CANCER ASSOCIATED THROMBOSIS - AMS...Risk of VTE in Acutely ILL Ca Patients In hospitalised medical...
Transcript of CANCER ASSOCIATED THROMBOSIS - AMS...Risk of VTE in Acutely ILL Ca Patients In hospitalised medical...
Pankaj Handa
Department of General Medicine
Tan Tock Seng Hospital
CANCER ASSOCIATED THROMBOSIS
My Talk Today
1.Introduction
2. Are All Cancer Patients at Risk of VTE ?
3. Should All VTE Patients Be Screened For Cancer ?
4. Are there any Biomarkers for VTE in Cancer Patients ?
5. Risk Stratification of VTE in Cancer Patients.
6. CAT at Tan Tock Seng Hospital .
7. Treatment Options/ ACCP Guidelines
TROUSSEAU’S SYNDROME 1865
“Spontaneous venous thromboembolism in association
with clinically occult malignant disease”
“when you are undecided about
the nature of the disease of the
stomach, when you hesitate
among chronic gastritis, simple
ulcer, and a carcinoma, a
phlegmatia alba dolens
occuring in the leg or arm will
enable you to assert positively
that a cancer is present”
-Armand Trousseau 1865 lecture in Paris
Introduction
Thrombosis – Cancer : A Double-Edged Sword.
Malignancy increases the risk of VTE by a factor of 7
15-20% cancer patients may develop with VTE
Development of VTE in a patient with known cancer is
the most common presentation, but VTE may precede
the diagnosis of malignancy by many months.
Introduction
Critical oncogenic events
Activation of the coagulation cascade
Prothrombotic environment
VTE Growth and Progression of
the Malignancy
Introduction
CAT is the 2nd leading cause of death in cancer patients
1-year survival
With VTE : Without VTE (12% vs. 36%)
In- hospital Mortailty
Double in the patients who develop VTE in hospital
Significant proportion of cancer patients with VTE have
limited cancer disease that in the absence of fatal PE
would have been associated with considerably longer
survival
Introduction
Cancer patients are also prone to adverse effects and failure of anticoagulant therapy.
Annual risk : recurrent VTE is 21%–27%
major bleeding is 12%–13%
On warfarin : 2 to 6 times more major bleeding episodes 2 to 3 times more VTE recurrences.
2. Are All Cancer Patients At Risk of VTE ?
Risk Factors for VTE in Cancer Patients
Risk Factors for VTE in Cancer Patients
Metastatic disease at the time of diagnosis is the strongest predictor of thromboembolism (1.4–21.5 fold higher risk of VTE than patients with localised disease)
VTE : chemotherapy three times radiotherapy two times distant metastases six times
Annual VTE Risk in Cancer Patient
(Solid Tumours)
Type of Cancer Localised Metastatic
Pancreas 4.2% 20%
Stomach 2.5% 10.7%
Uterus 0.8% 6.4%
Kidney 1.2% 6%
Lung 1.1% 5%
VTE and Type of Malignancy
Type Adjusted Odds Ratio
(95%CI)
Haematological 28 (4-199.7)
Lung 22.2 (3.6-136.1)
Gastrointestinal 20-3 (4.9-83)
Risk of VTE in Acutely ILL Ca Patients
In hospitalised medical patients with acute illness, cancer is independently associated with a 1.6-fold increase in the risk of VTE
In-hospital mortality rate is significantly greater
- VTE vs No VTE (OR 2.01; 95% CI 1.83–2.22)
- localised cancer as well as advanced disease
International guidelines recommend the use of prophylaxis with UFH or LMWH for patients with active cancer who are confined to bed in hospital
3. Should We Screen All VTE Patients for
Cancer ?
Screening for Occult Malignancy
The most appropriate strategy in patients with
unprovoked VTE is a thorough history and physical
examination, followed by patient-specific laboratory
testing and imaging.
Routine screening for cancer using extensive
investigations in these patients does not appear to
provide a survival advantage
4. Are There Any Biomarkers For Diagnosis
of VTE in Cancer Patients ?
Candidate Biomarkers
Blood Counts:
- Platelet count
- Leukocyte count
- Haemoglobin
Tissue Factor
Soluble P - selectin
D - dimer
C – reactive protein
Candidate Biomarkers
Tissue Factor
- physiologic initiator of the coagulation cascade,
but it appears to play multiple roles in cancer
pathogenesis and may be important for
angiogenesis in tumors as well.
- high levels have been identified in blood of
patients to be associated with the risk for VTE
Two-Way Biological Relationship
Activation of coagulation
Growth and Metastatic potential of
tumor cells
inhibition of the clotting cascade activation or
thrombin activity may have antineoplastic effects
(LMWH)
5.
Risk Stratification of VTE in Cancer Patients
6.
Cancer Associated Thrombosis At
Tan Tock Seng Hospital
CAT at Tan Tock Seng Hospital
Total 93
Age 68.9 years
Sex Male(47.31%) Female(52.68%)
Race Chinese (79.56 %)
Malay (13.97 %)
Indian (06.45 %)
Retrospective 5 year study (Jan 2006-December 2010)
Patients discharged with diagnosis of Cancer and
Thrombosis
VTE Association with Type of Cancer
Lung
Haematological Colon
Pancreas Stomach Breast Gall Bladder
0
5
10
15
20
25
VTE : Prevalence
DVT
67%
BOTH
16%
PE
17%
DVT
PE
BOTH
0
5
10
15
20
25
30
35
40
Proximal Distal Both UL DVT Others No DVT
40%
10% 11%
8%
14%
17%
Pe
rce
nta
ge
VTE - Deep Vein Thrombosis
Onset of VTE
0
5
10
15
20
25
30
35
Only VKA Only LMWH Only IVC VKA + LMWH VKA + IVC LMWH + IVC Nil
1
26
14 16
3
9
31
Axis
Tit
le
Axis Title
Treatment
7.
Treatment Options for VTE in Cancer
Patients
Treatment of VTE in Patients with Cancer
(A) Initial Treatment
LMWHs have become preferred mode of treatment for
the initial treatment of VTE in cancer
Hettiarachchi RJ, Curr Opin Pul Med, 1998
- A meta-analysis of studies: UFH vs LMWH.
LMWH : at least as safe and effective as UFH
: reduced mortality risk in these patients.
Treatment of VTE in Patients with Cancer
(B) Long-Term Treatment
Difficulties with (OAC) Warfarin :
Prandoni P; Blood,2002.
- OAC in patients with cancer( vs without cancer)
- two to three-fold increase in recurrent VTE
- two to six fold increase in major bleeding
Other problems :
potential for drug interactions( chemotherapy)
poor intestinal absorption
altered hepatic function
Treatment of VTE in Patients with Cancer
Difficulties with (OAC) Warfarin :
In patients with cancer receiving warfarin for VTE, the risk of bleeding and recurrent VTE remains high, even when the INR is within the target range.
Palareti G; Throb Haemost 2000.
Bleeding rate is consistently high and is independent of the INR value in patients with cancer.
Prandoni P; Blood,2002.
At the time of recurrence, the INR value is within or above the target range in a higher proportion of cancer
Treatment of VTE in Patients with Cancer
Meta-analysis of 4 studies:
- Prolonged treatment with LMWH
statistically significant and clinically important 50% reduction in the rate of recurrent VTE (6.5 vs12.6%,RR 0.52, 95% CI 0.35–0.76; p=0.001)
No significant difference between warfarin and LMWH for the risk of bleeding
LMWH :Treatment of VTE in Ca Patients
American College of Chest Physicians (ACCP) American Society of Clinical Oncology (ASCO)
National Comprehensive Cancer Network (NCCN)
The Italian Medical Oncology Society (AIOM)
Long-term anticoagulant therapy for patients with DVT and cancer should involve LMWH rather than VKAs.
Duration: at least three to six months
8.
Anticoagulant Treatment and Survival in
Cancer Patients
Effects of Anticoagulant treatment on
Survival in Patients with Cancer
Several studies have suggested a link between
anticoagulant therapy and improved survival in patients
with malignancy.
Zacharaski LR;Cancer,1984
a prospective, randomised clinical trial
warfarin was associated with significant prolongation of
progression-free and overall survival in patients with
small-cell lung cancer
However, in patients with other types of tumour, warfarin
had no effect on survival.
Effects of Anticoagulant treatment on
Survival in Patients with Cancer
Furthermore, subsequent trials of VKAs in patients with cancer have provided conflicting results.
Smorenburg SM;Thromb Haemost,2001
- a systematic review concluded that there was insufficient evidence that long-term VKA administration provided a survival benefit in patients with cancer
Smorenburg SM;Thromb Haemost, 1999
Similar uncertainty surrounds the effect of UFH on survival
LMWHs on Survival in Patients with
Cancer
Hettiarachchi RI. Curr Opin Pulm Med,1998.
- Ca patients who receive LMWH (vs UFH) for the initial treatment of acute DVT may have prolonged survival
Altinbas M. J Thromb Haemost,2004.
- small-cell lung cancer.
- overall survival - significantly prolonged (LMWH + Chemotherapy)
- both in patients with extensive / limited disease.
LMWHs on Survival in Patients with
Cancer
Improvement in survival associated with LMWHs may be independent of their anticoagulant effects.
Antitumour effects of LMWH:
- inhibition of neoangiogenesis
- inhibition of tumour-cell-derived heparanase activity,
- induction of apoptosis
- inhibition of tumour cell adhesion to endothelial cells
LMWHs on Survival in Patients with
Cancer
Clinical studies conducted so far have produced conflicting results, and evidence for prolonged survival in cancer patients with LMWH comes mainly from post hoc analyses
Additional studies conducted in patients with specific cancer types are needed to confirm these preliminary findings
Such studies are currently under way in several cancer types including lung, prostate, pancreas, ovary and stomach
ACCP Guidelines on VTE in
Cancer Patients A. P R O P H Y L A X I S
1. Ambulatory patients receiving chemotherapy.
Routine prophylaxis NOT recommended.(1C)
2. Patients with Central Venous Catheters.
Routine prophylaxis NOT recommended. (1A)
3. Hospitalised patients with Acute Medical Illness.
Routine Thrombo - prophylaxis recommended. (1A)
ACCP Guidelines on VTE in
Cancer Patients 4. Prophylaxis during Surgery
- Routine thrombo-prophylaxis that is appropriate for the type of surgery is recommended………………(1A)
5. Prophylaxis after discharge
- High risk GS patients, including those who have undergone major Ca surgery/ past DVT
: Continue LMWH thrombo- prophylaxis x 28/7…. (2A)
-Similar Gynaecology patients.
: Continue LMWH thrombo- prophylaxis x 28/7…..(2C)
ACCP Guidelines on VTE in
Cancer Patients
6. Suggested Regimen for Prophylaxis of VTE
- ACCP: No specific recommendation
- ASOC: UFH 5000 U TID
LMWH: Dalteparin 5000 U OD
Enoxaparin 40 mg OD
Fondaparinux 2.5 mg OD
- NCCN Tinzaparin 4500 U or 75 U/kg OD
ACCP Guidelines on VTE in
Cancer Patients
7. Mechanical Devices where anticoagulant treatment (ACT) is contraindicated
- graduated compression stockings
- intermittent pneumatic compression (1A)
When the bleeding risk decreases, pharmacological thrombo-prophylaxis be substituted for or added to the mechanical one (1C)
Recommendation against the use of IVC filter in trauma patients with acute spinal injury (1C)
ACCP Guidelines on VTE in
Cancer Patients
B. T R E A T M E N T
1. Acute DVT
- LMWH : first 3 – 6 months (1A)
- Subsequent LMWH/ VKA therapy indefinitely or until the cancer is resolved
2. Mechanical Devices where ACT is contraindicated
- IVC filter (1C)
- when the bleeding risk decreases, conventional course of ACT should be given.
ACCP Guidelines on VTE in
Cancer Patients
3. Treatment similar to that for DVT of the leg is also recommended for DVT of the upper extremity
4. Patients with lower- and upper-extremity DVT may be considered for thrombus removal using catheter-based thrombolytic techniques.
5. Prophylactic or four weeks of intermediate doses of LMWH or UFH should be used in patients with extensive Superficial Vein Thrombosis
Take Home Message
Patients with cancer are at high risk of thrombosis, and this is an important cause of avoidable mortality in these patients.
CAT is associated with : Higher - Mortality
- Recurrence of VTE
- Bleeding complications
These patients present unique challenges that affect the safety and efficacy of antithrombotic therapies.
Take Home Message
Current data indicate that LMWHs offer several practical
advantages for cancer patients, in addition to superior
efficacy to OAC without increasing the risk of bleeding.
Preliminary data suggest that LMWH administration may
be associated with an increase in patient survival
THANKS VERY MUCH
Treatment of VTE in Patients with Cancer
Other important issues of LMWH therapy:
- Heparin Induced Thrombocytopaenia (HIT)
- Drug Accumulation: Short term
Long term
LMWH :Treatment of VTE in Ca Patients
Heparin Induced Thrombocytopaenia (HIT)
Eight studies: Prospective cohorts; 900 patients
Not a single episode of HIT.
Thrombocytopenia is a common complication in cancer patients receiving chemotherapy
Lee; NEJM,2003
For the use of Dalteparin
Platelet >100,000/mm3 Standard Dose
50,000-100,000 Reduce dose to 3000 IU
< 50,000 Stop treatment
LMWH :Treatment of VTE in Ca Patients
Risk of Drug Accumulation
(A) Short Term
CLOT trial:
- 24 patients receiving dalteparin 200IU/kg once daily - anti-Xa measurement at weeks one and four.
- at week four, the mean anti-Xa level was 1.03 anti-Xa units/ml (95% CI 0.5–1.7) and did not differ significantly from the value obtained during week one.
LMWH :Treatment of VTE in Ca Patients
(B) Long Term:
Renal impairment is a frequent co-morbid condition in
patients having cancer.
Renal function may be further impaired as a result of
chemotherapy-related nephrotoxicity.
Measurement of creatinine clearance is recommended
before starting prolonged LMWH
LMWH :Treatment of VTE in Ca Patients
Tinzaparin may be the most suitable option for patients
with moderately impaired renal function.
Siguret; Thromb Haemost 2000.
The results of a study completed in a group of patients
with a wide distribution of creatinine clearance indicate
that the anti-Xa effect of tinzaparin does not increase
over 10 days of administration