Hematology & Oncology Medic DivisionDepartment Of Internal Medicine University Of North Sumatera /H. Adam Malik General Hospital MEDAN 2014Dr. Savita Handayani, Sp.PD

Agnelli G, Buller HR, Cohen A, et al. N Engl J Med 2013;368:699-708

http://atvb.ahajournals.org/content/32/3/569

http://atvb.ahajournals.org/content/32/3/569

Epidemiology & Risk

Cancer pts : 4-6 fold risk for VTE vs. non-cancer ptsCancer pts : 3 fold risk for recurrence of VTE Cancer pts undergoing surgery : 2 fold increased risk for postoperative VTEDeath rate from cancer : 4 fold higher if patient has concurrent VTEVTE : 2nd most common cause of death in ambulatory cancer patients (tied with infection)Heit et al Arch Int Med 2000;160:809-815 & 2002;162:1245-1248; Prandoni et al Blood 2002;100:3484-3488; White et al Thromb Haemost 2003;90:446-455; Sorensen et al New Engl J Med 2000;343:1846-1850); Levitan et al Medicine 1999;78:285-291; Khorana et al J Thromb Haemost 2007;5:632-4

Clinical Features of VTE in CancerVTE has significant negative impact on quality of lifeVTE may be the presenting sign of occult malignancy10% with idiopathic VTE develop cancer in 2 yrs20% have recurrent idiopathic VTE25% have bilateral DVTBura et. al., J Thromb Haemost 2004;2:445-51

Independent Risk Factors for DVT/PEHeit JA et al. Thromb Haemost. 2001;86:452-463

Risk Factor/CharacteristicO.R.Recent surgery with institutionalization21.72Trauma12.69Institutionalization without recent surgery7.98Malignancy with chemotherapy6.53Prior CVAD or pacemaker5.55Prior superficial vein thrombosis4.32Malignancy without chemotherapy4.05Neurologic disease w/ extremity paresis3.04Serious liver disease0.10

VTE Incidence In Various TumorsOtten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17

Oncology SettingVTE IncidenceBreast cancer (Stage I & II) w/o further treatment0.2%Breast cancer (Stage I & II) w/ chemo2%Breast cancer (Stage IV) w/ chemo8%Non-Hodgkins lymphomas w/ chemo3%Hodgkins disease w/ chemo6%Advanced cancer (1-year survival=12%)9%High-grade glioma26%Multiple myeloma (thalidomide + chemo)28%Renal cell carcinoma 43%Solid tumors (anti-VEGF + chemo)47%Wilms tumor (cavoatrial extension) 4%

Thrombosis & Survival After HospitalizationLevitan N, et al. Medicine 1999;78:285

Hospital Mortality With or Without VTEKhorana, JCO, 2006Mortality (%)N=66,016N=20,591N=17,360

Chart1

7.9814.85

10.5916.13

8.6716.41

No VTE

VTE

Sheet1

AllNon-metastaticMetastatic

No VTE7.9810.598.67

VTE14.8516.1316.41

Pathogenesis of Thrombosis in Cancer

1. StasisProlonged bed restExtrinsic compression of blood vessels by tumor2. Vascular InjuryDirect invasion by tumorProlonged use of central venous cathetersEndothelial damage by chemotherapy drugsEffect of tumor cytokines on vascular endothelium3. HypercoagulabilityTumor-associated procoagulants & cytokines (tissue factor, CP, TNF, IL-1, VEGF, etc.)Impaired endothelial cell defense mechanisms (APC resistance, deficiencies of AT, Protein C & S) Enhanced selectin/integrin-mediated, adhesive interactions between tumor cells,vascular endothelial cells, platelets & host macrophages

A Modification of Virchows Triad

VEGFAngiogenesisEndothelial cellsIL-8Blood CoagulationActivation PAR-2AngiogenesisFVII/FVIIaTHROMBINTumor CellFalanga and Rickles, New Oncology:Thrombosis, 2005;1:9-16Interface of Clotting Activation & Tumor Biology

Coagulation Cascade & Tumor BiologyTFThrombinClotting-dependentClotting-dependentClotting-independentClotting-dependentClotting-independentFernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007;5:1584VIIaXaAngiogenesis, Tumor Growth and Metastasis

Pharmacologic(Prophylaxis & Treatment)Nonpharmacologic(Prophylaxis)Antithrombotic TherapyIntermittentPneumaticCompressionElastic StockingsInferiorVena CavaFilterOralAnticoagulantsUnfractionatedHeparin (UH)Low Molecular Weight Heparin (LMWH)New Agents: e.g. Fondaparinux, Direct anti-Xa inhibitors, Direct anti-IIa, etc.?

Coagulation Cascade and Tumor BiologyTFThrombinClotting-dependentClotting-dependentClotting-independentClotting-dependentClotting-independentFernandez, Patierno and Rickles. Sem Hem Thromb 2004;30:31; Ruf. J Thromb Haemost 2007; 5:1584VIIaXaAngiogenesis, Tumor Growth and Metastasis?LMWHs (e.g. dalteparin)Non-anticoagulant heparins

Primary VTE Prophylaxis Recommended for hospitalized cancer patients

Not universally recommended for outpatients, but there are exceptionsNew data for certain agentsHeterogeneous population

Need for risk stratification

Oral Anticoagulant Therapyin Cancer Patients : Problematic Warfarin therapy is complicated by:

Difficulty maintaining tight therapeutic control, due to anorexia, vomiting, drug interactions, etc. Frequent interruptions for thrombocytopenia & proceduresDifficulty in venous access for monitoring Increased risk of both recurrence & bleeding

Is it reasonable to substitute long-term LMWH for warfarin ? When ? How ? Why ?

ASCO Guidelines 2007Hospitalized Patients with Cancer

Role of VTE ProphylaxisEvidencePatients with cancer should be considered candidates for VTE prophylaxis with anticoagulants UFH, LMWH - enoxaparin 1 mg/kg BB every 24 hoursor fondaparinux in the absence of bleeding or other contraindications to anticoagulationMultiple 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 bedridden patients with active cancer.

Patients with Cancer Undergoing Surgery

Role of VTE ProphylaxisEvidenceAll patients undergoing major surgical intervention for malignant disease should be considered for thromboprophylaxis with low- dose UFH, LMWH (enoxaparin 40 mg every 24 hrs), 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 agentsMechanical 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

Patients with Cancer Undergoing Surgery (continued)

Role of VTE ProphylaxisEvidenceLMWH for up to 4 weeks may be considered after major abdominal/pelvic surgery with residual malignant disease, obesity, and a previous history of VTERecent RCTs suggest that prolonging prophylaxis up to 4 weeks is more effective than short-course prophylaxis in reducing postoperative VTE.

Summary of the NCCN Guideline Update Volume.9 Version 2.2011

(VTE-D): Therapeutic Anticoagulation Treatment for VenousThromboembolismStage 1 Immediate: At diagnosis or during diagnostic evaluation :

Low-molecular-weight heparin (LMWH)Dalteparin (200 units/kg subcutaneous daily)Enoxaparin (1 mg/kg subcutaneous every 12 hours)Tinzaparin (175 units/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 2.0-2.5 x control or per hospital SOP)

(VTE-D): Therapeutic Anticoagulation Treatment for Venous ThromboembolismAdditional VTE risk factors for surgical oncology patients with a : previous episode of VTE include anesthesia times longer than 2 hours advanced stage disease, bed rest > 4 days & patients age 60 years or older. Extended prophylaxis out to 4 weeks post-surgery was associated with a greater than 50% reduction in venographic VTE

(VTE-D): Therapeutic Anticoagulation Treatment for VenousThromboembolism

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 2.0-3.0)

1 mg / kg BB SC every 12 hours

CONCLUSIONRisk factors for VTE in the setting of cancer have been well characterized : solid tumors, chemotherapy, surgery, thrombocytopeniaLong-term secondary prevention with LMWH has been shown to produce better outcomes than warfarinGuidelines and landmark trials support administration of LMWH in at risk patientsCancer patients are under-prophylaxed for VTEHealth system pharmacists can play a pivotal role in improving clinical outcomes in this patient population

VTE prophylaxis following cancer surgery for 4 weeks is recommended; longer periods may be necessary depending on risk assessmentVTE prophylaxis following established VTE in cancer for at least 6 months is recommended and for longer, indefinite periods with active cancer and/or chemotherapy.

Heart healthy lifestyle and statins reduce VTE risk.

Electronic, computerized alerts can reduce symptomatic VTE by at least 40%.

When human alerts are used, symptomatic VTE is reduced by about 20%.

PE/ DVT patients with cancer warrant LMWH monotherapy.

***Dr. John Heit and colleagues have provided some interesting information regarding the risk factors associated with developing DVT/PE based on a very thorough epidemiological study.This study, part of the Rochester Epidemiology Project, looked at all residents in Olmsted County, 90 miles southeast of Minneapolis, Minnesota. The study collected information on every patient that underwent a diagnostic test looking for DVT/PE over a 25 year period. The investigators also looked at all death certificates and autopsy reports to gather further data.Obviously, this was a large study covering a considerable period of time. Over 9,000 patients were included.What you see here are the relative odds ratios of various risk factors or risk characteristics from this study for developing either DVT or PE.Notice that malignancy with chemotherapy carried an odds ratio of 6.53 and malignancy without chemotherapy, an odds ratio of 4.05. In comparison to other well known risk factors, such as surgery alone, these data indicate malignancy with and without chemotherapy are frequently associated with the development of a DVT or PE.*****Several classes of agents have been used for prophylaxis and treatment of VTENonpharmacologic approaches to prophylaxis include: intermittent pneumatic compression (IPC), elastic stockings, and inferior vena cava filterMost commonly used pharmacologic agents for thromboprophylaxis and treatment of VTE include: unfractionated heparin (UH) (standard, low-dose, or adjusted-dose), oral anticoagulants such as warfarin, and low molecular weight heparins (LMWHs)

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