Transcript Extended Treatment of DVT in Cancer Patients

Extended Treatment of
VTE in Cancer Patients
Dr. Ayman Samir M.D.
Prof. of Vascular Surgery, Zagazig University
 In a population-based study, cancer was associated with a
4.1 fold greater risk of thrombosis, whereas the use of
chemotherapy increased the risk 6.5 fold. (1)
Introduction
 Of all patients with VTE, patients with cancer account for
20%, with patients receiving chemotherapy accounting for
as much as 13% of the total burden of VTE. (2)
(1) Heit JA, Silverstein MD, Mohr DN, et al: Risk factors for deep vein thrombosis and pulmonary embolism: A
population-based case-control study. Arch Intern Med 160:809-815, 2000
(2) Caine GJ, Stonelake PS, Lip GY, et al: The hypercoagulable state of malignancy: Pathogenesis and current debate.
Neoplasia 4:465-473, 2002
 In a recent analysis of more than 66,000 patients
with cancer hospitalized at 120 US academic
medical
Introduction
centers,
5.4%
developed
VTE
per
hospitalization, increasing by 36% from 1995 to
2002 (P .0001 for trend).
Khorana AA, Francis CW, Culakova E: Thromboembolism is a leading cause of death in cancer patients receiving
outpatient chemotherapy. J Thromb Haemost 5:632-634, 2007
 Vascular toxicity particularly thromboembolism, is
a specific toxicity of antiangiogenic drugs. Newer
cancer
Introduction
regimens
that
include
thalidomide,
lenalidomide, or bevacizumab have reported very
high rates of VTE.
Shah MA, Ilson D, Kelsen DP: Thromboem- bolic events in gastric cancer: High incidence in patients receiving
irinotecan- and bevacizumab- based therapy. J Clin Oncol 23:2574-2576, 2005
•Patient-related factors
1. Older age
2. Race (higher in African Americans; lower in Asian-Pacific
Risk Factors
for VTE in
Cancer
Patients
Islanders)
3. Comorbid conditions (obesity, infection, renal disease,
pulmonary disease, arterial thromboembolism). Prior
history of VTE
4.Elevated pre-chemotherapy platelet count
5. Heritable prothrombotic mutations
Cancer-related factors
1. Primary site of cancer (GI, brain, lung, gynecologic,
renal, hematologic)
Risk Factors
2. Initial 3-6 months after diagnosis
3. Current metastatic disease
Treatment-related factors
1. Recent major surgery
2. Current hospitalization
3. Active chemotherapy
Risk Factors
4. Active hormonal therapy
5. Current or recent antiangiogenic therapy (thalidomide,
lenalidomide, bevacizumab ), Current erythropoiesisstimulating agents
6. Presence of central venous catheters
SHOULD
HOSPITALIZED
PATIENTS WITH
CANCER RECEIVE
ANTICOAGULATION
FOR VTE
PROPHYLAXIS?
 According to ASCO Guidelines 2016:
Hospitalized patients with cancer should be considered candidates
for VTE prophylaxis with anticoagulants in the absence of bleeding
or other contraindications to anticoagulation.
 According to ASCO Guidelines 2016:
SHOULD
AMBULATORY
PATIENTS WITH
CANCER RECEIVE
ANTICOAGULATION
FOR VTE
PROPHYLAXIS
DURING SYSTEMIC
CHEMOTHERAPY?
(1) Routine prophylaxis with an antithrombotic agent is not
recommended.
(2) Patients receiving thalidomide or lenalidomide with chemotherapy or
dexamethasone are at high risk for thrombosis and warrant prophylaxis.
This recommendation is based on extrapolation from studies of
postoperative prophylaxis in orthopedic surgery and a trial of adjusted-dose
warfarin in breast cancer.
(3) Research identifying better markers of ambulatory patients with
cancer most likely to develop VTE is urgently needed.
 According to ASCO Guidelines 2016:
SHOULD PATIENTS
WITH CANCER
(1) All patients undergoing major surgical intervention for malignant
disease should be considered for thromboprophylaxis.
UNDERGOING
SURGERY RECEIVE
(2) Patients undergoing laparotomy, laparoscopy, or thoracotomy
PERIOPERATIVE VTE
lasting greater than 30 minutes should receive pharmacologic
PROPHYLAXIS?
thromboprophylaxis with either low-dose UFH or LMWH unless
contraindicated because of a high risk of bleeding or active bleeding.
(3) Mechanical methods may be added to pharmacologic methods, but
should not be used as monotherapy for VTE prevention unless
pharmacologic methods are contraindicated because of active bleeding.
(4) Prophylaxis should be continued for at least 7 to 10 days
postoperatively. Prolonged prophylaxis for up to 4 weeks may be
considered in patients undergoing major abdominal or pelvic surgery for
cancer with high-risk features such as residual malignant disease after
operation, obese patients, and those with a previous history of VTE.
Choice of Anticoagulation:
 LMWH is the recommended anticoagulant for the initial
Initial
therapy of VTE in most patients with cancer. (1,2)
management of
 However, UFH can be used in those with severe renal
a first episode of
impairment (creatinine clearance [CrCl] ,30 mL/min) given its
shorter half-life, reversibility with protamine sulfate, and
cancer-
associated VTE
dependence on hepatic clearance. (1,2)
 Fondaparinux is a reasonable choice in patients with a
history of HIT. (2)
(1) Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with
cancer: american society of clinical oncology clinical practice guideline update. J Clin Oncol. 2013;31(17): 2189-2204.
(2) National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology Venous Thromboembolic Disease
version 2.2013. Available at: http://www.nccn.org/professionals/ physician_gls/pdf/vte.pdf. Accessed July 9, 2013.
 Although vitamin K antagonists (VKAs) have been the
mainstay agents for long-term management and secondary
Long-term
management of
a first episode of
cancer-
associated VTE
prophylaxis of acute VTE in patients without cancer, their
use is problematic in oncology patients.
 VKAs are less effective in patients with cancer, with rates of
recurrent VTE three-fold higher than in patients without
cancer despite maintenance of the international normalized
ratio (INR) within the therapeutic range.
Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention
of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest.
2012;141(2 Suppl): e419S-94S.
LMWH also offers other advantages including
(a) no need for laboratory monitoring of its anticoagulant activity;
(b) shorter half-life that facilitates temporary interruption for procedures
or thrombocytopenia;
(c) limited drug interactions; and
(d) no food interactions or reliance on oral intake or gastrointestinal tract
absorption.
As a result, LMWH is recommended for both initial and
long-term
anticoagulation
in
cancer-associated
thrombosis by major consensus guidelines
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology Venous Thromboembolic Disease
version 2.2013. Available at: http://www.nccn.org/professionals/ physician_gls/pdf/vte.pdf. Accessed July 9, 2013.
 According to ASCO Guidelines 2016:
(1) LMWH is the preferred approach for the initial 5 to 10 days of anticoagulant
treatment of the cancer patient with established VTE.
(2) LMWH given for at least 6 months is also the preferred approach for longterm anticoagulant therapy. Vitamin K antagonists with a targeted INR of 2 to
Guidelines
3 are acceptable for long-term therapy when LMWH is not available.
(3) For patients with CNS malignancies, anticoagulation is recommended for
established VTE as described for other patients with cancer. Careful
monitoring is necessary to limit the risk of hemorrhagic complications.
(4) For elderly patients, anticoagulation is recommended for established VTE
as described for other patients with cancer.
Careful monitoring and dose
adjustment is necessary to avoid excessive anticoagulation and further
increase in the risk of bleeding.
 According to CHEST Guidelines 2016:
In patients with DVT of the leg or PE and cancer (“cancerassociated thrombosis”), as long-term (first 3 months)
anticoagulant therapy, we suggest LMWH over VKA therapy
(Grade 2C), dabigatran (Grade 2C), rivaroxaban (Grade 2C),
apixaban (Grade 2C), or edoxaban (Grade 2C).
Duration of
anticoagulation
and anticoagulant
 studies
regarding
the
optimal
duration
of
anticoagulant therapy are lacking in oncology patients.
 Given that the risk for recurrent thrombosis in patients
with active cancer is high even while they are receiving
options for
anticoagulation, it is generally recommended that
extended therapy
extended anticoagulation be considered in this
population.
 According to ASCO Guidelines 2016:
After 6 months, indefinite anticoagulant therapy should
be considered for selected patients with active cancer,
Guidelines
such as those with metastatic disease and those
receiving chemotherapy. This recommendation is based
on Panel consensus in the absence of clinical trials data.
 According to CHEST Guidelines 2016:
In patients with DVT of the leg or PE and active cancer
(“cancer-associated thrombosis”) and who
Guidelines
(i) do not have a high bleeding risk, we recommend extended
anticoagulant therapy (no scheduled stop date) over 3 months
of therapy (Grade 1B), or
(ii) have a high bleeding risk, we suggest extended
anticoagulant therapy (no scheduled stop date) over 3 months
of therapy (Grade 2B).
 As most trials of thrombolytic therapy exclude patients with
cancer because of a perceived higher risk of bleeding, evidence
Use of
for thrombolysis in patients with malignancy is limited to small
single-center, retrospective series.
Thrombolysis in
CancerAssociated VTE
 Although comparable results between cancer and non-cancer
patient groups were observed, these studies provide a low level of
evidence because of insufficient statistical power and patient
selection bias.
Vedantham S, Goldhaber SZ, Kahn SR, et al. Rationale and design of the ATTRACT Study:
a multicenter randomized trial to evaluate pharmacomechanical catheter-directed thrombolysis for the prevention of
postthrombotic syndrome in patients with proximal deep vein thrombosis. Am Heart J. 2013;165(4):523-530.e3.
 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. (1)
Inferior vena
cava (IVC)
filters
 Given the high rates of complications and the absence of
data to support their efficacy, IVC filters should be restricted
to patients with acute VTE and contraindications to
anticoagulation. (2)
(1) Elting LS, Escalante CP, Cooksley C, et al. Outcomes and cost of deep venous thrombosis among patients with cancer.
Arch Intern Med. 2004;164(15):1653-1661.
(2) Durack JC, Westphalen AC, Kekulawela S, et al. Perforation of the IVC: rule rather than exception after longer
indwelling times for the Gu ̈nther Tulip and Celect retrievable filters. Cardiovasc Intervent Radiol. 2012;35(2):299-308.
 According to ASCO Guidelines 2016:
The insertion of a vena cava filter is only indicated for
Guidelines
patients with contraindications to anticoagulant therapy
and in those with recurrent VTE despite adequate longterm therapy with LMWH.
 Once recurrent VTE is confirmed, it is essential that HIT be
Treatment of
excluded in patients who were first exposed to LMWH or UFH
within the past 10- 14 days. Compliance should also be reviewed.
recurrent VTE
 For patients who experienced warfarin failure while the INR values
had been therapeutic, transition to LMWH is recommended given
during
anticoagulant
its greater efficacy vs warfarin.
 Recurrent VTE events during LMWH therapy can be treated with a
dose escalation of LMWH.
therapy

Luk C, Wells PS, Anderson D, Kovacs MJ. Extended outpatient therapy with low molecular weight heparin for the treatment of
recurrent venous thromboembolism despite warfarin therapy. Am J Med. 2001;111(4):270-273.

Carrier M, Le Gal G, Cho R, Tierney S, Rodger M, Lee AY. Dose escalation of low molecular
weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients. J Thromb
Haemost. 2009;7(5):760-765.
Treatment of
cancer-
associated
thrombosis in
patients with a
high risk of
 Bleeding is frequently associated with anticoagulant
use in patients with cancer.
 In a prospective study including 181 oncology patients
receiving VKA for the treatment of DVT, the 1-year
cumulative incidence of major bleeding was 12.4%,
with one third of the bleeding events occurring during
the initial phase of anticoagulation.
bleeding
Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications
during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;100(10):34843488.
Acute DVT
Platelet
< 50*106/L
Platelet
>50*106/L
Platelet
< 20*106/L
Platelet
20-50*106/L
Transfuse to
maintain
Hold
Anticoagulation
Half-Dose
LMWH
Full dose LMWH
Full dose LMWH
Subacute/Chronic
VTE
Platelet
> 50*106/L
Platelet
20-50*106/L
Platelet
< 20*106/L
Full-Dose LMWH
Half-Dose LMWH
Hold
Anticoagulation
 To date, published data and clinical experience suggest that
catheter-related thrombosis is associated with a low risk for
Treatment of
catheterrelated
thrombosis
thrombosis recurrence and post-thrombotic syndrome.
 Therefore, conservative treatment is recommended. A sensible
approach is to remove the catheter only if
(1) central venous access is no longer required;
(2) the device is nonfunctional or defective; or
(3) line-related sepsis is suspected or documented
Elman EE, Kahn SR. The post-thrombotic syndrome after upper extremity deep venous thrombosis in
adults: a systematic review.Thromb Res. 2006;117(6):609-614.
 Unless contraindicated, therapeutic anticoagulation should
be given using either LMWH alone or LMWH followed by
warfarin therapy.
Treatment of
catheterrelated
thrombosis
 A short period of anticoagulation (3-5 days of LMWH) may
even salvage some thrombosed catheters and obviate the
need to remove and replace the line.
 Anticoagulation is recommended for a minimum of 3
months and while the catheter remains in place.
Agnes Y. Y. Lee and Erica A. Peterson. Treatment of cancer-associated thrombosis, Blood
2013;122(14):2310- 2317)
SHOULD PATIENTS
WITH CANCER
RECEIVE
 According to ASCO Guidelines 2016:
(1) Anticoagulants are not recommended to improve survival in
patients with cancer without VTE.
ANTICOAGULANTS IN
THE ABSENCE OF
ESTABLISHED VTE TO
IMPROVE SURVIVAL?
(2) Patients with cancer should be encouraged to participate in
clinical trials designed to evaluate anticoagulant therapy as an
adjunct to standard anticancer therapies.
Thank You