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Treatment of venous thromboembolism in patients with malignancy
Author:Kenneth A Bauer, MD
Section Editors:Lawrence LK Leung, MD, Jess Mandel, MD
Deputy Editor:Geraldine Finlay, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2018. | This topic last updated: Sep 20, 2018.
INTRODUCTION — The close relationship between malignancy and venous thromboembolism (VTE) is
well established. Patients with malignancy are in a hypercoagulable state and are more likely to develop
VTE during the course of their illness compared to those without malignancy. Thrombotic events are the
second leading cause of death in cancer patients after death from cancer itself.
The treatment of VTE (deep venous thrombosis and pulmonary embolism) in patients with malignancy
will be discussed here. The treatment of VTE in patients without malignancy, the pathogenesis and
epidemiology, and prevention of VTE in patients with malignancy are discussed separately. (See "Risk
and prevention of venous thromboembolism in adults with cancer", section on 'Prevention of VTE in
patients with cancer' and "Overview of the causes of venous thrombosis", section on 'Malignancy' and
"Overview of the treatment of lower extremity deep vein thrombosis (DVT)" and "Venous
thromboembolism: Initiation of anticoagulation (first 10 days)".)
ANTICOAGULATION THERAPY — The indications and contraindications to treatment of acute venous
thromboembolism (VTE) in patients with cancer are the same for patients without cancer. The goal of
therapy is to prevent recurrence, extension, and embolism while minimizing the risk of bleeding.
However, treatment of VTE in cancer is complicated due to higher than usual rates of recurrent VTE as
well as a higher risk of bleeding with anticoagulation treatment (table 1) [1-8].
In general, the same options for initial (immediate) anticoagulation (low molecular weight [LMW] heparin
and unfractionated heparin [UFH]) and long-term anticoagulation (LMW heparin, vitamin K antagonists
[VKAs], and direct oral anticoagulants [rivaroxaban, apixaban, edoxaban, dabigatran]) are similar for
patients with cancer and without cancer. Provided renal function is normal (creatinine clearance >30
mL/min), LMW heparin is preferred over UFH for initial therapy (up to 10 days); and LMW heparin is
preferred over VKAs (warfarin) or direct oral anticoagulants for long-term anticoagulation (at minimum
three months) beyond the initial period. (See 'Initial therapy' below and 'Long term therapy' below.)
Evidence-based society guidelines have been issued in 2012 and 2016 by the American College of Chest
Physicians (ACCP) and in 2013 by the American Society of Clinical Oncology (ASCO) and the National
Comprehensive Cancer Network (NCCN), for the management of acute VTE in patients with cancer [9-®

1/8/2019 Treatment of venous thromboembolism in patients with malignancy – UpT oDate
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[13-15].
Indications — Anticoagulant therapy is warranted in all cancer patients with new or recurrent VTE.
Untreated pulmonary embolism is associated with a mortality of 30 percent, usually due to recurrent
embolism. If left untreated, symptomatic deep venous thrombosis carries a 50 percent risk of pulmonary
embolism. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on
'Proximal DVT' and "Overview of acute pulmonary embolism in adults", section on 'Prognosis'.)
It is unknown whether the same risk of death or recurrence applies to pulmonary embolism (PE) found
incidentally on imaging during staging. One retrospective review of 59 patients with unsuspected PE
discovered during routine staging for cancer, reported a high rate of symptoms consistent with PE (75
percent of cases) in this population [16]. Despite the lack of data, we generally consider incidental PE as
an indication for anticoagulation. This preference is based upon the higher than usual risk of recurrence
as well as the high incidence of what appears to be symptomatic PE in cancer patients, when it is
diagnosed incidentally.
The potential benefits of anticoagulation should always be weighed against the risks, especially in those
with high risk of bleeding or with limited life expectancy. As for patients without cancer, the best
anticoagulant is one that can most effectively prevent VTE recurrence while minimizing bleeding risk.
(See 'Initial therapy' below and 'Long term therapy' below and 'Extended therapy' below.)
Contraindications — Anticoagulation for VTE should generally be avoided if there is active bleeding
and/or there are other contraindications to anticoagulant use (eg, recent surgery, coagulopathy) [10,12].
Thrombocytopenia is not a contraindication to anticoagulation, especially for individuals with platelet
counts >50,000/microL. For many individuals with cancer and acute VTE who have platelet counts below
50,000/microL, the risk of serious complications of VTE may be worse than the risk of bleeding
associated with anticoagulation, especially when anticoagulant dose modifications or platelet transfusions
are used. This subject is discussed in more detail separately. (See "Anticoagulation in individuals with
thrombocytopenia", section on 'Cancer-associated VTE'.)
When anticoagulation is absolutely contraindicated, one treatment option is the insertion of an inferior
vena cava filter. (See 'Inferior vena cava filter' below and "Placement of vena cava filters and their
complications".)
Bleeding complications — Treatment of VTE with anticoagulation, though effective in patients with
cancer, is fraught with higher morbidity, from bleeding (and recurrent VTE) despite anticoagulation [1-8].
Compared to patients without malignancy, patients with malignancy have a higher incidence of major
bleeding ranging from 6.5 to 18 percent that is not always explained by over anticoagulation [4,5].
Risk factors for bleeding are similar to those in patients without cancer including older age (>65 years),
higher intensity anticoagulation and prior gastrointestinal bleeding (table 2) [17]. However, several studies
including the RIETE registry identified the following additional risk factors in patients with cancer [18,19]:
immobilization (OR, 1.8; 95% CI 1.2-2.7), presence of metastases (OR, 1.6; 95% CI 1.1-2.3), recent
bleeding (OR, 2.4; 95% CI 1.1-5.1), and creatinine clearance <30 mL/min (OR, 2.2, 95% CI 1.5-3.4).
Careful observation of patients, particularly those at risk of bleeding is warranted so that the therapeutic
strategy can be altered when bleeding is detected (eg, reduction in intensity of anticoagulation, cessation

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below.)
Risk factors for bleeding in the general population are discussed separately. (See "Heparin and LMW
heparin: Dosing and adverse effects", section on 'Bleeding' and "Management of warfarin-associated
bleeding or supratherapeutic INR", section on 'Risk factors'.)
INITIAL THERAPY
Agent selection — Immediate anticoagulation (for up to five to ten days) is indicated as initial therapy for
patients with cancer who present with acute VTE. In general, low molecular weight (LMW) heparin is the
preferred agent over unfractionated heparin (UFH). Data are insufficient to support the routine use of
fondaparinux or newer oral anticoagulants (direct thrombin and factor Xa inhibitors) for initial treatment of
acute VTE in patients with cancer. UFH is preferred in those with renal dysfunction or those in whom a
need to discontinue or reverse anticoagulation is anticipated. Factors that affect agent selection for initial
anticoagulation in the general population, many of which may apply to patients with malignancy, are
discussed separately. (See "Venous thromboembolism: Initiation of anticoagulation (first 10 days)",
section on 'General population'.)
Efficacy — Few trials have directly compared anticoagulation therapies for the initial treatment of VTE in
cancer patients. The best evidence comes from a meta-analysis of 15 randomized controlled trials in
cancer patients receiving anticoagulation for VTE [20]. Compared with UFH for the initial treatment of
VTE, LMW heparin was associated with a small reduction in mortality at three months (relative risk [RR]
0.66; 95% CI 0.40-1.1) without an increased risk of bleeding. There was little change in the risk of
recurrent VTE. The efficacy of LMW heparin in this population assumes normal renal function (creatinine
clearance ≥30 mL/min) and does not apply to patients with renal impairment. Another meta-analysis of 18
trials in ambulatory patients with cancer showed no effect of heparin on mortality at 12 months, although
agents were not compared in this analysis [21].
Best studied are the LMW heparin formulations, enoxaparin, dalteparin, and tinzaparin. However, no
study has directly compared LMW heparin formulations with each other. Fondaparinux, the synthetic
pentasaccharide was evaluated in a post-hoc analysis of two randomized studies of initial treatment of
acute VTE in cancer patients [22]. Compared with enoxaparin, fondaparinux was associated with higher
rates of recurrence (12.7 versus 5.5 percent) with no difference in bleeding. Thus, LMW heparin
(enoxaparin, dalteparin, or tinzaparin) is preferred over both UFH and fondaparinux for the initial
treatment of acute VTE in patients with cancer.
Trials have not directly compared the efficacy and safety of LMW heparin with newer oral agents for
initial anticoagulation in cancer patients. Data to support the use of the direct oral anticoagulants as
long-term therapies for VTE in patients with cancer are derived from large randomized studies that
contained relatively small proportions of patients with cancer, the details of which are described
elsewhere. (See "Heparin and LMW heparin: Dosing and adverse effects" and "Prevention of venous
thromboembolism in adult orthopedic surgical patients" and "Venous thromboembolism: Initiation of
anticoagulation (first 10 days)", section on 'Direct factor Xa and thrombin inhibitors' and "Venous
thromboembolism: Anticoagulation after initial management", section on 'Direct thrombin and factor Xa
inhibitors'.)

1/8/2019 Treatment of venous thromboembolism in patients with malignancy – UpT oDate
https://www .uptodate.com/contents/treatment-of-venous-thromboembolism-in-patients-with-malignancy/print 4/18Outpatient therapy — Initiation of LMW heparin in the outpatient setting has not been formally studied in
patients with cancer. However, one study that included a small number of patients with cancer safely
administered five days of LMW heparin for DVT under the careful supervision of homecare nurses [23].
Extrapolating data from patients without cancer, we typically treat uncomplicated DVT (eg, without
concomitant PE) with LMW heparin as outpatients. The successful use of LMW heparin as a therapeutic
strategy for DVT and the requirements for early hospital discharge or outpatient therapy for patients
without cancer is discussed separately (table 3). (See "Treatment, prognosis, and follow-up of acute
pulmonary embolism in adults", section on 'Outpatient anticoagulation' and "Overview of the treatment of
lower extremity deep vein thrombosis (DVT)", section on 'Outpatient therapy'.)
LONG TERM THERAPY — Anticoagulant therapy should be administered for at least three to six months
in patients with cancer and acute VTE, provided the bleeding risk is low and no clinically relevant
complications from anticoagulation have occurred (bleeding, thrombocytopenia). Using extrapolated data
from the general population, it is our practice in this population to treat cases of unsuspected
asymptomatic PE or DVT in the same manner (ie, three to six months) [24]. Duration of therapy for
patients without cancer is discussed separately. (See "Venous thromboembolism: Anticoagulation after
initial management", section on 'Duration of treatment' and "Venous thromboembolism: Initiation of
anticoagulation (first 10 days)".)
Agent selection — Low molecular weight (LMW) heparin has traditionally been the preferred
anticoagulant for long term treatment in patients with cancer, including ambulatory patients [11,21,25-32];
however, a randomized trial reported favorable results with one of the oral factor Xa inhibitors, edoxaban,
after initial treatment with LMW heparin (see 'Direct oral anticoagulants versus low molecular weight
heparin' below). We suggest either LMW heparin or edoxaban for long term anticoagulation based upon
randomized trials and post hoc analyses that suggest comparable rates of VTE between these agents;
LMW heparin is preferred over warfarin based upon extensive experience with this agent and its superior
performance in reducing the rate of recurrent VTE [26,33]. (See 'Heparin versus warfarin' below.)
Oral anticoagulation with VKAs or direct oral anticoagulants other than edoxaban (rivaroxaban, apixaban,
dabigatran) is preferred over no therapy, particularly for patients with a preference for oral medication or
who are injection-averse; choosing among oral agents should be individualized. As an example, in
patients with renal insufficiency (eg, creatinine clearance <30 mL/minute), LMW heparin and the direct
oral anticoagulants should be avoided and warfarin is the preferred agent. (See 'Direct oral
anticoagulants versus warfarin' below.)
Comparative studies have not been performed to determine whether one formulation of LMW heparin
(enoxaparin, dalteparin, tinzaparin) or the synthetic pentasaccharide, fondaparinux, is superior over the
other. However, in clinical practice, dalteparin or enoxaparin are the most common agents used. (See
"Heparin and LMW heparin: Dosing and adverse effects" and "Prevention of venous thromboembolism in
adult orthopedic surgical patients".)
Factors that affect agent selection in the general population and may also apply to patients with cancer
(eg, comorbidities, life-expectancy, values, cost) (table 4) are discussed separately. (See "Venous
thromboembolism: Anticoagulation after initial management", section on 'Selection of agent'.)
Heparin versus warfarin

1/8/2019 Treatment of venous thromboembolism in patients with malignancy – UpT oDate
https://www .uptodate.com/contents/treatment-of-venous-thromboembolism-in-patients-with-malignancy/print 5/18Meta-analyses — A number of meta-analyses have explored the impact of long term
anticoagulation (up to six months) for VTE in cancer patients on rates of recurrence, complications (eg,
bleeding, thrombocytopenia), and mortality [29,30,32,34]. The largest of these meta-analyses (eight
randomized trials of 2327 cancer patients) reported reduced rates of recurrent VTE with LMW heparin
compared with warfarin (risk ratio [RR] 0.58; 95% CI 0.43-0.77) a benefit that occurred without a survival
advantage [32]. In addition, no difference in major bleeding events or reports of thrombocytopenia were
reported between the groups. However, the quality of evidence was low for mortality, major bleeding and
minor bleeding and moderate for recurrent VTE.
Randomized trials — Four major randomized trials, that were included in the meta-analysis above,
compared LMW heparin to VKAs for the treatment of VTE in cancer patients [26-28,35]. Two
demonstrated a reduction in the rates of recurrent VTE without an effect on mortality or bleeding [26,28]
and two showed no difference in any outcome [27,35].
The CLOT trial was a multicenter, international, randomized trial of 672 cancer patients with acute VTE
that compared six months of treatment with warfarin with the LMW heparin, dalteparin (Fragmin; 200
international units/kg SQ once per day for the first month, followed by 150 international units/kg for the
remaining five months) [26]. Dalteparin was associated with a significant reduction in the rate of recurrent
VTE at six months (9 versus 17 percent; HR, 0.48, 95% CI 0.30-0.77). There were no significant
differences in the rates of major bleeding (6 versus 4 percent), any bleeding (14 versus 19 percent), or
overall mortality (39 versus 41 percent). However, a post-hoc analysis indicated that, at 12 months (ie, six
months post treatment, off therapy), a mortality benefit was noted for dalteparin in the subgroup of
patients without metastatic disease (20 versus 36 percent, hazard ratio 0.50, 95% CI 0.27-0.95) [36].
The LITE trial was another multi-center randomized, open-label trial of 200 cancer patients
anticoagulated for acute VTE. This trial showed that compared with warfarin, the LMW heparin, tinzaparin
(Innohep; not available in the US), was associated with reduced rates of recurrent VTE (16 versus 7
percent) but had similar rates of bleeding (27 versus 24 percent) and mortality (47 percent in each group)
at 12 months [28].
The CANTHANOX trial compared therapy with either warfarin or the LMW heparin, enoxaparin (Lovenox;
1.5 mg/kg once daily for four days, followed by three months of either enoxaparin or warfarin) in cancer
patients with VTE [27]. The study was terminated early due to poor recruitment. At three months, there
was no difference in the combined outcome of recurrent VTE and/or major bleeding (20 versus 10
percent for warfarin and enoxaparin respectively). However, subset analysis showed that the majority of
the primary outcome events were major bleeding, with fewer events in the enoxaparin arm (12 versus 5
patients). Of these bleeding events, six were fatal and all occurred in the warfarin treatment arm. The
rates of recurrent VTE were similar in the enoxaparin and warfarin arms.
ONCENOX was a trial of 122 patients with cancer that were treated with either enoxaparin alone (1
mg/kg every 12 hours for 5 days, followed by 1 mg/kg daily or 1.5 mg/kg daily) or initial enoxaparin (1
mg/kg every 12 hours for at least 5 days) followed by warfarin; it too was terminated early. At 180 days
there were no significant differences in rates of recurrent VTE or bleeding events between treatment
groups [35].
The CATCH trial was a randomized, international, open-label study of 900 patients with VTE that
compared treatment with the LMW heparin, tinzaparin (175 international units/kg once daily), with

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lower with tinzaparin (7 versus 11 percent) at six months, it was not statistically significant. Similarly, no
differences were reported in mortality or rates of major bleeding, although lower rates of clinically relevant
non major bleeding were seen in patients on tinzaparin.
Direct oral anticoagulants versus warfarin — In patients who do not have cancer, direct thrombin
inhibitors (dabigatran) and direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) are the preferred
oral anticoagulant for the treatment of VTE [37-42]. Compared with warfarin, direct oral anticoagulants
(DOACs) offer the advantages of being fixed-dose agents, not requiring laboratory monitoring, and
achieving therapeutic efficacy within one to four hours after ingestion. Most of the major trials that
compared the safety and efficacy of these agents with warfarin in the general population either excluded
or included only a small number of patients with cancer; however meta-analyses that extracted data from
patients with “active” cancer in these studies have reported similar efficacy to that seen on the general
population [40-45]:
Although these data suggest similar efficacy with warfarin, the cancer patients included in these major
trials were heterogeneous. As an example, many "active" cancer patients receiving chemotherapy were
not entered in these trials whereas those who had completed therapy or who had a past history of cancer
were entered. Thus there was a selection bias towards having cancer patients with a lower risk of
recurrent thrombosis that limits interpretation of the results.
Use of DOACs in patients without cancer (including EINSTEIN and RECOVER) is discussed separately.
(See "Venous thromboembolism: Anticoagulation after initial management", section on 'Direct thrombin
and factor Xa inhibitors'.)
Direct oral anticoagulants versus low molecular weight heparin — An open-label noninferiority
randomized trial of 1050 patients with VTE compared anticoagulation with the LMW heparin, dalteparinIn a meta-analysis of five studies enrolling 982 participants, compared with warfarin, DOACS
reduced the rate of recurrent VTE RR 0.66; 95% CI, 0.33-1.31 without any effect on survival or
bleeding [32].●
In one meta-analysis of six studies that included 1132 patients with DVT and cancer, compared with
conventional therapy (heparin plus warfarin) similar rates of VTE recurrence (4 versus 6 percent;
odds ratio [OR], 0.63; 95% CI, 0.37-1.10) and major bleeding (OR, 0.77; 95% CI, 0.41-1.44) were
reported in those taking DOACs [40].●
Two separate pooled analyses of patients with DVT who were treated with rivaroxaban (EINSTEIN
studies) [41] or dabigatran (RECOVER studies) [42] assessed safety and efficacy in patients with
cancer. Although rates of recurrence and bleeding were higher among patients with cancer
compared to patients without cancer, events were no different between cancer patients treated with
DOACs or warfarin.●
Another post-hoc analysis of patients with VTE compared patients treated with apixaban with those
on standard anticoagulation [46]. Among those with active malignancy receiving apixaban, an
insignificant reduction in rates of recurrent VTE (4 versus 6 percent; relative risk 0.56; 95% CI 0.13-
2.17) and bleeding (2 versus 5 percent; RR 0.45, 95% CI 0.08-2.46) were reported. Similar findings
were also reported in those receiving apixaban who had a history of malignancy.●

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followed by the direct factor Xa inhibitor, edoxaban (60 mg once daily). Although there was no difference
in the composite outcome of recurrent VTE and major bleeding, anticoagulation for up to 12 months
(minimum 6 months) with edoxaban resulted in a nonsignificant reduction in the rate of recurrence as
compared with dalteparin (7.9 versus 11.3 percent) but at the expense of a higher rate of major bleeding
(6.9 versus 4.0 percent) [47]. However, the rate of serious bleeding events was equal between the groups
and most bleeding events occurred in patients with upper gastrointestinal cancers. Death occurred in 206
patients (39.5 percent) in the edoxaban group and in 192 patients (36.6 percent) in the dalteparin group.
Similarly, the outcomes with rivaroxaban (15 mg twice daily for three weeks, then 20 mg once daily for a
total of six months) given as monotherapy (ie, no previous treatment with LMW heparin) for six months
was compared with chronic LMW heparin (dalteparin; 200 international units [IU]/kg daily during month 1,
then 150 IU/kg daily for months 2 to 6) for cancer-associated thrombosis. This pilot study (SELECT-D) of
406 patients reported that rivaroxaban resulted in a reduction in the six-month VTE recurrence rate (4
versus 11 percent). While the rate of major bleeding was similar (6 versus 4 percent), there was an
excess number of clinically relevant non-major bleeds with rivaroxaban (13 versus 4 percent) especially
from cancers of the upper gastrointestinal tract [48].
In a prospective cohort study of 200 patients treated with rivaroxaban as monotherapy, the incidence of
recurrence was 4 percent, major bleeding 2 percent, and all-cause mortality 18 percent [49], rates that
were comparable with major studies of rivaroxaban in noncancer patients, suggesting that safety and
efficacy were preserved. However, this study did not use a direct comparator and is limited in its analysis.
EXTENDED THERAPY — Extended therapy refers to the administration of anticoagulants beyond the
conventional three to six months. Active malignancy is a risk factor for VTE with rates of recurrence
estimated to be as high as 10 to 20 percent per year [4,11,50,51]. However, the risk varies considerably
according to whether the cancer is active, progressive, metastatic, being treated, or cured. In addition,
rates of bleeding are higher in patients with active cancer. Thus, the decision to extend therapy
indefinitely in this population should carefully weigh the benefit of preventing VTE recurrence (see
'Recurrence risk' below) against the risk of bleeding (see 'Bleeding complications' above), while also
taking into consideration, the type of cancer, burden of disease, treatment received, patient preference,
and life expectancy. The indications for indefinite anticoagulation in the general population is discussed
separately. (See "Rationale and indications for indefinite anticoagulation in patients with venous
thromboembolism".)
We suggest extending therapy beyond the conventional period in those with active cancer (eg, cancer
recently diagnosed, receiving anti-tumor therapy) as well as in those who recur despite anticoagulation.
In addition, select patients assessed as high risk for recurrence by their physician may also be
considered for extended treatment (eg, persistent clot despite therapy, continued immobility, high clot
burden or hypotension at initial presentation). This preference is based upon consensus among
physicians and the rationale that the risk of recurrence of VTE beyond the first episode is likely higher in
such cancer patients [11]. Factors that influence the decision to extend anticoagulation in the general
population, some of which apply to patients with cancer, are discussed separately. (see "Rationale and
indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Making
the decision to indefinitely anticoagulate').

1/8/2019 Treatment of venous thromboembolism in patients with malignancy – UpT oDate
https://www .uptodate.com/contents/treatment-of-venous-thromboembolism-in-patients-with-malignancy/print 8/18The optimal agent is unknown but we suggest the agent selected for primary therapy (usually low
molecular weight heparin), provided the chosen anticoagulant was effective and administered without
complications during that period. Extended therapy should be evaluated yearly and take into
consideration completion of anti-tumor therapy, cure from cancer, bleeding risk, and life-expectancy. (See
"Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism",
section on 'Follow-up'.)
One theoretical benefit of LMW heparin as a therapy for the extended treatment of VTE, was a suggested
survival advantage reported in some trials in cancer patients with and without venous thromboembolism
[36,52-56]. The survival benefit in these trials persisted beyond the time of administration of the drug,
suggesting that LMW heparin may have a beneficial effect on tumor biology that is independent of its
effect on VTE. However, this potential benefit of extended LMW heparin therapy has not been confirmed
and cannot be supported for this indication [10].
Another retrospective database study reported that after 6 months of LMW heparin, continuing LMW
heparin was associated with similar rates of VTE recurrence and bleeding when compared with patients
who switched to warfarin (relative risk [RR] for recurrence 1.41, 95% CI 0.68-2.93; RR for bleeding 0.96,
95% CI 0.51-1/79) but a higher mortality rate (RR 1.58, 95% CI 1.13-2.20) [57]. However, flaws in this
study suggest that further studies are warranted.
Recurrence risk — VTE recurrence rates of up to 21 percent (ie, three to four times that of the general
population) have been reported in cancer patients despite anticoagulation and may be associated with
increased morbidity and mortality [4,5,26,31,58,59]. As examples:
In general, many of the risk factors for recurrent VTE are similar to those in patients without cancer.
However additional risk factors have been identified that may be specific to patients with cancer (table 2)
[18].In the CLOT trial, 9 (LMW heparin) and 17 (VKA) percent of cancer patients developed recurrent
VTE while on anticoagulant therapy [26]. However, the analysis was flawed such that these rates are
likely over estimated [60].●
In a trial of 334 patients treated with dalteparin, rates of recurrence and bleeding were highest in the
first month and declined over the subsequent 11 months (11 versus 4 percent for recurrent VTE; 4
versus 1 percent for major bleeding) [31].●
In a population-based cohort study, compared to idiopathic VTE, the six-month cumulative incidence
of recurrence on anticoagulant therapy was higher in cancer-related VTE (16 versus 4 percent) [58].●
Two prospective studies of 1191 patients reported that, compared with patients without malignancy,
patients with malignancy had a higher incidence of recurrent thromboembolism despite
anticoagulation (20.7 versus 6.8 percent respectively) [4,5].●
Frequently cited reasons for recurrent VTE in patients with cancer are poor adherence to medication,
cessation of therapy for procedures or bleeding, inadequate dosing, and the presence of heparin-
induced thrombocytopenia.●
Additional risk factors for recurrent thrombosis identified in one registry of 3805 cancer patients on
anticoagulant therapy (RIETE Registry) included: younger patients (<65 years) (odds ratio [OR], 3.0;●

1/8/2019 Treatment of venous thromboembolism in patients with malignancy – UpT oDate
https://www .uptodate.com/contents/treatment-of-venous-thromboembolism-in-patients-with-malignancy/print 9/18A clinical prediction rule for determining the risk of VTE recurrence in cancer patients has been
developed using data from a retrospective cohort study and two randomized trials (CLOT and
CANTHANOX trials) [51]. Factors in the final model included the following for a final score ranging from
-2 to +3:
Risk was categorized as low (19 percent of the population), intermediate (42 percent of the population),
and high (38 percent of the population) according to the incidence of recurrence:
This model requires validation before it can be routinely used to identify those patients with cancer and
acute VTE that are at greatest risk of recurrence. Further studies will also be needed to examine whether
models such as these can be used to target high risk patients who have not had a recurrence while on
therapy but may benefit from extended anticoagulation for acute VTE.
The rationale for indefinite anticoagulation in the general population is discussed separately. (See
"Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism",
section on 'Making the decision to indefinitely anticoagulate'.)95% CI 1.9-4.9), PE at study entry (OR, 1.9; 95% CI 1.2-3.1), and newly diagnosed cancer (<3
months) (OR, 2.0; 95% CI 1.5-3.6) [18].
A subsequent analysis of RIETE data reported that the risk of recurrence (and bleeding) was
influenced by site. Similar rates of recurrence and bleeding were reported in those with breast cancer
(5.6 and 4.1 percent, respectively) and colorectal cancer (10 and 12, respectively) while the
recurrence was two-fold higher than the rate of bleeding in those with lung cancer (27 and 11
percent, respectively) and the rate of recurrence was half the rate of bleeding in those with prostate
cancer (7 versus 13 percent, respectively).●
A separate study of 347 patients with deep venous thrombosis (DACUS), reported that the absence
of residual vein thrombosis following six months of anticoagulant therapy identified a population at
low risk for recurrence (3 percent at one year off of anticoagulation) [56]. In contrast, those with RVT,
had higher rates of recurrence, which were not significantly reduced by extended therapy with LMW
heparin (22 to 19 percent). Despite these data, many experts do not routinely perform surveillance
with ultrasound following completion of a three to six month course of anticoagulation.●
Breast cancer (-1 point) ●
Tumor node metastasis (TNM) stage I or II (-1 point) ●
Female gender (1 point) ●
Lung cancer (1 point) ●
Prior VTE (1 point) ●
Low (score <0): 5 percent ●
Intermediate (score = 0): 10 percent ●
High (score ≥1): 16 percent ●

1/8/2019 Treatment of venous thromboembolism in patients with malignancy – UpT oDate
https://www .uptodate.com/contents/treatment-of-venous-thromboembolism-in-patients-with-malignancy/print 10/18MANAGEMENT OF RECURRENCE — Management of patients with recurrent VTE despite
anticoagulant therapy is poorly studied. Similar to patients without cancer, patients with symptomatic
recurrence are often taking subtherapeutic doses of their medication (table 2). Recurrence in the setting
of adequate anticoagulation is more worrisome, indicating drug failure or resistance. Based upon our
experience and limited data, management options include switching to low molecular weight (LMW)
heparin when patients are taking an oral anticoagulant, escalating the dose of LMW heparin for those
already on LMW heparin, or addition of a vena cava filter [10]. Causes and management of recurrence in
the general population are discussed separately. (See "Treatment, prognosis, and follow-up of acute
pulmonary embolism in adults", section on 'Management of recurrence on therapy'.)
Switching or escalating medical therapy — Options for therapy for recurrent VTE in the setting of
adequate anticoagulation include using an alternate agent, and increasing the dose or frequency of
administration. As examples, recurrences that occur in patients on warfarin that is in the therapeutic
range (international normalized ratio [INR] 2 to 3) or on the recommended dose of a direct oral
anticoagulant (eg, edoxaban) should generally be switched to LMW heparin; recurrences on a single
daily dose of LMW heparin can be switched to every 12 hour administration at a therapeutic dose or
increased to 120 or 130 percent of the therapeutic dose. Rarely, for patients on warfarin in whom these
options are not feasible, some experts target a higher INR (eg, 2.5 to 3.5), although this strategy is
unproven. The benefits of switching to a direct oral anticoagulant in this population are also unknown.
There are limited studies on which to base the choice of treatment. A retrospective study evaluated the
effectiveness of escalating the dose of LMW heparin in 70 patients with active cancer who developed an
objectively documented episode of recurrent VTE while already receiving anticoagulation (LMW heparin
and warfarin) [61]. Twenty one percent of patients were on therapeutic doses of LMW heparin (dalteparin,
tinzaparin, enoxaparin) and were increased to 120 percent of a therapeutic dose. The remaining patients,
who were on subtherapeutic doses of LMW heparin (46 percent) or were warfarin failures (33 percent),
were switched over to therapeutic LMW heparin. Outcome at three months included the following:
Larger, prospective studies with longer follow-up are required before the safety and efficacy of dose
escalation with LMW heparin for cancer patients with recurrent VTE can be routinely applied.
The role of the direct oral anticoagulants has not been studied in cancer patients with recurrent VTE on
LMW heparin or warfarin. Data are insufficient to support routinely switching to one of these agents in this
population. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Direct
thrombin and factor Xa inhibitors'.)A second recurrent VTE was reported in six patients (8.6 percent) at an event rate of 9.9/100 patient-
years and time to second recurrent episode of two months (range: 0.6 to 3 months).●
Patients with recurrent VTE were treated by increasing the dose of LMW heparin by 20 to 25 percent
for at least four weeks, and one also had an IVC filter placed. No further recurrence was reported
during the three-month follow-up period.●
Bleeding complications were reported in 4 percent of patients, with only one major bleed (in a patient
with intracranial malignancy). Deaths in this study were not related to either recurrent VTE or
bleeding.●

1/8/2019 Treatment of venous thromboembolism in patients with malignancy – UpT oDate
https://www .uptodate.com/contents/treatment-of-venous-thromboembolism-in-patients-with-malignancy/print 11/18Inferior vena cava filter — The placement of a vena cava filter may be considered in patients with
recurrent VTE, particularly if anticoagulation therapy was already maximized or has been associated with
bleeding complications. (See 'Inferior vena cava filter' below.)
INFERIOR VENA CAVA FILTER — An inferior vena cava (IVC) filter is often placed when there are
contraindications to anticoagulation and is occasionally placed as a last resort in cases of recurrence
despite adequate anticoagulation. Importantly, they are not routinely placed for the initial management of
VTE in any population. (See 'Contraindications' above and 'Management of recurrence' above and
'Bleeding complications' above.)
Since the risk of DVT recurrence is thought to be higher in patients in whom a filter is placed, the decision
to place a filter in a patient with cancer should weigh the benefit of preventing death from PE against the
risks of recurrent DVT and chronic venous stasis/thrombophlebitis in the context of patient preference,
and life expectancy. The indications and complications of vena cava filters are discussed separately. (See
"Placement of vena cava filters and their complications".)
Although retrospective cohort studies suggest lower fatality rates in some cancer patients with IVC filters,
there are no large randomized trials in any patient population that have studied the safety and efficacy of
vena cava filters in the treatment and prevention of VTE [62]. Studies performed in the general population
(few study participants had cancer) suggested that filter placement was associated with a successful
reduction in the risk of PE but increase in the risk of DVT, the details of which are discussed separately.
(See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Inferior vena
cava filter'.)
Small observational case series of patients with cancer also describe a similar trend of increased
recurrence of DVT and reduction in PE associated with filter placement:
In contrast, one retrospective database study of patients >60 years with cancer and PE in whom IVC
filters were placed reported a lower in-hospital mortality (7 versus 11 percent) and all-cause 3 month
mortality ( 15 versus 17 percent) compared with patients who did not receive a filter [66]. Rates of DVT
were not measured
THERAPY IN SPECIAL POPULATIONS — Special consideration should be applied to select
populations, some of which are at risk of altered safety or efficacy of anticoagulation. These include:One retrospective study evaluated 308 patients with advanced metastatic cancer and acute VTE in
whom there was a contraindication to anticoagulation [63]. In this population, IVC filter placement
was associated with new caval thrombosis and PE in 5 and 1 percent, respectively.●
Another retrospective analysis of cancer patients with DVT suggested that compared to the group as
a whole, those with a filter in place had a higher rate of recurrence (32 versus 17 percent) [64].●
A third study assessed the outcome associated with perioperative filter placement in 274 patients
undergoing surgery for ovarian cancer, half of whom had a newly diagnosed VTE [65]. Compared to
patients without a filter, patients who had a filter placed for VTE had an increased rate of recurrent
DVT (25 versus 7.2 percent, odds ratio [OR] 4.31; 95% CI 1.40-13.3) and decreased overall survival
(22 versus 47 months).●

1/8/2019 Treatment of venous thromboembolism in patients with malignancy – UpT oDate
https://www .uptodate.com/contents/treatment-of-venous-thromboembolism-in-patients-with-malignancy/print 12/18FOLLOW-UP — It is advisable to frequently re-evaluate the risk-benefit ratio of ongoing anticoagulant
therapy in individual patients, taking into consideration the overall clinical status of the patient, including
their quality of life and life expectancy. Treatment of VTE with anticoagulation, though effective in patients
with cancer, is fraught with higher morbidity, from both bleeding and recurrent VTE despite
anticoagulation [1-8]. Careful observation of patients during therapy for these complications in those
particularly at risk (table 2) is warranted so that the therapeutic strategy can be altered when recurrent
VTE or bleeding is detected (eg, alternate medication, escalation or cessation of therapy). (See
'Recurrence risk' above and 'Bleeding complications' above.)Patients with intracranial malignancy (see "Treatment and prevention of venous thromboembolism in
patients with brain tumors", section on 'Treatment of venous thromboembolism')●
Older patients ●
Patients with thrombocytopenia (see "Anticoagulation in individuals with thrombocytopenia", section
on 'Cancer-associated VTE')●
Patients with renal insufficiency or on renal replacement therapy (see "Anticoagulation for continuous
renal replacement therapy" and "Heparin and LMW heparin: Dosing and adverse effects", section on
'Dosing')●
Obese patients ●
Patients with catheter-induced upper extremity venous thrombosis (see "Catheter-related upper
extremity venous thrombosis", section on 'Treatment')●
Patients with massive pulmonary embolism (see "Thrombolytic (fibrinolytic) therapy in acute
pulmonary embolism and lower extremity deep vein thrombosis" and "Treatment, prognosis, and
follow-up of acute pulmonary embolism in adults", section on 'Embolectomy')●
Patients with splanchnic or visceral vein thrombi (see "Epidemiology and pathogenesis of portal vein
thrombosis in adults" and "Acute portal vein thrombosis in adults: Clinical manifestations, diagnosis,
and management" and "Chronic portal vein thrombosis in adults: Clinical manifestations, diagnosis,
and management")●
Patients with pancreatic cancer (see "Supportive care of the patient with locally advanced or
metastatic exocrine pancreatic cancer", section on 'Venous thromboembolism')●
Patients with arterial thromboembolism – Arterial thromboembolism is less common than venous
thromboembolism in patients with cancer. Retrospective cohort analyses suggest that the incidence
of arterial thromboembolism ranges from 2 to 6 percent, higher in those who receive blood
transfusion [67,68]. In patients with malignancy the most common sources for arterial
thromboembolism are nonbacterial thrombotic endocarditis and paradoxical embolism arising from
deep vein thrombosis and a right-to-left shunt [69]. Embolism to the digits, brain, or solid organs can
be a paraneoplastic manifestation of solid tumors and are particularly associated with the
myeloproliferative disorders [70,71]. We typically anticoagulate patients with arterial
thromboembolism as long as it is consistent with the patient's overall management goals. (See
"Prognosis and treatment of essential thrombocythemia", section on 'Management' and
"Nonbacterial thrombotic endocarditis" and "Prognosis and treatment of polycythemia vera".)●

1/8/2019 Treatment of venous thromboembolism in patients with malignancy – UpT oDate
https://www .uptodate.com/contents/treatment-of-venous-thromboembolism-in-patients-with-malignancy/print 13/18In addition, clinical assessment for recurrent or progressive DVT, in patients with an inferior vena cava
filter or not on therapy, is also warranted to predict the likelihood of PE as a possible terminal event.
Prognostic information can be provided to the patient and healthcare providers to make informed end-of-
life decisions. (See "Communication of prognosis in palliative care".)
PATIENTS VALUES AND PREFERENCES — The rationale for clinical reassessment is multifactorial
(table 1). Factors that may alter the decision to initiate, continue, or stop anticoagulation include drug
interactions particularly with chemotherapeutic agents, the development of renal insufficiency, intermittent
periods of poor oral intake, malignancy-associated thrombocytopenia, and poor prognosis.
Patient preferences and values also weigh in heavily in cancer patients when making decisions regarding
the initiation and continuation of anticoagulation therapy. For example, patients in a hospice setting or
patients who are dying may prefer to stop therapy [72]. In addition, many patients may prefer to take an
oral anticoagulant over daily injections or wish to avoid the higher cost associated with LMW heparin. On
the other hand, the use of warfarin and direct oral anticoagulants in cancer can be complicated by drug
interactions and poor bioavailability from malabsorption or poor oral intake, or troublesome laboratory
draws (for warfarin only).
Thus, in clinical practice, the decisions over initial and continued anticoagulation, filter placement, or no
therapy should be shared and occur in the context of risks and benefits of the medication, life expectancy
and patient preference. (See "Discussing goals of care".)
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: Superficial
vein thrombosis, deep vein thrombosis, and pulmonary embolism".)
SUMMARY AND RECOMMENDATIONS — The following recommendations are generally consistent
with the 2013 clinical practice guidelines from the American Society of Clinical Oncology (ASCO), the
2012 and 2016 guidelines of the American College of Physicians, the 2015 National Comprehensive
Cancer Network (NCCN) Guidelines, and the 2013 International Practice Guidelines.
Anticoagulant therapy is warranted in cancer patients with new or recurrent VTE. (See 'Indications'
above.)●
Treatment of VTE with anticoagulation, though effective in patients with cancer, is associated with
higher morbidity, from both recurrent VTE and bleeding associated with anticoagulation. (See
'Recurrence risk' above and 'Bleeding complications' above.)●
For patients with malignancy and VTE, a reasonable quality of life and life expectancy, who do not
have severe renal insufficiency (creatinine clearance <30 mL/minute), or a contraindication to
anticoagulation, we suggest initial treatment (5 to 10 days) with low molecular weight (LMW) heparin
(enoxaparin, dalteparin, or tinzaparin) over the use of unfractionated heparin (UFH) (Grade 2C).
UFH is preferred in those with renal dysfunction or those in whom a need to discontinue or reverse
anticoagulation is anticipated. (See 'Initial therapy' above.)●
In patients with malignancy (with the exception of gastrointestinal malignancy) and VTE who do not
have severe renal insufficiency, we suggest the continued use of LMW heparin after initial treatment
or edoxaban rather than vitamin K antagonists (VKAs) or other direct oral anticoagulants●

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Topic 1340 Version 51.0(rivaroxaban, apixaban, dabigatran) for a minimum of three to six months (Grade 2C). For patients
with gastrointestinal cancer, LMW heparin is preferred over edoxaban due to the potential for an
increased risk of major gastrointestinal bleeding. Oral anticoagulation is preferred over no therapy,
particularly for patients with a preference for oral medication or who are injection-averse; choosing
among warfarin and direct oral anticoagulants other than edoxaban should be individualized. (See
'Long term therapy' above and 'Follow-up' above and "Venous thromboembolism: Anticoagulation
after initial management", section on 'Selection of agent'.)
For patients with malignancy and VTE, we suggest extended anticoagulation beyond three to six
months for patients with active malignancy and those with recurrence despite therapy (Grade 2C).
We also administer extended therapy in selected patients considered to be at high risk of recurrence
(eg, high clot burden). The decision to anticoagulate for extended periods, should be balanced
against the risk of bleeding, cost of therapy, quality of life, life expectancy, and patient preference.
(See 'Extended therapy' above and 'Follow-up' above and "Rationale and indications for indefinite
anticoagulation in patients with venous thromboembolism".)●
Management options for recurrence include switching to LMW heparin if taking an oral anticoagulant,
escalation of the dose of LMW heparin for those already on LMW heparin, addition of an inferior
vena cava filter, or rarely, increasing the dose of warfarin when other options are not feasible. (See
'Management of recurrence' above.)●
Anticoagulation for VTE should generally be avoided if there is active bleeding and/or there are other
contraindications to anticoagulant use (eg, recent surgery, coagulopathy). Thrombocytopenia is not a
contraindication in most patients. When anticoagulation is contraindicated, one treatment option is
insertion of an inferior vena cava filter. (See 'Contraindications' above and "Anticoagulation in
individuals with thrombocytopenia", section on 'Cancer-associated VTE' and "Placement of vena
cava filters and their complications".)●
It is advisable to frequently re-evaluate the risk-benefit ratio of ongoing anticoagulant therapy in
individual patients, taking into consideration the overall clinical status of the patient, including the
quality of life and life expectancy. (See 'Follow-up' above and 'Patients values and preferences'
above.)●
Anticoagulation for VTE in select populations (eg, intracranial tumors, renal insufficiency) requires
special consideration. (See 'Therapy in special populations' above.)●

1/8/2019 Treatment of venous thromboembolism in patients with malignancy – UpT oDate
https://www .uptodate.com/contents/treatment-of-venous-thromboembolism-in-patients-with-malignancy/print 15/18GRAPHICS
Issues to be considered when making decisio ns concerning the use or non-
use of anticoagulation in patients with malignancy
Overall treatment plan and prognosis
Therapeutic goal (eg, palliation of symptoms related to VTE, planned oncologic intervention, immediate
prognosis, Hospice care)
Planned chemotherapy
Stage of the malignancy, overall prognosis
Other causes for hypercoagulability (eg, bed ridden, pathologic fracture, recent surgery or invasive
procedures, use of hormonal agents or other medications with a high incidence of thrombotic side-effects,
presence of a central venous access line)
Patient preferences, lo gistic, and financial issu es
Inpatient or outpatient care planned
Who will supervise medication's use and required monitoring, if any?
Patient preferences (eg, oral versus injectable agent, need for frequent monitoring of coagulation status)
Food and Drug Administration approval of agent chosen
Treatment costs. Will the patient's insurance pay for the medication?
Relative contraindications to anticoagulation
Presence of central nervous system involvement
– Central nervous system primary or metastases
– Prior intracerebral hemorrhage
Thrombocytopenia or bleeding diathesis present?
Are risk factors for bleeding after use of warfarin present? (eg, impaired liver function, hepatic metastases,
concomitant medication, poor nutrition)
Technical issu es
Selection of appropriate dosing (eg, impaired renal function, obesity, advanced age)
Need for monitoring of treatment (eg, INR for treatment with warfarin)
Ability or inability to reverse anticoagulation if bleeding occurs
Graphic 81646 Version 5.0

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https://www .uptodate.com/contents/treatment-of-venous-thromboembolism-in-patients-with-malignancy/print 16/18Risk factors for recurrent venous thromboembolism and bleeding in patients
with malignancy
Recurrent VTE Bleed ing
General factors
Poor adherence to medication Older age (>65 years)
Inadequate dosing Higher intensity anticoagulation
Presence of HIT Prior gastrointestinal bleeding
Inherited thrombophilia disorders Thrombocytopenia
Acquired factors (eg, presence of venous catheter,
recent surgery)Overdosing
Interruption of therapy for procedures Bleeding diathesis (eg, elevated INR in cirrhosis)
Drugs (eg, tamoxifen bevacizumab)
Prolonged immobilization
Heart failure
Smoking
Inflammatory bowel disease
Patient-related factors
Younger patients (<65 years) Immobilization
PE at study entry Presence of metastases
Newly diagnosed cancer (<3 months) Creatinine clearance <30 mL/min
VTE: venous thromboembolism; HIT: heparin-induced thrombocytopenia; INR: international normalized ratio; PE:
pulmonary embolism.
Reference:
1. Trujillo-Santos J, Nieto JA, Tiberio G, et al. Predicting recurrences or major bleeding in cancer patients with
venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008; 100:435.
Graphic 90440 Version 2.0[1]

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https://www .uptodate.com/contents/treatment-of-venous-thromboembolism-in-patients-with-malignancy/print 17/18Minimal requirements for early hospital discharge or outpatient therapy of
venous thromboembolic disease
The responsible physician must ensure that all of the following conditions apply:
The patient is ambulatory and in stable condition, with normal vital signs
There is a low a priori risk of bleeding in the patient
Severe renal insufficiency is not present
There is a practical system in place for the following:
Administration of LMW heparin and/or warfarin with appropriate monitoring, and
Surveillance and treatment of recurrent VTE and bleeding complications
VTE: venous thromboembolism; LMW heparin: low molecular weight heparin.

Adapted from Hyers, TM, Agnelli, G, Hull, RD, et al. Antithrombotic therapy for venous thromboembolic disease.
Chest 2001; 119:176S. (Sixth ACCP Consensus Conference on Antithrombotic Therapy).
Graphic 70140 Version 2.0

1/8/2019 Treatment of venous thromboembolism in patients with malignancy – UpT oDate
https://www .uptodate.com/contents/treatment-of-venous-thromboembolism-in-patients-with-malignancy/print 18/18Factors that influence agent sele ction for anticoagulation in patients with
acute venous thromboembolism
FactorPreferred
anticoagulantQualifying remarks
Cancer LMWH More so if: Just diagnosed, extensive VTE, metastatic cancer,
very symptomatic; vomiting; on cancer chemotherapy.
Parenteral therapy
to be avoidedRivaroxaban;
apixabanVKA, dabigatran, and edoxaban require initial parenteral therapy.
Once daily oral
therapy preferredRivaroxaban;
edoxaban; VKA
Liver disease and
coagulopathyLMWH DOACs contraindicated if INR raised because of liver disease; VKA
difficult to control and INR may not reflect antithrombotic effect.
Renal disease and
creatinine clearance
<30 mL/minVKA DOACs and LMWH contraindicated with severe renal impairment.
Dosing of DOACs with levels of renal impairment differ with the
DOAC and among jurisdictions.
Coronary artery
diseaseVKA, rivaroxaban,
apixaban, edoxabanCoronary artery events appear to occur more often with
dabigatran than with VKA. This has not been seen with the other
DOACs, and they have demonstrated efficacy for coronary artery
disease. Antiplatelet therapy should be avoided if possible in
patients on anticoagulants because of increased bleeding.
Dyspepsia or
history of GI
bleedingVKA, apixaban Dabigatran increased dyspepsia. Dabigatran, rivaroxaban, and
edoxaban may be associated with more GI bleeding than VKA.
Poor compliance VKA INR monitoring can help to detect problems. However, some
patients may be more compliant with a DOAC because it is less
complex.
Thrombolytic
therapy useUFH infusion Greater experience with its use in patients treated with
thrombolytic therapy.
Reversal agent
neededVKA, UFH,
dabigatranReversal agents for dabigatran may not be universally readily
available.
Pregnancy or
pregnancy riskLMWH Potential for other agents to cross the placenta.
Cost, coverage,
licensingVaries among
regions and with
individual
circumstances
LMWH: low molecular weight heparin; VTE: venous thromboembolism; VKA: vitamin K-dependent antagonist;
DOACs: direct oral anticoagulants; INR: international normalized ratio; GI: gastrointestinal; UFH: unfractionated
heparin.
Original figure modified for this publication. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE
Disease: CHEST Guideline and Expert Panel Report. Chest 2016; 149:315. Table used with the permission of Elsevier
Inc. All rights reserved.
Graphic 107541 Version 3.0