daily) followed by VKAs for 3, 6 or 12 months in the EINSTEIN-PE study . Rivaroxaban was non-inferior to enoxaparin/warfarin for recurrent VTE (HR 1.12; 95% CI 0.75–1.68) and major bleeding (HR 0.49; 95% CI 0.31–0.79); the number of patients with active cancer in either treatment group was small.
Anticoagulants and survival in cancer
Several studies have examined the effect of anticoagulants on the survival of cancer patients without VTE. In a post hoc analysis of an open-label randomized trial, the probability of death at 12 months was reduced following 6 months of treatment with dalteparin as compared with VKAs (20% vs. 36%; HR 0.50; 95% CI 0.27–0.95) in acute VTE patients with solid tumors . There was no difference in mortality between treatment groups in patients with metastatic disease. A systematic review and meta-analysis by Kuderer et al.  included 11 randomized controlled trials of cancer patients (without VTE) who had received LMWH, UFH, VKAs, or placebo as part of prophylaxis study. Anticoagulation was associated with a small but significant decrease in 1-year overall mortality (RR 0.905; 95% CI 0.847–0.967) and an increase in major bleeding (RR 2.598; 95% CI 1.936–3.488) as compared with placebo. LMWH, however, reduced mortality (RR 0.977; 95% CI 0.847—0.967), with no increased risk of major bleeding, as compared with placebo. Treatment with warfarin did not reduce mortality (RR 0.942; 95% CI 0.854–1.040), but was associated with an increased risk of major bleeding (RR 2.979; 95% CI 2.134–4.157), as compared with placebo. In patients with hormone-refractory prostate cancer, non-small cell lung cancer and locally advanced prostate cancer receiving nadroparin or placebo in addition to standard anti-cancer treatment there was no difference in all-cause mortality, median survival, time to progression or bleeding . A Cochrane review of UFH or LMWH compared with no treatment in cancer patients without VTE showed a small but statistically significant reduction in mortality at 24 months (RR 0.92; 95% CI 0.88–0.97) . Conversely, warfarin increased major bleeding (RR 4.24; 95% CI 1.85–9.68), with no mortality benefit, as compared with placebo or no treatment. A combined analysis of the Cochrane review, van Doormaal et al. and the SAVE-ONCO trial found that, as compared with no treatment, anticoagulation with LMWH was associated with a small but statistically significant relative risk reduction for death (RR 0.94; 95% CI 0.88–1.0), with an HR of 0.83 (95% CI 0.72–0.95), in survival analysis . Prophylactic LMWH for 12 months in 1000 cancer patients would be expected to prevent death in 30 patients and VTE in 20 patients, with one patient experiencing a major bleeding event. Although these findings are promising, the impact of such observations is limited by the wide range of cancer types and disease stages seen in clinical practice.
Anticoagulants for cancer patients in practice
Warfarin remains a common treatment strategy for cancer patients with VTE, despite high-quality evidence of superior safety and efficacy of LMWH. The use of warfarin in cancer patients, however, may be limited by complications of malignancy and/or its treatment, including drug reactions, malnutrition, liver or renal dysfunction, gastrointestinal disturbance, and frequent need for dose adjustment. In the FRONTLINE survey of 3891 physicians treating cancer patients, oral anticoagulation with VKAs was favored for long-term treatment of VTE (66–80%) . Similarly, the majority of patients with cancer-associated VTE were treated with long-term VKAs (81%) as opposed to LMWH monotherapy (19%) in a retrospective cohort study . The reasons for the choice of VKAs included lack of coverage or inability to afford LMWH (49%), physician preference (32%), refusal of long-term injections (13%), heparin-induced thrombocytopenia (2%), and renal failure (2%). In the prospective MASTER registry, the majority (64%) of patients with cancer and acute VTE were treated with VKAs; only 30% were treated with LMWH . An analysis of the Swiss Venous Thromboembolism Registry showed that long-term LMWH monotherapy was planned in only 39% of patients with cancer . Fifty-one per cent of patients with cancer received VKAs at any time. Fewer than one-third of patients with active cancer received LMWH monotherapy in a retrospective review of patients treated for VTE . A recent retrospective cohort study showed that treatment of acute VTE consisted of VKAs in 74%, LMWH monotherapy in 25% and fondaparinux in 1% of patients with advanced breast, colorectal, lung and prostate cancer . The use of LMWH monotherapy was more likely with year of VTE diagnosis, recent chemotherapy, previous history of VTE, and recent invasive surgery.
Factors such as the high cost of LMWH and need for daily injections may influence the choice of anticoagulant in individual patients. Limited data suggest that physician perception about the magnitude of VTE risk in cancer patients and the best approach for VTE prophylaxis/treatment may also be an important factor. A questionnaire of oncologists in northern England on the use of thromboprophylaxis in cancer patients found that 27% thought that cancer patients were not at risk of VTE, and 78% believed that chemotherapy posed little or no additional risk . In another global observational study, only 52% of surgical and < 5% of medical cancer patients received thromboprophylaxis . The reasons for omitting thromboprophylaxis included concerns regarding bleeding (55%) and a belief that there was a low risk of VTE (38%).
Cancer patients are at high risk for VTE and its clinical sequelae, including mortality. Key issues remain unresolved, highlighting the considerable need for additional high-quality evidence from clinical trials. The benefit of anticoagulant prophylaxis in the surgical setting is clear, but studies addressing patient-important outcomes are needed to define the risks and benefits in non-surgical cancer patients undergoing chemotherapy. The use of anticoagulants (LMWH in particular) in cancer patients without VTE may offer a small survival benefit, but the clinical implications of these data are limited by the heterogeneity of the patients and trials from which they were generated. Specific patient populations that may derive the most benefit from primary prevention with anticoagulants have yet to be defined. Although LMWH is the preferred treatment for acute VTE, logistic issues such as cost and patient preference may represent challenges to its use in this clinical setting. Furthermore, the optimal duration of treatment for VTE in cancer patients remains unclear. Novel oral anticoagulants may add additional options to prevent or treat VTE in patients with cancer, but we will need comparative trials to establish the efficacy and safety of these target-specific agents in this population.
Disclosure of Conflict of Interests
D. Garcia has chaired or served on advisory boards for Bristol Meyers Squibb, Pfizer and Boehringer Ingelheim, Bayer, Daiichi Sankyo, Ortho McNeill Janssen and CSL Behring. D. M. Siegal has no conflict of interest to declare.