DIAGNOSIS AND MANAGEMENT OF DEEP VENOUS THROMBOSIS · • FDA Approved for DVT PE and prevention of Stroke in 2015. COMPLICATIONS. XII XIIa VIIa VII XI XIa X Xa X ... LMWH, Warfarin

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)


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)


Va

Mechanism of Anticoagulation

HEPARIN (1930)XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)


Va

ENOXAPARIN (1993)XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)


Va

WARFARIN

XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)


Va

WARFARIN

XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)


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)


Va

DABIGATRAN 2010/2014XII XIIa

VIIa VII

XI XIa

XX Xa

IX IXa

Prohrombin (II)

Thromboplastin

Thrombin (Iia)


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)


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)


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)


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)


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


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


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










PHARMACOKINETICS










PHARMACOKINETICS










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

• Connolly, SJ; Ezekowitz, MD; Yusuf, S; et al. (September 2009). "Dabigatran versus warfarin in patients with atrial fibrillation" (PDF). N Engl J Med. 361 (12): 1139–51. doi:10.1056/NEJMoa0905561. PMID 19717844.

• Turpie AG (January 2008). "New oral anticoagulants in atrial fibrillation". Eur Heart J. 29 (2): 155–65. doi:10.1093/eurheartj/ehm575. PMID 18096568.

• 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.

• Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. Schulman S1, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. N Engl J Med. 2013 Feb 21;368(8):709-18. doi: 10.1056/NEJMoa1113697.

• Oral rivaroxaban for symptomatic venous thromboembolism. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, AgnelliG, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S. N Engl J Med. 2010 Dec 23;363(26):2499-510. doi: 10.1056/NEJMoa1007903. Epub 2010 Dec 3.

• Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Halperin JL, Hankey GJ, Wojdyla DM, Piccini JP, Lokhnygina Y, Patel MR, Breithardt G, Singer DE, Becker RC, Hacke W, Paolini JF, Nessel CC, Mahaffey KW, Califf RM, Fox KA; ROCKET AF Steering Committee and Investigators. Circulation. 2014 Jul 8;130(2):138-46. doi: 10.1161/CIRCULATIONAHA.113.005008. Epub 2014 Jun 3.

• Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: analysis from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). Patel MR1, HellkampAS, Lokhnygina Y, Piccini JP, Zhang Z, Mohanty S, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Becker RC, Nessel CC, Berkowitz SD, Califf RM, Fox KA, Mahaffey KW. J Am Coll Cardiol. 2013 Feb 12;61(6):651-8. doi: 10.1016/j.jacc.2012.09.057.

• Efficacy and safety of prothrombin complex concentrate in patients treated with rivaroxaban or apixaban compared to warfarin presenting with major bleeding. Arachchillage DRJ1,2,3, Alavian S1, Griffin J1, Gurung K1, Szydlo R1, Karawitage N1, Laffan M1,2. Br J Haematol. 2018 Dec 4. doi: 10.1111/bjh.15705. [Epubahead of print]

• Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Kearon C, Akl EA, Ornelas J, et al. Chest. 2016;149(2):315-352.

• "FDA Drug Safety Communication: FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared to warfarin".

• Dabigatran: how the drug company withheld important analyses. BMJ. 349: g4670. doi:10.1136/bmj.g4670. PMID 25055829. Cohen, D July 2014.

• Direct oral anticoagulants in patients with VTE and cancer: a systematic review and meta-analysis. Chest. 2015 Feb;147(2):475-483. doi: 10.1378/chest.14-0402.

• Should symptomatic, isolated distal deep vein thrombosis be treated with anticoagulation? Int J Angiol. 2009 Summer; 18(2): 83–87.

• Venous Thromboembolism. Advances in Diagnosis and Treatment. Tobias Tritschler, MD1; Noémie Kraaijpoel, MD2; Grégoire Le Gal, MD, PhD, MSc3,4; et al Philip S. Wells, MD, FRCPC, MSc3,4. JAMA. 2018;320(15):1583-1594. doi:10.1001/jama.2018.14346

• 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

• How to choose appropriate direct oral anticoagulant for patient with nonvalvular atrial fibrillation. Jordan K. Schaefer, Robert D. McBane, and Waldemar E. Wysokinski. Ann Hematol. 2016; 95: 437–449.

• Anticoagulation Reversal and Treatment Strategies in Major Bleeding: Update 2016. Steve Christos, DO, MS* and Robin Naples, MD. West J Emerg Med. 2016 May; 17(3): 264–270.

• 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.

• The accuracy of MRI in diagnosis of suspected deep vein thrombosis: systematic review and meta-analysis. Sampson FC1, Goodacre SW, Thomas SM, van Beek EJ. Eur Radiol. 2007 Jan;17(1):175-81. Epub 2006 Apr 21.

• S. G. Fronas, H. S. Wik, A. E. A. Dahm, C. T. Jørgensen, J. Gleditsch, N. Raouf, F. A. Klok, W. Ghanima. (2018) Safety of D-dimer testing as a stand-alone test for the exclusion of deep vein thrombosis as compared with other strategies. Journal of Thrombosis and Haemostasis 16:12, 2471-2481.

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

Documents

DIAGNOSIS AND MANAGEMENT OF DEEP VENOUS THROMBOSIS · • FDA Approved for DVT PE and prevention of Stroke in 2015. COMPLICATIONS. XII XIIa VIIa VII XI XIa X Xa X ... LMWH, Warfarin