DIAGNOSIS AND MANAGEMENT OF DEEP VENOUS THROMBOSIS · • FDA Approved for DVT PE and prevention of...

DIAGNOSIS AND MANAGEMENT OF DEEP VENOUS THROMBOSIS

OBJECTIVES

• Discuss workup and evaluation

• Understand the therapeutic options

• Comfort in prescribing Anticoagulation

• Reversal Options

• Review the Guidelines

XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)

Fibrin (I Fibrinogen (Ia)

Va

OBJECTIVES

VENOUS THROMBOLEMBOLISM

• Tends to be over 55 years old

• Presentation is non-specific

• Common and Incidence is constant

• Hospitalizations have doubled (imaging)

• Cost in the United states is $15-$30 billion dollars

CASE PRESENTATION

• 55 year old male presents complaining of unilateral leg swelling after a transcontinental flight. Denies, cough, chest pain, or shortness of breath. Vital Signs are normal.

DECISION TO WORKUP PULMONARY EMBOLUS

• Suspected VTE

• Pretest Decision rules

• D-dimer

D-DIMER IN DVT - 2003

EVOLUTION OF MANAGEMENT

THEN VS NOW

DVT OLD SCHOOL

• Swollen Leg = ED Evaluation

• Confirmed DVT = Hospitalization

• Management = Bridge to Warfarin

ORAL ANTICOAGULANTS

MANAGEMENT AND THE

COAGULATION CASCADE

XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)

Fibrin (I Fibrinogen (Ia)

Va

COAGULATION AND THE EM PHYSICIAN

COAGULATION AND THE EM PHYSICIAN

• Blood Clot

• Blood Anticoagulant Blood is thin

• Blood Clot TPA Clot broken apart

XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)

Fibrin (I Fibrinogen (Ia)

Va

Mechanism of Anticoagulation

HEPARIN (1930)XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)

Fibrin (I Fibrinogen (Ia)

Va

ENOXAPARIN (1993)XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)

Fibrin (I Fibrinogen (Ia)

Va

WARFARIN

XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)

Fibrin (I Fibrinogen (Ia)

Va

WARFARIN

XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)

Fibrin (I Fibrinogen (Ia)

Va

PROBLEM WITH OLD SCHOOL

ORAL ANTICOAGULANTS

NOVEL ORAL ANTICOAGULANT (NOAC)

• No longer “Novel”

• Renamed to “Non-vitamin K OAC” in 2016

• Renamed Direct Oral Anticoagulant (DOAC)

• TSOAC (target-specific oral anticoagulant)

DABIGATRAN 2010/2014XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)

Fibrin (I Fibrinogen (Ia)

Va

DABIGATRAN 2010/2014XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)

Fibrin (I Fibrinogen (Ia)

Va

DABIGATRAN

• Non inferiority study vs Warfarin – Stroke

• Prevention was similar at 110 mg PO BID

• Lower rates of stroke at 150 mg PO BID

• Similar rates of bleeding

• FDA Approval in 2010

DABIGATRAN USE FOR VTE

DABIGATRAN – VTE STUDIES

• RE-COVER

• RE-COVER II

• RE-MEDY

• RE-SONATE

RE-COVER AND RE-COVER II TRIALS

• Heparin for 5-10 days + (Dabigatran vs Warfarin) x 6m

• Non-inferior to Warfarin

• Lower rates of overall bleeding

• Slight increase in GI bleeding (3.1% vs 2.4%)

RE-MEDY AND RE-SONATE TRIALS

• Standard for 3-12 months then extended treatment

• Dabigatran vs Warfarin vs Placebo (mean 534 d)

• Non-inferior to warfarin

• Lower overall bleeding

• Higher GI bleeding (3.1% vs 2.2%)

• FDA Approval 2014

RIVAROXABAN 2011

RIVAROXABAN 2011XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)

Fibrin (I Fibrinogen (Ia)

Va

RIVAROXABAN 2011

• Rivaroxaban alone vs standard treatment (Warfarin)

• Efficacy was non-inferior to warfarin

• FDA Approved for DVT and PE in 2011

APIXABAN 2014XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)

Fibrin (I Fibrinogen (Ia)

Va

APIXABAN 2014

• Apixaban alone vs standard therapy (Warfarin)

• Efficacy was non-inferior to warfarin

• Significantly less bleeding than warfarin.

• FDA Approved for DVT and PE in 2014

EDOXABAN 2015XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)

Fibrin (I Fibrinogen (Ia)

Va

EDOXABAN 2015

• Heparin then Edoxaban vs Warfarin

• Non-inferior to Warfarin

• Significantly less bleeding

• FDA Approved for DVT PE and prevention of Stroke in 2015

COMPLICATIONS

XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)

Fibrin (I Fibrinogen (Ia)

Va

Inactive

Vit K

Oxidized

Zymogen (Inactive Carboxylated)

Active Factor

Vit K

Reduced

Dabigatraninhibit

inh

ibit

Rivaroxaban

Apixaban

Edoxaban

AT III + Heparin

Warfarin

Inactive

Vit K

Oxidized

Zymogen (Inactive Carboxylated)

Active Factor

Vit K

Reduced

Dabigatraninhibit

inh

ibit

Rivaroxaban

Apixaban

Edoxaban

AT III + Heparin

Warfarin

FFP

PROTHROMBIN COMPLEX CONCENTRATE 2013

• kCentra

• Concentrated Factors (II, VII, IX, X)

• Faster than FFP

– Stopping bleeding (72% vs 65% at 24 hours)

– Correcting INR (60% vs 10% at 30 minutes)

• FDA Approved 2013

Inactive

Vit K

Oxidized

Zymogen (Inactive Carboxylated)

Active Factor

Vit K

Reduced

Dabigatraninhibit

inh

ibit

Rivaroxaban

Apixaban

Edoxaban

AT III + Heparin

Warfarin

PCC25x (2013)

(II VII IX X)

REVERSAL OPTIONS• FFP

• PCC 2013

• Praxbind 2015

• Andexxa 2018

• Ciraparantag (In clinical Trial)

• PCC 2013 (II, VII, IX, X) (approx. $900 to reverse)

• Praxbind 2015 (approx. $4,000 to reverse)

• Andexxa 2018 (approx. $60,000 to reverse)

PHARMACOKINETICS

Dabigatran Rivaroxaban Apixaban Edoxaban

Mechanism Thrombin (Iia) Xa Xa Xa

Onset 1-2 hours 2-4 hours 1-2 hours 1-2 hours

Half Life 12-17 hours 5-9 hours 12 hours 10-14 hours

Liver Metabolism CYP3A4 No Yes Minor Minor

PTT Prolonged Not useful Not useful Not useful

PT Insensitive Prolonged Prolonged Not useful

INR Insensitive Not useful Not useful Not useful

Measurement Various Chromogenic Assay Chromogenic Assay Chromogenic Assay

PHARMACOKINETICS

Dabigatran Rivaroxaban Apixaban Edoxaban

Mechanism Thrombin (Iia) Xa Xa Xa

Onset 1-2 hours 2-4 hours 1-2 hours 1-2 hours

Half Life 12-17 hours 5-9 hours 12 hours 10-14 hours

Liver Metabolism CYP3A4 No Yes Minor Minor

PTT Prolonged Not useful Not useful Not useful

PT Insensitive Prolonged Prolonged Not useful

INR Insensitive Not useful Not useful Not useful

Measurement Various Chromogenic Assay Chromogenic Assay Chromogenic Assay

PHARMACOKINETICS

Dabigatran Rivaroxaban Apixaban Edoxaban

Mechanism Thrombin (Iia) Xa Xa Xa

Onset 1-2 hours 2-4 hours 1-2 hours 1-2 hours

Half Life 12-17 hours 5-9 hours 12 hours 10-14 hours

Liver Metabolism CYP3A4 No Yes Minor Minor

PTT Prolonged Not useful Not useful Not useful

PT Insensitive Prolonged Prolonged Not useful

INR Insensitive Not useful Not useful Not useful

Measurement Various Chromogenic Assay Chromogenic Assay Chromogenic Assay

PHARMACOKINETICS

Dabigatran Rivaroxaban Apixaban Edoxaban

Mechanism Thrombin (Iia) Xa Xa Xa

Onset 1-2 hours 2-4 hours 1-2 hours 1-2 hours

Half Life 12-17 hours 5-9 hours 12 hours 10-14 hours

Liver Metabolism CYP3A4 No Yes Minor Minor

PTT Prolonged Not useful Not useful Not useful

PT Insensitive Prolonged Prolonged Not useful

INR Insensitive Not useful Not useful Not useful

Measurement Various Chromogenic Assay Chromogenic Assay Chromogenic Assay

ADMINISTRATION

• Dabigatran Heparin x 5 -10 days then 150 mg PO BID

• Rivaroxaban 15 mg PO BID x 21d (then 20 mg PO QD)

• Apixaban 10 mg PO BID x 7 days (then 5 mg PO BID)

• Edoxaban Heparin x 5 -10 days then 60 mg PO QD

30 DAYS SUPPLY

– Dabigatran $420

– Rivaroxaban$450

– Apixaban $450

– Edoxaban $385

– Warfarin $5

ADVANTAGES

– Oral

– Rapid Onset

– No need to take with food

– No need for monitoring

– No dosage adjustments

– Fewer drug-drug interaction than warfarin

CONTRAINDICATIONS

• Active Bleeding

• Renal Impairment

• Pregnancy

• Breast Feeding

• Medication interactions (cP450 inhibitors, HIV meds etc)

Amiodarone (no dose adj for dabi) Ledipasvir

Clarithromycin

Barbiturates (e.g., phenobarbital)

Azithromycin Lovastatin Cobicistat Carbamazepine

Bepridil Mefloquine Conivaptan Dexamethasone

Boceprevir Mifepristone Indinavir Phenytoin

Carvedilol Nelfinavir Itraconazole Rifampin

Clarithromycin (no dose adj for dabi) Nicardipine

Ketoconazole St. John’s Wort

Cobicistat PosaconazolePosaconazole

Conivaptan Propafenone Ritonavir Bosentan

CyclosporineQuinidine (no dose adj for dabi) Saquinavir Efavirenz

Diltiazem Ranolazine Teleprevir Enzalutamide

Dronedarone Ritonavir Telithromycin Etravirine

Duloxetine Saquinavir Voriconazole Nafcillin

Fenofibrate Tacrolimus Nevirapine

Grapefruit Tamoxifen Oxcarbazepine

Imatinib Telaprevir Primidone

Indinavir Telithromycin

ItraconazoleTicagrelor (no dose adj for dabi)

Ketoconazole Valspdar

LapatinibVerapamil (no dose adj for dabi)

WHICH DOAC IS BEST

• No comparison studies

• Dabigatran and Edoxaban (LMWH x 5 days first)

• Rivaroxaban and Apixaban (alone)

• Regimen

• Patient preference

• Patient characteristics

FOLLOW THE GUIDELINES (ACCP - 2016)

DISTAL VERSES PROXIMAL

• Without Severe symptoms

– Serial Ultrasound for 2 weeks (1 & 2)

• Severe Symptoms or risk of extension

– Anticoagulation

• Proximal DVT (No Cancer)

– Anticoagulation for 3 months

– Recommend DOAC over Warfarin

• Proximal DVT with Cancer

– Anticoagulation with LMWH for 3 months

– Alternative = DOAC or VKA

DURATION

STANDARD DURATION ANTICOAGULATION

• Provoked or transient risk DVT = 3 months

• Unprovoked DVT = at least 3 months

EXTENDED DURATION (NO STOP)

• Unprovoked DVT, Low risk bleeding = extended

• Second unprovoked DVT, Low and Mod = extended

• Cancer associated DVT, all risk = extended

AFTER ANTICOAGULATION

• Aspirin is recommended

RECURRENT DVT ON ANTICOAGULATION

• On DOAC = Switch to LMWH

• On LMWH = Increase LMWH

THROMBOLYSIS

• Catheter directed thrombolysis

• Anticoagulation

• Combination better than anticoagulation alone

TAKE HOME POINTS

• Consider risk Stratifying

• Heparin, LMWH, Warfarin =

• Consider newer Pharmaceuticals

• DOACs equally efficacious and less bleeding

• DOACs are expensive (reversal really expensive)

• 3 months or more of anticoagulation

TAKE HOME POINTS

FINAL TAKE HOME POINT

REFERENCES

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• Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342–2352.

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• Anticoagulation in patients with isolated distal deep vein thrombosis: ameta-analysis. Franco L, Giustozzi M, AgnelliG, Becattini C. J. Thromb Haemost. 2017;15(6):1142-1154. doi:10.1111/jth.13677

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• Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. Wells PS1, Anderson DR, Rodger M, Forgie M, Kearon C, Dreyer J, Kovacs G, Mitchell M, Lewandowski B, Kovacs MJ. N Engl J Med. 2003 Sep 25;349(13):1227-35.

• Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. Hokusai-VTE Investigators, Büller HR, Décousus H, Grosso MA, MercuriM, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P. N Engl J Med. 2013 Oct 10;369(15):1406-15.

• Safety of D-dimer testing as a stand-alone test for the exclusion of deep vein thrombosis as compared with other strategies. Fronas SG1,2, Wik HS3, Dahm AEA2,4, Jørgensen CT1, Gleditsch J5, Raouf N1, Klok FA6, Ghanima W1,2. J Thromb Haemost. 2018 Dec;16(12):2471-2481.

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DIRECT ORAL ANTICOAGULANT

• Dabigatran (Pradaxa 2010/2014 - IIa)

• Rivaroxaban (Xarelto 2011- Xa)

• Apixaban (Eliquis 2014 Xa)

• Edoxaban (Savaysa 2015 Xa)

– Non-inferior or superior in efficacy

– Significantly less bleeding than warfarin