Anticoagulation therapy for

venous thromboembolism(VTE)
in adult Cancer patients

E. K. Antiri

12/20/2020 1
Outline
• General principles
• Venous thromboembolism
• Various anticoagulants
• Venous thromboembolism management in malignancy
• Conclusion
• References

12/20/2020 2
 General principles
• Haemostasis is the normal process of blood coagulation in vivo to
stop normal, surgical or pathological bleeding.
• Thrombosis is the pathological formation of clots within blood vessels
Vascular integrity
Haemostasis Natural anticoagulants
Platelets
just right
Coagulation cascade

thrombosis

Bleeding
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Major components of haemostasis

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Venous thrombosis
• Thrombosis occurs when the fine delicate balance between procoagulant and anticoagulant
mechanisms are broken with procoagulant state been favoured.

• Virchow’s triad suggests that there are three components that are important in thrombus
formation:

• Hypercoagulability of the blood

• Slowing down of blood flow
• Vessel wall damage

• Malignancy linked to a hypercoagulable state though other mechanisms like endothelial damage
and stasis overlap.

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 Hoffbrand's
Essential
Haematology, 8th
Edition

12/20/2020 6
 Malignancy

• Patients with carcinoma of the ovary, brain and pancreas have a particularly
increased risk of venous thrombosis or its recurrence.

• There is an increased risk with all cancers including myeloproliferative

diseases.

• The tumours produce tissue factor and a procoagulant that directly activates
factor X resulting in thrombosis.

• Mucin‐secreting adenocarcinomas may be associated with DIC.

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Khorana Risk Score for Venous
Thromboembolism in Cancer Patients

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 Venous thromboembolism (VTE)
• Is a significant cause of morbidity and mortality in patients
with cancer irrespective of cancer stage.

• There is a steady increase in the incidence of cancer-associated

thrombosis over the past 2 decades possibly due to :
• Increasing survival of the aged population
• Improvements in imaging technology (advanced investigations for
early detection)
• Extended survival duration of patients with cancer developing
incidental VTE.
• Increasing cancer prevalence in our population (could be due to
lifestyle modifications)
• Greater thrombogenicity of some chemotherapeutic regimens
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• Limited advancement in the management
• Trials focused on cancer associated thrombosis lacking
• Associated with a high risk of bleeding
• Limitation in the therapeutic options to treat the underlying cancer

• Low-molecular-weight heparin(LMWH) monotherapy has been identified as a

simple and efficacious regimen
• Compared with an initial parenteral anticoagulant followed by long-term therapy with
a vitamin K antagonist.

• Treatment recommendations available from consensus clinical guidelines,

largely based on
• Retrospective reports
• Extrapolated data from the noncancer population with VTE.
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However, many clinical questions remain
unanswered.
• These include:

• Optimal duration of anticoagulant therapy?

• Treatment of recurrent VTE?

• Treatment of patients with concurrent bleeding or those with a high risk of

bleeding?

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 Hoffbrand's
Essential

Anticoagulants Haematology, 8th

Edition

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VTE management in Malignancy
• Initial management of a first episode of cancer-associated VTE
• Long-term management of a first episode of
cancer-associated VTE
• Duration of anticoagulation and anticoagulant options for extended therapy
• Use of thrombolysis in cancer-associated VTE
• Anticoagulation in patients with renal impairment
• Inferior vena cava (IVC) filters
• Treatment of recurrent VTE
• Treatment of incidental VTE
• Treatment of cancer-associated thrombosis in patients with a high risk of bleeding
• Treatment of splanchnic vein thrombosis in patients with cancer
• Use of NOACs in cancer-associated thrombosis
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 Agnes Y. Y. Lee,
Erica A. Peterson;
Treatment of
cancer-associated
thrombosis. Blood 
2013; 122 (14):
2310–2317.

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Initial management of a first episode of
cancer-associated VTE
• Initial treatment options:
• LMWH
• Unfractionated heparin (UFH)
• Fondaparinux.

• Studies directly comparing these agents are lacking in cancer patients

• Data extrapolated from trials in unselected patients: No difference in efficacy between LMWH and UFH in
patients with cancer.

• Statistically significant reduction in mortality risk with LMWH at 3 months of follow-up has been
noted.
• Reason for this survival benefit is unknown, but research exploring the antineoplastic properties of LMWH
is ongoing.

• LMWH provides other advantages vs UFH

• Lower cost (hospitalization and laboratory monitoring are not required).
• LMWH associated with a lower risk for heparin-induced thrombocytopenia (HIT) and osteoporosis
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• Data on the use of fondaparinux
• 3-month rate for symptomatic, recurrent VTE was higher for fondaparinux
vs enoxaparin in DVT treatment (12.7% vs 5.4%) but was lower for
fondaparinux vs UFH in PE treatment (8.9% vs 17.2%).

• Advantages
• Fondaparinux like LMWH, it is administered as a once-daily, weight-based
subcutaneous injection.
• Rarely associated with the development of drug-induced thrombocytopenia
and has been used off label for the management of HIT.

• Barriers
• Relatively long half-life of 17 to 21 hours
• Lack of a reversal agent
• 100% dependence on renal clearance.
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On the basis of currently available
evidence….
• LMWH is the recommended anticoagulant for the initial therapy of VTE
in most patients with cancer.

• However, UFH used in severe renal impairment ([CrCl]<30 mL/min) given

its
• Shorter half-life
• Reversibility with protamine sulfate
• Dependence on hepatic clearance.

• Fondaparinux is a reasonable choice in patients with a history of HIT.

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Long-term management of a first episode of
cancer-associated VTE
• Vitamin K antagonists (VKAs) have been the mainstay agents for long-term management
and secondary prophylaxis of acute VTE in patients without cancer.

• VKAs are less effective in patients with cancer

• Rates of recurrent VTE 3 fold higher than in patients without cancer despite maintenance of INR
within the therapeutic range.

• Several trials have compared LMWH with VKA therapy for long-term management of
cancer associated PE or proximal DVT.
• LMWH preparations: Enoxaparin, Tinzaparin, and Dalteparin were investigated for 3 to 6 months in
similarly designed studies.
• Overall, the results from these trials provide consistent evidence of improved efficacy of LMWH vs
VKA in the prevention of recurrent VTE in patients with cancer-associated VTE.
• Relative risk reduction of 53%.
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• LMWH also offers other advantages(in a addition to improved efficacy):
• No need for laboratory monitoring of its anticoagulant activity
• Shorter half-life that facilitates temporary interruption for procedures or thrombocytopenia
• Limited drug interactions
• No food interactions or reliance on oral intake or gastrointestinal tract absorption.

• LMWH is hence recommended for both initial and long-term anticoagulation in cancer-associated thrombosis
by major consensus guidelines

• Barriers
• High cost associated with LMWH therapy
• Requirement for daily subcutaneous injections

• Qualitative studies have reported that patient acceptance of daily injections is quite favourable and more
convenient than VKA.

• If LMWH is unavailable?
• American Society of Clinical Oncology (ASCO) 2013 VTE Prevention and Treatment Guideline recommends the use of VKA
with a target INR of 2 to 3 as an acceptable alternative.
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Duration of anticoagulation and anticoagulant
options for extended therapy
• Studies regarding the optimal duration of anticoagulant therapy are lacking in oncology
patients.

• The decision for continuation of anticoagulation beyond the first 3 to 6 months is largely
based on weighing the risk for recurrent thrombosis against the risk of major bleeding.

• Studies have been done to determine whether biomarkers, radiologic imaging, and clinical
prediction models can identify patients
• With a sufficiently high risk for recurrent thrombosis to benefit from extended anticoagulation
• With an acceptably low risk to allow discontinuation of anticoagulation.

• A clinical model to predict the risk for recurrent VTE during anticoagulation therapy in cancer-
associated thrombosis has been proposed but not yet validated.
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• In patients with active cancer, risk for recurrent thrombosis is high even
while receiving anticoagulation.
• Recommended that extended anticoagulation be considered in this population.

• Patients given extended anticoagulation require frequent reassessment

to review the risk-benefit balance of continuing anticoagulant therapy.

• Factors that need to be taken into account, aside from the risk for
recurrent VTE and the risk of bleeding, include
• Status of the malignancy
• Type of cancer (if any)
• Quality of life
• Patient preference

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• The choice of anticoagulant for extended anticoagulant therapy
(beyond 6 months) also has not been fully investigated.

• Patient preference and tolerance of previous therapy play significant

roles in this decision
• As with duration of therapy, the anticoagulant of choice needs to be discussed
with each patient and individualized.

• Long-term toxicity associated with VKA or LMWH has not been a

concern
• Remains controversial whether prolonged exposure to LMWH accelerates
clinically significant bone loss.

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Use of thrombolysis in cancer-associated
VTE
• Most trials of thrombolytic therapy exclude patients with cancer because of a
perceived higher risk of bleeding

• Evidence for thrombolysis in patients with malignancy is limited.

• Nonetheless, there is no strong evidence to routinely exclude patients for

consideration of thrombolysis on the basis of the presence of malignancy alone.

• Safety, cost-effectiveness, and longterm benefit of thrombolysis remain

uncertain
• Each patient must be carefully reviewed to exclude central nervous system lesions or
other risk factors for bleeding.
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Anticoagulation in patients with renal
impairment
• Renal impairment is not uncommon among patients with malignancy.

• LMWH is metabolised and partially cleared by renal excretion, hence drug

accumulation is expected with long-term use in those with significant renal
insufficiency (CrCl < 30 mL/min).
• Enoxaparin shows significant accumulation in renal insufficiency.

• Limited data on the use of LMWH in patients with significant renal dysfunction, but
they do indicate that the risk of bleeding is higher in patients with renal impairment.

• Manufacturer-recommended dose reduction in renal impairment exists for

enoxaparin but not for other LMWH preparations.

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• Most experts and guidelines recommend dose adjustment based on
anti-factor Xa activity in patients with a CrCl < 30 mL/min.

• If anti-factor Xa monitoring is not readily available, VKA therapy is likely

a safer option for long-term anticoagulation in these patients.

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Inferior vena cava (IVC) filters
• Frequently used in cancer patients.
• Data on the efficacy and safety in this population are limited.
• Data on the efficacy and safety in the general population is also sparse.

• Rates of recurrent VTE up to 32% have been reported in patients

with cancer treated with IVC filters, and fatal PE after filter insertion
has been well documented.

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• Major indication for filter insertion: Patients
who cannot receive anticoagulation(high risk
of bleeding).

• Complications associated with IVC filters raise

further concern about the appropriateness of
their use.
• Insertion problems occur in 4% to 11% of patients
• Long-term adverse effects such as thrombosis of
the IVC or lower extremity veins occur in 4% to
32%. Holleck, J.L., Chen, E.Y. & Bonomo, J. Caval
Perforation from a Malpositioned Inferior
Vena Cava Filter. J GEN INTERN
• High incidence of mechanical or device MED 34, 1358–1359 (2019).
https://doi.org/10.1007/s11606-019-04933-
failures. 8
• Filter migration
• Strut fracture with embolization
• Caval perforation.
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• IVC filters however should be restricted to patients with acute VTE and
contraindications to anticoagulation
• Due to high rates of complications
• Absence of data to support their efficacy

• Use in recurrent thrombotic events despite standard anticoagulant therapy goes

against biological rationale because
• Filters do not treat the underlying thrombotic condition
• The presence of an intravascular foreign body is likely to promote thrombus formation, which can
occur proximally or distally to the filter.
• Provide a sense of false security regarding the risk for recurrent PE, causing delays or
discontinuation of anticoagulant therapy.

• If retrievable filters are placed, efforts should be made to remove the device and
reinitiate anticoagulation as soon as the high-risk period for bleeding has passed.
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Management algorithm of recurrent VTE in
patients with cancer.

Agnes Y. Y. Lee,
Erica A. Peterson;
Treatment of
cancer-associated
thrombosis. Blood 
2013; 122 (14):
2310–2317.

12/20/2020 29
Treatment of recurrent VTE during
anticoagulant therapy
• A retrospective study of 70 patients with cancer with recurrent VTE demonstrated a
prevention of an additional VTE in 91% of patients during a minimum of 3 months of
follow-up due to
• Transition to LMWH (from VKA therapy at the time of recurrence)
• LMWH dose escalation by 20% to 25% (in patients receiving LMWH at
recurrence)

• If recurrent VTE episode occurs after the first dose escalation:

• Further dose increase or twice-daily dosing of LMWH

• The use of anti-factor Xa levels to tailor LMWH escalation

• Published evidence to support this strategy is lacking.
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Treatment of incidental VTE
• Definition:
• Incidental or unsuspected VTE is defined as evidence of thrombosis detected on
imaging studies performed for other indications such as cancer staging.

• Retrospective studies in unselected oncology patients have demonstrated

incidental VTE rates of up to 6%
• Thrombotic events evenly distributed between PE and/or DVT and intra-abdominal
thrombosis.

• Up to date, it is recommended that patients with incidental DVT and PE

receive therapeutic anticoagulation if there are no contraindications.
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• In a retrospective study comparing 51 unselected oncology patients with
incidental PE and 144 patients with symptomatic PE, the 12-month rates of
recurrent VTE, bleeding, and mortality were similar between the groups.

• In another study, a comparison of cancer patients with and without

incidental PE found that patients with incidental PE had a higher mortality
rate than those without PE.

• Few studies support its indication and its benefits:

• In a cohort of 113 patients with lung cancer and incidental PE, the 62 patients who
did not receive anticoagulation had higher mortality rates compared with patients
who were treated.
• In patients with pancreatic cancer with incidental VTE, the use of anticoagulant
therapy was associated with a 70% reduction in mortality rate.
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Management algorithm of VTE in patients with cancer and
thrombocytopenia.

Limited evidence suggests

that the use of prophylactic
doses of LMWH can be
tolerated in patients with
platelet counts < 20 x 109/L
Agnes Y. Y. Lee, with associated resolution
Erica A. Peterson; of thrombotic symptoms.
Treatment of
cancer-associated
thrombosis. Blood 
2013; 122 (14):
2310–2317.

12/20/2020 33
Treatment of cancer-associated thrombosis in
patients with a high risk of bleeding
• The most feared complication of anticoagulant treatment of VTE in
cancer patients is major bleeding
• Rate of 7.22 per 100 patient years with a case fatality rate of 9%.

• Risk of bleeding is high

• During the first months of anticoagulant treatment initiation
• When patients are receiving thrombolytic treatment.

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Treatment of cancer-associated thrombosis in
patients with a high risk of bleeding
• The first assessment of bleeding risk should be performed at the time of the VTE diagnosis
• Assessment of bleeding risk should be individualized

• Bleeding risk assessment can be used to

• Reduce the overall risk of bleeding by targeting identified risk factors
• Determine the optimal anticoagulant drug class
• Determine the optimal drug dose
• Determine the optimal treatment duration

• Although subtherapeutic INR values are associated with recurrent VTE, there appears to be no correlation between the
INR level and bleeding in patients with cancer.

• Prospective RCTs comparing LMWH and VKA therapy for cancer associated VTE have reported similar bleeding rates.
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• Features specific to oncology patients that contribute to bleeding include
the:
• Extent
• Location
• Histologic features of the cancer
• Need for invasive diagnostic or treatment procedures
• Development of thrombocytopenia from chemotherapy

• Other comorbidities may further predispose them to bleeding:

• Renal impairment
• Coagulopathy from liver dysfunction
• Disseminated intravascular coagulopathy
• Sepsis
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Proposed risk stratification schemes to
predict bleeding in patients with VTE

Frederikus A. Klok, Menno V.

Huisman; How I assess and
manage the risk of bleeding in
patients treated for venous
thromboembolism. Blood 2020;
12/20/2020 135 (10): 724–734. 37
 Frederikus A. Klok, Menno V.
Huisman; How I assess and
manage the risk of bleeding in
patients treated for venous
thromboembolism. Blood 2020;
135 (10): 724–734.

12/20/2020 38
 Frederikus A. Klok, Menno V.

Most relevant risk stratification schemes Huisman; How I assess and

manage the risk of bleeding in

derived in different settings than VTE patients treated for venous

thromboembolism. Blood 2020;
135 (10): 724–734.

12/20/2020 39
Current status of best-studied risk stratification
schemes for major bleeding in patients with VTE

Frederikus A. Klok,
Menno V. Huisman;
How I assess and
manage the risk of
bleeding in patients
treated for venous
thromboembolism. 
Blood 2020; 135
(10): 724–734.

12/20/2020 40
 Frederikus A. Klok,
Menno V. Huisman;
How I assess and
manage the risk of
bleeding in patients
treated for venous
thromboembolism. Blo
od 2020; 135 (10):
724–734.

12/20/2020 41
Management points
• For minor bleeding, anticoagulation may be continued as long as close
follow-up is available.

• In patients with absolute contraindications to anticoagulation, the risk of

bleeding likely outweighs the benefit of treatment, and anticoagulants
should be withheld.
• Follow-up imaging should be performed to assess for thrombus progression, and
IVC filter insertion can be considered.

• If severe cancer- or chemotherapy-induced thrombocytopenia is present,

platelet transfusions may be used to allow anticoagulation.
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Treatment of splanchnic vein thrombosis(SVT) in
patients with cancer
• SVT typically involves:
• Portal, splenic, mesenteric and hepatic veins

• Typically uncommon in the general population, but significant rates have been reported in patients with
intraabdominal malignancies.

• In a retrospective single-institution study of 135 consecutive patients with pancreatic adenocarcinoma,

incidental splanchnic vein thrombosis was present in 23%.

• Limited studies in management of SVT.

• Limited experience is available from few studies.

• An international registry of 613 patients with splanchnic vein thrombosis reported that most patients are
treated with anticoagulation and that the risk of major bleeding is low. Whether such results apply to cancer-
related SVT is not known.
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• In patients with acute, symptomatic splanchnic vein thrombosis
without contraindications to anticoagulation, guidelines recommend
the use of anticoagulant therapy.

• In incidentally detected SVT, there is no specific guidance on

treatment. It is reasonable to withhold anticoagulation if the patient
is truly asymptomatic, especially if radiologic evidence indicates that
the thrombus is chronic in nature.

• Repeated imaging is prudent to detect thrombus progression if

anticoagulation is not given.

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Use of NOACs in cancer-associated
thrombosis
• NOACs directly inhibit factor Xa or thrombin in the prevention and treatment of VTE.

• These agents are more attractive to patients and clinicians because

• They are taken by mouth in fixed doses once or twice daily
• Have few drug and food interactions (interactions do exist with some chemotherapeutic agents, Whether these interactions are clinically
significant is not known)
• Do not require laboratory monitoring

• Agents include:
• Dabigatran, a direct thrombin inhibitor
• Rivaroxaban and apixaban, 2 direct factor Xa inhibitors

• Shown to be effective in VTE prophylaxis after major hip and knee arthroplasty and in stroke prevention in patients with
non valvular atrial fibrillation.

• They are also noninferior to warfarin for the prevention of recurrent VTE without an increased risk of bleeding

• Rivaroxaban has received regulatory approval as monotherapy in the treatment of DVT.

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• All 3 agents are effective and safe for long-term secondary VTE
prophylaxis.

• No studies have specifically addressed the treatment of cancer-

associated VTE using these direct inhibitors.
• Extrapolation of published results to the cancer population.

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• Current ASCO Guideline does not recommend the use of these new
agents because of various shortcomings:
• Gastrointestinal tract problems in patients with cancer can potentially alter drug
delivery and absorption
• Higher rates of gastrointestinal tract bleeding have been reported with dabigatran
compared with warfarin.
• Lack of reversal agents to rapidly normalize haemostasis
• Lack of widely available laboratory assays to measure the anticoagulant activity.
• Cost

• Clinical trials are strongly encouraged to address these shortcomings.

• Clinicians need to discuss these limitations to fully inform their patients

decision.
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In conclusion
• Treatment options for VTE management in adult cancer patients remain very limited.

• Treatment recommendations from consensus clinical guidelines are largely based on

retrospective reports or extrapolated data from the noncancer population with VTE, as
randomized controlled trials focused on cancer-associated thrombosis are sorely lacking.

• Although LMWH monotherapy has been identified as a simple and efficacious regimen
compared with other anticoagulants, many clinical questions remain partially answered.

• These include
• Optimal duration of anticoagulant therapy
• Treatment of recurrent VTE
• Treatment of patients with concurrent bleeding or those with a high risk of bleeding.
• Clinical trials henceforth are strongly encouraged.
12/20/2020 48
References
• Holleck, J.L., Chen, E.Y. & Bonomo, J. Caval Perforation from a Malpositioned Inferior Vena Cava
Filter. J GEN INTERN MED 34, 1358–1359 (2019). https://doi.org/10.1007/s11606-019-04933-8

• Frederikus A. Klok, Menno V. Huisman; How I assess and manage the risk of bleeding in patients
treated for venous thromboembolism. Blood 2020; 135 (10): 724–734. doi: https://
doi.org/10.1182/blood.2019001605

• Agnes Y. Y. Lee, Erica A. Peterson; Treatment of cancer-associated thrombosis. Blood 2013; 122

(14): 2310–2317. doi: https://doi.org/10.1182/blood-2013-04-460162

• Hoffbrand's Essential Haematology, 8th Edition

12/20/2020 49
Thank you
• Any questions?

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