Updates in prophylaxis and management of venous thromboembolism VTE in cancer patients 2020

1. Venous
Thromboembolism
in Cancer Patients
By
Dina Barakat
Assistant Lecturer
Clinical Oncology Department
Faculty of Medicine
Assiut University

2. Learning Objectives
 Scope of the problem
 VTE risk assessment for patients
 Thromboprophylaxis
 Management of VTE

3. Introduction
 Venous thromboembolism (VTE) represents one
of the most important causes of morbidity and
mortality in cancer patients.
 According to population-based case–control
studies, the 2-year cumulative incidence of VTE is
between 0.8 and 8%

4. Patients at risk
 Patients with the highest 1-year incidence rate of VTE
are those with advanced disease of :
 the brain,
 lung,
 uterus,
 bladder,
 pancreas,
 stomach and
 kidney.
 For these histotypes, the rate of VTE is 4–13 times
higher among patients with metastatic disease as
compared with those with localized disease

6.  The increased risk of recurrent VTE in cancer
patients is greatest in the first few months
after malignancy is diagnosed and can persist
for many years after an initial episode of
symptomatic VTE.
 While receiving chemotherapy, cancer
patients have a 7-fold risk of developing VTE
as compared with other patients without
cancer.
 Cancer patients, once hospitalized, are at an
even higher risk of developing VTE.

7. Clinical Risk Factors
 Since VTE is a multifactorial event, the absolute risk
depends on several factors including:
 tumour type,
 stage of disease,
 the administration of chemotherapy and/or hormone
therapy,
 surgical interventions, length of anaesthesia,
 The presence of an indwelling central venous catheter,
 age,
 immobilization
 and previous history of VTE

9. How cancer treatment can
increase patient risk for
developing VTE?

10. Chemotherapy…
 One of the most important factors promoting VTE
may be the use of cytotoxic drugs.
 Chemotherapy can increase the risk of VTE by at
least four mechanisms:
 (i) acute damage to vessel walls;
 (ii) non-acute damage of the endothelium;
 (iii) a decrease in natural coagulation inhibitors
(reduced level of C and S proteins or antithrombin
III); and
 (iv) platelet activation.

11. Target therapy and …
 Antiangiogenic agents such as bevacizumab, thalidomide and lenalidomide
also contribute to thrombosis, through:
 endothelial cell and platelet activation
 and damage to the vascular endothelium.
 The thrombogenic effect of antiangiogenic agents is amplified by the co-
administration of chemotherapy and steroids.
 In a recent meta-analysis of clinical trials of bevacizumab administered
concomitantly with chemotherapy, the use of bevacizumab was associated
with a 33% relative increase of VTE. Among patients receiving
bevacizumab, the overall incidence of any-grade and high-grade VTE was
11.9 and 6.3%, respectively.
 With regards to multiple myeloma, the highest incidence of VTE was
observed in patients treated with thalidomide- and doxorubicin-containing
chemotherapy (VTE rate of up to 34%) [9] and in patients with relapsed
myeloma treated with lenalidomide and high-dose dexamethasone [10

13. Fighting VTE has two main arms
Prophylaxis
Early
detection and
management
Prevent
morbidity
and
mortality

14. Prophylaxis

15. Prophylaxis
When?
How?
For how long?

16. When? (Indications):
 Cancer patients undergoing surgeries?
 Hospital admission.. (risk assessment?)
 Patients on active cancer treatment?
 Patients with central lines?

17. How?
Prophylaxis
Mechanical
Graduated compression
stockings
Pneumatic compression
devices
IVC filters
Pharmacological
Unfractionated heparin
LMWH
Fondaparinux
Warfarin
DOACs

20. When to start it ??
For how long?????

21. Cancer patients undergoing
surgery..
 Cancer patients who undergo surgery are at high
risk of developing a VTE complication.
 It has been reported that cancer patients undergoing
a surgical procedure have twice the risk of
postoperative VTE and more than three times the
risk of fatal PE than patients who undergo surgery
for benign diseases.
 In addition to the cancer-associated risk, a large
group of patients presents with additional risk factors
for thrombosis, such as increasing age, prolonged
immobility, obesity and indwelling central venous
catheters.
 The role of prophylaxis is unquestionable!!

22. Dosing and duration
 In cancer patients undergoing major cancer
surgery, prophylaxis with LMWHs or UFH is
recommended.
 Mechanical methods such as pneumatic calf
compression may be added to
pharmacological prophylaxis but should not
be used as monotherapy unless
pharmacological prophylaxis is
contraindicated because of active bleeding.

23.  Dosing in the perioperative setting; In surgical
cancer patients, highdose s.c. LMWH (e.g.
enoxaparin 4000 U of anti-Xa activity, dalteparin
5000 U of anti-Xa activity) once daily, or s.c.UFH
5000 U (three times daily) are recommended
 Duration; For patients having a laparotomy,
laparoscopy, thoracotomy or thoracoscopy lasting
>than 30 min, consider s.c. LMWH for at least 10
days postoperatively.
 Two randomized controlled, prospective trials
have shown that, in cancer patients undergoing
elective major abdominal or pelvic surgery,
continuing prophylaxis with a LMWH up to 30
days postoperatively can reduce the risk of VTE
by 60% without increasing the risk of bleeding

24. Cancer patients on hospital
admission
 Three large, high quality clinical trials, in
hospitalized ‘medical patients’, which included
cancer patients, have demonstrated that
prophylaxis leads to a lower VTE incidence
compared with placebo, without increasing
major bleeding
 Prophylaxis with UFH, LMWH or fondaparinux
in hospitalized cancer patients confined to
bed with an acute medical complication is
recommended

26. How to apply the
recommendations in our daily
practice???

27. Risk Assessment
Q1: Is the patient to be admitted
at risk at all???

29. Please remember
you need to balance between risk of
thrombosis and risk of bleeding..
So the next step in your assessment
should be…

30. Assessment for risk of bleeding..

32. Well…
Now I know my patient is AT
RISK of thrombosis..
What’s next….

34. Enoxaparin (LMWH)
 Dose of Enoxaparin (Clexane) LMWH
 Usual Adult Dose for Deep Vein Thrombosis -
Prophylaxis
 40 mg subcutaneously once a day
Duration of therapy: Usually 6 to 11 days; up to 14
days has been well tolerated in clinical trials.
Use: Prophylaxis of deep vein thrombosis (DVT) in
medical patients at risk for thromboembolic
complications due to severely restricted mobility
during acute illness.

35. Patients on active cancer
treatment
 Extensive, routine prophylaxis for advanced
cancer patients receiving chemotherapy is not
recommended, but may be considered in high-
risk ambulatory cancer patients.
 Consider LMWH, aspirin or adjusted-dose
warfarin (INR 1.5) in myeloma patients receiving
thalidomide plus dexamethasone or thalidomide
plus chemotherapy.
 Prophylaxis in cancer patients receiving adjuvant
chemotherapy and/or hormone therapy is not
recommended.

36. In this study 123 patients were randomized; the
incidence of VTE, during the first 3 months, was
25% vs 3.5% in the standard and the experimental
group, respectively. Lethal VTE and sudden deaths
were seen only in the standard arm (9%), with none
in the experimental arm.

37. In this trial 1150 patients were randomized to receive nadroparin or
placebo; among those, 53 patients had locally advanced or
metastatic pancreatic cancer. The primary endpoint was the
composite of symptomatic venous or arterial thromboembolic events.
Thromboembolic events occurred in 2.0 and 3.9% of patients treated
with nadroparin and placebo, respectively, without increasing major
or minor bleeding. This trial, by using a LMWH, demonstrated for
the first time a statistically significant reduction of
thromboembolic events in ambulatory cancer patients receiving
chemotherapy for locally advancer or metastatic cancer.

38.  Patients with lung or pancreatic cancer were
more likely to experience thromboembolic
events than were patients with breast,
gastrointestinal, ovarian, or head and neck
cancers, which suggested that these patient
groups may benefit from LMWH prophylaxis.

39.  In a recent retrospective study involving >66 000
adults with cancer, 5.4% of patients developed
VTE over the 8 years of the study
 Furthermore, in a retrospective study, cancer
patients were found to have a 3-fold higher risk for
recurrent VTE than patients who had an initial
VTE in the absence of malignancy
 The probability of readmission for recurrent VTE
within 183 days was 22% for cancer patients
compared with 6.5% for those without malignancy.

41. Patients with Central Venous
Catheters
 In the last two decades, two open-label randomized
clinical trials suggested a role for prophylaxis with
warfarin or a LMWH in patients with a CVC
 Four recent studies have assessed that the
incidence of symptomatic CVC-related VTE is in
general low, 3–4%, and that there is no statistically
significant difference between patients undergoing
and patients not undergoing prophylaxis
 Extensive, routine prophylaxis to prevent CVC-
related VTE is not recommended

42. What Guidelines say about
it??

46. ASCO 2019 update
Changes to previous recommendations:
 Clinicians may offer thromboprophylaxis with apixaban,
rivaroxaban, or LMWH to selected high-risk outpatients with cancer
(Khorana score ≥2); rivaroxaban and edoxaban have been added
as options for VTE treatment.
 Patients with brain metastases are now addressed in the VTE
treatment section; and the recommendation regarding long-term
postoperative LMWH has been expanded.
 Re-affirmed recommendations: Most hospitalized patients with
cancer and an acute medical condition require thromboprophylaxis
throughout hospitalization.
 Thromboprophylaxis is not routinely recommended for all
outpatients with cancer.
 Patients undergoing major cancer surgery should receive
prophylaxis starting before surgery and continuing for at least 7 to
10 days.
 Patients with cancer should be periodically assessed for VTE risk,
and oncology professionals should provide patient education about
the signs and symptoms of VTE.

47. Management of Patients
with VTE
 The aim of VTE treatment can be summarized
as follows:
 To prevent fatal PE
 To prevent recurrent VTE
 To prevent long-term VTE and PE complication
such as post-thrombotic syndrome and chronic
thromboembolic pulmonary hypertension

48. Now, you have a patient
presenting with suspected lower
limb DVT…
How to deal with??

49. Investigation of DVT
A. Request baseline bloods (full blood count,
coagulation screen, renal and liver biochemistry) for
all patients.
B. Risk stratify for the likelihood of DVT:
 Risk stratify patients using the two-level DVT
Wells score to estimate the clinical probability of
DVT.

50. 1st step…
Calculate his WELLs risk score

51. Next… Apply the algorithm

52.  If DVT LIKELY: Arrange proximal leg vein ultrasound
scan within 4 hours.
o If scan result cannot be obtained within 4 hours of
requesting, obtain a D-dimer and start treatment dose
dalteparin (or unfractionated heparin infusion if
creatinine clearance <20mL/min).
o Scan should be carried out within 24 hours and
anticoagulation reviewed when result available.
o If scan negative and D-dimer positive, do not continue
anticoagulant treatment, re-scan in 6 to 8 days. If repeat
scan negative consider alternative diagnosis.
o If patient was already on therapeutic anticoagulation at
presentation, continue anticoagulation and arrange senior
clinical review.
o Consider alternative diagnosis; if thought DVT most likely
diagnosis repeat scan should be performed in 6-8 days.
 If scan establishes diagnosis of DVT…continue your
treatment

53. i. If DVT UNLIKELY: Request D-dimer and obtain
results.
 If the D-dimer result is negative, consider
alternative diagnosis.
 If the D-dimer result is positive (or patient is already
on anticoagulation), arrange proximal leg vein
ultrasound scan within 4 hours.
 If scan result cannot be obtained within 4 hours
of requesting, start treatment dose dalteparin
(or unfractionated heparin infusion if creatinine
clearance <20mL/min). Scan should be carried
out within 24 hours and anticoagulation
reviewed when result available.
 If scan establishes diagnosis of DVT, treat

56. Another patient with suspected
Pulmonary Embolism??
What are you going to do??

57. Massive Pulmonary Embolism
 When to suspect massive PE:
Suspect massive PE if:
 Circulatory collapse (systolic BP < 100mmHg, HR > 120 beats
per minute)
 Signs of shock or an episode of collapse
 Start treatment pending results of investigations:
 Bolus IV unfractionated heparin (5000 units) followed by
maintenance infusion
 Call Chest Department residents
 Arrange EMERGENCY CTPA with radiologists Imaging must
be performed immediately
 If collapsed patient or too unwell for CTPA, make emergency
referral to the Cardiologists for urgent echocardiogram, or
consider thrombolysis on clinical grounds.

59. Streptokinase
 Pulmonary embolism
By intravenous infusion
• For Adult
250 000 units, dose to be given over 30 minutes, then
100 000 units every 1 hour for 24 hours, alternatively
1 500 000 units, dose to be given over 1–2 hours.
 Deep-vein thrombosis,
Central retinal venous or arterial thrombosis
By intravenous infusion
• For Adult
250 000 units, dose to be given over 30 minutes, then
100 000 units every 1 hour for 12 hours for central
retinal venous or arterial thrombosis, or for 72 hours for
deep-vein thrombosis.

60. Non-massive Pulmonary
Embolism
 Non-massive PE is PE without circulatory collapse.
1) Clinical
 History – acute persisting dyspnoea, haemoptysis, pleuritic chest pain,
syncope
 Examination – breathless, hypotension, cyanosis, tachycardia
 These symptoms may be absent in some cases and may be subtle in
young, previously healthy individuals.
2) Investigation of suspected non-massive PE
 See algorithm ii: investigation and management of Pulmonary Embolism
A. Request D-dimer test and baseline bloods (full blood count, coagulation
screen, renal and liver biochemistry) for all patients.
B. Risk stratify the patient using the two-level PE Wells score to estimate
the clinical probability of PE

61. Risk assessment…

62. Follow the Algorithm..

63.  If PE LIKELY: Arrange immediate CTPA.
 If scan is negative, obtain results of D-dimer test.
 Start therapeutic anticoagulation at same time as
requesting scan: treatment dose dalteparin (or
unfractionated heparin infusion if creatinine clearance
<20mL/min). Scan should be carried out as soon as
possible, and anticoagulation reviewed when result
available.
o If CTPA indeterminate, consider a proximal leg vein
ultrasound scan if symptomatic.
o If scans show no PE and no DVT, consider alternative
diagnosis.
 If CTPA positive, commence initial treatment with
dalteparin (or unfractionated heparin infusion if
creatinine clearance <20mL/min)

64. If PE UNLIKELY: Obtain D-dimer results:
 If the D-dimer result is negative, consider alternative
diagnosis
 If the D-dimer result is positive (or patient is already on
anticoagulation), arrange immediate CTPA
 Start therapeutic anticoagulation at same time as
requesting scan: treatment dose dalteparin (or
unfractionated heparin infusion if creatinine clearance
<20mL/min). Scan should be carried out as soon as
possible, and anticoagulation reviewed when result
available.
o If CTPA indeterminate, consider a proximal leg vein
ultrasound scan if symptomatic.
o If scans show no PE and no DVT, consider alternative
diagnosis.
o If scan positive, commence initial treatment with
dalteparin (or unfractionated heparin infusion if
creatinine clearance <20mL/min) (see below)

65. Enoxapren (LMWH)
Usual Adult Dose for Deep Vein Thrombosis
Outpatient: 1 mg/kg subcutaneously every 12 hours
Inpatient: 1 mg/kg subcutaneously every 12 hours or 1.5 mg/kg
subcutaneously once a day at the same time every day.
Duration of therapy: At least 5 days and until a therapeutic oral
anticoagulant effect has been achieved (INR 2 to 3). Average duration
is 7 days; up to 17 days has been well tolerated in controlled clinical
trials.
Comments: In both outpatient and inpatient treatments, warfarin
sodium therapy should be initiated when appropriate (usually within
72 hours of commencing enoxaparin).
Uses:
-Outpatient treatment of acute deep vein thrombosis (DVT) without
pulmonary embolism (PE) when administered in conjunction with
warfarin sodium.
-Inpatient treatment of acute DVT with or without PE when
administered in conjunction with warfarin sodium.

66. Further investigations??
 ECG / blood gases - are not diagnostic and may be normal. Exclude other
causes for symptoms and signs.
 Chest X-ray - PE is supported by atelectasis, oligaemic defect, pleural
effusion. However, the chest X-ray may be normal.
 Laboratory investigations – FBC, coagulation screen, and renal and liver
biochemistry should be checked prior to anticoagulation. Do not request
thrombophilia investigations as they will not change acute management.
 Troponin - Patients with clinical signs of acute right heart failure and a raised
troponin are at higher risk of complications, even if haemodynamically stable.
Troponin measurement should be undertaken in all patients for risk
stratification and monitoring.
 Echocardiography – routine echo is not necessary and adds little
prognostic value to Troponin assessment.
 A low D-dimer result (<500ng/mL) EXCLUDES a PE in patients who are
‘PE unlikely’ if the patient is not receiving anticoagulant therapy and the
onset of symptoms has been within the last week.
 Remember that D-dimers are raised in many other clinical situations
(e.g. infection, malignancy, postoperatively, pregnancy, disseminated
intravascular coagulopathy)
 Consider ultrasound leg scan if symptomatic of DVT and high PESI score
to assist further management plan (as in table below: patients with high PESI
score and acute DVT have an increased mortality risk).

67. PESI score for risk stratification of
patients with non-massive PE:
Criteria Score
Age 1 point per year
Male gender 10 points
Active cancer within 6 months 30 points
History of heart failure 10 points
History of chronic lung disease 10 points
Pulse ≥110 bpm 20 points
Systolic BP <100 mmHg 30 points
Respiratory rate ≥30 bpm 20 points
Temperature <36o
C 20 points
Altered mental status (disorientation, lethargy, stupor, or coma) 60 points
Arterial oxygen saturation < 90% 20 points
Total score:

68. Interpretation of PESI score: 30 day mortality risk
Score Class Mortality risk Management
<66 Class 1 Very low 0 to 1.6% Consider for ambulatory care / early discharge
if fulfil criteria – see Appendix 2. If not suitable
for ambulatory care, admit to hospital and
triage to acute respiratory take
66 - 85 Class 2 Low 1.7 to 3.5%
86 - 105 Class 3 Moderate 3.2 to 7.1% Manage as inpatient. Respiratory team
review. Repeat PESI at 48 hours: if repeat
PESI ≤ 85 they may be suitable for early
discharge.
106 - 125 Class 4 High 4.0 to 11.4% Manage as inpatient. Respiratory team
review. Assess troponin and leg ultrasound to
further risk stratify if possible candidate for
thrombolysis.
>125 Class 5 Very high 10.0 to 24.5%

69.  Additional early management of PE
 Patients with higher risk PESI score, raised
troponin and acute DVT should be considered
for a 24-48hr period of monitoring on ICU.
 Thrombolysis should be considered if there are
signs of haemodynamic instability.
 Supportive therapy with oxygen and analgesia
as required (maintain O2 sats >94-98% unless
underlying hypercapnia) - see oxygen guidelines
 Patients at moderate risk (PESI score 86-105)
should be admitted and reassessed with the
PESI score at 48hours. If there score
subsequently falls into the low risk category, they
may be suitable for early discharge.

71. Anticoagulation therapy in
patients with recurrent VTE
 Patients adequately anticoagulated who develop VTE recurrence
should be checked for progression of their malignancy.
 Cancer patients have a 3-fold risk of recurrent VTE and a 3- to 6-fold
risk of major bleeding while receiving anticoagulant treatment with a
VKA, as compared with patients without cancer [46].
 Patients on long-term anticoagulation with VKA who develop VTE
when their INR is in the subtherapeutic range can be retreated with
UFH or LMWH until VKA anticoagulation achieves a stable INR
between 2.0 and 3.0.
 If VTE recurrence occurs while the INR is in the therapeutic range
there are two options:
 (i) either shift to another method of anticoagulation, such as s.c.
UFH maintaining a therapeutic aPTT (aPTT ratio from 1.5 to 2.5), or
LMWH at a weight-adjusted dose;
 or (ii) or increase the INR (to a target of 3.5).
 Full-dose LMWH (200 U/kg once daily) can be resumed in patients
with a VTE recurrence while receiving a reduced dose of LMWH or
VKA anticoagulation as a long-term therapy. Escalating the dose of
LMWH results in a second recurrent VTE rate of 9%; it is well
tolerated, with few bleeding complications

73. Role of Direct Oral Anticoagulants in
VTE in cancer patients
 DOACs are now approved by the US Food and Drug
Administration and European Medicines Agency for selected
indications in VTE prevention and treatment, but are not routinely
recommended in cancer patients.
 These agents inhibit activated factor X (rivaroxaban,
apixaban, edoxaban) or thrombin (dabigatran etexilate)
 The major concerns about DOACs in cancer patients include:
 unpredictable absorption and higher risk of GI bleeding in
patients with mucositis,
 inability to measure the anticoagulant activity by using
standard assays,
 potential interaction with hormonal and chemotherapeutic
agents, altered metabolism in patients with renal dysfunction or
hepatic metastasis,
 and lack of antidote when patients are actively bleeding

74.  The DOACs, including the direct factor IIainhibitor
dabigatran and the factor Xainhibitors apixaban,
rivaroxaban, and edoxaban, are being investigated for
use in cancer patients
 These agents offer many benefits over traditional
anticoagulants, including no requirement for laboratory
monitoring, feasibility of oral administration and a
reduced risk for food-drug interactions
 All three agents have received regulatory approval for
the treatment of acute VTE in the general population,
but there remains a paucity of data on the efficacy and
safety of these agents in patients with cancer and
European regulatory authorities have advised against
the use of apixaban for the treatment of cancer-
associated VTE

75.  A recent meta-analysis evaluated 9 RCTs and included
2,310 patients treated with DOACs
 This analysis demonstrated a reduction in recurrent
VTE in patients treated with LMWH compared with
those receiving warfarin (RR, 0.52; 95% CI, 0.36–0.74)
 Conversely, compared with warfarin, DOACs were not
associated with a significant reduction in recurrent VTE
(RR, 0.66; 95% CI, 0.39–1.11)
 In this study, LMWH was associated with a
nonsignificant increase in major bleeding (RR, 1.06;
95% CI, 0.5–2.23), whereas DOACs showed a
nonsignificant decrease (RR, 0.78; 95% CI, 0.42–1.44)
 Overall, in light of the paucity of data demonstrating the
safety and efficacy of these agents in cancer patients
and lack of appropriate control arms, current published
consensus guidelines do not recommend their use in
patients with cancer

79. Dosing of DOACS
 Treatment of deep-vein thrombosis,
Treatment of pulmonary embolism
By mouth For Adult
Initially 15 mg twice daily for 21 days, then maintenance
20 mg once daily, to be taken with food, for duration of
treatment
 Prophylaxis of recurrent deep-vein thrombosis,
Prophylaxis of recurrent pulmonary embolism
By mouth For Adult
10 mg once daily, following completion of at least 6 months
of anticoagulant treatment, to be taken with food, consider
20 mg once daily in those at high risk of recurrence (such as
complicated comorbidities, or previous recurrence with
rivaroxaban 10 mg once daily).

80. ASCO 2019 Update
 Initial anticoagulation may involve LMWH, UFH,
fondaparinux, or rivaroxaban.
 For patients initiating treatment with parenteral
anticoagulation, LMWH is preferred over UFH for
the initial 5 to 10 days of anticoagulation for the
patient with cancer with newly diagnosed VTE
who does not have severe renal impairment
(defined as creatinine clearance less than 30
mL/min)

81.  For long-term anticoagulation, LMWH, edoxaban,
or rivaroxaban for at least 6 months are preferred
because of improved efficacy over vitamin K
antagonists (VKAs).
 VKAs are inferior but may be used if LMWH or
direct oral anticoagulants (DOACs) are not
accessible.
 There is an increase in major bleeding risk with
DOACs, particularly observed in GI and potentially
genitourinary malignancies. Caution with DOACs is
also warranted in other settings with high risk for
mucosal bleeding. Drug-drug interaction should be
checked prior to using a DOAC

82.  Anticoagulation with LMWH, DOACs, or VKAs
beyond the initial 6 months should be offered
to select patients with active cancer, such as
those with metastatic disease or those
receiving chemotherapy.
 Anticoagulation beyond 6 months needs to be
assessed on an intermittent basis to ensure a
continued favorable risk-benefit profile

83. Take home messages
Can you answer the following
questions now???

84. 1. Should hospitalized patients with cancer receive
anticoagulation for VTE prophylaxis?
2. Should ambulatory patients with cancer receive
anticoagulation for VTE prophylaxis during systemic
chemotherapy?
3. Should patients with cancer undergoing surgery receive
perioperative VTE prophylaxis?
4. What is the best method for treatment of patients with
cancer with established VTE to prevent recurrence?
5. Should patients with cancer receive anticoagulants in the
absence of established VTE to improve survival?
6. What is known about risk prediction and awareness of VTE
among patients with cancer?
7. What is WELLs score?
8. What is Khorana score and when to use it?