PRESENTER:DR.SATHISH,JR,RTMODERATOR:DR.SHYAMA(ASSISTANT PROFESSOR OF RADIOTHERAPY)
INTRODUCTION VTE(VENOUS THROMBOEMBOLISM)=DVT+PE In 1865-Armand Trousseau first described venous thrombosis 1 Risk of mortality doubles if cancer pts develop DVT VTE is the second leading cause of death in hospitalized cancer patients11. J Thromb Haemost 2007;5(3):632.
Likelihood of Death After Hospitalization 1.00 DVT/PE and Malignant Disease 0.80Probability of Death 0.60 Malignant Disease 0.40 DVT/PE Only 0.20 Nonmalignant Disease 0.00 0 20 40 60 80 100 120140 160 180 Number of Days Levitan N, et al. Medicine 1999;78:285
GENETIC MUTATIONS TP53 KRASTISSUE FACTOR AND TF CONTAINING VESICLES CANCER CELLS ENDOTHELIAL CELLS UPREGULATION VEGF DOWNREGULATION THROMBOSPONDIN HYPERCOAGULABILITY
OTHER AGENTS• Cancer procoagulant----Xa Activation• PAI• TNF,1L-1 and 6• IFNs• Increased 8-vWF• Decreased protein C and S, Antithrombin
Risk factors Patient related Disease related Treatment related• Age • Site of primary • Surgery• Race • Brain,lung • Prechemo platelet• Obesity • Stomach,pancreas count>350000• Infection • Kidney,ovary • Hormonal therapy-• Genetic mutations • Lymphomas,mela tamoxifen,OCP • V leiden noma • Chemo- 6.5 fold risk • Metastatic disease of DVT- • Prothrombin thalidomide, • h/o DVT lenalidomide and • Renal disease bevacizumab • Pulmonary disease • Erythropoeitin • Central vein catheter
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 dyingLee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21
VTE Incidence In Various Tumors Oncology Setting VTE Incidence Breast cancer (Stage I & II) w/o further 0.2% treatment 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%Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17
OCCULT CANCER AND VTE SOMIT(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/PE Clinical assessment + D- dimer assay False negative rates high for D-dimer assay Duplex 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 Common femoral vein Thrombus Proximal Knee Distal Veins of the leg
Post-thrombotic syndrome Pain Oedema Discoloration Varices Ulceration Symptoms of post-thrombotic syndrome – long “lag-phase” (years)
DVT – Wells Score The following were assigned a point value of 1 if present: Cancer Entire leg swollen Paralysis or plaster Calf > 3cm larger immobilization than unaffected leg Bedrest > 3 d or Pitting edema surgery in past 4 greater than wks unaffected leg Localized Collateral tenderness superficial veins• 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 PE Swelling Unexplained shortness of Pain or tenderness -the pain is breath usually in 1 leg and may only Chest pain and/or palpitations be present when standing or walking Anxiety and/or sweating Warm skin Coughing/coughing up blood Red or discolored skin Fatigue and/or faintingNot all people with DVT have signs or symptoms.
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! 16
Chest X-ray Eponyms of PE Westermarks 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. 19
Diagnostic Testing- CXR’sChest 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 21
Diagnostic Testing- CXR’sChest radiograph findings in patient with pulmonary embolismResult PercentCardiomegaly 27%Normal study 24%Atelectasis 23%Elevated Hemidiaphragm 20%Pulmonary Artery Enlargement 19%Pleural Effusion 18%Parenchymal Pulmonary Infiltrate 17% 22
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. 23
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. 24
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? 25
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) 26
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 27
CT revealing emboli in pulmonary artery.
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” 29
Antithrombotic Therapy: Choices Nonpharmacologic Pharmacologic (Prophylaxis) (Prophylaxis & Treatment)Intermittent Elastic Unfractionated Low MolecularPneumatic Stockings Heparin (UH) Weight HeparinCompression (LMWH) Inferior Vena Cava Oral Filter Anticoagulants New Agents: e.g. Fondaparinux, Direct anti-Xa inhibitors, Direct anti-IIa, etc.?
ASCO Guidelines 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.
VTE Prophylaxis Is Underused in Patients With Cancer Cancer: Major 100 FRONTLINE Survey1— Surgery2 3891 Clinician 89 90 Respondents Rate of Appropriate Prophylaxis, % 80 Cancer: 70 Surgical Major Confirmed DVT ABDominothoracic (Inpatients)5 60 Medical 52 Surgery (Elderly)3 Inpatients4 50 42 40 38 Cancer: 33 30 Medical 20 10 5 0 FRONTLINE FRONTLINE: Stratton Bratzler Rahim DVT FREE Surgical Medical1. Kakkar AK et al. Oncologist. 2003;8:381-3882. Stratton MA et al. Arch Intern Med. 2000;160:334-340 4. Rahim SA et al. Thromb Res. 2003;111:215-2193. Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912 5. Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262
PREVENTION OF DVT IN SURGICALPATIENTS 7 fold risk of post-op DVT and 54 fold in first three months Risk of VTE as high as 50% without prophylaxis If LMWH/UFH 7-10 days post-op VTE risk -15% and bleeding risk is 4% UFH vs LMWH? No difference in efficacy 15% develop DVT inspite of either S/c fondaparinux –equivalent efficacy and low incidence of hit Graduated 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
Incidence of VTE in Surgical Patients Cancer patients have 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis: No Cancer Cancer P-value N=16,954 N=6124 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% <0.0001Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732
ENOXACAN II STUDY ENOXAPARIN SAME UPTO 31DAYS 40MG/D SC OD FOR POST OP FIRST 10D POST-OP 12% DVT 4% INCIDENCE 3.6% BLEEDING 4.7% INCIDENCE8th ACCP GUIDELINES RECOMMENDS EXTENDED LMWH IN CANCERSURGERY PTSENOXACAN Study Group. Br J Surg 1997;84:1099–103
Extended Prophylaxis in Surgical Patients 15% Incidence of Outcome Event 12.0% ENOXACAN II 10% P=0.02 placebo N=167 5.1% enoxaparin 40 mg 4.8% 5% 3.6% N=165 1.8% 0.6% 0% 0.4% NNT = 14 0% VTE Prox Any Major DVT Bleeding BleedingBergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980
SOME SPECIAL SCENARIOS Prophylaxis in laparascopic surgery-no consensus CNS tumors and neurosurgery pts-both thrombosis and bleeding risk high Extremely cautious use of ACGs and the decision to start anticoagulation rests with the treating oncologist Some consider it an absolute contraindication
PROPHYLAXIS IN CVC None of the ACGs are beneficial Thrombosis rates were similar with or without ACG but risk of bleeding was high for pts on ACG Placebo vs. anticoagulants?-No difference SO 8TH ACCP CONSENSUS guidelines-no routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH and fixed- dose warfarin
TREATMENT OF CVC THROMBOSIS Remove the catheter Follow the same guidelines as for DVT in any other site Decisions about duration, dose etc., of therapy rests with treating oncologist
PROPHYLAXIS IN MEDICALONCOLOGY In myeloma patients receiving thalidomide+dexa and/or doxorubicin The reason is not fully understood NCCN recommends prophylaxis but no clear cut regimens so far ACCP –Assume that all inpatients on chemo/chemoradiation/hormone therapy are at high risk for VTE and should be considered for ACGs
AMBULATORY PATIENTS ONCHEMO ACG not routinely recommended(no studies till now) special consideration for prophylaxis Prechemo platelet>350000 GIT,lung and lymphoid malignancies Anemic pts on epoeitin
IVC FILTERS Used if ACGs C/I or in recurrent VTE Invasive procedure and requires expertise Paradoxically risk of thrombosis is high Usually considered as a last resort for recurrent VTE
TREATMENT OF DVT INITIAL TREATMENT LMWH vs. UFH ?- equivalent efficacy Fondaparinux – 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 Dalteparin DalteparinCANCER PATIENTS WITH ACUTEDVT or PE Randomization [N = 677] Dalteparin Oral Anticoagulant ► Primary Endpoints: Recurrent VTE and Bleeding ► Secondary Endpoint: SurvivalLee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
Landmark CLOT Cancer Trial Reduction in Recurrent VTE 25 Risk reduction = 52% Recurrent VTE p-value = 0.0017 Probability of Recurrent VTE, % 20 15 OAC 10 Dalteparin 5 0 0 30 60 90 120 150 180 210Lee, Levine, Kakkar, Rickles et.al. N Days Post RandomizationEngl J Med, 2003;349:146
Bleeding Events in CLOT Dalteparin OAC P-value* N=338 N=335 Major bleed 19 ( 5.6%) 12 ( 3.6%) 0.27 Any bleed 46 (13.6%) 62 (18.5%) 0.093 * Fisher’s exact testLee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146
THE LITE TRIAL(LONG TERMINNOVATIONS IN TREATMENT) INITIAL UFH INITIAL AND THEN TINZAPARIN WARFARIN 175IU/KG/DAY CONTINUE CONTINUE DALTEPARIN FOR THREE MONTHS WARFARIN AND SHIFT TO WARFARIN AFTER 16% 7% 1 YEAR RECURRENCE RECURRENCE•N=200 CANCER PATIENTS•BLEEDING COMPLICATIONS COMPARABLE IN BOTH ARMS
DURATION OF TREATMENT Usually six months for responsive patients without active cancer or metastatic disease For patients with active malignancy and metastatic disease duration is based on the treating physician’s opinion If patients tolerate continue LMWH/warfarin
THROMBOLYSIS Used in PE with severe hemodynamic instability Severe DVT leading to arterial insufficiency Clinically significant thrombus extension To maintain patency of occluded CVC
SIDE EFFECTS OF LONG TERMTREATMENT Bleeding Decreased bone density –LMWH Fetal warfarin syndrome Drug interactionsACCP recommends LMWH for long term therapy
CONTRAINDICATIONS FORANTICOAGULATION Major active bleed- only absolute contraindication Recent CNS bleed;recent craniotomy Bleeding diathesis Paraspinal tumours CNS tumors
RECURRENCE OF VTE No guidelines for optimal treatment Trial evidence lacking for duration of therapy
Cancer, clots and consensus 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? noLyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.
THE JIPMER CONSENSUS PT INR EVERYHISTORY/CLINI PT INR 14D FOR A CAL EXAM --- MONTHLY FOR MONTH OR DVT SIX MONTHS TWO IF WITHIN INFORM SOS IFCOMPRESSION TARGET MAJOR ACTIVE USG RANGE(ABOVE BLEED 1.8) WARN ABOUT TWICE WEEKLYLMWH FOR 3D DRUG PT INR INTERACTIONSWARFARIN FOR STABILISE WITH CONSIDER 3D WITH WARFARIN INR PROLONGED OVERLAP 2-3 (above 1.8) THERAPY?
WHERE ALL CAN WE GO WRONG? PT INR monitoring and target range Warfarin drug interactions Warfarin step up dose Missing a PE Missing occult bleed-e.g. melaena Restarting Rx after major bleed-weigh the risk vs. Benefit Follow up and patient education Lab limitations