DVT IN MALIGNANCY PRESENTER:DR.SATHISH,JR,RT MODERATOR:DR.SHYAMA(ASSISTANT PROFESSOR OF RADIOTHERAPY)
DVT IN MALIGNANCYPRESENTER:DR.SATHISH,JR,RT
MODERATOR:DR.SHYAMA(ASSISTANT PROFESSOR OF RADIOTHERAPY)
INTRODUCTIONVTE(VENOUS
THROMBOEMBOLISM)=DVT+PEIn 1865-Armand Trousseau first described
venous thrombosisRisk of mortality doubles if cancer pts
develop DVT1
VTE is the second leading cause of death in hospitalized cancer patients1
1. J Thromb Haemost 2007;5(3):632.
Likelihood of Death After Hospitalization
0 20 40 60 80 100 120140 160 1800.00
0.20
0.40
1.00
0.80
0.60
DVT/PE and Malignant Disease
Malignant Disease
DVT/PE Only
Nonmalignant Disease
Number of Days
Pro
babi
lity
of D
eath
Levitan N, et al. Medicine 1999;78:285
PATHOPHYSIOLOGYVIRCHOW’S TRIAD
STASIS
HYPERCOAGULABILITY
VESSEL INJURY
OTHER AGENTS
•Cancer procoagulant----Xa Activation•PAI•TNF,1L-1 and 6•IFNs•Increased 8-vWF•Decreased protein C and S, Antithrombin
Patient related
• Age• Race• Obesity• Infection• Genetic
mutations• V leiden• Prothrombin
Disease related• Site of primary
• Brain,lung• Stomach,panc
reas• Kidney,ovary• Lymphomas,
melanoma• Metastatic
disease• h/o DVT• Renal disease• Pulmonary
disease
Treatment related• Surgery• Prechemo
platelet count>350000
• Hormonal therapy-tamoxifen,OCP
• Chemo- 6.5 fold risk of DVT-thalidomide, lenalidomide and bevacizumab
• Erythropoeitin• Central vein
catheter
Risk factors
VTE and Cancer: Epidemiology
Of all cases of VTE:● About 20% occur in cancer patients● Annual incidence of VTE in cancer
patients ≈ 1/250
Of all cancer patients:● 15% will have symptomatic VTE● As many as 50% have VTE at autopsy
Compared to patients without cancer:● Higher risk of first and recurrent VTE● Higher risk of bleeding on anticoagulants● Higher risk of dying
Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21
VTE Incidence In Various Tumors
Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17
Oncology Setting VTE Incidence
Breast cancer (Stage I & II) w/o further treatment 0.2%
Breast cancer (Stage I & II) w/ chemo 2%Breast cancer (Stage IV) w/ chemo 8%Non-Hodgkin’s lymphomas w/ chemo 3%Hodgkin’s disease w/ chemo 6%Advanced cancer (1-year survival=12%) 9%High-grade glioma 26%Multiple myeloma (thalidomide + chemo) 28%Renal cell carcinoma 43%Solid tumors (anti-VEGF + chemo) 47%Wilms tumor (cavoatrial extension) 4%
OCCULT CANCER AND VTESOMIT(Screening For Occult Malignancy In
Patients With Symptomatic Idiopathic VTE Trial) concluded that most cancers are diagnosed within four to six months of diagnosis of DVT and 40% will have metastasized
Greatest risk of DVT is within few months of diagnosis of cancer
No evidence of survival benefit due to screening and earlier detection
NCCN does not recommend screening VTE pts for cancer
DIAGNOSIS OF DVT/PEClinical assessment + D-
dimer assayFalse negative rates high
for D-dimer assayDuplex USG is the
investigation of choice for lower limb DVT
CT angiogram is the IOC for PE
CT/MRI is more sensitive for upper limb DVT
Deep vein thrombosis
Veins of the leg
Common femoral vein
Thrombus
KneeProximal
Distal
Symptoms of post-thrombotic syndrome – long “lag-phase” (years)
PainOedemaDiscolorationVaricesUlceration
Post-thrombotic syndrome
DVT – Wells Score
CancerParalysis or plaster
immobilizationBedrest > 3 d or
surgery in past 4 wks
Localized tenderness
Entire leg swollenCalf > 3cm larger
than unaffected legPitting edema
greater than unaffected leg
Collateral superficial veins
The following were assigned a point value of 1 if present:
• Probability High (≥ 3), Moderate (1-2) or Low (0 or less)• DVT risk: High – 75%, Moderate – 17%, Low – 3%
Wells PS, Andersen DR, Bormanis J et al. Lancet. 1997;350:1795-8
Symptoms of DVT and PE
.
DVT
Swelling Pain or tenderness -the
pain is usually in 1 leg and may only be present when standing or walking
Warm skin Red or discolored skin
PE
Unexplained shortness of breath
Chest pain and/or palpitations
Anxiety and/or sweating Coughing/coughing up
blood Fatigue and/or fainting
Not all people with DVT have signs or symptoms
16
Myths of the great masquerader!
Myth
– “Patients with pulmonary embolism are short of breath and have chest pain!”
Reality: You can forget about making the
diagnosis on clinical grounds, but wait…don’t plan on completely ruling it out either!
17
Clinical Features Symptoms in Patients with Angio Proven
PTE
Symptom Percent
Dyspnea 84Chest Pain, pleuritic 74Anxiety 59Cough 53Hemoptysis 30Sweating 27Chest Pain, nonpleuritic 14Syncope 13
18
Clinical Features Signs with Angiographically Proven PE
Sign Percent
Tachypnea > 20/min 92Rales 58Accentuated S2 53Tachycardia >100/min 44Fever > 37.8 43Diaphoresis 36S3 or S4 gallop 34
Thrombophebitis 32Lower extremity edema 24
19
Chest X-ray Eponyms of PE Westermark's sign
– A dilation of the pulmonary vessels proximal to the embolism along with collapse of distal vessels, sometimes with a sharp cutoff.
Hampton’s Hump
– A triangular or rounded pleural-based infiltrate with the apex toward the hilum, usually located adjacent to the hilum.
20
Radiographic Eponyms- Hampton’s Hump, Westermark’s Sign
Westermark’s Sign
Hampton’s Hump
21
Diagnostic Testing- CXR’s
Chest X-Ray Myth:
“You have to do a chest x-ray so you can find Hampton’s hump or a Westermark sign.”
Reality:
Most chest x-rays in patients with PE are nonspecific and insensitive
22
Diagnostic Testing - CXR’s
Chest radiograph findings in patient with pulmonary embolism
Result PercentCardiomegaly 27%Normal study 24%Atelectasis 23% Elevated Hemidiaphragm 20%Pulmonary Artery Enlargement 19%Pleural Effusion 18%Parenchymal Pulmonary Infiltrate 17%
23
Diagnostic Testing - Pulse Oximetry
The Pulse Oximetry Myth:
– “ You must do a pulse oximetry reading, since patients with pulmonary embolism are hypoxemic!”
Reality:
– Most patients with a PE have a normal pulse oximetry, and most patients with an abnormal pulse oximetry will not have a PE.
24
Diagnostic Testing - ABG’s
The ABG/ A-a Gradient myth:
– “You must do an arterial blood gas and calculate the alveolar-arterial gradient. Normal A-a gradient virtually rules out PE”.
Reality:
– The A-a gradient is a better measure of gas exchange than the pO2, but it is nonspecific and insensitive in ruling out PE.
25
So What Do We Do ???
Confusing for Emergency Physician
Do we under diagnose/over diagnose?
Why don’t we have a standardized method of work up after all these years?
26
Ventilation/Perfusion Scan- “V/Q Scan”
A common modality to image the lung.
Relatively noninvasive and sadly most often nondiagnostic!
In many centers it remains the initial test of choice
Preferred test in pregnant patients 50 mrem vs 800mrem (with spiral CT)
27
Spiral (Helical) Chest CT Advantages
– Noninvasive and Rapid– Alternative Diagnosis
Disadvantages
– Costly– Risk to patients with borderline renal
function– Hard to detect subsegmental pulmonary
emboli
CT revealing emboli in pulmonary artery.
29
Pulmonary Angiography
“Gold Standard”– Performed in an Interventional Cath Lab
Positive result is a “cutoff” of flow or intraluminal filling defect
“Court of Last Resort”
Pharmacologic(Prophylaxis & Treatment)
Nonpharmacologic(Prophylaxis)
Antithrombotic Therapy: Choices
IntermittentPneumaticCompression
Elastic Stockings
InferiorVena CavaFilter
OralAnticoagulants
UnfractionatedHeparin (UH)
Low Molecular Weight Heparin (LMWH)
New Agents: e.g. Fondaparinux,Direct anti-Xa inhibitors,Direct anti-IIa, etc.?
1. Should hospitalised cancer patients receive anticoagulation for VTE prophylaxis?
2. Should ambulatory cancer patients receive prophylactic anticoagulation during systemic chemotherapy for VTE?
3. Should patients with cancer undergoing surgery receive peri-op prophylaxis?
4. What is the best method to treat patients with cancer with VTE to prevent recurrence?
5. Should patients with cancer receive anticoagulation in the absence of established VTE to improve survival?
Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
ASCO Guidelines
VTE Prophylaxis Is Underused in Patients With Cancer
FRONTLINE Surgical
FRONTLINE: Medical
Stratton Bratzler Rahim DVT FREE0
10
20
30
40
50
60
70
80
90
100
52
5
89
3833
42
1.Kakkar AK et al. Oncologist. 2003;8:381-3882.Stratton MA et al. Arch Intern Med. 2000;160:334-3403.Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912
Cancer:FRONTLINE Survey1— 3891 Clinician Respondents
Rate
of
Ap
pro
pri
ate
Pro
ph
ylaxi
s, %
Major Surgery2
Major ABDominothoracic Surgery (Elderly)3 Medical
Inpatients4
Confirmed DVT (Inpatients)5
Cancer: Surgical
Cancer: Medical
4.Rahim SA et al. Thromb Res. 2003;111:215-219
5.Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
PREVENTION OF DVT IN SURGICAL PATIENTS7 fold risk of post-op DVT and 54 fold in first three
months Risk of VTE as high as 50% without prophylaxisIf LMWH/UFH 7-10 days post-op VTE risk -15% and
bleeding risk is 4%UFH vs LMWH? No difference in efficacy15% develop DVT inspite of either S/c fondaparinux –equivalent efficacy and low incidence
of hitGraduated Compression Stockings(GCS) and Intermittent
Pneumatic Compression (IPC) devices can be used as an adjunct but not as a primary prophylaxis unless ACGs are contraindicated
Cancer patients have 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis:
Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732
Incidence of VTE in Surgical Patients
No CancerN=16,954
CancerN=6124
P-value
Post-op VTE 0.61% 1.26% <0.0001
Non-fatal PE 0.27% 0.54% <0.0003
Autopsy PE 0.11% 0.41% <0.0001
Death 0.71% 3.14% <0.0001
ENOXACAN II STUDYENOXAPARIN 40MG/D SC OD FOR FIRST
10D POST-OP
12% DVT INCIDENCE
3.6% BLEEDING INCIDENCE
8th ACCP GUIDELINES RECOMMENDS EXTENDED LMWH IN CANCER SURGERY PTS
ENOXACAN Study Group. Br J Surg 1997;84:1099–103
-5%
0%
5%
10%
15%
placebo
enoxaparin 40 mg
VTE Prox Any Major DVT Bleeding Bleeding
P=0.02
5.1%
1.8%
Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980
ENOXACAN II
In
cid
en
ce o
f O
utc
om
e E
ven
t
N=167
N=165
0% 0.4%
12.0%
4.8%
NNT = 140.6%
3.6%
Extended Prophylaxis inSurgical Patients
SOME SPECIAL SCENARIOSProphylaxis in laparascopic surgery-no
consensusCNS tumors and neurosurgery pts-both
thrombosis and bleeding risk highExtremely cautious use of ACGs and the
decision to start anticoagulation rests with the treating oncologist
Some consider it an absolute contraindication
PROPHYLAXIS IN CVCNone of the ACGs are beneficialThrombosis rates were similar with or
without ACG but risk of bleeding was high for pts on ACG
Placebo vs. anticoagulants?-No differenceSO 8TH ACCP CONSENSUS guidelines-no
routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH and fixed-dose warfarin
TREATMENT OF CVC THROMBOSISRemove the catheterFollow the same guidelines as for DVT in any
other site Decisions about duration, dose etc., of
therapy rests with treating oncologist
PROPHYLAXIS IN MEDICAL ONCOLOGYIn myeloma patients receiving
thalidomide+dexa and/or doxorubicinThe reason is not fully understoodNCCN recommends prophylaxis but no clear
cut regimens so farACCP –Assume that all inpatients on
chemo/chemoradiation/hormone therapy are at high risk for VTE and should be considered for ACGs
AMBULATORY PATIENTS ON CHEMOACG not routinely recommended(no studies
till now)special consideration for prophylaxis
Prechemo platelet>350000GIT,lung and lymphoid malignanciesAnemic pts on epoeitin
IVC FILTERSUsed if ACGs C/I or in recurrent VTE
Invasive procedure and requires expertiseParadoxically risk of thrombosis is highUsually considered as a last resort for
recurrent VTE
TREATMENT OF DVTINITIAL TREATMENT
LMWH vs. UFH ?- equivalent efficacyFondaparinux – equivalent to LMWH in efficacy
but no RCTs in cancer patients
1 mg/kg BD vs 1.5 mg/kg OD enox?Recurrence rate 6.4% in BD and 12.2% in OD
OD dosing is approved for inpatients and BD is preferred for outpatients
HOW TO INITIATE THERAPY?UFH/LMWH ONLY OR WITH
WARFARIN OVERLAP
OVERLAP HEPARIN AND WARFARIN TILL 2 PT INR
VALUES 24 HRS APART ARE IN THE RANGE OF 2-3 (usually first 5 days)
STOP HEPARIN AND CONTINUE WARFARIN OR CONTINUE LMWH FOR MINIMUM 6 MONTHS
REASSESS PERIODICALLY AND CONSIDER DISCONTINUATION
CLOT: Landmark Cancer/VTE Trial
CANCER PATIENTS WITH ACUTE DVT or PE Randomization
[N = 677]
► Primary Endpoints: Recurrent VTE and Bleeding► Secondary Endpoint: Survival
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
Dalteparin Dalteparin
Dalteparin Oral Anticoagulant
Landmark CLOT Cancer TrialReduction in Recurrent VTE
0
5
10
15
20
25
Days Post Randomization
0 30 60 90 120 150 180 210
Pro
babi
lity
of R
ecur
rent
VT
E,
%Risk reduction = 52%p-value = 0.0017
Dalteparin
OAC
Recurrent VTE
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
Dalteparin N=338
OACN=335
P-value*
Major bleed 19 ( 5.6%) 12 ( 3.6%) 0.27
Any bleed 46 (13.6%) 62 (18.5%) 0.093
* Fisher’s exact test
Bleeding Events in CLOT
Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
THE LITE TRIAL(LONG TERM INNOVATIONS IN TREATMENT)
INITIAL UFH AND THEN WARFARIN
CONTINUE WARFARIN
16% RECURRENCEAFTER 1 YEAR
•N=200 CANCER PATIENTS•BLEEDING COMPLICATIONS COMPARABLE IN BOTH ARMS
DURATION OF TREATMENTUsually six months for responsive patients
without active cancer or metastatic diseaseFor patients with active malignancy and
metastatic disease duration is based on the treating physician’s opinion
If patients tolerate continue LMWH/warfarin
THROMBOLYSISUsed in PE with severe hemodynamic
instabilitySevere DVT leading to arterial insufficiencyClinically significant thrombus extensionTo maintain patency of occluded CVC
SIDE EFFECTS OF LONG TERM TREATMENT BleedingDecreased bone density –LMWHFetal warfarin syndromeDrug interactionsACCP recommends LMWH for long term
therapy
CONTRAINDICATIONS FOR ANTICOAGULATIONMajor active bleed- only absolute
contraindicationRecent CNS bleed;recent craniotomyBleeding diathesisParaspinal tumoursCNS tumors
RECURRENCE OF VTENo guidelines for optimal treatmentTrial evidence lacking for duration of therapy
1. Should hospitalised cancer patients receive anticoagulation for VTE prophylaxis? yes
2. Should ambulatory cancer patients receive prophylactic anticoagulation during systemic chemotherapy for VTE?no
3. Should patients with cancer undergoing surgery receive peri-op prophylaxis? yes
4. What is the best method to treat patients with cancer with VTE to prevent recurrence? LMWH
5. Should patients with cancer receive anticoagulation in the absence of established VTE to improve survival? no
Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
Cancer, clots and consensus
THE JIPMER CONSENSUSHISTORY/CLINICAL EXAM ---DVT
COMPRESSION USG
LMWH FOR 3D
WARFARIN FOR
3D WITH OVERLAP
STABILISE WITH
WARFARIN INR 2-3 (above
1.8)TWICE WEEKLY PT INR
IF WITHIN TARGET
RANGE(ABOVE 1.8)
PT INR EVERY
14D FOR A
MONTH OR TWO
PT INR MONTHL
Y FOR SIX
MONTHS
INFORM SOS IF MAJOR ACTIVE BLEED WARN
ABOUT DRUG
INTERACTIONS
CONSIDER
PROLONGED
THERAPY?
WHERE ALL CAN WE GO WRONG?PT INR monitoring and target rangeWarfarin drug interactionsWarfarin step up doseMissing a PEMissing occult bleed-e.g. melaenaRestarting Rx after major bleed-weigh the
risk vs. BenefitFollow up and patient educationLab limitations
THANK YOU