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