TREATING VTE TODAY: PRACTICE YOUR SKILLS

LITERATURE REVIEW

Venous thromboembolism (VTE) includes 2 interrelated conditions: deep venous thrombosis (DVT)
and pulmonary embolism (PE).1 There are approximately 10 million cases of VTE globally each year,
causing 100,000–300,000 deaths in the United States and 544,000 deaths in Europe.2 Patients with a
first VTE may experience a recurrence, and the risk is higher in patients with a cancer-associated
thrombosis and in those with an unprovoked VTE.3

Strong risk factors for VTE include cancer and chemotherapy, extended hospital stays, surgeries
(especially for the hips, knees, and cancer), and long periods of immobility (eg, bed rest). Moderate risk
factors include age > 60 years, a personal or family history of blood clots, trauma, and the use of oral
contraceptives or hormone-replacement therapies. It is worth noting that most studies suggest that VTE
associated with hormone therapy has a low risk of recurrence if the hormonal therapy is stopped. Other
risk factors include obesity, pregnancy or recent childbirth, long-haul travel, and smoking.2

PRESENTATION AND DIAGNOSIS

The most frequent symptom of DVT is unilateral leg swelling, pain in the distribution of the deep veins,
oedema, and a dusky erythema, not similar to cellulitis. The most frequent symptom of PE is dyspnoea;
other findings may include pleuritic chest pain, cough, haemoptysis, syncope, tachypnoea, tachycardia,
accentuated second heart sound, and rarely, low-grade fever or cyanosis.1

The differential diagnosis for DVT includes ruptured Baker cyst, musculoskeletal disorders, superficial
phlebitis, trauma, iliac vein compression, and lymphoedema. In patients with (suspected) PE, clinicians
also need to exclude congestive heart failure, acute respiratory distress syndrome, pulmonary infection,
myocardial infarction, cardiac tamponade, right-sided heart failure, pleurisy, musculoskeletal disorders,
and oesophageal spasm/reflux esophagitis. Central chest pain is uncommon with PE.4

Risk Assessment

Clinicians may use pre-established criteria or scoring systems to determine the likelihood of VTE,
especially in emergency-department settings, before proceeding with testing.5 There are several
versions of the Wells' score for DVT and PE, and the Wells' criteria have been used in both inpatient
and outpatient populations.5, 6 A patient who is low risk for DVT by Wells' criteria and who has a
negative D-dimer test does not need ultrasound to rule out DVT. The Wells' criteria include active
cancer; recently bedridden for > 3 days or major surgery within 12 weeks; calf swelling > 3 cm
compared to other leg; collateral (nonvaricose) superficial veins present; entire leg swollen; localized
tenderness along the deep venous system; pitting oedema only in the symptomatic leg; paralysis, paresis,
or recent plaster immobilization of the lower extremity; previous DVT; and an alternative diagnosis as
likely or more likely than DVT.6 The Wells score for PE in combination with D-dimer can be used in a
similar manner.

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The revised Geneva score for PE has only been validated in an outpatient population.5 It includes the
following variables: age > 65 years, previous DVT or PE, surgery under general anaesthesia or lower
limb fracture in the past month, active malignancy, unilateral lower limb pain, haemoptysis, heart rate,
and lower limb pain or unilateral oedema. The results are used to stratify patients into low-,
intermediate-, or high-risk groups to inform further testing.7

If clinicians deem the patient to be at low risk, they can use the Pulmonary Embolism Rule-out Criteria
(PERC). PERC includes the following variables: age < 50 years, pulse < 100 beats/min, oxygen
saturation ≥ 95%, no haemoptysis, no oestrogen use, no surgery/trauma requiring hospitalization within
4 weeks, no prior VTE, and no unilateral leg swelling. If all criteria are satisfied, then further workup is
unnecessary.8

Diagnosis

Timely and accurate diagnosis of VTE is critical to prevent life-threatening or fatal complications.5 The
2018 American Society of Hematology (ASH) guidelines for the management of VTE recommend an
initial D-dimer test to exclude PE in patients with a low or intermediate probability of PE. Additional
testing, if necessary, includes a ventilation/perfusion (VQ) scan or computed tomography pulmonary
angiography (CTPA), and these tests may also be used in cases where D-dimer testing is unavailable.
Patients with a high probability of PE should receive CTPA testing first.5

Similarly, the guidelines recommend an initial D-dimer test to exclude DVT in patients with a low
probability. D-dimer testing should be followed by proximal lower extremity ultrasound or whole-leg
ultrasound, if indicated by a positive D-dimer or intermediate/high pretest probability. Ultrasound may
also be used when D-dimer testing is unavailable. Intermediate-probability patients should receive
whole-leg ultrasound, and no further testing is required if the results are negative. Patients with a high
probability should receive proximal lower extremity or whole-leg ultrasound, followed by serial
ultrasound if the initial ultrasound was negative and no alternative diagnosis can be identified.5

VTE in Patients with Cancer

Patients with cancer deserve careful consideration and attention regarding VTE. Cancer patients are 4
times more likely to develop blood clots compared to people without cancer, and patients with cancer
have higher rates of VTE recurrence as well as bleeding complications during treatment.2, 10, 11, 12
Additionally, VTE may go undiagnosed since patients (or clinicians) may attribute typical symptoms of
fatigue or dyspnoea to the cancer or its treatment.13

Incidental VTE is often detected in oncology centres when patients with cancer are undergoing routine
imaging for staging purposes or response assessment. This diagnosis is widely accepted even though the
standard imaging studies are not normally used to confirm the diagnosis.13

According to the International Society on Thrombosis and Haemostasis (ISTH) guidelines, for cancer
patients with a diagnosis of incidental VTE, the clinician should carefully review the patient history to
exclude symptomatic VTE. In patients with incidental PE involving the main, lobar, segmental or
multiple subsegmental pulmonary arteries, further testing is unnecessary. For patients with incidental
iliofemoral DVT on computed tomography (CT) of the abdomen and pelvis, the diagnosis should be

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confirmed with Doppler/colour ultrasonography of the pelvis and compression ultrasonography of the
lower limbs.13 ASCO guidelines note that patients with incidental VTE should receive the same
treatment as for symptomatic VTE, given the similar patient outcomes.10

Observational evidence and retrospective data show that incidental VTE carries similar risks for
mortality and morbidity as symptomatic VTE, with autopsy results indicating that incidental VTE is a
frequently unrecognised cause of death in patients with cancer. Most guidelines recommend
anticoagulant treatment for patients with cancer and VTE (see below); however, the clinician and
patient should reach a shared decision based on the risks for bleeding and for interactions with the
antineoplastic agents used in cancer therapy.13

Assessment of VTE Risk in Patients With Cancer

The American Society for Clinical Oncology (ASCO) guidelines recommend an initial assessment of
VTE risk in patients with cancer, with periodic assessment thereafter, especially when a patient starts
systemic antineoplastic treatment or is hospitalized.10

The Khorana risk score may be used to estimate VTE risk in patients with cancer. It assigns points to
variables to determine overall risk: Very high risk cancer (stomach, pancreas) is 2 points, high-risk
cancer (lung, lymphoma, gynaecologic, bladder, or testicular) is 1 point, prechemotherapy platelet count
≥ 350 x 109/L is 1 point, prechemotherapy haemoglobin level < 100 g/L or use of red cell growth
factors is 1 point, prechemotherapy leukocyte count > 11 x 109/L is 1 point, and body mass index ≥ 35
is 1 point. Patients with a score of 1 are considered low risk, a score of 1–2 points is considered
intermediate risk, and a score of ≥ 3 is considered high risk.14

Assessing Bleeding Risk

Before beginning anticoagulant therapy, clinicians must evaluate the patient's risk for bleeding. The
Hypertension, Abnormal renal/liver function, Stroke, Bleeding, Labile International Normalized Ratio
(INR), Elderly, Drugs or alcohol use (HAS-BLED) score has strong predictive validity for major
bleeding complications and is widely used in the assessment of bleeding risk in patients with atrial
fibrillation. A recent study investigated the HAS-BLED score in VTE patients and found that it had
good predictive abilities, with a 1-point score increase associated with a 20%–30% bleeding rate
increase overall. However, in a cancer cohort, only the increase from 3 to 4 points was significant for all
bleeds and major bleeds. Adding cancer to the model as an independent covariate provided the
strongest association among all covariates, and the study authors conclude that adding cancer "as an
independent bleeding risk factor merits consideration."15

The recently developed VTE-BLEED score includes 6 variables (active cancer, uncontrolled
hypertension [male patients only], anaemia, history of bleeding, age ≥ 60 years, and renal dysfunction)
and can be used to estimate the risk of major bleeding during long-term anticoagulation. Researchers
attempted to externally validate VTE-BLEED in a post hoc study using data from the HOKUSAI-VTE
trial and determined that patients identified as high risk by VTE-BLEED had a 4-fold increased risk of
bleeding during the chronic phase of treatment. In the overall study population, the risks of bleeding in
the low- and high-risk groups were 0.51% and 2.03%, respectively (odds ratio 4.04 [95% confidence
interval (CI): 2.51, 6.48]). VTE-BLEED was consistently able to identify patients at a 2.5- to 11-fold

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higher bleeding risk across all the predefined subcategories, as well as for the treatment period between
day 30 to day 180, and beyond day 180.16

Assessing the Risk of VTE Recurrence

Several calculators are available to aid clinicians in determining the risk of VTE recurrence. The DASH
prediction score for recurrent VTE uses the following variables: D-dimer level, age, sex, and hormone
use (female) and provides information about the annual risk of VTE recurrence.17 The Vienna
prediction model uses the following variables: patient's sex, location of first VTE, serial D‐dimer
measurements, and time since discontinuing anticoagulant to determine the predicted probability of
recurrence.18 The HERDOO2 prediction model uses the following variables: post-thrombotic signs,
D-dimer level, body mass index, and age to determine predicted probability of recurrence. Only the
HERDOO2 model has been validated.19

Published findings using serial D-dimer measurements in patients with a first, unprovoked VTE suggest
that negative D-dimer results in men are not sufficient to justify stopping anticoagulant therapy.
However, it may be a reasonable strategy in female patients with VTE not associated with oestrogen
therapy.9

TREATMENT

Anticoagulants are used both for the prevention of stroke in patients with atrial fibrillation and for the
treatment and prevention of VTE.20 The focus of this literature review is the use of oral anticoagulants
to treat patients with VTE; however, it is important to note that other anticoagulant therapies are
available. These are often used in the acute setting and before certain oral anticoagulants are initiated.
Currently, treatment is recommended for at least 3 months in all patients after a first acute VTE, but
after 3 to 6 months, continued treatment depends the risk for recurrence. However, this needs to be
balanced with the risk for bleeding, and this risk is not altered, regardless of duration.3

Both heparin and low molecular weight heparin (LMWH) (eg, dalteparin, enoxaparin) work in a similar
fashion and are used for VTE treatment and prophylaxis. LMWH inhibits the final common pathway of
the coagulation cascade by activating antithrombin III. Antithrombin III binds to and inhibits thrombin
and factor Xa, ultimately preventing fibrinogen from being converted to fibrin to form a blood clot.
Heparin inhibits both factor Xa and thrombin. LMWH is given via subcutaneous injection and can
typically be dosed once per day. If bleeding occurs, administering protamine sulphate may help to
(partially) neutralize the LMWH.21 Though LMWH has been used as the comparator drug in trials of
patients with cancer and VTE, LMWH is underused in cancer-associated VTE, likely because of patient
preference, convenience, and cost concerns.22

Oral Anticoagulants

The first oral anticoagulant, warfarin, was approved in the United States in 1954. It was the most widely
used oral anticoagulant until the direct oral anticoagulants (DOACs) were approved beginning in 2010.
The DOAC class is increasingly popular because these agents are effective, safe, and do not require
international normalized ratio (INR) monitoring.20

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As the use of DOACs increases, so too does the number of bleeding events. Until 2015, warfarin was
the only oral anticoagulant with a specific reversal agent. Today, idarucizumab is available to reverse
dabigatran and andexanet alfa is approved to reverse apixaban or rivaroxaban in patients with
life-threatening or uncontrolled bleeding. However, these reversal therapies are very expensive, and
many clinicians use prothrombin complex concentrate (PCC) or activated PCC (off label) to manage
DOAC-related bleeding.20 In many cases, reversal agents are unlikely to be needed or of benefit. Case
fatality rates are lower with DOAC-associated bleeds.23

An additional concern when selecting anticoagulant therapy is renal function. For patients with renal
dysfunction (creatinine clearance [CrCl] < 30 mL/min), who require anticoagulation, the ASH
guidelines recommend adjusting doses for renal function as described in the product labelling rather
than monitoring anti-factor Xa concentrations. Clinicians can also switch patients to another
anticoagulant with lower renal clearance (eg, unfractionated heparin or LMWH).24

Direct Oral Anticoagulants (DOACs)

Apixaban

Apixaban is a factor Xa inhibitor approved in the United States and Europe for prophylaxis of DVT in
patients who have undergone hip or knee replacement surgery, for the treatment of DVT and PE, and to
reduce the risk of recurrent DVT and PE after initial therapy. In the United States, the drug's labelling
carries a black box warning of the risks for thrombotic events due to premature discontinuation of the
drug and for spinal/epidural hematoma in patients undergoing spinal procedures. The recommended
dose to treat VTE is 10 mg taken orally twice daily for 7 days and then 5 mg twice daily afterward. For
prevention of recurrent VTE, the dose is 2.5 mg twice daily. Apixaban use should be avoided in patients
with prosthetic heart valves and in those taking P-gp and strong CYP3A4 inhibitors. Bleeding is the
most common adverse effect.25, 26

The AMPLIFY-EXT study enrolled 2482 patients who had been treated with anticoagulant therapy for
DVT and/or PE for 6 to 12 months without a recurrence to investigate apixaban therapy vs placebo.
Patients in the apixaban arm were treated with either 2.5 mg of apixaban twice daily or 5 mg twice
daily for a mean duration of 330 days. Apixaban was found to be superior to placebo in the primary
endpoint of symptomatic, recurrent VTE (nonfatal DVT or nonfatal PE) or all-cause death: relative risk
0.33; CI: 0.22, 0.48 for the 2.5 mg, twice-daily dose and relative risk 0.36, CI: 0.25, 0.53 for the 5-mg,
twice-daily dose (P < .0001 for both comparisons). Adverse reactions related to bleeding occurred in
219 (13.3%) apixaban-treated patients compared to 72 (8.7%) placebo-treated patients.25 The study is
limited by the relatively brief treatment timeframe.

Apixaban was evaluated in the placebo-controlled, double-blind AVERT trial in 563 patients with
cancer who were at intermediate to high risk for VTE and who were beginning chemotherapy. VTE
occurred in 4.2% of patients in the apixaban group and in 10.2% of patients in the placebo group
(hazard ratio 0.41; 95% CI: 0.26, 0.65; P < 0.001). In the on-treatment analysis, major bleeding was
higher in the apixaban group than in the placebo group (2.1% vs 1.1%). Limitations include the fact
that many study participants had advanced cancers that were the ultimate cause of death and the
relatively short follow-up duration (up to 210 days).27

The ADAM-VTE trial enrolled 300 patients and investigated apixaban vs dalteparin in patients with

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cancer. Patients treated with apixaban had a lower bleeding risk and lower VTE recurrence compared
with dalteparin. Major bleeding occurred in 0% of 145 patients receiving apixaban, compared with
1.4% of 142 patients receiving dalteparin (P = .138; HR not estimable because of 0 bleeding events in
apixaban group). Recurrent VTE occurred in 0.7% of apixaban-treated patients vs 6.3% of
dalteparin-treated patients (HR 0.099, 95% CI: 0.013, 0.780, P = .0281). However, the small study size
limits the generalizability of the findings.29

The CARAVAGGIO study is a larger trial that is expected to provide more data about the safety and
effectiveness of apixaban vs dalteparin in patients with cancer and acute DVT or PE. As of May 2019,
1135 patients had been enrolled, and the follow-up for the last patient enrolled should have been
completed in November 2019, with published results expected in the spring of 2020.22, 28, 30

Dabigatran

Dabigatran is a direct thrombin inhibitor approved in the United States for prophylaxis of DVT in
patients who have undergone hip replacement surgery and in Europe for those who have had total hip or
total knee replacement surgery. It is approved in the United States and Europe for the treatment of
DVT and PE in patients who have been treated with a parenteral anticoagulant for 5–10 days, and to
reduce the risk of recurrent DVT and PE after initial therapy. In the United States, the drug's labelling
carries a black box warning of the risks for thrombotic events due to premature discontinuation of the
drug and for spinal/epidural haematoma in patients undergoing spinal procedures. The recommended
dose to treat VTE is 150 mg taken orally twice daily in patients with CrCl > 30 mL/min after 5–10 days
of parenteral anticoagulation. For prevention of recurrent VTE, the dose is 150 mg twice daily in
patients with CrCl > 30 mL/min after previous treatment. Dabigatran use should be avoided in patients
with prosthetic heart valves and in those taking P-gp inducers or inhibitors. Dosing recommendations
for patients with CrCl < 30 mL/min are not provided since these patients were excluded from clinical
trials of the drug. Dabigatran should not be used in patients with CrCl < 50 mL/min who are taking
concomitant P-gp inhibitors. Commonly reported adverse effects include gastritis-like symptoms and
bleeding. 31, 32

Extended treatment with dabigatran was evaluated in the RE-MEDY and RE-SONATE trials. In both
trials, participants had symptomatic VTE and had completed 3 months of treatment with warfarin or
dabigatran. RE-MEDY was a double-blind, noninferiority trial of dabigatran 150 mg twice daily vs
dose-adjusted warfarin. The trial enrolled 2856 patients and demonstrated that dabigatran was
noninferior to warfarin for the primary efficacy endpoint of recurrent VTE or VTE-related death (HR
= 1.44; 95% CI: 0.78, 2.64; P = 0.014 for noninferiority). Major bleeding was lower with dabigatran
than with warfarin, but the rate did not reach statistical significance (P = 0.06). There was also an
increased risk of acute coronary syndrome (ACS) in patients randomized to dabigatran (0.9% vs 0.2%;
P = 0.02). Trial limitations include that the majority of patients enrolled were white (90%) and male
(61%).33, 31

RE-SONATE was a double-blind, placebo-controlled superiority trial of dabigatran 150 mg twice daily.
The trial enrolled 1343 patients. Dabigatran significantly reduced the primary endpoint of objectively
confirmed symptomatic VTE or unexpected death (92%), representing superiority over placebo (HR
0.08; 95% CI: 0.02, 0.25; P < 0.001 for superiority). Major bleeding alone was not significantly
increased with dabigatran, but the composite of major or clinically relevant nonmajor bleeding was
significantly higher with dabigatran (HR 2.92; 95% CI: 1.52, 5.60; P = 0.0013). Unlike the RE-MEDY
study, there was no difference between the 2 groups in RE-SONATE in terms of ACS. The trial is

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limited by the short treatment duration of 6 months.33

A clinical trial of dabigatran in patients with cancer-associated VTE is recruiting participants and is
expected to be complete in December 2021.34

Edoxaban

Edoxaban is a factor Xa inhibitor approved in the United States to treat DVT and PE after 5–10 days of
parenteral anticoagulation. In the United States, the drug's labelling carries a black box warning of the
risks for thrombotic events due to premature discontinuation of the drug and for spinal/epidural
haematoma in patients undergoing spinal procedures.35 In Europe, edoxaban is approved for treatment
of DVT and PE as well as prevention of recurrent DVT and PE.36 The recommended dose is 60 mg
taken orally once daily following initial parenteral anticoagulation. A reduced dose of 30 mg once daily
is recommended in patients with a CrCl of 15–50 mL/min or a body weight ≤ 60 kg or in patients
taking certain P-gp inhibitors (eg, ketoconazole, ciclosporin, dronedarone, erythromycin). Commonly
reported adverse effects include bleeding, rash, abnormal liver function tests, and anaemia.35, 36

The open-label HOKUSAI-VTE Cancer trial enrolled 1050 patients with cancer and acute symptomatic
or incidental VTE. Patients were randomised to treatment with LMWH for at least 5 days followed by
edoxaban (60 mg daily) or dalteparin (200 IU/kg daily for 1 month followed by 150 IU/kg daily) for a
treatment period of at least 6 months and up to 1 year. The primary composite outcome of recurrent
VTE or major bleeding in the 12 months following randomization was 12.8% in the edoxaban arm and
13.5% in the dalteparin arm (hazard ratio 0.97; 95% CI: 0.70, 1.36; P = 0.006 for noninferiority, P =
0.87 for superiority).11, 12 Rates of recurrent VTE were lower in the edoxaban arm than in the
dalteparin arm (7.9% vs 11.3%). Rates of major bleeding were higher in the edoxaban arm than the
dalteparin arm (6.9% vs 4.0%).11 The risk of major bleeding was very high in patients with
gastrointestinal (GI) cancers.12 The trial could be limited by better adherence to edoxaban therapy than
dalteparin or the fact that edoxaban was used for longer than dalteparin (median treatment duration:
211 days for edoxaban vs 184 days for dalteparin).11

Rivaroxaban

Rivaroxaban is a factor Xa inhibitor approved in the United States and Europe for prophylaxis of DVT
in patients who have undergone hip or knee replacement surgery, for the treatment of DVT and PE, and
to reduce the risk of recurrent DVT and PE after initial treatment lasting at least 6 months.37, 38 In the
United States, the drug's labelling carries a black box warning of the risks for thrombotic events due to
premature discontinuation of the drug and for spinal/epidural haematoma in patients undergoing spinal
procedures.37 For treatment of DVT or PE, the recommended dose is 15 mg orally twice daily with
food for the first 21 days and then 20 mg orally once daily with food. To reduce the risk of recurrent
VTE, the dose is 10 mg orally once daily with or without food after at least 6 months of standard
anticoagulant therapy. The 10-mg, once-daily oral dose has not been evaluated in patients with active
cancer. Rivaroxaban should be used cautiously in patients with a CrCl 30–50 mL/min. The CrCl cut-off
recommendation for when rivaroxaban should not be used varies by indication and country. Patients
taking combined P-gp and strong CYP3A inhibitors and inducers should avoid using rivaroxaban. The
most common adverse effect is bleeding.37, 38

The open-label SELECT-D trial enrolled 406 patients with cancer and acute VTE who were randomised

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to rivaroxaban (15 mg twice daily for 3 weeks and then 20 mg daily) or to dalteparin (200 IU/kg daily
for 1 month and then 150 IU/kg daily). Patients were treated for 6 months. The primary outcome of
VTE recurrence during a 6-month period occurred in 11% (95% CI: 7%, 16%) of dalteparin-treated
patients and 4% (95% CI: 2%, 9%) of rivaroxaban-treated patients (HR, 0.43; 95% CI: 0.19, 0.99) .
However, major bleeding rates were higher with rivaroxaban than with dalteparin (6% vs 4%; HR, 1.83;
95% CI: 0.68, 4.96).11 As in the HOKUSAI-VTE trial, patients with GI cancer were found to be at
higher risk for major bleeding, and such patients were excluded toward the end of the trial.12 Since the
trial had an open-label design, there is still a risk of investigator or reporter bias. Additionally,
treatment-group differences could be the result of an imbalance in incidental PE rather than because of
symptomatic events.11

The EINSTEIN extension study investigated 20 mg of rivaroxaban daily vs placebo for an additional 6
or 12 months in 1196 patients who had already completed 6–12 months of therapy. A total of 73.7% of
patients had an unprovoked VTE. The primary efficacy endpoint, recurrent VTE, occurred in 1.3% of
rivaroxaban-treated patients and 7.1% of placebo-treated patients (HR 0.18; 95% CI: 0.09, 0.39; P <
0.001). Major bleeding was similar in both groups (0.6% in the rivaroxaban group vs 0% in the placebo
group, P = 0.11).The study only included patients with equipoise about the need for extended
anticoagulation; therefore, patients at the highest risk for VTE recurrence may have been
underrepresented.3

The EINSTEIN CHOICE study enrolled 3396 patients who had completed 6–12 months of VTE
therapy and randomized them into 3 arms: 10 mg of rivaroxaban daily, 20 mg of rivaroxaban daily, and
100 mg of aspirin daily for a treatment period of 12 months. The primary efficacy endpoint was a
composite of symptomatic, recurrent fatal or nonfatal VTE and unexplained death with bleeding as the
primary safety outcome. The composite endpoint was lower with both doses of rivaroxaban than with
aspirin (1.2% for the 10-mg rivaroxaban dose, 1.5% for the 20-mg rivaroxaban dose, and 4.4% for
aspirin; P < 0.001 for both comparisons). Bleeding rates were similar across groups: 0.4% in the 10-mg
rivaroxaban group, 0.5% in the 20-mg rivaroxaban group, and 0.3% in the aspirin group. Adverse
events were also similar across groups. The positive results of this study prompted both the US Food
and Drug Administration and the European Medicines Agency to approve the 10-mg dose of
rivaroxaban for extended VTE prevention after 6 months of standard anticoagulant therapy. Since this
study only included patients with equipoise about the need for extended anticoagulation, patients at the
highest risk for VTE recurrence may have been underrepresented in this trial.3

Guidelines for Treating Patients Without Cancer

In 2016, the American College of Chest Physicians (ACCP) issued revised guidelines about
antithrombotic therapy for VTE. The ACCP recommends that patients with proximal DVT or PE
should receive long-term (3 months) anticoagulant therapy (Grade 1B). Dabigatran, rivaroxaban,
apixaban, or edoxaban are preferred over vitamin K antagonist (VKA) therapy (Grade 2B). In patients
not treated with dabigatran, rivaroxaban, apixaban, or edoxaban, VKA therapy is suggested over
LMWH (Grade 2C). Patients with VTE provoked by surgery should receive anticoagulant therapy for 3
months (Grade 1B). Patients with VTE provoked by a nonsurgical, transient risk factor should receive
anticoagulant therapy for 3 months (Grade 1B). Patients who have a first occurrence of unprovoked
proximal DVT of the leg or PE and who have low or moderate bleeding risk should receive extended
anticoagulant therapy (no scheduled stop date) beyond the first 3 to 6 months of therapy (Grade 2B);
such patients with high bleeding risk should receive 3 months of therapy rather than extended therapy
(Grade 1B).9

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Patients who had an unprovoked proximal DVT or PE who choose to stop anticoagulant therapy could
consider taking aspirin (if not contraindicated) to prevent recurrent VTE, though the efficacy of aspirin
to prevent recurrent VTE is inferior to that of anticoagulant therapy. In patients who are receiving
anticoagulant therapy, the ACCP recommends against the use of inferior vena cava filters. Compression
stockings are not recommended for acute DVT of the leg to prevent post thrombotic syndrome. The
ACCP advises clinicians to reassess the use of anticoagulant therapy periodically in patients receiving
extended therapy.9

In 2018, ASH published guidelines on optimal management of anticoagulant therapy for patients with
VTE. The panel made 25 recommendations, among these are: dosing LMWH based on actual body
weight in obese patients, using VKAs or LMWH instead of DOACs in patients who require
concomitant P-gp or cytochrome P450 inhibitors or inducers, and suggested resumption of oral
anticoagulant therapy within 90 days for patients who survive an episode of major bleeding (in patients
requiring long-term anticoagulation).24

Guidelines for Treating Patients With Cancer

The 2015 ISTH guidelines for the diagnosis and treatment of incidental VTE in cancer patients
recommend LMWH for cancer-associated VTE. LMWH can be given at full therapeutic doses for the
first month, and then the dose can be tapered to 75% of the full dose. Warfarin may be used if LMWH
is not available or acceptable to patients, or in patients without active cancer.13

In 2018, the ISTH published specific guidance on the use of DOACs in cancer-associated VTE based
on emerging clinical trial data. The guidelines note that although clinical trial data point to improved
efficacy with DOAC therapy in cancer patients, there is concern for an increased risk of major
bleeding. As there are no formal bleeding assessment scores to predict the risk of bleeding in cancer
patients receiving DOACs, the ISTH advises caution when using these therapies in patients with GI or
genitourinary cancers based on available clinical trial data. The ISTH suggests using specific DOACs
for patients with cancer and acute VTE who have a low bleeding risk and no drug-drug interactions with
current systemic therapies. LMWH is recommended for patients with a high risk of bleeding and for
those with GI cancers or GI mucosal abnormalities. In all cases, final treatment decisions should be
made only after a shared decision-making discussion with patients.12

A separate guidance document from ISTH specifically addresses VTE management in patients with
cancer who have thrombocytopenia (platelet count < 100 x 109/L). Thrombocytopenia is a common
complication that affects nearly all patients receiving certain chemotherapy regimens. Full
anticoagulation without platelet transfusion is recommended for patients with cancer-associated
thrombosis and a platelet count ≥ 50 x 109/L. Patients with an acute cancer-associated thrombosis and
severe thrombocytopenia (platelet count < 50 x 109/L) should receive full-dose anticoagulation with
LMWH or unfractionated heparin along with a platelet transfusion. Those with a lower risk of
progression can be treated with a reduced dose of LMWH (for those with a platelet count 25–50 x 109
/L) or temporary discontinuation of anticoagulant therapy (for those with a platelet count < 20 x 109/L).
Inferior vena cava filters should only be used in patients with absolute contraindications to
anticoagulation.40

Canadian guidelines from 2018 provide a treatment algorithm for treating cancer-associated
thrombosis. For patients without contraindications to anticoagulation, the clinician should begin by

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assessing bleeding risk. Factors to consider include GI comorbidities, previous GI bleeding,
thrombocytopenia (< 50,000 platelets/mL), renal impairment (glomerular filtration rate per the
Gockcroft-Gault formula of 30–50 mL/min), recent or life-threatening bleeding, intracranial lesions,
and current antiplatelet therapy. Patients at high risk of bleeding should be treated with LMWH as
should lower-risk patients with active GI or urothelial tumours as well as lower-risk patients with other
cancer types who have drug-drug interactions with DOACs. If no drug-drug interactions are expected,
then treatment with a DOAC is recommended. Regardless of the therapy chosen, clinicians should
evaluate patients at least every 3 months or if there are changes in the patient's condition. Once a
patient's cancer is no longer active, the clinician should consider stopping anticoagulant therapy.11

More recent guidance from the American Society of Clinical Oncology (ASCO) in 2019 provides the
following recommendations for the prevention and treatment of VTE in patients with cancer10:

● Hospitalized patients with active cancer and an acute medical condition should receive
thromboprophylaxis while hospitalized
● Thromboprophylaxis is not routinely recommended for all outpatients with cancer
● Patients with cancer who are undergoing major surgery should be offered thromboprophylaxis
with unfractionated heparin or LMWH unless contraindicated, with therapy starting preoperatively
and continuing for 7–10 days
● LMWH, unfractionated heparin, fondaparinux, or rivaroxaban can be used for initial
anticoagulation in patients with VTE to prevent recurrence
● For long-term anticoagulation, LMWH, edoxaban, or rivaroxaban are recommended for at least 6
months and preferred over VKAs
● Anticoagulation with LMWH, DOACs, or VKAs should be offered beyond 6 months in select
outpatients with cancer (eg, those with metastatic disease or those receiving chemotherapy)
● Though more research is needed, it appears that insertion of vena cava filters may cause long-term
harm; therefore, filter insertion should be used only in patients with absolute contraindications to
anticoagulants for the acute treatment of life-threatening thrombi

Finally, though DOACs may be used to prevent VTE in patients with cancer, LMWH is preferred in the
guidelines as clinical trial data for DOACs as primary thromboprophylaxis are still immature.22

Conclusion

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are collectively referred to as venous
thromboembolism (VTE) and are responsible for several hundred thousand deaths annually worldwide.
Timely diagnosis of VTE is critical, but clinicians must be aware of the elevated risk for VTE in
patients with cancer and the associated complications. An array of treatments, from warfarin to LMWH
to the new class of medicines called DOACs, are available. The increase in the use of DOACs has also
led to an increase in bleeding events.20 Regardless of the anticoagulant prescribed, clinicians must
carefully balance the risk of bleeding during anticoagulant therapy with the risk for a first VTE in
cancer patients and recurrent VTE in any patient with a history of VTE.

10
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