Abstract

Therapeutic options for the management of venous thromboembolism (VTE) in patients with cancer remain very limited. Although low-molecular-weight heparin monotherapy has been identified as a simple and efficacious regimen compared with an initial parenteral anticoagulant followed by long-term therapy with a vitamin K antagonist, many clinical questions remain unanswered. These include optimal duration of anticoagulant therapy, treatment of recurrent VTE, and the treatment of patients with concurrent bleeding or those with a high risk of bleeding. Treatment recommendations from consensus clinical guidelines are largely based on retrospective reports or extrapolated data from the noncancer population with VTE, as randomized controlled trials focused on cancer-associated thrombosis are sorely lacking. Furthermore, with improvements in imaging technology and extended survival duration of patients with cancer, we are encountering more unique challenges, such as the management of incidental VTE. Clinicians should be aware of the limitations of the novel oral anticoagulants and avoid the use of these agents because of the paucity of evidence in the treatment of cancer-associated thrombosis.

Introduction

Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in patients with cancer.1  Although deep vein thrombosis (DVT) and pulmonary embolism (PE) are the most commonly encountered venous thrombotic complications, other vascular territories, such as the splanchnic veins and upper extremity venous system, can also be involved. With the increasing age and cancer prevalence of our population, enhanced detection of incidental thrombosis and greater thrombogenicity of multiagent chemotherapeutic regimens, we have observed a steady increase in the incidence of cancer-associated thrombosis during the past 2 decades.2,3  A leading cause of death in patients with cancer,4  thrombosis is associated with higher mortality risk, irrespective of cancer stage.5,6 

Unfortunately, despite the burden of VTE in oncology patients, there has been limited advancement in the management of cancer-associated thrombosis since the introduction of low-molecular-weight heparin (LMWH) for long-term therapy. Anticoagulant therapy in malignancy remains burdensome and is viewed as having a negative impact on patient quality of life. It is also associated with a high risk of bleeding and may limit the therapeutic options to treat the underlying cancer.7 

In this review, we outline the current evidence and consensus guideline recommendations for the initial and long-term management of the first and recurrent episodes of VTE in patients with cancer. We also discuss the management of commonly encountered thrombotic complications, recognizing the lack of rigorous evidence in these areas, such as incidentally detected VTE, splanchnic vein thrombosis, catheter-related thrombosis, and VTE treatment in patients with a high risk of bleeding. We close with a critical look at the use of the novel oral anticoagulants (NOACs) in the treatment of cancer-associated thrombosis.

Initial management of a first episode of cancer-associated VTE

Choice of anticoagulant

Options for the initial treatment of cancer-associated thrombosis include LMWH, unfractionated heparin (UFH), and fondaparinux. Although studies directly comparing these agents are lacking in oncology patients, data extrapolated from subgroup analysis of trials in unselected patients showed no difference in efficacy between LMWH and UFH in patients with cancer.8  However, a statistically significant reduction in mortality risk with LMWH at 3 months of follow-up has been noted. The reason for this survival benefit is unknown, but research exploring the antineoplastic properties of LMWH is ongoing. In addition to better efficacy, LMWH provides other advantages vs UFH, including lower cost (because hospitalization and laboratory monitoring are not required) and simple dosing (because the total daily dose is based on body weight). LMWH is also associated with a lower risk for heparin-induced thrombocytopenia (HIT).9 

Data on the use of fondaparinux for the initial management of DVT and PE in patients with cancer are also derived from post hoc subgroup analysis. In the Matisse trials, the 3-month rate for symptomatic, recurrent VTE was higher for fondaparinux vs enoxaparin in DVT treatment (12.7% vs 5.4%) but was lower for fondaparinux vs UFH in PE treatment (8.9% vs 17.2%).10  Like LMWH, fondaparinux is administered as a once-daily, weight-based subcutaneous injection. Fondaparinux is rarely associated with the development of drug-induced thrombocytopenia and has been used off label for the management of HIT.11  Barriers to its use in oncology patients include a relatively long half-life of 17 to 21 hours, the lack of a reversal agent, and 100% dependence on renal clearance.12 

On the basis of currently available evidence, LMWH is the recommended anticoagulant for the initial therapy of VTE in most patients with cancer (Table 1).13-16  However, UFH can be used in those with severe renal impairment (creatinine clearance [CrCl] <30 mL/min) given its shorter half-life, reversibility with protamine sulfate, and dependence on hepatic clearance. Fondaparinux is a reasonable choice in patients with a history of HIT.

Table 1

Consensus guidelines on treatment of deep vein thrombosis or pulmonary embolism in patients with cancer

ACCP 201221 NCCN 201113 ASCO 201314 
Initial/acute treatment Not addressed in cancer patients. LMWH LMWH is preferred for initial 5-10 d of treatment in patients with a CrCl >30 mL/min. 
Dalteparin 200 U/kg OD 
Enoxaparin 1 mg/kg BID 
Tinzaparin 175 U/kg OD 
Fondaparinux 5 mg (<50 kg), 7.5 mg (50-100 kg), or 10 mg (>100 kg) OD 
APTT-adjusted UFH infusion 
Long-term treatment LMWH preferred to VKA [2B].* LMWH is preferred for first 6 mo as monotherapy without warfarin in patients with proximal DVT or PE and metastatic or advanced cancer. LMWH is preferred for long-term therapy. 
In patients not treated with LMWH, VKA therapy is preferred to dabigatran or rivaroxaban [2C].* Patients receiving extended therapy should continue with the same agent used for the first 3 mo of treatment [2C].* Warfarin 2.5-5 mg every day initially with subsequent dosing based on INR value targeted at 2-3. VKAs (target INR, 2-3) are acceptable for long-term therapy if LMWH is not available. 
Duration of treatment Extended anticoagulant therapy is preferred to 3 mo of treatment [2B].* Minimum 3 mo. At least 6 mo duration. 
Indefinite anticoagulant if active cancer or persistent risk factors. Extended anticoagulation with LMWH or VKA may be considered beyond 6 mo for patients with metastatic disease or patients who are receiving chemotherapy. 
ACCP 201221 NCCN 201113 ASCO 201314 
Initial/acute treatment Not addressed in cancer patients. LMWH LMWH is preferred for initial 5-10 d of treatment in patients with a CrCl >30 mL/min. 
Dalteparin 200 U/kg OD 
Enoxaparin 1 mg/kg BID 
Tinzaparin 175 U/kg OD 
Fondaparinux 5 mg (<50 kg), 7.5 mg (50-100 kg), or 10 mg (>100 kg) OD 
APTT-adjusted UFH infusion 
Long-term treatment LMWH preferred to VKA [2B].* LMWH is preferred for first 6 mo as monotherapy without warfarin in patients with proximal DVT or PE and metastatic or advanced cancer. LMWH is preferred for long-term therapy. 
In patients not treated with LMWH, VKA therapy is preferred to dabigatran or rivaroxaban [2C].* Patients receiving extended therapy should continue with the same agent used for the first 3 mo of treatment [2C].* Warfarin 2.5-5 mg every day initially with subsequent dosing based on INR value targeted at 2-3. VKAs (target INR, 2-3) are acceptable for long-term therapy if LMWH is not available. 
Duration of treatment Extended anticoagulant therapy is preferred to 3 mo of treatment [2B].* Minimum 3 mo. At least 6 mo duration. 
Indefinite anticoagulant if active cancer or persistent risk factors. Extended anticoagulation with LMWH or VKA may be considered beyond 6 mo for patients with metastatic disease or patients who are receiving chemotherapy. 

ACCP, American College of Chest Physicians; BID, twice-daily dosing; NCCN, National Comprehensive Cancer Network; OD, once-daily dosing.

*

ACCP adaptation of the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) Working Group evidence-based recommendations: 2B, weak recommendation, moderate-quality evidence; 2C, weak recommendation, low- or very-low-quality evidence.16 

Use of thrombolysis in cancer-associated VTE

As most trials of thrombolytic therapy exclude patients with cancer because of a perceived higher risk of bleeding, evidence for thrombolysis in patients with malignancy is limited to small single-center, retrospective series. These studies compared the degree of clot lysis and short-term complications between patients with vs those without cancer who had presented with extensive DVT or PE.17-19  Although comparable results between cancer and noncancer patient groups were observed, these studies provide a low level of evidence because of insufficient statistical power and patient selection bias. Nonetheless, there is no strong evidence to routinely exclude patients for consideration of thrombolysis on the basis of the presence of malignancy alone. Because the safety, cost-effectiveness, and long-term benefit of thrombolysis remain uncertain,20  it is prudent to review each patient carefully and exclude patients with central nervous system lesions or other risk factors for bleeding.

Long-term management of a first episode of cancer-associated VTE

Choice of anticoagulant

Although vitamin K antagonists (VKAs) have been the mainstay agents for long-term management and secondary prophylaxis of acute VTE in patients without cancer,21  their use is problematic in oncology patients. VKAs are less effective in patients with cancer, with rates of recurrent VTE threefold higher than in patients without cancer despite maintenance of the international normalized ratio (INR) within the therapeutic range.22,23 

Several open-label, randomized controlled trials have compared LMWH with VKA therapy for long-term management of cancer-associated PE or proximal DVT (Figure 1).24-27  Three different LMWH preparations, enoxaparin, tinzaparin, and dalteparin, were investigated for 3 to 6 months in similarly designed studies. Overall, the results from these trials provide consistent evidence of improved efficacy of LMWH vs VKA in the prevention of recurrent VTE in patients with cancer-associated VTE. A meta-analysis of 7 studies confirms this finding, reporting a relative risk reduction of 53%.28 

Figure 1

Comparison of randomized controlled trials of different preparations of LMWH vs VKA for the long-term management of cancer-associated thrombosis. Recurrent VTE (A), major bleeding episodes (B), and mortality (C) during the anticoagulant treatment period are shown for the CLOT24  (6 months of dalteparin or VKA), LITE25  (3 months of tinzaparin or warfarin), and CANTHANOX27  (3 months of enoxaparin or warfarin) trials. NS, not statistically significant.

Figure 1

Comparison of randomized controlled trials of different preparations of LMWH vs VKA for the long-term management of cancer-associated thrombosis. Recurrent VTE (A), major bleeding episodes (B), and mortality (C) during the anticoagulant treatment period are shown for the CLOT24  (6 months of dalteparin or VKA), LITE25  (3 months of tinzaparin or warfarin), and CANTHANOX27  (3 months of enoxaparin or warfarin) trials. NS, not statistically significant.

In addition to improved efficacy vs VKA therapy, LMWH also offers other advantages including (a) no need for laboratory monitoring of its anticoagulant activity; (b) a shorter half-life that facilitates temporary interruption for procedures or thrombocytopenia; (c) limited drug interactions; and (d) no food interactions or reliance on oral intake or gastrointestinal tract absorption. As a result, LMWH is recommended for both initial and long-term anticoagulation in cancer-associated thrombosis by major consensus guidelines (Table 1).13-15,21  The high cost associated with LMWH therapy and the requirement for daily subcutaneous injections are the major barriers to its use. Yet, qualitative studies have reported that patient acceptance of daily injections is quite favorable.29  In fact, in those who had used warfarin and LMWH therapy, most prefer the convenience and “empowerment” with LMWH. If LMWH is unavailable, the American Society of Clinical Oncology (ASCO) 2013 VTE Prevention and Treatment Guideline recommends the use of VKA with a target INR of 2 to 3 as an acceptable alternative.14 

Anticoagulation in patients with renal impairment

Renal impairment is not uncommon among patients with malignancy. Because LMWH is partially cleared by renal excretion and metabolism, drug accumulation is expected with long-term use in those with significant renal insufficiency (CrCl <30 mL/min). Of the major LMWH preparations, tinzaparin appears to have the lowest potential to accumulate, whereas enoxaparin shows significant accumulation in renal insufficiency.30  This property reflects the chain length of the LMWH, with the longer-chain tinzaparin being partially cleared by the reticuloendothelial system.30,31 

Limited data are available on the use of LMWH in patients with significant renal dysfunction, but they do indicate that the risk of bleeding is higher in patients with renal impairment.32,33  Manufacturer-recommended dose reduction in renal impairment exists for enoxaparin but not for other LMWH preparations.34  Most experts and guidelines recommend dose adjustment based on anti-factor Xa activity in patients with a CrCl <30 mL/min.13,21  If anti-factor Xa monitoring is not readily available, VKA therapy is likely a safer option for long-term anticoagulation in these patients. A warning against the use of tinzaparin in elderly patients with renal impairment has been issued by the US Food and Drug Administration after the results of an interim analysis of a randomized trial comparing tinzaparin with UFH for initial VTE therapy in this vulnerable population.35  Only 33 patients with a history of ongoing malignancy were enrolled in this study; 20 of them were in the tinzaparin group.36 

Duration of anticoagulation and anticoagulant options for extended therapy

The decision regarding the continuation of anticoagulation beyond the first 3 to 6 months is largely based on weighing the risk for recurrent thrombosis against the risk of major bleeding. This evaluative process is best developed in patients with unprovoked VTE, in whom studies have been done to determine whether biomarkers, radiologic imaging, and clinical prediction models can identify patients with a sufficiently high risk for recurrent thrombosis to benefit from extended anticoagulation, or an acceptably low risk to allow discontinuation of anticoagulation.37-39  A clinical model to predict the risk for recurrent VTE during anticoagulation therapy in cancer-associated thrombosis has been proposed but not yet validated.40  In addition, studies regarding the optimal duration of anticoagulant therapy are lacking in oncology patients.

Given that the risk for recurrent thrombosis in patients with active cancer is high even while they are receiving anticoagulation, it is generally recommended that extended anticoagulation be considered in this population.14,21  It has not been established whether risk factors for a first episode of VTE, such as metastatic or progressive disease and ongoing chemotherapy, will also increase the risk for recurrent VTE, but it has been generally accepted that continuing anticoagulation in patients with these ongoing risk factors is warranted.13-15  Patients given extended anticoagulation require frequent reassessment to review the risk-benefit balance of continuing anticoagulant therapy. Factors that need to be taken into account, aside from the risk for recurrent VTE and the risk of bleeding, include the status of the malignancy, type of cancer treatment (if any), quality of life, and patient preference.

The choice of anticoagulant for extended anticoagulant therapy (beyond 6 months) also has not been investigated. A randomized trial is currently addressing this question.41  Patient preference and tolerance of previous therapy play significant roles in this decision. Thus far, long-term toxicity associated with VKA or LMWH has not been a concern, although it remains controversial whether prolonged exposure to LMWH accelerates clinically significant bone loss.42  As with duration of therapy, the anticoagulant of choice needs to be discussed with each patient and individualized.

Inferior vena cava (IVC) filters

Patients with cancer are frequent recipients of IVC filters. Yet, data on the efficacy and safety in this population are limited to retrospective single-center series or anecdotal reports.43,44  Rates of recurrent VTE up to 32% have been reported in patients with cancer treated with IVC filters, and fatal PE after filter insertion has been well documented.45 

Evidence on the safety and efficacy of IVC filters in the general population is also sparse. Only 1 randomized trial has been done to evaluate filter placement in patients with proximal DVT who are at high risk for PE. In the PREPIC (Prévention du Risque d'Embolie Pulmonaire par Interruption Cave) trial, the use of permanent IVC filters in conjunction with anticoagulation resulted in a decreased incidence of PE at the expense of an increase risk for recurrent DVT and without any reduction in overall mortality rate during 8 years of follow-up.46,47  Results for the included 56 patients with cancer have not been published. Most importantly, the value of an IVC filter in patients who cannot receive anticoagulation, the major indication for filter insertion, has not been examined in prospective studies.

Complications associated with IVC filters raise further concern about the appropriateness of their use. Insertion problems occur in 4% to 11% of patients, and long-term adverse effects such as thrombosis of the IVC or lower extremity veins occur in 4% to 32%.48  A high incidence of mechanical or device failures associated with retrievable filter models led the US Food and Drug Administration to issue a Safety Alert in 2010.49  These problems include filter migration, strut fracture with embolization, and caval perforation.50,51 

Given the high rates of complications and the absence of data to support their efficacy, IVC filters should be restricted to patients with acute VTE and contraindications to anticoagulation. Their use in patients with recurrent thrombotic events despite standard anticoagulant therapy goes against biological rationale because filters do not treat the underlying thrombotic condition, and the presence of an intravascular foreign body is likely to promote thrombus formation, which can occur proximally or distally to the filter. In addition, the use of IVC filters may provide a sense of false security regarding the risk for recurrent PE, causing delays or discontinuation of anticoagulant therapy. If retrievable filters are placed, efforts should be made to remove the device and reinitiate anticoagulation as soon as the high-risk period for bleeding has passed.

Treatment of recurrent VTE during anticoagulant therapy

Failure of anticoagulation in cancer-associated thrombosis is common, but there is a paucity of data to help guide treatment. An empiric approach for the treatment of recurrent VTE during anticoagulant therapy is outlined in Figure 2. Once recurrent VTE is confirmed, it is essential that HIT be excluded in patients who were first exposed to LMWH or UFH within the past 10 to 14 days. Compliance should also be reviewed. In patients who experience a recurrent event while receiving VKA therapy and have a subtherapeutic INR, options include continuation of VKA after a bridging period with LMWH (or UFH) or switching to LMWH monotherapy. The latter is likely a better option, especially in patients who had unstable INR values and the time-in-therapeutic range was low. For patients who experienced warfarin failure while the INR values had been therapeutic, transition to LMWH is recommended given its greater efficacy vs warfarin.24,25,27,52  Recurrent VTE events during LMWH therapy can be treated with a dose escalation of LMWH. A retrospective study of 70 patients with cancer with recurrent VTE demonstrated that transition to LMWH (in patients receiving VKA therapy at the time of recurrence) or LMWH dose escalation by 20% to 25% (in patients receiving LMWH at recurrence) prevented additional VTE in 91% of patients during a minimum of 3 months of follow-up.53  Only 1 patient had a major bleeding event. If another recurrent VTE episode occurs after the first dose escalation, further dose increase or twice-daily dosing of LMWH are reasonable options. The use of anti-factor Xa levels may help to further tailor LMWH escalation (Figure 2), although published evidence to support this strategy is lacking.

Figure 2

Management algorithm of recurrent VTE in patients with cancer. BID, twice-daily dosing; INR, international normalized ratio; OD, once-daily dosing.

Figure 2

Management algorithm of recurrent VTE in patients with cancer. BID, twice-daily dosing; INR, international normalized ratio; OD, once-daily dosing.

Treatment of incidental VTE

Incidental or unsuspected VTE is defined as evidence of thrombosis detected on imaging studies performed for other indications such as cancer staging.54  Retrospective studies in unselected oncology patients have demonstrated incidental VTE rates of up to 6%,55,56  with thrombotic events evenly distributed between PE and/or DVT and intra-abdominal thrombosis.55  A prevalence of incidental PE of 3.1% was reported in a meta-analysis that included data from more than 6000 oncology patients.57  Incidental VTE also represents a significant proportion of thrombotic complications in patients with cancer, comprising up to 60% in large series.58 

Studies have suggested that, like suspected or symptomatic VTE, the occurrence of incidental VTE can have a negative impact on both patient quality of life and clinical outcomes. Patients with incidental PE often have symptoms such as fatigue and shortness of breath.59  In a retrospective case-control study comparing 51 unselected oncology patients with incidental PE and 144 patients with symptomatic PE, the 12-month rates of recurrent VTE, bleeding, and mortality were similar between the groups.60  A retrospective cohort of 135 consecutive patients with pancreatic cancer reported similar findings.61  In another study, a comparison of cancer patients with and without incidental PE matched for age, cancer diagnosis, and stage of disease at the time of a restaging computed tomography scan of the chest found that patients with incidental PE had a higher mortality rate than those without PE.62 

Whether anticoagulation is indicated or beneficial in patients with incidental VTE remains controversial. Evidence is limited to 2 retrospective studies in patients with lung and pancreatic cancer. In a cohort of 113 patients with lung cancer and incidental PE, the 62 patients who did not receive anticoagulation had higher mortality rates compared with patients who were treated.63  Similarly, in patients with pancreatic cancer with incidental VTE, the use of anticoagulant therapy was associated with a 70% reduction in mortality rate.61  However, these studies are potentially biased to favor anticoagulation because anticoagulant therapy is likely to be withheld in those with a short life expectancy.

Nonetheless, based on published literature to date, it is recommended that patients with incidental DVT and PE receive therapeutic anticoagulation if there are no contraindications.14,21  However, caution should be exercised in cases where the diagnosis of PE or DVT is questionable, especially for isolated subsegmental PE. Confirming the diagnosis with the appropriate testing (ie, computed tomographic pulmonary angiography or compression venous ultrasonography) is strongly encouraged in such cases.

Treatment of cancer-associated thrombosis in patients with a high risk of bleeding

Bleeding is frequently associated with anticoagulant use in patients with cancer. In a prospective study including 181 oncology patients receiving VKA for the treatment of DVT, the 1-year cumulative incidence of major bleeding was 12.4%, with one third of the bleeding events occurring during the initial phase of anticoagulation.23  Although subtherapeutic INR values are associated with recurrent VTE, there appears to be no correlation between the INR level and bleeding in patients with cancer.22,64  Bleeding complications are not restricted to VKA therapy, as prospective randomized controlled trials comparing LMWH and VKA therapy for cancer-associated VTE have reported similar bleeding rates.24-26  Features specific to oncology patients that contribute to bleeding include the extent, location, and histologic features of the cancer, need for invasive diagnostic or treatment procedures, and the development of thrombocytopenia from chemotherapy or from the underlying malignancy. Other comorbidities such as renal impairment and coagulopathy from liver dysfunction, disseminated intravascular coagulopathy, or sepsis further predispose them to bleeding.

Because of potentially serious and life-threatening bleeding complications, all patients require an individualized assessment of their bleeding risk before the initiation of anticoagulation. Current and potential bleeding sources should be identified and managed, and the risk of serious bleeding should be weighed against the severity of the thrombotic event and risk for recurrent VTE. In patients with minor bleeding, anticoagulation may be continued as long as close follow-up is available. In patients with absolute contraindications to anticoagulation, the risk of bleeding likely outweighs the benefit of treatment, and anticoagulants should be withheld.14  In these patients, follow-up imaging should be performed to assess for thrombus progression, and IVC filter insertion can be considered. If severe cancer- or chemotherapy-induced thrombocytopenia is present, platelet transfusions may be used to allow anticoagulation. Most experts agree that therapeutic anticoagulation with LMWH may be administered if the platelet count can be maintained above 50 × 109/L.65  For platelet counts between 20 and 50 × 109/L, half-dose LMWH can be administered with close follow-up for possible bleeding. If platelet count is <20 × 109/L, therapeutic doses of anticoagulation should be held. Limited evidence from case series suggests that the use of prophylactic doses of LMWH can be tolerated in patients with platelet counts <20 × 109/L with associated resolution of thrombotic symptoms.66  VKA therapy should be avoided in patients with severe thrombocytopenia from the prolonged anticoagulant effect and unpredictable dose response. Figure 3 illustrates a reasonable approach to the treatment of cancer-associated thrombosis in patients with thrombocytopenia.65 

Figure 3

Management algorithm of VTE in patients with cancer and thrombocytopenia. Management of acute VTE (<1 month) and subacute or chronic VTE (≥1 month) are outlined in panels A and B, respectively.

Figure 3

Management algorithm of VTE in patients with cancer and thrombocytopenia. Management of acute VTE (<1 month) and subacute or chronic VTE (≥1 month) are outlined in panels A and B, respectively.

Management of VTE in patients with intracranial malignancies is particularly challenging because of the fear of intracranial hemorrhage. No randomized controlled data exist for management of patients with primary or metastatic intracranial tumors and VTE; however, small retrospective studies indicate that anticoagulation can be safely used. Anticoagulation with intravenous UFH followed by VKA or subcutaneous UFH has been associated with rates of symptomatic intracranial hemorrhage between 0% and 7%.67-70  Similar results have been reported with LMWH in patients with glioma or metastatic brain tumors with a trend toward improved survival duration.71-73  The ASCO 2013 VTE Guideline recommends treating patients with intracranial malignancies with standard anticoagulation.14 

Treatment of catheter-related thrombosis

Treatment of catheter-related thrombosis is largely inferred from treatment of DVT because randomized controlled trials evaluating management strategies have not been performed. Whether line removal is necessary (to eliminate the thrombotic source), harmful (because it can trigger PE), or beneficial (in shortening or avoiding anticoagulation therapy) has not been studied in clinical trials. A small prospective study evaluating the use of anticoagulation alone reported that in 74 patients with active cancer, LMWH for 5 to 7 days followed by warfarin with a target INR of 2.0 to 3.0 for 3 months resulted in no recurrent VTE at the expense of 3 episodes of major bleeding, including 1 fatal hemorrhage.74  After 3 months of treatment, 57% of patients had functional catheters in situ, whereas the remainder had catheter removal for reasons other than progressive thrombosis or device failure. A small patient series observed that a short course of low-dose LMWH is effective and safe in treating catheter-related thrombosis in patients with severe thrombocytopenia.75 

To date, published data and clinical experience suggest that catheter-related thrombosis is associated with a low risk for thrombosis recurrence and postthrombotic syndrome.76,77  Therefore, conservative treatment is recommended. A sensible approach is to remove the catheter only if (1) central venous access is no longer required; (2) the device is nonfunctional or defective; or (3) line-related sepsis is suspected or documented. Unless contraindicated, therapeutic anticoagulation should be given using either LMWH alone or LMWH followed by warfarin therapy. A short period of anticoagulation (3-5 days of LMWH) may even salvage some thrombosed catheters and obviate the need to remove and replace the line. Anticoagulation is recommended for a minimum of 3 months and while the catheter remains in place.

Treatment of splanchnic vein thrombosis in patients with cancer

Splanchnic vein thromboses, involving the portal, splenic, mesenteric, or hepatic veins, are uncommon in the general population, but significant rates have been reported in patients with intraabdominal malignancies.78  In a retrospective single-institution study of 135 consecutive patients with pancreatic adenocarcinoma, incidental splanchnic vein thrombosis was present in 23%.60 

Management of splanchnic vein thrombosis has not been well studied. Limited experience is available from studies that included both patients with and without cancer. In a retrospective cohort of 832 patients with splanchnic vein thrombosis, of which 27% had underlying cancer, warfarin therapy and gastrointestinal tract varices were independent predictors of bleeding.79  Furthermore, VTE recurrence was not reduced after anticoagulant therapy. An international registry of 613 patients with splanchnic vein thrombosis reported that most patients are treated with anticoagulation and that the risk of major bleeding is low.80  Whether such results apply to cancer-related splanchnic vein thrombosis is not known.

In patients with acute, symptomatic splanchnic vein thrombosis without contraindications to anticoagulation, guidelines recommend the use of anticoagulant therapy.21  For patients with incidentally detected splanchnic vein thrombosis, there is no specific guidance on treatment. It is reasonable to withhold anticoagulation if the patient is truly asymptomatic, especially if radiologic evidence indicates that the thrombus is chronic in nature. Repeated imaging is prudent to detect thrombus progression if anticoagulation is not given.

Use of NOACs in cancer-associated thrombosis

The development of NOACs that directly inhibit factor Xa or thrombin is a milestone achievement in the prevention and treatment of VTE. These agents are more attractive to patients and clinicians because they are taken by mouth in fixed doses once or twice daily, have few drug and food interactions, and do not require laboratory monitoring. Dabigatran, a direct thrombin inhibitor, and rivaroxaban and apixaban, 2 direct factor Xa inhibitors, are the forerunners in this class of agents. These drugs have been shown to be effective in VTE prophylaxis after major hip and knee arthroplasty and in stroke prevention in patients with nonvalvular atrial fibrillation.81  They are also noninferior to warfarin for the prevention of recurrent VTE without an increased risk of bleeding, and rivaroxaban has received regulatory approval as monotherapy in the treatment of DVT.82-87  All 3 agents are effective and safe for long-term secondary VTE prophylaxis in patients who have already received 6 to 12 months of anticoagulation.82,85,87  Unfortunately, very small numbers of patients with cancer were included in these trials, and the results of this patient subgroup have not been published. A small phase 2 study evaluating the safety and tolerability of apixaban found a low risk of major bleeding (2.2%) during 12 weeks of therapy in 125 patients with metastatic or advanced cancer without thrombosis.88  No studies have specifically addressed the treatment of cancer-associated VTE using these direct inhibitors.

Despite the undeniable practical advantages of these agents vs VKA and LMWH therapy for the prevention and treatment of cancer-associated thrombosis, important and clinically relevant concerns prevail regarding the extrapolation of published results to the cancer population. These include the small number of highly selected patients with cancer (approximately 5%) enrolled in each study and the use of warfarin or placebo rather than LMWH in the control group. In addition, although these anticoagulants have fewer drug interactions than VKAs, interactions do exist with some chemotherapeutic agents (Table 2). Whether these interactions are clinically significant is not known. Finally, gastrointestinal tract problems in patients with cancer can potentially alter drug delivery and absorption, and higher rates of gastrointestinal tract bleeding have been reported with dabigatran compared with warfarin.81  These shortcomings are compounded by the lack of reversal agents to rapidly normalize hemostasis and the lack of widely available laboratory assays to measure the anticoagulant activity. Clinicians need to discuss these limitations to fully inform their patients with cancer and know that the current ASCO Guideline does not recommend the use of these new agents.14  Clinical trials are strongly encouraged to address this and the many other unmet clinical needs in patients with cancer-associated thrombosis.

Table 2

Interactions between chemotherapeutic agents and immunosuppressants with NOACs based on known metabolic pathway activity

DabigatranRivaroxabanApixaban
Interaction effect*P-glycoproteinP-glycoprotein CYP3A4P-glycoprotein CYP3A4
Increases NOAC plasma levels Cyclosporine Cyclosporine Cyclosporine 
Tacrolimus Tacrolimus Tacrolimus 
Tamoxifen Tamoxifen Tamoxifen 
Lapatinib Lapatinib Lapatinib 
Nilotinib Nilotinib Nilotinib 
Sunitinib Sunitinib Sunitinib 
Imatinib Imatinib 
Reduces NOAC plasma levels Dexamethasone Dexamethasone Dexamethasone 
Doxorubicin Doxorubicin Doxorubicin 
Vinblastine Vinblastine Vinblastine 
DabigatranRivaroxabanApixaban
Interaction effect*P-glycoproteinP-glycoprotein CYP3A4P-glycoprotein CYP3A4
Increases NOAC plasma levels Cyclosporine Cyclosporine Cyclosporine 
Tacrolimus Tacrolimus Tacrolimus 
Tamoxifen Tamoxifen Tamoxifen 
Lapatinib Lapatinib Lapatinib 
Nilotinib Nilotinib Nilotinib 
Sunitinib Sunitinib Sunitinib 
Imatinib Imatinib 
Reduces NOAC plasma levels Dexamethasone Dexamethasone Dexamethasone 
Doxorubicin Doxorubicin Doxorubicin 
Vinblastine Vinblastine Vinblastine 

CYP3A4, cytochrome P450 3A4.

*

Clinicians should consult with the pharmacist to determine if these and other drug interactions exist when NOACs are being considered.

Drugs that inhibit P-glycoprotein transport or CYP3A4 pathway can increase NOAC levels.

Drugs that induce P-glycoprotein transport or CYP3A4 pathway can lower NOAC levels.

Authorship

Contribution: A.Y.Y.L. and E.A.P. wrote the manuscript.

Conflict-of-interest disclosure: A.Y.Y.L. reports receiving research funding from LEO Pharma and honoraria from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, LEO Pharma, Pfizer, and Sanofi Aventis. The remaining author declares no competing financial interests.

Correspondence: Agnes Y. Y. Lee, University of British Columbia and Vancouver Coastal Health Diamond Health Care Centre, 2775 Laurel St, 10th Floor, Vancouver, BC, Canada; email: alee14@bccancer.bc.ca.

References

References
1
Lee
 
AY
Levine
 
MN
Venous thromboembolism and cancer: risks and outcomes.
Circulation
2003
, vol. 
107
 
23 Suppl 1
(pg. 
I17
-
I21
)
2
Khorana
 
AA
Francis
 
CW
Culakova
 
E
Fisher
 
RI
Kuderer
 
NM
Lyman
 
GH
Thromboembolism in hospitalized neutropenic cancer patients.
J Clin Oncol
2006
, vol. 
24
 
3
(pg. 
484
-
490
)
3
Stein
 
PD
Beemath
 
A
Meyers
 
FA
Skaf
 
E
Sanchez
 
J
Olson
 
RE
Incidence of venous thromboembolism in patients hospitalized with cancer.
Am J Med
2006
, vol. 
119
 
1
(pg. 
60
-
68
)
4
Khorana
 
AA
Francis
 
CW
Culakova
 
E
Kuderer
 
NM
Lyman
 
GH
Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy.
J Thromb Haemost
2007
, vol. 
5
 
3
(pg. 
632
-
634
)
5
Chew
 
HK
Wun
 
T
Harvey
 
DJ
Zhou
 
H
White
 
RH
Incidence of venous thromboembolism and the impact on survival in breast cancer patients.
J Clin Oncol
2007
, vol. 
25
 
1
(pg. 
70
-
76
)
6
Rodriguez
 
AO
Wun
 
T
Chew
 
H
Zhou
 
H
Harvey
 
D
White
 
RH
Venous thromboembolism in ovarian cancer.
Gynecol Oncol
2007
, vol. 
105
 
3
(pg. 
784
-
790
)
7
Kuderer
 
NM
Ortel
 
TL
Francis
 
CW
Impact of venous thromboembolism and anticoagulation on cancer and cancer survival.
J Clin Oncol
2009
, vol. 
27
 
29
(pg. 
4902
-
4911
)
8
Akl
 
EA
Vasireddi
 
SR
Gunukula
 
S
, et al. 
 
Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev. 2011;(6):CD006649
9
Martel
 
N
Lee
 
J
Wells
 
PS
Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis.
Blood
2005
, vol. 
106
 
8
(pg. 
2710
-
2715
)
10
van Doormaal
 
FF
Raskob
 
GE
Davidson
 
BL
, et al. 
Treatment of venous thromboembolism in patients with cancer: subgroup analysis of the Matisse clinical trials.
Thromb Haemost
2009
, vol. 
101
 
4
(pg. 
762
-
769
)
11
Warkentin
 
TE
Pai
 
M
Sheppard
 
JI
Schulman
 
S
Spyropoulos
 
AC
Eikelboom
 
JW
Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series.
J Thromb Haemost
2011
, vol. 
9
 
12
(pg. 
2389
-
2396
)
12
Nagler
 
M
Haslauer
 
M
Wuillemin
 
WA
Fondaparinux - data on efficacy and safety in special situations.
Thromb Res
2012
, vol. 
129
 
4
(pg. 
407
-
417
)
13
National Comprehensive Cancer Network
 
Clinical Practice Guidelines in Oncology Venous Thromboembolic Disease version 2.2013. Available at: http://www.nccn.org/professionals/physician_gls/pdf/vte.pdf. Accessed July 9, 2013
14
Lyman
 
GH
Khorana
 
AA
Kuderer
 
NM
, et al. 
Venous thromboembolism prophylaxis and treatment in patients with cancer: american society of clinical oncology clinical practice guideline update.
J Clin Oncol
2013
, vol. 
31
 
17
(pg. 
2189
-
2204
)
15
Mandalà
 
M
Falanga
 
A
Roila
 
F
ESMO Guidelines Working Group
Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines.
Ann Oncol
2011
, vol. 
22
 
Suppl 6
(pg. 
vi85
-
vi92
)
16
Guyatt
 
GH
Norris
 
SL
Schulman
 
S
, et al. 
 
Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):53S-70S
17
Maleux
 
G
Marchal
 
P
Palmers
 
M
, et al. 
Catheter-directed thrombolytic therapy for thoracic deep vein thrombosis is safe and effective in selected patients with and without cancer.
Eur Radiol
2010
, vol. 
20
 
9
(pg. 
2293
-
2300
)
18
Kim
 
HS
Preece
 
SR
Black
 
JH
Pham
 
LD
Streiff
 
MB
Safety of catheter-directed thrombolysis for deep venous thrombosis in cancer patients.
J Vasc Surg
2008
, vol. 
47
 
2
(pg. 
388
-
394
)
19
Mikkola
 
KM
Patel
 
SR
Parker
 
JA
Grodstein
 
F
Goldhaber
 
SZ
Attenuation over 24 hours of the efficacy of thrombolysis of pulmonary embolism among patients with cancer.
Am Heart J
1997
, vol. 
134
 
4
(pg. 
603
-
607
)
20
Vedantham
 
S
Goldhaber
 
SZ
Kahn
 
SR
, et al. 
 
Rationale and design of the ATTRACT Study: a multicenter randomized trial to evaluate pharmacomechanical catheter-directed thrombolysis for the prevention of postthrombotic syndrome in patients with proximal deep vein thrombosis. Am Heart J. 2013;165(4):523-530.e3
21
Kearon
 
C
Akl
 
EA
Comerota
 
AJ
, et al. 
 
Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e419S-94S
22
Hutten
 
BA
Prins
 
MH
Gent
 
M
Ginsberg
 
J
Tijssen
 
JG
Büller
 
HR
Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis.
J Clin Oncol
2000
, vol. 
18
 
17
(pg. 
3078
-
3083
)
23
Prandoni
 
P
Lensing
 
AW
Piccioli
 
A
, et al. 
Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis.
Blood
2002
, vol. 
100
 
10
(pg. 
3484
-
3488
)
24
Lee
 
AY
Levine
 
MN
Baker
 
RI
, et al. 
Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators
Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.
N Engl J Med
2003
, vol. 
349
 
2
(pg. 
146
-
153
)
25
Hull
 
RD
Pineo
 
GF
Brant
 
RF
, et al. 
LITE Trial Investigators
Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer.
Am J Med
2006
, vol. 
119
 
12
(pg. 
1062
-
1072
)
26
Deitcher
 
SR
Kessler
 
CM
Merli
 
G
Rigas
 
JR
Lyons
 
RM
Fareed
 
J
ONCENOX Investigators
Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period.
Clin Appl Thromb Hemost
2006
, vol. 
12
 
4
(pg. 
389
-
396
)
27
Meyer
 
G
Marjanovic
 
Z
Valcke
 
J
, et al. 
Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study.
Arch Intern Med
2002
, vol. 
162
 
15
(pg. 
1729
-
1735
)
28
Akl
 
EA
Labedi
 
N
Barba
 
M
, et al. 
 
Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev. 2011;(6):CD006650
29
Noble
 
SI
Finlay
 
IG
Is long-term low-molecular-weight heparin acceptable to palliative care patients in the treatment of cancer related venous thromboembolism? A qualitative study.
Palliat Med
2005
, vol. 
19
 
3
(pg. 
197
-
201
)
30
Crowther
 
M
Lim
 
W
Low molecular weight heparin and bleeding in patients with chronic renal failure.
Curr Opin Pulm Med
2007
, vol. 
13
 
5
(pg. 
409
-
413
)
31
Lim
 
W
Low-molecular-weight heparin in patients with chronic renal insufficiency.
Intern Emerg Med
2008
, vol. 
3
 
4
(pg. 
319
-
323
)
32
Lim
 
W
Dentali
 
F
Eikelboom
 
JW
Crowther
 
MA
Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency.
Ann Intern Med
2006
, vol. 
144
 
9
(pg. 
673
-
684
)
33
Duplaga
 
BA
Rivers
 
CW
Nutescu
 
E
Dosing and monitoring of low-molecular-weight heparins in special populations.
Pharmacotherapy
2001
, vol. 
21
 
2
(pg. 
218
-
234
)
34
Nutescu
 
EA
Spinler
 
SA
Wittkowsky
 
A
Dager
 
WE
Low-molecular-weight heparins in renal impairment and obesity: available evidence and clinical practice recommendations across medical and surgical settings.
Ann Pharmacother
2009
, vol. 
43
 
6
(pg. 
1064
-
1083
)
35
United States Food and Drug Administration Center for Drug Evaluation and Research
 
Communication about an Ongoing Safety Review of Innohep (tinzaparin sodium injection). Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm136254.htm. Accessed March 23, 2013
36
Leizorovicz
 
A
Siguret
 
V
Mottier
 
D
, et al. 
Innohep® in Renal Insufficiency Study Steering Committee
Safety profile of tinzaparin versus subcutaneous unfractionated heparin in elderly patients with impaired renal function treated for acute deep vein thrombosis: the Innohep® in Renal Insufficiency Study (IRIS).
Thromb Res
2011
, vol. 
128
 
1
(pg. 
27
-
34
)
37
Eichinger
 
S
Heinze
 
G
Jandeck
 
LM
Kyrle
 
PA
Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model.
Circulation
2010
, vol. 
121
 
14
(pg. 
1630
-
1636
)
38
Tosetto
 
A
Iorio
 
A
Marcucci
 
M
, et al. 
Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH).
J Thromb Haemost
2012
, vol. 
10
 
6
(pg. 
1019
-
1025
)
39
Rodger
 
MA
Kahn
 
SR
Cranney
 
A
, et al. 
TIPPS investigators
Long-term dalteparin in pregnancy not associated with a decrease in bone mineral density: substudy of a randomized controlled trial.
J Thromb Haemost
2007
, vol. 
5
 
8
(pg. 
1600
-
1606
)
40
Louzada
 
ML
Carrier
 
M
Lazo-Langner
 
A
, et al. 
Development of a clinical prediction rule for risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism.
Circulation
2012
, vol. 
126
 
4
(pg. 
448
-
454
)
41
Kamphuisen
 
PW
 
Long-term treatment for cancer patients with deep vein thrombosis or pulmonary embolism (LONGEVA). ClinicalTrials.gov Identifier: NCT01164046. Available at: http://clinicaltrials.gov/ct2/show/NCT01164046?term=LONGHEVA&rank=1. Accessed March 23, 2013
42
Wawrzyńska
 
L
Tomkowski
 
WZ
Przedlacki
 
J
Hajduk
 
B
Torbicki
 
A
Changes in bone density during long-term administration of low-molecular-weight heparins or acenocoumarol for secondary prophylaxis of venous thromboembolism.
Pathophysiol Haemost Thromb
2003
, vol. 
33
 
2
(pg. 
64
-
67
)
43
Wallace
 
MJ
Jean
 
JL
Gupta
 
S
, et al. 
Use of inferior vena caval filters and survival in patients with malignancy.
Cancer
2004
, vol. 
101
 
8
(pg. 
1902
-
1907
)
44
Schunn
 
C
Schunn
 
GB
Hobbs
 
G
Vona-Davis
 
LC
Waheed
 
U
Inferior vena cava filter placement in late-stage cancer.
Vasc Endovascular Surg
2006
, vol. 
40
 
4
(pg. 
287
-
294
)
45
Elting
 
LS
Escalante
 
CP
Cooksley
 
C
, et al. 
Outcomes and cost of deep venous thrombosis among patients with cancer.
Arch Intern Med
2004
, vol. 
164
 
15
(pg. 
1653
-
1661
)
46
Decousus
 
H
Leizorovicz
 
A
Parent
 
F
, et al. 
A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group.
N Engl J Med
1998
, vol. 
338
 
7
(pg. 
409
-
415
)
47
PREPIC Study Group
Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study.
Circulation
2005
, vol. 
112
 
3
(pg. 
416
-
422
)
48
Streiff
 
MB
Vena caval filters: a comprehensive review.
Blood
2000
, vol. 
95
 
12
(pg. 
3669
-
3677
)
49
United States Food and Drug Administration
 
Removing Retrievable Inferior Vena Cava Filters: Initial Communication. Available at: http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm221676.htm. Accessed March 22, 2013
50
Durack
 
JC
Westphalen
 
AC
Kekulawela
 
S
, et al. 
Perforation of the IVC: rule rather than exception after longer indwelling times for the Günther Tulip and Celect retrievable filters.
Cardiovasc Intervent Radiol
2012
, vol. 
35
 
2
(pg. 
299
-
308
)
51
Nicholson
 
W
Nicholson
 
WJ
Tolerico
 
P
, et al. 
Prevalence of fracture and fragment embolization of Bard retrievable vena cava filters and clinical implications including cardiac perforation and tamponade.
Arch Intern Med
2010
, vol. 
170
 
20
(pg. 
1827
-
1831
)
52
Luk
 
C
Wells
 
PS
Anderson
 
D
Kovacs
 
MJ
Extended outpatient therapy with low molecular weight heparin for the treatment of recurrent venous thromboembolism despite warfarin therapy.
Am J Med
2001
, vol. 
111
 
4
(pg. 
270
-
273
)
53
Carrier
 
M
Le Gal
 
G
Cho
 
R
Tierney
 
S
Rodger
 
M
Lee
 
AY
Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients.
J Thromb Haemost
2009
, vol. 
7
 
5
(pg. 
760
-
765
)
54
Khorana
 
AA
O’Connell
 
C
Agnelli
 
G
Liebman
 
HA
Lee
 
AY
Subcommittee on Hemostasis and Malignancy of the SSC of the ISTH
Incidental venous thromboembolism in oncology patients.
J Thromb Haemost
2012
, vol. 
10
 
12
(pg. 
2602
-
2604
)
55
Cronin
 
CG
Lohan
 
DG
Keane
 
M
Roche
 
C
Murphy
 
JM
Prevalence and significance of asymptomatic venous thromboembolic disease found on oncologic staging CT.
AJR Am J Roentgenol
2007
, vol. 
189
 
1
(pg. 
162
-
170
)
56
Douma
 
RA
Kok
 
MG
Verberne
 
LM
Kamphuisen
 
PW
Büller
 
HR
Incidental venous thromboembolism in cancer patients: prevalence and consequence.
Thromb Res
2010
, vol. 
125
 
6
(pg. 
e306
-
e309
)
57
Dentali
 
F
Ageno
 
W
Becattini
 
C
, et al. 
Prevalence and clinical history of incidental, asymptomatic pulmonary embolism: a meta-analysis.
Thromb Res
2010
, vol. 
125
 
6
(pg. 
518
-
522
)
58
Di Nisio
 
M
Ferrante
 
N
De Tursi
 
M
, et al. 
Incidental venous thromboembolism in ambulatory cancer patients receiving chemotherapy.
Thromb Haemost
2010
, vol. 
104
 
5
(pg. 
1049
-
1054
)
59
O’Connell
 
CL
Boswell
 
WD
Duddalwar
 
V
, et al. 
Unsuspected pulmonary emboli in cancer patients: clinical correlates and relevance.
J Clin Oncol
2006
, vol. 
24
 
30
(pg. 
4928
-
4932
)
60
den Exter
 
PL
Hooijer
 
J
Dekkers
 
OM
Huisman
 
MV
Risk of recurrent venous thromboembolism and mortality in patients with cancer incidentally diagnosed with pulmonary embolism: a comparison with symptomatic patients.
J Clin Oncol
2011
, vol. 
29
 
17
(pg. 
2405
-
2409
)
61
Menapace
 
LA
Peterson
 
DR
Berry
 
A
Sousou
 
T
Khorana
 
AA
Symptomatic and incidental thromboembolism are both associated with mortality in pancreatic cancer.
Thromb Haemost
2011
, vol. 
106
 
2
(pg. 
371
-
378
)
62
O’Connell
 
CL
Razavi
 
PA
Liebman
 
HA
Symptoms adversely impact survival among patients with cancer and unsuspected pulmonary embolism.
J Clin Oncol
2011
, vol. 
29
 
31
(pg. 
4208
-
4209, author reply 4209-4210
)
63
Sun
 
JM
Kim
 
TS
Lee
 
J
, et al. 
Unsuspected pulmonary emboli in lung cancer patients: the impact on survival and the significance of anticoagulation therapy.
Lung Cancer
2010
, vol. 
69
 
3
(pg. 
330
-
336
)
64
Palareti
 
G
Legnani
 
C
Lee
 
A
, et al. 
A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy.
Thromb Haemost
2000
, vol. 
84
 
5
(pg. 
805
-
810
)
65
Carrier
 
M
Khorana
 
A
Zwicker
 
J
Noble
 
S
Lee
 
A
 
The subcommittee on Haemostasis Malignancy for the SSC of the ISTH. Management of challenging cases of patients with cancer-associated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH [published online ahead of print June 27, 2013]. J Thromb Haemost
66
Herishanu
 
Y
Misgav
 
M
Kirgner
 
I
Ben-Tal
 
O
Eldor
 
A
Naparstek
 
E
Enoxaparin can be used safely in patients with severe thrombocytopenia due to intensive chemotherapy regimens.
Leuk Lymphoma
2004
, vol. 
45
 
7
(pg. 
1407
-
1411
)
67
Schiff
 
D
DeAngelis
 
LM
Therapy of venous thromboembolism in patients with brain metastases.
Cancer
1994
, vol. 
73
 
2
(pg. 
493
-
498
)
68
Olin
 
JW
Young
 
JR
Graor
 
RA
Ruschhaupt
 
WF
Beven
 
EG
Bay
 
JW
Treatment of deep vein thrombosis and pulmonary emboli in patients with primary and metastatic brain tumors. Anticoagulants or inferior vena cava filter?
Arch Intern Med
1987
, vol. 
147
 
12
(pg. 
2177
-
2179
)
69
Choucair
 
AK
Silver
 
P
Levin
 
VA
Risk of intracranial hemorrhage in glioma patients receiving anticoagulant therapy for venous thromboembolism.
J Neurosurg
1987
, vol. 
66
 
3
(pg. 
357
-
358
)
70
Altschuler
 
E
Moosa
 
H
Selker
 
RG
Vertosick
 
FT
The risk and efficacy of anticoagulant therapy in the treatment of thromboembolic complications in patients with primary malignant brain tumors.
Neurosurgery
1990
, vol. 
27
 
1
(pg. 
74
-
76, discussion 77
)
71
Alvarado
 
G
Noor
 
R
Bassett
 
R
, et al. 
Risk of intracranial hemorrhage with anticoagulation therapy in melanoma patients with brain metastases.
Melanoma Res
2012
, vol. 
22
 
4
(pg. 
310
-
315
)
72
Schmidt
 
F
Faul
 
C
Dichgans
 
J
Weller
 
M
Low molecular weight heparin for deep vein thrombosis in glioma patients.
J Neurol
2002
, vol. 
249
 
10
(pg. 
1409
-
1412
)
73
Vitale
 
FV
Rotondo
 
S
Sessa
 
E
, et al. 
Low molecular weight heparin administration in cancer patients with hypercoagulability-related complications and carrying brain metastases: a case series study.
J Oncol Pharm Pract
2012
, vol. 
18
 
1
(pg. 
10
-
16
)
74
Kovacs
 
MJ
Kahn
 
SR
Rodger
 
M
, et al. 
A pilot study of central venous catheter survival in cancer patients using low-molecular-weight heparin (dalteparin) and warfarin without catheter removal for the treatment of upper extremity deep vein thrombosis (The Catheter Study).
J Thromb Haemost
2007
, vol. 
5
 
8
(pg. 
1650
-
1653
)
75
Drakos
 
PE
Nagler
 
A
Or
 
R
Gillis
 
S
Slavin
 
S
Eldor
 
A
Low molecular weight heparin for Hickman catheter—induced thrombosis in thrombocytopenic patients undergoing bone marrow transplantation.
Cancer
1992
, vol. 
70
 
7
(pg. 
1895
-
1898
)
76
Elman
 
EE
Kahn
 
SR
The post-thrombotic syndrome after upper extremity deep venous thrombosis in adults: a systematic review.
Thromb Res
2006
, vol. 
117
 
6
(pg. 
609
-
614
)
77
Frank
 
DA
Meuse
 
J
Hirsch
 
D
Ibrahim
 
JG
van den Abbeele
 
AD
The treatment and outcome of cancer patients with thromboses on central venous catheters.
J Thromb Thrombolysis
2000
, vol. 
10
 
3
(pg. 
271
-
275
)
78
Ogren
 
M
Bergqvist
 
D
Björck
 
M
Acosta
 
S
Eriksson
 
H
Sternby
 
NH
Portal vein thrombosis: prevalence, patient characteristics and lifetime risk: a population study based on 23,796 consecutive autopsies.
World J Gastroenterol
2006
, vol. 
12
 
13
(pg. 
2115
-
2119
)
79
Thatipelli
 
MR
McBane
 
RD
Hodge
 
DO
Wysokinski
 
WE
Survival and recurrence in patients with splanchnic vein thromboses.
Clin Gastroenterol Hepatol
2010
, vol. 
8
 
2
(pg. 
200
-
205
)
80
Ageno
 
W
Riva
 
N
Bang
 
S
, et al. 
Antithrombotic Treatment of Splanchnic Vein Thrombosis: Results of an International Registry.
 
In: Proceedings from the American Society of Hematology; December 8-11, 2012; Atlanta, GA. Abstract 499
81
Schulman
 
S
Crowther
 
MA
How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch.
Blood
2012
, vol. 
119
 
13
(pg. 
3016
-
3023
)
82
Bauersachs
 
R
Berkowitz
 
SD
Brenner
 
B
, et al. 
EINSTEIN Investigators
Oral rivaroxaban for symptomatic venous thromboembolism.
N Engl J Med
2010
, vol. 
363
 
26
(pg. 
2499
-
2510
)
83
Büller
 
HR
Prins
 
MH
Lensin
 
AW
, et al. 
EINSTEIN–PE Investigators
Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
N Engl J Med
2012
, vol. 
366
 
14
(pg. 
1287
-
1297
)
84
Schulman
 
S
Kearon
 
C
Kakkar
 
AK
, et al. 
RE-COVER Study Group
Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
N Engl J Med
2009
, vol. 
361
 
24
(pg. 
2342
-
2352
)
85
Schulman
 
S
Kearon
 
C
Kakkar
 
AK
, et al. 
RE-MEDY Trial Investigators; RE-SONATE Trial Investigators
Extended use of dabigatran, warfarin, or placebo in venous thromboembolism.
N Engl J Med
2013
, vol. 
368
 
8
(pg. 
709
-
718
)
86
Agnelli
 
G
Buller
 
HR
Cohen
 
A
, et al. 
 
Oral apixaban for the treatment of acute venous thromboembolism. [published online ahead of print July 1, 2013]. N Engl J Med
87
Agnelli
 
G
Buller
 
HR
Cohen
 
A
, et al. 
PLIFY-EXT Investigators
Apixaban for extended treatment of venous thromboembolism.
N Engl J Med
2013
, vol. 
368
 
8
(pg. 
699
-
708
)
88
Levine
 
MN
Gu
 
C
Liebman
 
HA
, et al. 
A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer.
J Thromb Haemost
2012
, vol. 
10
 
5
(pg. 
807
-
814
)