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Treatment and Management of Venous Thromboembolism (VTE)
Jaclyn D. Cole, PharmD, BCPS
University of South Florida
College of Pharmacy
Objectives: Pharmacists
• Discuss the pathophysiology of venous thromboembolism (VTE) • Analyze the epidemiology of VTE• Evaluate appropriate treatment options for VTE• Develop clinical recommendations for VTE patient care
22
Objectives: Technicians
• Discuss pathophysiology of venous thromboembolism (VTE) • Analyze the epidemiology of VTE • Differentiate medications appropriate for the treatment of VTE
33
Pathophysiology & epidemiology
4
Venous Thromboembolism (VTE)
• Blood clots can form in: • Arms, legs, lungs
• Venous thromboembolism (VTE)• Blood clot that forms in a vein
• Deep venous thrombosis (DVT)• Blood clot in a deep vein
• Pulmonary embolism (PE)• Blood clot in the lungs
55
Epidemiology
• 900,000 VTE incidences annually • First VTE occurs in 100/100,000 persons annually
• Approximately 1/3 = PE, 2/3 = DVT alone • Idiopathic condition in 25-50% patients
• Recurrence rate ~7% at 6 months (despite therapy) • Death ~6% DVT, ~12% PE within 1 month diagnosis
66
NQF-Endorsed Voluntary Consensus Standards for Hospital Care: VTE-1.Kaatz, et Al., 2011.Caprini, et al. 200.White RH. Circulation. 2003.
Pathophysiology
• Normal clotting
7Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014.
Pathophysiology
• Coagulation cascade
8http://www.coagadex.com/coagulation-cascade
Pathophysiology
• Thrombus formation
9Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014.
“Triad” Causal Factors
• Blood stasis• Vessel damage• Hypercoagulable State
1010
Morris, et. al, 2004. http://www.thrombosisadviser.com/en/image.php?image=virchow-triad&category=haemostasis
Risk Factors
• Recent orthopedic/general surgery • Limited physical
movement/immobile • Hx stroke, heart attack, heart
failure, paralyzed• Broken bone (leg, hip, pelvis) • Cancer• Blood circulation problems • Personal or family history of blood
clots • Hormones (birth control, hormone
replacement)
• Obesity • > 60 years of age • Smoker • Implanted vascular access • Previous thromboembolism (high
risk)• Anti-phospholipid syndrome (high
risk)
1111
Caprini, et. al., 2004
VTE Risk Score
• Assess patient specific risk factors • Scores categorize the risk of that patient having a VTE • Evidence-based standardized scoring systems
• Caprini VTE Risk Score (surgical) • Rogers VTE Risk Score (surgical) • Padua VTE Prediction Score (non-surgical) • Kucher VTE Risk Score (non-surgical)
1212
Symptoms
• Depends on location of blood clot • Deep Venous Thrombosis (DVT)• Pulmonary Embolism (PE)
1313
Symptoms of DVT: Leg or Arm
• Unilateral swelling • Warmth, redness• Pain
• Worsens when standing or walking
1414
http://www.elastictherapy.com/problems.html
Symptoms of PE: Lungs • Difficulty Breathing • Shortness of breath (SOB) • Chest pain
• Worse with deep breaths
• Coughing• May cough up blood or bloody phlegm
• Rapid HR• Fainting/Dizziness
1515
http://www.beltina.org/health-dictionary/pulmonary-embolism-diagnosis-symptoms-treatment.html
Diagnosis
• Clinical assessment • Elevated D-dimer*• Diagnostic studies
16Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014.
VTE Event Diagnostic Study
DVT Venography*
Compression ultrasound
PE Pulmonary angiography*
Computerized tomography
Ventilation-perfusion (V/Q) scan
Prognosis
• Fatality • DVT: Rarely fatal • PE: Death can occur within minutes of symptom onset
• Complications • Postthrombotic syndrome• Chronic thromboembolic pulmonary hypertension (CTPH)
17Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014.
Treatment of VTE
18
• Treatment of venous thromboembolism (VTE)
19Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014
Non-pharmacologic treatment
20
IVC Filter • Implanted in inferior vena cava • Captures an embolism on its way to
heart/lungs• Allows blood flow around trapped clots • Option when unable to take
anticoagulants: • Contraindicated• Previous failure on therapy
2121
https://www.drugwatch.com/ivc-filters/
Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014.http://www.uofmmedicalcenter.org/HealthLibrary/Article/41273
Pharmacologic treatment options
22
Drugs & the Clotting Cascade
2323
http://www.nature.com/nrcardio/journal/v10/n7/fig_tab/nrcardio.2013.73_F1.html
Treatment of VTE
• Heparin• Low Molecular Weight Heparins (LMWH)
• Lovenox®, Fragmin®• Factor Xa Inhibitors
• Arixtra®, Xarelto®, Eliquis®, Savaysa® • Vitamin K Antagonist (VKA)
• Coumadin®• Direct Thrombin Inhibitor
• Pradaxa® • Thrombolytic therapy • Surgical removal
24
Heparin
• MOA: acts on multiple sites of the normal coagulation system
• Combines with antithrombin III to inactivate Factor Xa, which inhibits conversion of prothrombin thrombin
• Dose: adjust to target aPTT (60-85 sec) per nomogram• IV: 80 U/kg (or 5000 U) x 1, then 1000 U/Hr• SQ: 333 U/kg x1, then 250 U/kg Q12H• Caution: check dosage strength before administration
• Side Effects: bleeding, heparin-induced thrombocytopenia (HIT)
2525
Heparin sodium® [package insert].http://fdb.rxlist.com/drugs/search.aspx?simprint=&scolor=4&sshape=&pagenumber=47
Low Molecular Weight Heparin (LMWH) • Lovenox® (enoxaparin) • Fragmin® (dalteparin)
2626
http://www.rxzone.us/product.cfm/rx/Lovenox-40Mg-Prefill-Syringes-10X4-Ml-471771.htmlhttps://healthy.kaiserpermanente.org/health/care/
Low Molecular Weight Heparin (LMWH)
• MOA: higher activity with anti-factor Xa than anti-thrombin compared to heparin
• Dose: • Enoxaparin: 1 mg/kg SQ Q12H <or> 1.5 mg/kg SQ Q24H • Dalteparin: 100 units/kg SQ Q12H <or> 200 mg/kg SQ Q24H
• Dose adjust• CrCl <30 ml/min• Anti-factor Xa level: 0.5-1 units/mL
• Side Effects: bleeding, anemia, diarrhea, nausea, thrombocytopenia
2727
Lovenox® [package insert], Fragmin® [package insert]. Leyvraz, et.al. 1991, CHEST 2012
Factor Xa Inhibitors
• Injectable• Arixtra® (fondaparinux)
• Oral tablet • Xarelto® (rivaroxaban) • Eliquis® (apixaban)• Savaysa® (edoxaban)• Future: betrixaban
2828
Factor Xa Inhibitors • MOA: selectively inhibits active binding site for factor Xa
on the coagulation cascade• Side Effects: hemorrhage, anemia, thrombocytopenia
2929
Arixtra® [package insert]. , Xarelto® [package insert], Eliquis® [Package Insert].
Factor Xa Inhibitors
• Fondaparinux (Arixtra®)• Dose:
• 5 mg SQ Q24H (<50 kg)• 7.5 mg SQ Q24H (50-100 kg) • 10 mg SQ Q24H (>100 kg)
• Caution: • Bleeding risk increased in renal impairment and BW < 50 kg • Needle guard may cause allergic reaction in latex sensitive individuals
30Arixtra® [package insert].
Factor Xa Inhibitors • Rivaroxaban
• 15 mg PO BID x 21 days, then 20 mg PO Daily• CrCl < 30: Avoid use
• Patient Counseling• Take with food• Missed dose
• If miss dose and taking BID- may take 2 doses at once! (max 2 tablets in one day, 30 mg/24 hours)
• If miss dose and taking once daily- take as soon as remember on that day, do NOT double dose
3131
Xarelto® [package insert]
Factor Xa Inhibitors • Apixaban (Eliqius®)
• 10 mg PO BID x 7 days, then 5 mg PO BID • Patient counseling:
• With or without food
3232
Eliquis® [Package Insert].
Factor Xa Inhibitors
• Edoxaban• 60 mg PO Daily after 5-10 days parenteral anticoag
• Decrease dose to 30 mg PO Daily if: CrCL 15-50 mL/min, ≤ 60 kg, or certain P-gp inhibitors
• Not Recommended (not studied)
• Mechanical heart valves• Moderate to severe mitral stenosis
33Savaysa® [Package Insert].
Vitamin K Antagonist (VKA)
• Coumadin® (warfarin)• Jantoven® (warfarin)
3434
http://drugline.org/drug/medicament/24873/
Vitamin K Antagonist (VKA)
• MOA: inhibits vitamin K-dependent clotting factors (factors II, VII, IX, X) and anticoagulant proteins C and S
• Dose (patient specific): • Start with 5 mg PO daily (alt: 10 mg load x 2 days)• Adjust to INR 2-3 (goal 2.5) for VTE
• Side Effects: hemorrhage, skin necrosis, systemic atheroemboli, hypersensitivity
3535Coumadin® [package insert].
CHEST, 2012Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014
Bridge Therapy
• Heparin or LMWH given with warfarin• Start warfarin on day 1 or 2 of UFH or LMWH• At least 5 days and with 2 consecutive
therapeutic INR readings
36CHEST, 2012
Factor Half-Life
Protein C 8 hours
Protein S 8 hours
Factor VII 4-6 hours
Factor IX 21-30 hours
Factor X 27-48 hours
Factor II 42-72 hours
SNOT
Vitamin K Antagonist (VKA)
• Dietary Considerations• Consistent intake of Vitamin K foods
• Drug Interactions (lots!)• CYP2C9, CYP1A2, CYP3A4• Antibiotics, antifungals, NSAIDS• Amiodarone
• Decrease warfarin dose 30-50% when starting amiodarone!
• Frequent monitoring and dose adjustments
37
http://www.healthclaps.com/images/Drugs/Vitamins/Health-Benefits-of-VitaminK-Highest-Foods-and-Deficiency-Symptoms.jpg
Vitamin K Antagonist (VKA)
• Atheroembolism (Purple Toe Syndrome) • Cholesterol embolization syndrome • Multiple small emboli move to hands and feet obstruct small arteries • Occurs within first 3-8 weeks of therapy
38http://www.medscape.com/viewarticle/724274_5
Vitamin K Antagonist (VKA)
• Genomic Considerations• VKORC1 (where warfarin works)• CYP2C9 (warfarin elimination)
3939
Lee. Clinical Medicine and Research.2005.
Polymorphisms Effect Observed
CYP2C9*2 or *3 allele Require significantly lower doses of warfarin
CYP2C9*1/*1 (wild type) Higher risk sub therapeutic INR, longer to stabilize dosing, increased bleed risk
VKORC1 haplotype group A Low-dose haplotype group *more common in Asian Americans
VKORC1 haplotype group B High-dose haplotype group *more common in African Americans
Direct Thrombin Inhibitor
• Pradaxa® (dabigatran)
4040
http://www.healthcareglobal.com/news_archive/sectors/pharmaceuticals/pradaxa-be-available-us-says-boehringer, http://www.drugs.com/pradaxa.html, http://www.drugs.com/pradaxa.html
Direct Thrombin Inhibitor
• MOA: directly inhibits thrombin, which prevents conversion of fibrinogen fibrin
• Dose:• 150 mg PO BID after 5-10 days of parenteral anticoagulation• Adjust if CrCl < 30 ml/min or acute renal failure
• Side Effects: bleeding, GI effects,hypersensitivity• Counseling Points
• Keep in original container• Bottle is only good for 4 months after opening• Swallow whole with full glass of water
4141
Pradaxa® [package insert]
42
Drug VTE Treatment Dose Renal Dosing
Heparin IV: 80 U/kg (or 5000 U) x 1, then 1000 U/HrSQ: 333 U/kg x1, then 250 U/kg Q12H
None
Enoxaparin 1 mg/kg SQ Q12H 1.5 mg/kg SQ Q24H
CrCl< 30: 1 mg/kg SQ Daily
Dalteparin 100 units/kg SQ Q12H 200 mg/kg SQ Q24H
Not defined
Fondaparinux 7.5 mg SQ Q24H *5 mg if <50 kg, 10 mg if >100 kg
CrCl 30-50: CautionCrCl < 30: Contraindicated
Warfarin 2-10 mg PO Daily, adjusted to INR (bridge therapy required)
None
Rivaroxaban 15 mg PO BID x 21 days, then 20 mg PO Daily
CrCl < 30: Avoid use
Apixaban 10 mg PO BID x 7 days, then 5 mg PO BID None
Edoxaban 60 mg PO Daily after 5-10 days parenteral anticoagulation
CrCl 15-50 mL/min: 30 mg PO Daily
Dabigatran 150 mg PO BID after 5-10 days parenteral anticoagulation
CrCl 15-30: 75 mg PO BIDCrCl < 15: Avoid use
Thrombolytic Therapy
• Not required for most patients• Patients eligible:
• High-risk patients without hypotension • Massive PE with evidence of hemodynamic compromise (hypotension,
shock)
• Treatment: • IV UFH, then Alteplase 100 mg IV over 2 H• Must assess risk of bleed first
43Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014
Thrombolytic Administration
• Systemic (preferred) • Peripheral vein
• Catheter-directed thrombolysis• CI to thrombolytic therapy • Failed thrombolytic therapy • Death is likely before onset of thrombolysis
44
https://vascular.org/patient-resources/vascular-treatments/thrombolytic-therapy/catheter-directed-thrombolytic-therapy
CHEST, 2016.
Surgical Removal
• Thrombectomy• Embolectomy
• Reserved for massive PE
45Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014
http://content.onlinejacc.org/article.aspx?articleid=1902254
Treatment recommendations
46
Initiation of Treatment
• Requires accurate diagnosis • High probability: parenteral anticoagulation while awaiting results
47Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014
Phase of treatment Goal
Acute (7 days) Rapid-acting agents (UFH, LMWH, fondaparinux, rivaroxaban)
Early maintenance (7 days to 3 months) Reduce risk of long-term complications (i.e. postthrombotic syndrome)
Long-term (> 3 months) Secondary prevention
Duration of Treatment • “Long-term therapy”
• Minimum duration for DVT or PE: 3 months• “Extended anticoagulant therapy”
• Usually means therapy continues indefinitely• Recommended In:
• Second unprovoked VTE with low or moderate bleeding risk
• VTE and active cancer
4848
CHEST, 2016.CHEST. 2012.Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, et al. 2014
CHEST 2016 Guidelines
Clinical Presentation Treatment (Grade of Recommendation)
VTE (no cancer) – long term txt Dabigatran, rivaroxaban, apixaban, edoxaban(2B) > VKA (2C) > LMWH
VTE with cancer LMWH > VKA (2B), dabigatran, rivaroxaban, apixaban, edoxaban (2C)
VTE treated with anticoagulants No IVC filter (1B)
Recurrent VTE on non-LMWH anticoagulant
LMWH (2C) for at least 1 month
Recurrent VTE on LMWH Increase LMWH dose (2C)
49CHEST, 2016
Location of DVT
Location Treatment Notes
Proximal Anticoagulation
Acute isolated distal
• Without severe symptoms / risks
Serial imaging of deep veins for 2 weeks
• No anticoagulation:• If thrombus does not extend
• Anticoagulation:• If thrombus extends but
remains in distain veins• If thrombus extends into
proximal veins
• With severe symptoms / risks
Anticoagulation Same txt as acute proximal DVT
Upper extremity (axillary or more proximal veins)
Anticoagulation > thrombolysis
50CHEST, 2016.CHEST. 2012.
https://www.pinterest.com/pin/574771971165805960/
Location of PE
Clinical Presentation Treatment (Grade of Recommendation)
Subsegmental PE and no proximal DVT (low risk recurrence)
Clinical surveillance > anticoagulation (2C)
Subsegmental PE and no proximal DVT (high risk recurrence)
Anticoagulation > clinical surveillance (2C)
PE with hypotension (SBP < 90 mm Hg for 15 minutes)
Thrombolytic therapy (2B)Systemic therapy > catheter directed thrombolysis (2C)
51CHEST, 2016
http://www.bodyteen.com/anterms.html
Summary
• VTE is common, deadly, and recurrent• Confirm diagnosis and location of VTE • Identify appropriate anticoagulation therapy • Determine duration of therapy • Minimize recurrence
52
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