Management of VTE in The Cancer Patients By Dr: Wesal Mohamed Associate Leucturer of Clinical Oncology Mansoura University

Annual At-Risk for VTE in U.S.Hospitals: 7.7 million Medical Service inpatients. 3.4 million Surgical Service inpatients. Based upon ACCP guidelines for VTE prophylaxis 74% of VTEs present in outpatients. 42% of outpatient VTE patients have had recent surgery or hospitalization. 40% had received VTE prophylaxis.

Cancer patients found to have a 3-fold higher risk for recurrent VTE than patients who had an initial VTE in the absence of malignancy which is greatest in the first few months after diagnosis of malignancy and can persist for many years. Cancer patients, once hospitalized, are at higher risk of developing VTE. While receiving chemotherapy, cancer patients have a 7-fold risk of developing VTE as compared with other patients without cancer.

Antiangiogenic agents as (bevacizumab, thalidomide and lenalidomide) also contribute to thrombosis, through endothelial cell, platelet activation and damage to the vascular endothelium which is amplified by the co- administration of Ch.T. and steroids. Bevacizumab administered concomitantly with Ch.T. is associated with a 33% relative increase of VTE. With regards to multiple myeloma, the highest incidence of VTE observed in patients treated with thalidomide- and doxorubicin-containing Ch.T.(VTE rate up to 34%).

There are two pathways: the contact activation pathway (also known as the intrinsic pathway) and the tissue factor pathway (known as the extrinsic pathway). Contact activation pathway: is disrupted by heparin, not working properly in Haemophilia, and can be measured using the aPTT clotting test.heparinHaemophiliaPTT Tissue factor pathway: is interrupted by warfarin, and is measured using INR or PT.warfarinINRPT

Prophylaxis Modalities

Reversible Risk Factors: 1. Nutrition: eat fruits, veggies, fish; less red meat. 2. Quit cigarettes. 3. Lose weight/ exercise. 4. Prevent DM/ metabolic syndrome. 5. Control hypertension. 6. Lower cholesterol. 7. Avoid air pollution.

ASCO Guidelines Hospitalized Patients with Cancer Role of VTE Prophylaxis Evidence Patients with cancer should be considered candidates for VTE prophylaxis with anticoagulants (UFH, LMWH, or fondaparinux) in the absence of bleeding or other contraindications to anticoagulation Multiple RCTs of hospitalized medical patients with subgroups of patients with cancer. The 8th ACCP guidelines strongly recommend (1A) prophylaxis with either low- dose heparin or LMWH for bed ridden patients with active cancer.

Ambulatory Patients with Cancer Without VTE Receiving Systemic Chemotherapy: Role of VTE Prophylaxis Evidence Routine prophylaxis with an antithrombotic agents is not recommended except as noted below Routine prophylaxis in ambulatory patients receiving chemotherapy is not recommended due to conflicting trials, potential bleeding, the need for laboratory monitoring and dose adjustment, and the relatively low incidence of VTE. LMWH or adjusted dose warfarin (INR ~ 1.5) is recommended in myeloma patients on thalidomide or lenalidomide plus ch.t. or dexamethasone This recommendation is based on nonrandomized trial data and extrapolation from studies of postoperative prophylaxis in orthopedic surgery and a trial of adjusted-dose warfarin in breast cancer

Patients with Cancer Undergoing Surgery: Role of VTE Prophylaxis Evidence All patients undergoing major surgical intervention for malignant disease should be considered for thromboprophylaxis with low- dose UFH, LMWH, or fondaparinux starting as early as possible for at least 7-10 days unless contraindicated. RCTs of UFH and those comparing the effects of LMWH and UFH on DVT rates on patients with cancer indicate broadly similar prophylactic efficacies for these two agents Mechanical methods may be added to anticoagulation in very high risk patients but should not be used alone unless anticoagulation in contraindicated. A Cochrane review of 19 studies A Cochrane review of 19 studies

Patients with Cancer Undergoing Surgery (continued): Role of VTE Prophylaxis Evidence LMWH for up to 4 weeks may be considered after major abdominal/pelvic surgery with residual malignant disease, obesity, and a previous history of VTE Recent RCTs suggest that prolonging prophylaxis up to 4 weeks is more effective than short- course prophylaxis in reducing postoperative VTE by 60% without Increasing risk of bleeding.

There are important advantages of LMWH because they can be administered once daily, have a better pharmacokinetic profile and are less likely to cause heparin induced thrombocytopenia(HIT). So, LMWH can be considered as the first choice in this setting. Several studies suggest that in cancer patients LMWH and UFH appear to be equally effective and safe. These results have been confirmed by at least three studies,one of them specifically designed for surgical cancer patients

therapeutic Modalities

Treatment of Patients with Established VTE to Prevent Recurrence: Role of VTE Prophylaxis Evidence LMWH is the preferred approach for the initial 5-10 days in cancer patient with established VTE. LMWH for 3-6 months is more effective than vitamin K antagonists given for a similar duration for preventing recurrent VTE. LMWH for at least 6 months is preferred for long-term anticoagulant therapy. Vitamin K antagonists are acceptable when LMWH is not available. The CLOT study demonstrated a relative risk reduction of 49% with LMWH Vs. a vitamin K antagonist.

Treatment of Patients with Established VTE to Prevent Recurrence (continued): Role of VTE Prophylaxis Evidence Anticoagulation for an indefinite period should be considered for patients with active cancer (metastatic disease, continuing chemotherapy) In the absence of clinical trials, benefits and risks of continuing LMWH beyond 6 months is a clinical judgment in the individual patient. Caution is urged in elderly patients and those with intracranial malignancy. Inferior vena cava filters are reserved for those with contraindications to anticoagulation or PE despite adequate long-term LMWH. Consensus recommendations due to lack of date in cancer-specific populations

Therapeutic Anticoagulation Treatment for VTE: Stage 1 (Immediate): At diagnosis or during diagnostic evaluation: Low-molecular-weight heparin (LMWH): Low-molecular-weight heparin (LMWH): Dalteparin (200 units/kg subcutaneous daily). Dalteparin (200 units/kg subcutaneous daily). Enoxaparin (1 mg/kg subcutaneous every 12 hours). Enoxaparin (1 mg/kg subcutaneous every 12 hours). Tinzaparin (175 units/kg subcutaneous daily). Tinzaparin (175 units/kg subcutaneous daily). Fondaparinux: (5 mg [ 100 kg] subcutaneous daily. Fondaparinux: (5 mg [ 100 kg] subcutaneous daily. Unfractionated heparin: (IV) (80 units/kg load, then 18 units/kg per hour, target : aPTT of ( ) x control. Unfractionated heparin: (IV) (80 units/kg load, then 18 units/kg per hour, target : aPTT of ( ) x control. A full dose of heparin is continued for at least 5 days & suspended when full anticoagulation by VKA (i.e. INR >2.0) is achieved for at least two consecutive days.

Therapeutic Anticoagulation Treatment for VTE: Stage 2 Acute: Short term, during transition to chronic phase: ► LMWH (category 1) is preferred as monotherapy, without warfarin in patients with proximal DVT or PE and prevention of recurrent VTE in patients with advanced or metastatic cancer. ► If UFH or factor Xa antagonist, transition to LMWH or warfarin. Warfarin: (2.5-5 mg every day initially, subsequent dosing based on INR value; target INR ). Warfarin: (2.5-5 mg every day initially, subsequent dosing based on INR value; target INR ). started within 24 h from initiating heparin (UFH or LMWH) administration.

It is well known that LMWH is cleared only by the kidneys and has a significant accumulative effect in patients with impaired renal function (creatinine clearance <30 ml/min). Patients with a creatinine clearance of <30 ml/min who are treated with standard therapeutic doses of enoxaparin have elevated levels of anti-Xa and an increased risk for major Bleeding, so in these patients on UFH i.v. or LMWH with anti-Xa activity monitoring is recommended.

Thrombolytic treatment should be considered for specific subgroups of patients such as those with PE presenting with severe right ventricular dysfunction, and for patients with massive ilio-femoral thrombosis at risk for limb gangrene, where rapid venous decompression and flow restoration may be desirable. Urokinase, streptokinase and tissue- type plasminogen activator are able to achieve a rapid lysis of fresh pulmonary emboli.

05/00 medslides.com56  HIT, an antibody-mediated syndrome, is associated with significant morbidity and mortality.  Considered rare in the past, unrecognized by many clinicians.  Diagnoses can be difficult to confirm.  Serologically proven HIT occurs in (1.5-3)% of patients with heparin exposure.  Present with mucocutaneous bleeding, ranging from (petechiae and ecchymoses) to life-threatening gastrointestinal and intracranial hemorrhage.

 Paradoxically, HIT, an immune reaction to an anticoagulant that lowers platelet count, rarely causes bleeding, it causes thromboses, and platelet transfusions are contraindicated.  Heparin, the most powerful anticoagulant, saving uncountable lives and limbs, it produces the most extreme hypercoagulable disorder, costing thousands yearly their lives and limbs.  Health professionals should know about a reaction that is common, often iatrogenic, catastrophic preventable and treatable.  Venous thrombosis developed may result in: Bilateral deep venous thrombosis of the legs. Pulmonary embolism. Venous gangrene of fingers, toes, penis, or nipples. Myocardial infarction, stroke. Mesenteric arterial thrombosis. Limb ischemia and amputation.

Therapeutic Anticoagulation Failure Therapeutic INR Switch to heparin (LMWH preferred) or fondaparinux Increase warfarin dose and treat with parenteral agent until INR target achieved or consider switching to heparin (LMWH preferred) or fondaparinux Patient on warfarin Check INR Sub- therapeutic INR

Therapeutic Anticoagulation Failure Therapeutic PTT Increase dose of heparin or Switch to LMWH or Switch to fondaparinux and Consider placement of IVC filter and Consider HIT Increase dose of heparin to reach therapeutic level Patient on heparin Check aPTT levels Sub- therapeutic aPTT

Anticoagulant therapy in patients with recurrence of VTE: 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. Patients on long-term anticoagulation with VKA who develop VTE when their INR: In the subtherapeutic range: retreated with UFH or LMWH until VKA anticoagulation achieves a stable INR (2-3). 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).

Warfarin mechanism & SE: Warfarin is an oral anticoagulant, a drug that inhibits the clotting of blood. It prevents the formation of blood clots by reducing the production of factors by the liver that promote clotting, factors II, VII, IX, and X, and the anticoagulant proteins C and S. The production of these factors by the liver are dependent on adequate amounts of vitamin K. Warfarin reduces the production of the factors because it antagonizes vitamin K.anticoagulantblood clotslivervitamin K Treatment usually is started at 2 to 5 mg once daily and the dose is adjusted based in INR tests. Patients typically require 2 to 10 mg of warfarin daily.

 Certain foods and beverages can make warfarin less effective in preventing blood clots, SO avoid eating or drinking large amounts of vit K containing food Spinach, Brussels sprouts, Parsley, Collard greens, Mustard greens, Chard, Green tea.  Certain drinks can increase the effect of warfarin, leading to bleeding problems. Avoid or drink only small amounts of these drinks when taking warfarin: Cranberry juice.

There is no evidence to recommend the use of anticoagulation to influence prognosis of cancer

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