Cancer Associated Venous Thromboembolic disease

  Patient risk factors for CAT:

·         Advanced age

·         Obesity

·         Hospitalization

·         Poor performance status

·         History of VTE

·         Platelets >350 

·         Leukocytes >11  

Elevated inflammatory markers (d-dimer, TF, CRP)  

Cancer Risk factors for CAT:

·         Pancreas

·         Brain

·         Lung

·         Ovarian

·         GI/gastric

·         Kidney

·         Lymphoma

·         Myeloma

·         Metastatic cancer

Treatment risk factors for CAT:

·         Hospitalization

·         Chemotherapy (

·         Angiogenesis inhibitors

·         Immunomodulators

·         Hormonal therapy

·         Immunotherapy

·         Surgery

·         Radiation therapy

·         Central venous catheters

What is DVT?

§  Clot in a deep vein, such as the leg or arm

§  Symptoms:

·          Redness

·          Swelling

·         Pain

·         typically, unilateral

  What is a PE?

§  Occurs when DVT breaks from a vein wall, travels to the lungs, and blocks blood supply.

§  Symptoms:

·          Dyspnea

·         Cough

·         shortness of breath

  What is Catheter associated VTE?

§  Occurs due to endothelial irritation and coagulation from central venous catheter or peripheral line.

§  May occur in upper extremity.

§  VTE is a common cause of death and complication in patients with cancer.

What is the pathophysiology of CAT?

§  Pro-coagulation factors:

·         Tissue factor leads to thrombin and fibrin formation.

§  Fibrinolytic activities:

·         Plasminogen activator inhibitor-1 ( PAI-1)

§  Platelet activation:

·         ADP, thromboxane A2 (TxA20, CD40L

§  Endothelial damage:

·         Cytokine release from cancer cells of WBCs

  What are the NCCN Guidelines for treatment of CAT?

§  In the absence of contraindications, DOACs, LMWH, and warfarin can be considered for treatment of cancer associated VTE:

·         DOACs preferred for patients without gastric or gastroesophageal lesions:

o   Apixaban (category 1)

o   Edoxaban (category 1) 

o   Rivaroxaban 

§  LMWH preferred for patients with gastric or gastroesophageal lesions:

·         Dalteparin (category 1) 

·         Enoxaparin

§  Alternative Agents :

·         Warfarin

·         Dabigatran 

·         Fondaparinux

·         UFH

§  Duration of treatment:

·         At least 6 months if provoked.

·         Indefinite if active cancer, persistent thrombophilic state, or unprovoked

What are some considerations of DOAC use?

§  Patients with gastric or gastroesophageal lesions:

·         Major bleed risk, including the risk of GI bleed limits the use of DOACs

Hokusai VTE (2018):

§  Compared Edoxaban  to Dalteparin

§  Edoxaban 60 mg po daily following LMWH > 5 days for at least 6 months.

§  Dalteparin 200 IU/kg SC Q24Hrs x30 days , followed by 150 IU/kg SC Q24Hrs for at least 6 months.

§  Results:

·         Edoxaban is non-inferior for treatment of CAT but has increased bleeding risk.

Select-D (2018):

§  Compared Rivaroxaban to Dalteparin

§  Excluded patients with primary esophageal or gastro-esophageal cancer ( due to interim safety analysis-concerns for bleeding).

§  Rivaroxaban:

·         Initial dose: 15 mg po bid x 21 days.

·         Maintenance dose: 20 mg po daily for at least 6 months.

§  Dalteparin: 200 IU/kg SC Q24Hrs x30 days, followed by 150 IU/kg SC Q24Hrs for at least 6 months.

§  Failed to meet power to compare efficacy and safety.

§  Results:

·         Rivaroxaban decreased the risk of VTE recurrence but increased the risk of bleeding.

CARAVAGGIO (2020):

§  Compared Apixaban to Dalteparin.

§  Apixaban:

·         Initial dose: 10 mg po bid x7 days.

·         Maintenance dose: 5 mg po bid or at least 6 months.

§  Results:

·         Apixaban is non-inferior to dalteparin for treatment of CAT.

·         Reduced risk of recurrent VTE.

·         No increased risk of major bleeding.

Medications for the treatment of CAT:

§  Edoxaban (Savaysa):

·         Dose: 60 mg po daily ; if <60 kg: 30 mg.

·         Renal Function: Avoid if CrCl > 95 ; CrCl 15-50: 30 mg ; CrCl < 15: Avoid.

·         Use A Parenteral Overlap for 5 days before starting Edoxaban.

§  Rivaroxaban (Xarelto):

·         Dose: 15 mg po bid x21 days , then 20 mg po daily with food.

·         Renal Function: Avoid if CrCl <30.

·         No parenteral overlap

§  Apixaban (Eliquis):

·         Dose: 10 mg po bid x7 days, then 5mg po bid.

·         Renal Function: can be used in all types of renal function.

·         No parenteral overlap.

What are some absolute contraindications to anticoagulation therapy?

·         Active bleeding (major)

·         Indwelling neuraxial catheters

·         Neuraxial anesthesia/lumbar puncture

·         Interventional spine and pain

What are the relative contraindications to anticoagulation therapy?

·         Clinically significant measurable bleeding

·         Thrombocytopenia (platelets <30-50)

·         Underlying coagulopathy

·         Severe platelet dysfunction

·         Recent surgery at high risk for bleeding

·         High fall risk

·         Primary and metastatic brain tumors

·         Long term antiplatelet therapy

NCCN Inpatient VTE/PE Prophylaxis guidelines:

·         Recommended for patients with confirmed or suspected cancer diagnosis.

·         UFH or LMWH (has a short half-life).

ASCO inpatient VTE/PE Prophylaxis guidelines:

·         Recommended for patients with active cancer and acute medical illness or reduced mobility.

·         Not recommended for patients with minor procedures or chemotherapy infusions.

ASH inpatient VTE/PE prophylaxis guidelines:

·         Recommended for acutely ill hospitalized medical patients.

·         UFH, LMWH, or fondaparinux preferred over DOACs.

Outpatient VTE/PE Prophylaxis:

§  Khorana Score

§  Intermediate to high-risk score >2:

·         Consider anticoagulant prophylaxis for up to 6 months or longer.

·         Low risk VTE: < 2:

o   No routine prophylaxis.

Multiple Myeloma:

§  Increased risk of VTE due to pathophysiology.

§  Highest risk of VTE is within 6 months of diagnosis.

§  Increased risk with treatment (immunomodulatory drugs).