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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


“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


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)


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].


• 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].


• 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/


• 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


• 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


• 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


• 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


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


http://content.onlinejacc.org/article.aspx?articleid=1902254

Treatment recommendations

46

Initiation of Treatment

• Requires accurate diagnosis • High probability: parenteral anticoagulation while awaiting results


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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2. Aspirin [comprehensive prescribing information]. Bayer Corporation. Morristown, NJ; Accessed November 2012

3. Barbar S, Noventa F, Rossetto V, Ferrari A, Brandolin B, Perlati M, et al. A risk assessment model fo the idenfication of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost. 2010 Nov;8(11):2450-7.

4. Caprini JA, Botteman MF, Stephens JM, et al. Economic burden of long-term complications of deep vein thrombosis after total hip replacement surgery in the United States. Value Health. 2003;6:59-74.

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7. Fragmin® [package insert]. Pfizer Inc. New York, NY; April 2007.

8. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuunemann HJ. Executive Summary: Anti-Thrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST. 2012;141:7S-47S.

9. Heparin sodium® [package insert]. Hospira, Inc. Lake Forest, IL; March 2008.

10.Kaatz S, Spyropoulos AC. Venous thromboembolism prophylaxis after hospital discharge: transition to preventative care. Hosp Pract (Minneap). 2011 Aug;39(3):7-15.

11.Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris T, Sood N, Stevens SM, Vintch JRE, Wells P, Woller SC, Moores CL, Antithrombotic Therapy for VTE Disease: CHEST Guideline, CHEST (2016), doi: 10.1016/j.chest.2015.11.026.

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Safer: A Critical Analysis of Patient Safety Practices. Agency for Healthcare Research and Quality (AHRQ). Online http://www.ahrq.gov/clinic/ptsafety/chap31a.htm>. Accessed December 2012.

13.Kucher N, Koo S, Quiroz R, Cooper JM, Paterna MD, Soukonnikov B, et al. Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med. 2005 Mar 10;352(10):969-77.

14.Lee Cr. Warfarin initiation and the potential role of genomic-guided dosing. Clinical medicine and Research. 2005;3(4):205-206.

15.Lovenox® [package insert]. Sanofi-aventis U.S. LLC, Bridgewater, NJ; April 20, 2011.

16.Manual for National Hospital Inpatient Quality Measures Discharges 01-01-13 (1Q13) through 12-31-13 (4Q13). Version 4.2.

17.Ollendorf DA, Vera-Llonch M, Oster G. Cost of venous thromboembolism following major orthopedic surgery in hospitalized patients. Am J Health Syst Pharm. 2002;59:1750-1754.

18.Oster G, Ollendorf DA, Vera-Llonch M, Hagiwara M, Berger A, Edelsberg J. Economic consequences of venous thromboembolism following major orthopedic surgery. Ann Pharmacother. 2004;38:377-382.

19.Pradaxa® [package insert]. Boehringer Ingelheim Pharmaceuticals Inc., Ridegefield, CT; May 2012. 20.Praxbind® [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT; October 2015.

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21. Rogers Jr SO, Kilaru RK, Hosokawa P, Henderson WG, Zinner MJ, Khuri SF. Multivariable Predictors of Postoperative Venous Thromboembolic Events after General and Vascular Surgery: Results from the Patient Safety in Surgery Study. J Am Coll Surg. 2007 Jun;204(6):1211-21.

22. Savaysa® [package insert]. Daiichi Sankyo, Inc., Parsippany, NJ; January 2015.

23. Venous Thromboembolism. The Joint Commission. Available at: https://www.jointcommission.org/venous_thromboembolism/. Updated June 17, 2016. Accessed October 11, 2016.

24. White RH. The epidemiology of venous thromboembolism. Circulation. June 17, 2033;107(23 Suppl1):I4-8.

25. Witt DM, Clark NP. Chapter 9. Venous Thromboembolism. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014.

26. Xarelto® [package insert]. Jansen Pharmaceuticals, Inc., Titusville, NJ; September 2015.

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