INTRODUCTION — Individuals with cancer are at risk for thrombotic complications due to a hypercoagulable state. The spectrum of hemostatic abnormalities ranges from abnormal coagulation tests in the absence of clinical manifestations, to massive or fatal thromboembolism. Thrombosis may precede the diagnosis of malignancy by months, or it may only occur during treatment or hospitalization. Individuals with cancer may also have a higher risk of bleeding with anticoagulation, making decisions about the use of prophylactic anticoagulants more challenging.
Here we discuss the risks of venous thromboembolism (VTE), which typically presents as deep vein thrombosis (DVT) and/or pulmonary embolism (PE), in adults with cancer, as well as the primary prevention of VTE in these individuals. The following are discussed in detail separately:
●Treatment and secondary prevention of VTE in adults with cancer – (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy" and "Catheter-related upper extremity venous thrombosis in adults" and "Multiple myeloma: Prevention of venous thromboembolism in patients receiving immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide)".)
●Prevention and treatment of thromboembolism in children with cancer – (See "Thromboembolism in children with cancer".)
●Evaluation for occult malignancy in patients with VTE – (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors", section on 'Evaluation for occult malignancy'.)
INCIDENCE AND RISK FACTORS — VTE is a common complication of malignancy. In most cases, thromboembolic events occur in the setting of a clinically evident malignancy [1,2]. However, some patients who present with VTE are only found to have a malignancy at the time the VTE occurs or months later. Despite the high frequency of VTE in individuals with cancer, it is important to remember that most individuals with cancer do not develop VTE.
Overall risk of VTE in individuals with cancer — Clinically apparent VTE occurs in as many as 10 percent of patients with cancer [3-7]. Autopsy series have described even higher rates of thrombosis for certain tumor types. One study, for example, found evidence of thrombosis in 30 percent of patients who died of pancreatic cancer; the incidence was over 50 percent in those with tumors in the body or tail of the pancreas [8].
The tumor type, location, stage, and time since diagnosis influence VTE risk, along with patient comorbidities and certain cancer therapies [9-15]. Our approach to estimating VTE risk distinguishes between individuals who are hospitalized or outpatient. Within those groups, risk is affected by the following factors:
●Tumor-specific factors – Tumor cells can express procoagulant activity that induces thrombin generation; in addition, the patient's non-cancerous tissues may express procoagulant activity in response to the tumor. Blood-borne tissue factor in microparticles may play a role in the pathogenesis of the hypercoagulable state accompanying cancer. (See "Cancer-associated hypercoagulable state: Causes and mechanisms".)
●Anatomic factors – Some tumors increase VTE risk by externally compressing or directly invading large vessels. As examples, renal cell carcinoma infiltrates the inferior vena cava in 5 to 9 percent of patients [16]; hepatocellular carcinoma can compress or invade the hepatic vein; and large mediastinal tumors or bulky axillary lymphadenopathy can compress upper extremity veins, leading to thrombosis. Large abdominal/pelvic tumors can compress major veins leading to deep venous thrombosis in the legs [17,18]. (See "Clinical manifestations, evaluation, and staging of renal cell carcinoma" and "Clinical features and diagnosis of hepatocellular carcinoma" and "Primary (spontaneous) upper extremity deep vein thrombosis".)
●Patient-specific factors – VTE risk is increased in patients with prior VTE, advanced age, obesity, and inherited thrombophilia [9,19-30]. In contrast, smoking does not appear to significantly increase risk.
●Therapy-associated factors – Some chemotherapy agents and high-risk surgeries (eg, large intraabdominal or pelvic procedures) increase VTE risk. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects" and "Cancer-associated hypercoagulable state: Causes and mechanisms", section on 'Therapy-related factors'.)
The overall risk of VTE per patient is greater in inpatients, but the vast majority of VTE events occur in outpatients (around 80 percent) because most patients with cancer are treated in the outpatient setting [31].
Inpatients (VTE risk) — An estimate of the magnitude of VTE risk in inpatients with cancer was obtained from a review of the records of eight million individuals in the United States over age 65 (patients receiving Medicare) who were admitted to a hospital between 1988 and 1990 [32]. Compared with those who did not have a malignancy, patients with a diagnosis of malignancy had a greater incidence of VTE during the initial hospitalization (0.60 versus 0.57 percent, a statistically significant difference). In this study, the malignancies with the highest rates of VTE were cancers of the ovary, brain, pancreas, and lymphoma [32]. Malignancies associated with the greatest absolute number of episodes of VTE were cancers of the lung, colon, and prostate, due to the relatively high frequency of these cancers in the population.
In a Danish cohort of 57,591 individuals hospitalized with cancer, the incidence rates of VTE were highest in individuals with cancer of the pancreas, brain, liver, multiple myeloma, and any form of advanced-stage cancer (incidence rates: 41, 18, 20, 23, and 28, respectively) [12].
Some cancer surgeries, especially large intraabdominal or pelvic procedures, are associated with a higher risk of VTE than other types of surgery (eg, mastectomy). This was demonstrated in a review of 43,808 cancer surgeries from a surgical database, which found that the risk of VTE was highest in patients undergoing esophagectomy, followed by cystectomy, pancreatectomy, gastrectomy, colectomy, lung cancer surgery, and hysterectomy [14].
The effect of patient comorbidities on postoperative VTE risk was demonstrated in a review of 43,808 patients undergoing cancer surgery [14]. The following factors were found to be significant predictors for the development of VTE on multivariate analysis:
●Increased age
●Recent steroid use
●Body mass index (BMI) ≥35 kg/m2
●Postoperative complications (eg, wound infection, reintubation, cardiac arrest, sepsis)
●Longer hospitalization (>1 week)
Additional risk factors for VTE following cancer surgery were illustrated in a review of 44,656 patients undergoing surgery for solid tumors [33]. The overall risk of VTE was 1.6 percent. The following findings were associated with increased risk of postoperative VTE:
●Age ≥65
●Metastatic disease
●Ascites
●Congestive failure
●BMI ≥25 kg/m2
●Platelet count >400,000/microL
●Serum albumin <3 g/dL
●Duration of surgery >2 hours
In this study, one-third of the VTE events occurred after hospital discharge, and 30-day mortality was more than six-fold higher in patients with VTE than in those without VTE (8.0 versus 1.2 percent, respectively). The high rates of VTE after hospital discharge and high VTE-associated mortality support a longer duration of postoperative anticoagulation in patients with cancer than that used for individuals without cancer. (See 'Surgical patients' below.)
Outpatients (VTE risk) — A number of studies suggest that the incidence of VTE is highest during the first year after a cancer diagnosis, during chemotherapy, and in those with advanced disease. As examples:
●In a Danish cohort study of 57,591 individuals with cancer, the incidence of VTE was highest within the first year after cancer diagnosis (incidence rate: 15.0 versus 8.6) [12].
●A study of 235,149 cancer cases from a United States cancer registry reported a diagnosis of VTE in 3775 (1.6 percent); 12 percent of VTE events occurred at the time of diagnosis [10]. Additional findings included the following:
•The incidence of VTE was higher during the first year of follow-up than the second year for virtually all types and stages of cancer
•Metastatic disease at the time of diagnosis was the strongest predictor for the development of VTE
•The diagnosis of VTE was a significant predictor for decreased survival during the first follow-up year for all cancer types (median overall relative risk: 3.7)
●In a study of 68,142 patients with colorectal cancer, the two-year cumulative incidence of VTE was 3.1 percent [11]. Events per 100 person-years during the first six months, second six months, and second year were 5.0, 1.4, and 0.6, respectively. Other findings included:
•Significant predictors of VTE included metastatic disease and the presence of three or more comorbid conditions
•In risk-adjusted models, VTE was a significant predictor of death within one year of cancer diagnosis among patients with local or regional disease, but not among those with metastatic disease
●In a retrospective study of 497,180 Taiwanese patients with cancer, VTE risk was over 10-fold higher than the reported incidence in the general Taiwanese population (185 versus 15.9 cases per 100,000 person-years, respectively) [34]. VTE risk was greater in those with prior history of VTE; multiple myeloma, prostate cancer, lung cancer, gynecologic cancer, sarcoma, or metastasis of unknown origin; and female sex in patients age 40 to 80 years. VTE risk was lower among patients >80 years, and those with head and neck, endocrine, esophageal, or breast cancer.
●The SAVE-ONCO trial, which randomized 3212 ambulatory outpatients with cancer to receive the ultra-low molecular weight heparin semuloparin versus no anticoagulation for VTE prophylaxis, used a post-hoc analysis to identify patient factors associated with VTE [35]. Implicated factors included a central venous catheter, obesity, age >75 years, chronic respiratory failure, chronic heart failure, venous insufficiency/varicose veins, and prior VTE. The incidence of VTE was 12.5 percent in those with ≥3 of these risk factors, and 2.5 percent in those with none of these features.
VTE risk also varies with the primary tumor type and is especially high with certain solid tumors such as pancreatic cancer and brain tumors, as discussed separately. (See "Cancer-associated hypercoagulable state: Causes and mechanisms".)
Certain agents used in cancer therapy have been associated with increased risks of venous and arterial thrombosis (eg, thalidomide, lenalidomide, tamoxifen, bevacizumab) [36]. These risks are discussed in detail separately. (See "Multiple myeloma: Prevention of venous thromboembolism in patients receiving immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide)" and "Cancer-associated hypercoagulable state: Causes and mechanisms", section on 'Therapy-related factors'.)
ASSOCIATION BETWEEN VTE AND MORTALITY — VTE is associated with increased morbidity and mortality in individuals with cancer in a variety of settings (eg, unresectable tumor, curative resection) [37-40]. Causality has not been demonstrated, however; and VTE may be a marker rather than an independent risk factor for early mortality. High-quality data to support an improvement in mortality with anticoagulation are lacking. (See 'Effects on survival' below.)
VTE-related deaths are especially common in those with exocrine pancreatic cancer. A systematic literature review of patients with pancreatic cancer reported VTE incidences from 5 to 36 percent, representing a 50-fold increase over the general population [40]. One of the studies reported on 1915 patients with pancreatic cancer treated with chemotherapy, in which 690 (36 percent) developed a VTE [41]. Development of VTE, especially within 1.5 months of diagnosis, conferred a greater likelihood of death (HR: 2.1; 95% CI 1.7-2.5).
Cancer-associated VTE is associated with a higher mortality than VTE in the population without cancer. This was shown in a review of eight million patients admitted to the hospital for VTE [32]. Those with concurrent malignancy had a 94 percent probability of death within six months, whereas those without cancer had a 29 percent probability of dying within the same time period.
Of note, arterial thrombosis can account for a substantial number of deaths in individuals undergoing chemotherapy. A review of 4466 ambulatory patients with cancer who were receiving chemotherapy reported that thrombosis was one of the three most common causes of death [42]. The majority of the deaths related to thromboembolic disease were due to arterial thrombosis (eg, myocardial infarction, stroke) rather than venous thromboembolism. Of the 141 deaths that occurred during chemotherapy administration (3.2 percent), the three leading causes of death were cancer progression (71 percent), infection (9 percent), and thromboembolic disease (9 percent total, 5.6 percent arterial, 3.5 percent venous).
PRIMARY PREVENTION
Overview of approach to prevention — The decision to use anticoagulation for primary prevention takes into account the risk of VTE as well as the risk of bleeding from anticoagulants, costs of medication, and mode of administration, which may negatively impact quality of life (eg, need for injections). Patients are generally stratified according to whether they are inpatients hospitalized for an acute medical illness or surgery, or ambulatory outpatients. Individuals with cancer represent a particularly high-risk group in all of these settings. However, the benefit of prophylactic anticoagulation is unclear in many subsets of patients [43,44].
●As a general rule, we use short-term anticoagulation during periods of high risk (eg, hospitalization for acute medical illness, those with reduced mobility, and/or following major surgery), similar to patients without cancer. We do not use anticoagulation for individuals admitted for minor procedures or chemotherapy administration. Low molecular weight (LMW) heparin, unfractionated heparin, or fondaparinux are all reasonable options. Direct oral anticoagulants (eg, rivaroxaban, apixaban) are options in patients undergoing major orthopedic surgery (eg, total hip or knee replacement). The choice among these agents depends on whether the patient is hospitalized or outpatient, cost, availability, and other patient-specific factors. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)
●Warfarin generally is not used as prophylactic anticoagulation of relatively brief duration (ie, days to a few weeks) in individuals with cancer, due to its delayed onset of antithrombotic action along with its requirement for dose adjustment based on international normalized ratio (INR) monitoring. Although the efficacy of LMW heparin is greater than warfarin for treatment of cancer-associated VTE, its benefit over warfarin has not been demonstrated in the prophylactic setting. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".)
●Mechanical prophylaxis is an option for hospitalized patients with cancer for whom the risk of bleeding is considered too high for anticoagulant use. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Mechanical methods of thromboprophylaxis'.)
●All individuals should have risk assessment for VTE and education regarding VTE risk. For ambulatory outpatients, anticoagulation has been reserved for those who have had a prior VTE and those with high-risk features. Two randomized trials evaluated the role of the direct oral anticoagulants (DOACs) apixaban and rivaroxaban for primary prevention of VTE in individuals with cancer and showed that these agents can significantly reduce the incidence of VTE in high-risk patients. These trials are discussed below. (See 'Outpatients (VTE prophylaxis)' below.)
●Management of anticoagulation in individuals who have concomitant thrombocytopenia is discussed separately. (See "Anticoagulation in individuals with thrombocytopenia".)
In contrast to primary prevention, anticoagulation for VTE treatment and secondary prevention is usually warranted, as discussed in detail separately. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy" and "Treatment and prevention of venous thromboembolism in patients with brain tumors".)
A number of studies have evaluated the use of statins to decrease the risk of VTE in healthy adults, individuals with atherosclerosis, and others with mixed results. The effect of statins on reduction of VTE risk in patients with cancer was evaluated in a retrospective, case-control study of 740 consecutive patients with a diagnosis of a solid tumor followed for an average of 10.2 months (range: 2 to 41 months) [45]. Multivariate analysis indicated that statin use was associated with a significant reduction in the risk of VTE (OR 0.33; 95% CI 0.18-0.59). Routine use of statins to prevent VTE is premature, pending further data from prospective trials. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Effect of statin or aspirin on risk'.)
Inpatients (VTE prophylaxis)
Hospitalized medical patients — Patients hospitalized with an acute medical illness are at high risk for the development of VTE that is further increased by the presence of malignancy [46-48]. Anticoagulant prophylaxis has been shown to reduce the risk of VTE in medical patients, but an effect on mortality has not been demonstrated. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)
The efficacy of thromboprophylaxis in the subset of hospitalized medical patients with cancer was evaluated in a systematic review of randomized trials that compared anticoagulation (LMW heparin or fondaparinux) with no anticoagulation [43]. For the 307 patients in these trials with cancer, there was not a significantly reduced risk of VTE, and the pooled relative risk with anticoagulation was 0.91 (95% CI 0.21-4.0). However, this was a relatively small cohort in a subset analysis. It is possible that hospitalized patients with active cancer require higher anticoagulant doses with these agents than non-cancer patients to provide a similar reduction in VTE rates.
The optimal duration of thromboprophylaxis was evaluated in a meta-analysis of 3655 patients with cancer (active or in the past) participating in one of four randomized trials (EXCLAIM, MAGELLAN, APEX, and MARINER) that compared extended-duration versus standard-duration thromboprophylaxis during hospitalization [49]. Pooled analysis revealed that extended prophylaxis did not provide a statistically significant reduction in VTE risk relative to standard-duration thromboprophylaxis (odds ratio [OR], 0.85; 95% CI 0.61-1.18). The rate of clinically relevant bleeding was twofold higher in the extended duration group (OR, 2.11; 95% CI 1.33-3.35); clinically relevant bleeding was defined as major bleeding and clinically relevant non-major bleeding based on International Society of Thrombosis and Haemostasis (ISTH) criteria [50]. The increase in clinically relevant bleeding was mainly driven by data from MAGELLAN participants. A limitation of this meta-analysis was that the majority of patients in the trials had a history of cancer; the number with active cancer was relatively small.
Our general practice is as follows:
●For hospitalized patients with cancer and reduced mobility, we suggest pharmacologic thromboprophylaxis using an anticoagulant rather than mechanical prophylaxis or no anticoagulation, as long as there are no contraindications (eg, recent surgery, bleeding diathesis, platelet count <50,000/microL) [51-53]. (See 'Contraindications to anticoagulation' below.)
This is based on extrapolation from studies of hospitalized medical patients in the general population, which included patients with cancer. These studies have uniformly found a benefit from LMW heparin or fondaparinux in VTE prevention for hospitalized patients at high VTE risk. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)
Doses of these agents are presented in the table (table 1).
●Hospitalized cancer patients without immobility may also benefit from pharmacologic thromboprophylaxis based on their increased VTE risk due to malignancy alone, if there is no active bleeding or contraindications to anticoagulant use. Individual patient bleeding and thromboembolic risks may be helpful in determining the appropriateness of anticoagulation in this setting.
●Mechanical thromboprophylaxis can be used in those who cannot receive anticoagulants due to increased bleeding risk or other concerns. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Mechanical methods of thromboprophylaxis'.)
●For most patients with cancer admitted for minor procedures or short chemotherapy infusion, there are insufficient data to support routine thromboprophylaxis.
●Individuals with acute lymphoblastic leukemia (ALL) are at especially high risk of VTE during treatment with L-asparaginase, which causes antithrombin deficiency. Recommendations are provided separately. (See "Antithrombin deficiency", section on 'Patients receiving asparaginase'.)
●We generally use standard-duration thromboprophylaxis, unless there are extenuating circumstances (eg, individual with active cancer who has a prior history of VTE and low risk of bleeding; such an individual might receive full therapeutic-dose, rather than prophylactic-dose, anticoagulation).
Our practice is consistent with guidelines published by the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and an international consensus group. (See 'Recommendations from guidelines' below.)
For patients with cancer who are hospitalized with an acute medical illness and require thromboprophylaxis, we suggest LMW heparin rather than a DOAC due to the lower risk of bleeding with LMW heparin. This lower risk has been demonstrated in large randomized trials such as MAGELLAN (rivaroxaban at prophylactic dosing [10 mg daily] versus the LMW heparin enoxaparin for 35 days in hospitalized patients with an acute medical illness), in which the risk of bleeding was approximately twofold greater with rivaroxaban (2.8 versus 1.2 percent); 7 percent of patients in this trial had active cancer [54]. The ADOPT trial (apixaban versus enoxaparin for 30 days in acutely ill medical patients) also found increased bleeding with apixaban compared with LMW heparin, although bleeding incidence for both groups was <0.5 percent; 3 percent of patients in this trial had active cancer [55]. As noted above, a meta-analysis of trials comparing LMW heparin versus placebo in patients with cancer found a trend towards increased risk of major bleeding that did not reach statistical significance (relative risk, 1.30; 95% CI 0.94-1.79) [56]. Further details regarding these trials are presented separately. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Duration of prophylaxis'.)
Additional aspects of VTE prevention in hospitalized medical patients (eg, dosing, timing of initiation) are discussed separately. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)
Surgical patients — Postoperative VTE is more frequent in patients with known cancer than in the general population, occurring in as many as 40 percent of patients in clinical trials employing venography for diagnosis [46,57-60]. As a result, individuals with cancer should be considered high risk for development of postoperative VTE. This increased risk is reflected in the Caprini score for VTE in surgical patients, which assigns two points for the presence of malignancy (table 2).
●For most patients with cancer undergoing surgery, we recommend perioperative VTE prophylaxis using an anticoagulant rather than mechanical prophylaxis or no prophylaxis. This is largely extrapolated from trials that evaluated surgical patients without cancer, for whom the risk of perioperative VTE and the benefit of prophylactic anticoagulation, for both VTE prevention and reduction of mortality, are well studied. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)
●Exceptions include those undergoing minor procedures (eg, central venous catheter placement), who may not require anticoagulation, and those with a contraindication, who should receive mechanical thromboprophylaxis. (See 'Contraindications to anticoagulation' below.)
●Commonly used agents for surgical VTE prophylaxis in patients with cancer include LMW heparin, unfractionated heparin, and fondaparinux. Direct oral anticoagulants are under study and may be appropriate in some cases. Decisions among these agents may be guided by individual patient factors (eg, renal function, ability to give self-injections). (See "Heparin and LMW heparin: Dosing and adverse effects" and "Fondaparinux: Dosing and adverse effects" and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)
Similar efficacy of these agents in perioperative VTE prevention in patients with cancer was reported in a meta-analysis of 16 randomized trials (12,890 patients) [61]. Similar risks were seen for the following outcomes with LMW versus unfractionated heparin:
•Mortality (risk ratio [RR] 0.89; 95% CI 0.74-1.08)
•Pulmonary embolism (RR 0.73; 95% CI 0.34-1.54)
•Symptomatic deep vein thrombosis (RR 0.50; 95% CI 0.20-1.28)
•Major bleeding (RR 0.85; 95% CI 0.52-1.37)
Doses of these agents are shown in the table (table 1).
●The optimal duration of postoperative anticoagulation in patients with cancer is unknown, but it is likely to be longer than that for patients without cancer. We generally initiate anticoagulation approximately 12 hours postoperatively and continue it for 10 to 14 days. Four weeks may be reasonable in those undergoing extensive abdominal or pelvic surgery [62]. Some clinicians, especially in European countries, will initiate prophylactic anticoagulation the day before surgery rather than postoperatively. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients", section on 'Timing of initiation'.)
The benefit of a longer duration of postoperative anticoagulation than typically used for individuals without cancer was shown in three separate trials that randomized patients undergoing major cancer surgery to one week versus four weeks of a LMW heparin (1247 patients total) [63-65]. These trials all showed a significant reduction in the incidence of VTE after four weeks of anticoagulation compared with one week (5 versus 12, 7 versus 16, and 13 versus 10 percent). None of the trials showed increased bleeding in the prolonged anticoagulation group.
Experience with DOACs in patients undergoing cancer surgery is limited. In one trial involving 400 women undergoing surgery for gynecologic cancers, apixaban and enoxaparin were associated with similar efficacy in VTE prevention and similarly low bleeding rates [66]. A DOAC may be used for prophylaxis in cancer patients undergoing orthopedic surgery.
Our practice is consistent with guidelines published by the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and an international consensus group. (See 'Recommendations from guidelines' below.)
Additional aspects of perioperative anticoagulation are discussed separately. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)
Outpatients (VTE prophylaxis)
VTE risk assessment/Khorana score — Several scores for predicting the risk of VTE in ambulatory outpatients with cancer have been developed [34,67-75]. Among these, the Khorana score, introduced in 2008, has been validated in large cohorts of patients with a variety of malignancies who are undergoing chemotherapy [67]. We prefer the Khorana score over other scoring systems for estimating VTE risk.
The Khorana score is calculated by assigning points for clinical parameters available for most patients (ie, site of primary tumor, hematologic parameters, and body mass index) (calculator 1). These parameters are summarized in the table (table 3). It was derived in a cohort of 2701 patients with cancer undergoing chemotherapy and validated in an independent cohort of 1365 patients [67]. Patients were stratified into three risk groups to predict the development of VTE. The cumulative incidence of VTE at 2.5 months ranged from 0.3 percent to 6.7 percent in patients with the fewest and most risk factors, respectively.
Most studies of the Khorana score evaluate the performance of the score over six months of observation, which often corresponds with the duration of chemotherapy. Evidence for the predictive value of the score in various cancer populations includes the following:
●The score was evaluated in a meta-analysis that determined VTE risk in nearly 35,000 ambulatory cancer patients who were followed for six months; most were retrospective analyses that included a number of tumor types [76]. The majority of patients had a Khorana score of 1 or 2 (64 percent); the score was 0 in 19 percent and 3 or greater in 17 percent. Six-month VTE risk correlated with the score: those with a score of 0 had a risk of 5 percent; those with a score of 1 or 2 had a risk of 6.6 percent; and those with a score of 3 or greater had a risk of 11 percent. Because most of the patients had a score of 1 or 2, this group accounted for most of the events. The VTE risk for individuals with a score of 2 or greater (the criterion used in the AVERT and CASSINI trials (see 'Evidence from clinical trials' below)) was 8.9 percent. The authors noted that there is debate about whether this risk of 9 percent justifies thromboprophylaxis.
●The Khorana score was also validated in an independent study of 1415 patients with advanced malignancy enrolled in phase I chemotherapy trials, and a modified version of the score was used in an observational cohort study (the Vienna Cancer and Thrombosis Study) [77,78]. The modified score included additional high risk tumor types (brain, myeloma, kidney) and two additional laboratory values (soluble P-selectin and D-dimer levels). In a retrospective analysis, the cumulative incidence rates of VTE at six months were 1 percent for the lowest risk group (0 points) and 35 percent for the highest risk group (≥5 points).
Additional studies of individuals with cancer have confirmed a higher incidence of VTE in those with abnormal coagulation studies, including elevated D-dimer levels, peak thrombin generation, prothrombin fragment 1+2, tissue factor, and fibrinogen [68,69,79,80].
Whom to anticoagulate — Evidence from randomized trials has demonstrated that anticoagulation with direct factor Xa inhibitors or LMW heparin can reduce VTE risk in outpatients (see 'Evidence from clinical trials' below). At the same time, anticoagulation likely increases the risk of bleeding. Thus, the decision to use prophylactic anticoagulation is generally individualized according to the specific thrombotic and bleeding risks for the individual patient, along with the relative values placed on avoiding thrombosis and avoiding bleeding.
Until the trials with direct factor Xa inhibitors were available, guidelines published by the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), and an international consensus group did not recommend routine VTE prophylaxis in ambulatory patients with cancer, except for those at very high risk of VTE (eg, multiple myeloma receiving thalidomide or lenalidomide plus chemotherapy or dexamethasone). Based on the results of the AVERT and CASSINI trials (see 'Evidence from clinical trials' below), updated guidelines from 2019 state that anticoagulation (apixaban, rivaroxaban, or low molecular weight heparin) may be offered to outpatients with a Khorana score of 2 or higher who are starting a new chemotherapy regimen, as long as there are no significant risk factors for bleeding or drug interactions. (See 'Recommendations from guidelines' below.)
Other considerations include the associated risks and burdens of continuing anticoagulation when the optimal duration is not well established (table 4).
For most individuals at relatively low risk of VTE (eg, Khorana score <2), we suggest not using anticoagulation for primary VTE prophylaxis; however, secondary prophylaxis may be considered for selected patients such as those with a prior history of a major venous thromboembolic event if they are not chronically maintained on anticoagulation.
We are most likely to suggest anticoagulation for primary VTE prophylaxis in individuals at especially high VTE risk, as they are likely to have a greater absolute risk reduction. Examples include the following:
●Individuals with multiple myeloma or non-Hodgkin lymphoma treated with an immunomodulatory drug (IMiD; eg, thalidomide or lenalidomide)-containing regimen [81]. Arterial events (eg, stroke, myocardial infarction) are also increased in this population. The need for prophylaxis and the choice of agent depends on the patient's risk stratification. This issue is discussed in detail separately. (See "Multiple myeloma: Prevention of venous thromboembolism in patients receiving immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide)".)
●Selected ambulatory patients with a Khorana score ≥3, or individuals with a Khorana score of 2 who place a higher value on avoiding VTE than on avoiding bleeding. In a meta-analysis of randomized trials that included over 4000 patients, the number needed to treat (NNT) to prevent a VTE declined as the Khorana score increased [82]:
•Khorana score of 2 – 34 patients needed to treat to prevent VTE (95% CI 23-84)
•Khorana score of ≥3 – 17 patients needed to treat (95% CI 13-28)
The Khorana score is well validated and easy to calculate based on available clinical information (table 3). Many of these patients will have high-risk malignancies such as pancreatic cancer. (See "Supportive care of the patient with locally advanced or metastatic exocrine pancreatic cancer", section on 'Venous thromboembolism'.)
●Some individuals with a prior history of unprovoked VTE unrelated to their tumor who are not already on chronic anticoagulation. Prior VTE is not included in the Khorana score. Decisions for these patients should be individualized to reflect the relative risks and benefits of anticoagulation, and the values and preferences of the patient.
Choice of agent and dose — When anticoagulation is used in these individuals, a direct factor Xa inhibitor such as apixaban or rivaroxaban or a LMW heparin may be selected. A prophylactic dose level should be used. Patients should be aware that their baseline bleeding risk may be higher than the general population (table 5), and that anticoagulation may further increase this risk, as discussed below. (See 'Evidence from clinical trials' below.)
Evidence from clinical trials — Data on the reduction of VTE risk with anticoagulants in ambulatory individuals with cancer are available from randomized trials that have compared LMW heparins with placebo and direct factor Xa inhibitors with placebo. Trials comparing LMW heparin with a factor Xa inhibitor or different factor Xa inhibitors with each other are not available. Overall, most trials have shown a reduction of symptomatic VTE with anticoagulation. As expected, the absolute risk reduction is greatest in those with the highest baseline VTE risk [82,83].
●Apixaban or rivaroxaban in patients with a Khorana score ≥2 receiving chemotherapy (AVERT and CASSINI trials) – Two trials published in 2019 addressed the use of a direct factor Xa inhibitor in patients with a Khorana score ≥2 who were receiving chemotherapy. As noted above, the Khorana score assigns 2 points for pancreatic and gastric cancers; 1 point for several other high-risk tumors; and 1 point each for high white blood cell count, high platelet count, high body mass index, and low hemoglobin (table 3). The baseline risk of VTE correlates with the score; a score of 2 has been reported to be associated with a risk of VTE of approximately 10 percent over six months and a score of 3 with a risk of 18 percent over six months. (See 'VTE risk assessment/Khorana score' above.)
•The AVERT trial randomly assigned 574 ambulatory individuals with cancer who had Khorana score ≥2 and were starting chemotherapy to receive the direct factor Xa inhibitor apixaban at prophylactic dose (2.5 mg twice daily) or placebo for 180 days [84]. Compared with placebo, apixaban resulted in a 6 percent absolute risk reduction in VTE (from 10.2 percent with placebo to 4.2 percent with apixaban in a modified intention-to-treat analysis [number needed to treat 17]; hazard ratio [HR] 0.41; 95% CI 0.26-0.65; adjusted odds ratio [OR] 0.39; 95% CI 0.20-0.76). VTE events included one fatal pulmonary embolism in the placebo group. Apixaban was also associated with an increase in major bleeding (3.5 percent, versus 1.8 percent with placebo [number needed to harm 59]; absolute difference, 1.7 percent; HR 2.0; 95% CI 1.01-3.95). Most of the bleeding events were gastrointestinal, urinary, or gynecologic, and there was no fatal bleeding. However, the major bleed rate was not significantly higher during the treatment period (2.1 percent with apixaban and 1.1 percent with placebo, respectively [HR 1.89; 95% CI 0.39-9.24, number needed to harm 100]). Approximately one-fourth to one-fifth of patients in both arms were receiving an anti-platelet agent and one-fourth had gynecologic tumors. There were no other major treatment-related adverse events. Mortality was 12 percent with apixaban and 10 percent with placebo; most deaths were associated with cancer progression.
•The CASSINI trial randomly assigned 841 individuals with cancer who had a Khorana score ≥2 who were starting chemotherapy to receive rivaroxaban (10 mg once daily) or placebo for 180 days [85]. Unlike the AVERT trial, in CASSINI, all participants underwent baseline screening with bilateral leg duplex compression ultrasonography. Compared with placebo, rivaroxaban resulted in a 2.8 percent absolute risk reduction in VTE (from 8.8 percent with placebo to 6 percent with rivaroxaban; HR 0.66; 95% CI 0.40-1.09) in the intention-to-treat analysis. Many of the thrombotic events, however, occurred when patients were off anticoagulation. In the pre-specified intervention period analysis, VTE occurred in 2.6 percent in the rivaroxaban group and 6.4 percent in the placebo group (HR 0.40; 95% CI 0.20-0.80). Arterial thromboembolism occurred in 1.7 percent of placebo-treated patients and 1 percent of rivaroxaban-treated patients. Rivaroxaban was associated with an increase in major bleeding that did not reach statistical significance (2.0 percent, versus 1 percent with placebo; HR 1.96; 95% CI 0.59-6.49) and a reduction in mortality that barely reached significance (29.5 versus 23.1 percent; HR 0.75; 95% CI 0.57-0.97). There was one fatal bleeding event in the rivaroxaban group.
Taken together, data from these trials are consistent with the expected baseline risks of VTE and bleeding in this population and suggest that the absolute difference in VTE risk between the anticoagulant and placebo groups was 4 to 6 percentage points; the number needed to treat in the intention-to-treat analysis was 24; and the number needed to harm with major bleeding was 77 [86]. An editorialist noted some potential concerns with extrapolating these data to the general population, such as that the score does not take into account the specific chemotherapy regimen, most common types of cancer (colorectal, breast, prostate) were underrepresented in these trials, and the proportion of patients who completed the entire anticoagulant regimen was low, leading to significant equipoise regarding the implications for practice [86]. The absolute benefit is expected to be greater in those with a Khorana score of 3 rather than 2.
These data contribute to our decision not to use prophylactic anticoagulation in individuals with a low baseline risk of VTE (Khorana score <2) and to be most likely to recommend anticoagulation in those with the highest baseline risk, as these individuals are likely to receive the greatest absolute benefit. (See 'Whom to anticoagulate' above.)
●LMW heparin in patients with solid tumors – The absolute VTE risk reduction was summarized in a 2017 Cochrane review of trials involving parenteral anticoagulation in ambulatory patients with cancer, which found a reduction in symptomatic VTE (relative risk [RR], 0.56; 95% CI 0.47-0.68) and an increase in major bleeding that did not reach statistical significance (RR 1.30; 95% CI 0.94-1.79) [56].
The following trials illustrate typical findings when comparing LMW heparin with placebo in individuals with cancer who were not preselected for a high baseline VTE risk:
•PROTECHT – The Prophylaxis of Thromboembolism during Chemotherapy (PROTECHT) trial randomly assigned 1150 patients with metastatic or locally advanced cancer to the LMW heparin nadroparin versus placebo for VTE prevention [87]. Patients had lung, breast, gastrointestinal, ovarian, or head and neck cancer; an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 (table 6); and were receiving active chemotherapy. Nadroparin (3800 anti-Xa international units subcutaneously once daily) or placebo was given for the duration of chemotherapy, up to a maximum of four months. Compared with placebo, patients receiving nadroparin had a lower incidence of symptomatic venous and arterial thromboembolic events (3.9 percent with placebo versus 2.0 percent with nadroparin). The risk of bleeding was similar between groups (major bleeding, 0 versus 0.7 percent).Thromboembolic rates in the control group were highest in those with cancers of the lung (8.8 percent) and pancreas (5.9 percent).
•SAVE-ONCO – The SAVE-ONCO trial randomly assigned 3212 patients with metastatic or locally advanced solid tumors who were beginning a course of chemotherapy to the ultra-LMW heparin semuloparin (20 mg once daily) versus placebo during chemotherapy [35]. Compared with placebo, those receiving semuloparin had a lower risk of symptomatic VTE (3.4 with placebo versus 1.2 percent with semuloparin; HR 0.36; 95% CI 0.21-0.60). The incidence of major bleeding was similar (1.1 versus 1.2 percent), as was clinically relevant non-major bleeding (2.0 versus 2.8 percent). Survival was similar between the groups at approximately 44 percent. Semuloparin was not approved by the US Food and Drug Administration, and production was halted.
●LMW heparin in pancreatic cancer – In patients with pancreatic cancer, randomized trials comparing LMW heparin with placebo (eg, PROSPECT, FRAGEM) have shown greater reductions in the incidence of VTE than in other solid tumors, without increased bleeding or a difference in survival. Recommendations for VTE prophylaxis in patients with pancreatic cancer are presented separately. (See "Supportive care of the patient with locally advanced or metastatic exocrine pancreatic cancer", section on 'Venous thromboembolism'.)
Central venous catheter — Although the presence of a central venous catheter is a risk factor for VTE in individuals with cancer, there is no evidence to support the routine use of VTE prophylaxis to prevent central venous catheter thrombosis. This issue is discussed separately. (See "Catheter-related upper extremity venous thrombosis in adults", section on 'Thrombosis prevention'.)
Recommendations from guidelines — Guidelines for VTE prophylaxis in patients with cancer have been published by several groups (see 'Society guideline links' below). These are mostly consistent with our practice, and with each other, in recommending VTE prophylaxis in hospitalized medical patients, especially those with an acute illness or immobility; perioperative VTE prophylaxis, especially for major abdominal or pelvic surgery; and no prophylaxis for ambulatory outpatients, with the exception of a high-risk subgroup that includes patients with multiple myeloma receiving combination therapy that includes a thalidomide analog, and possibly others (eg, those with advanced pancreatic or lung cancer receiving chemotherapy, those with Khorana scores ≥3) (table 3). With the availability of effective oral anticoagulants such as direct factor Xa inhibitors, there has been a trend towards expanding the possible indications for anticoagulation to selected individuals with a Khorana score of ≥2.
Three cancer-specific guidelines include the following:
●American Society of Clinical Oncology (ASCO) – Updated guidelines were published 2019; these recommend expanding the use of VTE prophylaxis in outpatients to include selected individuals with a Khorana score of 2 or higher [88]. Previous versions had suggested anticoagulation for those with a Khorana score of 3 or higher [51,89].
●National Comprehensive Cancer Network (NCCN) – Updated guidelines were published in 2019; these do not recommend routine VTE prophylaxis in outpatients, with the exception of high-risk multiple myeloma [90,91].
●International consensus working group – Updated guidelines were published in 2019; these do not specifically address outpatients [92]. A previous guideline from this group had recommended prophylactic anticoagulation for those with acute lymphoblastic leukemia receiving L-asparaginase [93].
VTE TREATMENT AND SECONDARY PREVENTION — The use of anticoagulation for VTE treatment and secondary VTE prevention (ie, prevention of VTE recurrence) in patients with cancer is discussed in detail separately. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".)
CONTRAINDICATIONS TO ANTICOAGULATION — Patients with malignancy may have tumor-specific factors that lead to an unacceptably high bleeding risk with anticoagulation (table 7). These include active major bleeding, severe uncompensated coagulopathy, thrombocytopenia or severe platelet dysfunction, uncontrolled hypertension, and recent or planned surgery or invasive procedure (eg, lumbar puncture, spinal or epidural anesthesia) [51].
Possible relative contraindications to anticoagulation include intracranial or spinal lesions, active gastrointestinal ulceration, or recent severe bleeding (table 7). The presence of an intracranial or spinal tumor alone is not an absolute contraindication to anticoagulation, although many experts would avoid anticoagulation in the presence of central nervous system tumors at high risk of bleeding (eg, associated with a platelet count <50,000/microL or in patients expected develop this degree of thrombocytopenia from cancer therapy) [94,95]. The approach to anticoagulation in individuals with platelet counts <50,000/microL may include temporarily holding anticoagulation or using a lower dose of the anticoagulant, as discussed separately. (See "Anticoagulation in individuals with thrombocytopenia".)
Mechanical methods may be used for individuals who require thromboprophylaxis but cannot receive an anticoagulant. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Mechanical methods of thromboprophylaxis'.)
EFFECTS ON SURVIVAL — In addition to preventing VTE, some people wonder if anticoagulation could potentially prolong survival through another mechanism (eg, through a direct anti-tumor effect). Available data are mixed. However, evidence from clinical trials does not support the use of anticoagulation to prolong survival through a direct anti-tumor effect in the absence of another indication:
●LMW heparin – Several meta-analyses of randomized trials comparing low molecular weight (LMW) heparin with placebo have not found any improvement (or reduction) in survival [56,96-98]. Individual trials of extended anticoagulation with LMW heparin postoperatively also have not shown a survival benefit [99].
●Oral anticoagulants – Cochrane reviews from 2017 and 2014 (mostly evaluating warfarin versus no warfarin) and randomized trials from 2019 comparing direct factor Xa inhibitors versus placebo have not found any survival benefit with oral anticoagulants [84,100,101]. A study that evaluated DOACs in an animal model did not show any effect on tumor growth [102].
In the absence of consistent data indicating a survival benefit, we agree with guidelines that recommended against the use of anticoagulants for the purpose of improving survival in patients with cancer who do not have VTE. (See 'Recommendations from guidelines' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation".)
SUMMARY AND RECOMMENDATIONS
●VTE risk in people with cancer – Clinical venous thromboembolism (VTE) occurs in as many as 10 percent of patients with cancer and is associated with increased mortality. Risk factors include hospitalization, surgery, and with tumor-, patient-, and therapy-specific factors. (See 'Incidence and risk factors' above and 'Association between VTE and mortality' above.)
●VTE prophylaxis in inpatients – For most hospitalized medical patients with cancer and reduced mobility who do not have an increased bleeding risk, we suggest pharmacologic thromboprophylaxis rather than no anticoagulation (Grade 2B). (See 'Hospitalized medical patients' above.)
For patients with cancer undergoing surgery, we recommend perioperative VTE prophylaxis using an anticoagulant rather than no prophylaxis (Grade 1B). (See 'Surgical patients' above and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)
Commonly used agents for VTE prophylaxis in hospitalized patients with cancer include low molecular weight (LMW) heparin, unfractionated heparin, and fondaparinux; the choice among these agents depends on patient-specific factors. Doses of these agents are shown in the table (table 1). Warfarin generally is not used for brief-duration anticoagulation due to its delayed onset of antithrombotic action and requirement for dose adjustment. We generally do not use the direct oral anticoagulants (DOACs; eg, direct thrombin inhibitors or direct factor Xa inhibitors), as they are associated with a greater risk of bleeding than heparins. An exception is patients who are already receiving these agents when admitted to the hospital.
When indicated, anticoagulation for VTE prophylaxis is generally considered safe if the platelet count is ≥50,000/microL, its use is individualized for those with counts between 25,000 and 50,000/microL, and it is generally not used for those with platelet counts <25,000/microL, as discussed in more detail separately. (See "Anticoagulation in individuals with thrombocytopenia".)
VTE prophylaxis in individuals receiving asparaginase is presented separately. (See "Antithrombin deficiency", section on 'Patients receiving asparaginase'.)
●VTE prophylaxis in outpatients – Evidence regarding the role of anticoagulation for primary prevention of VTE in outpatients with cancer is evolving. Anticoagulation has consistently been demonstrated to reduce VTE risk in randomized trials, with the absolute risk reduction dependent on the baseline risk of VTE. Bleeding risk is increased by anticoagulation. Thus, the decision to use prophylactic anticoagulation is individualized according to the patient's baseline risks of thrombosis and bleeding and the relative value they place on avoiding these risks. VTE risk assessment can be quantified using the Khorana score (calculator 1); parameters and associated VTE risk are summarized in the table (table 3). (See 'Outpatients (VTE prophylaxis)' above.)
For most individuals with cancer, we suggest not using anticoagulation for primary prophylaxis (Grade 2B).
However, individuals with a higher baseline risk (eg, Khorana score ≥3, or Khorana score ≥2 with a high value placed on avoiding VTE) may reasonably choose anticoagulation, using either a direct factor Xa inhibitor such as apixaban or rivaroxaban or a LMW heparin, at prophylactic doses. They should be aware that their baseline bleeding risk may also be increased and anticoagulation may further increase this risk (table 5). Other caveats of which to be aware are summarized in the table (table 4).
Management of selected populations with a very high baseline risk of VTE (eg, multiple myeloma receiving an immunomodulatory drug, pancreatic cancer, prior VTE) is discussed in detail separately. (See "Multiple myeloma: Prevention of venous thromboembolism in patients receiving immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide)", section on 'VTE prophylaxis' and "Supportive care of the patient with locally advanced or metastatic exocrine pancreatic cancer", section on 'Prophylaxis'.)
●VTE treatment – VTE treatment and secondary VTE prevention in patients with cancer (ie, prevention of recurrence in individuals who have already had a VTE event) are discussed separately. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".)
●Effect of anticoagulation on survival – The use of anticoagulation to prolong survival in the absence of another indication is not supported by available data. (See 'Effects on survival' above.)
