Antithrombotic Therapy for VTE Disease: 10th editionALLYSON CORD, PHARMD CANDIDATE 2016

VENOUS THROMBOEMBOLISM

DVT: blood clot formed in a vein that partially or completely blocks circulation

PE: obstruction of the pulmonary artery or one of its branches by material that originated elsewhere in the body (thrombus)

Causes: Virchow’s triad Alterations in blood flow (stasis) Vascular endothelial injury Hypercoagulable state

Malignancy, Factor V Leiden mutation, protein S deficiency, protein C deficiency, antiphospholipid antibodies, IBD, pregnancy

Clinical Presentation DVT

Unilateral extremity swelling, discoloration, pain, tenderness

PE SOB Chest pain Tachypnea Tachycardia Hypotension (hemodynamically unstable or massive PE)

SBP <90 mmHg for a period >15 minutes, or requires vasopressors or inotropic support

http://www.dvtforum.com/index.asp?action=start

Diagnosis D-dimer

Degradation product of fibrin clot Sensitive but not specific

Radiographic contrast studies – venography, pulmonary angiography Gold standard

Most accurate and reliable Expensive and invasive

Ultrasound Less invasive

Etiology Classification

Provoked Transient/reversible

Surgery, pregnancy, immobilization Persistent

Malignancy, indefinite hypercoagulable state Unprovoked

Unidentifiable cause

Anticoagulation Therapy for VTE DiseaseCHEST GUIDELINE, 10TH ED

Choice of Anticoagulant  DVT/PE and no cancer  (Grade 2B)

Recommend dabigatran, rivaroxaban, apixaban, or edoxaban over VKA therapy, and VKA therapy over LMWH

DVT/PE and cancer (Grade 2C) Recommend LMWH over dabigatran, rivaroxaban, apixaban, edoxaban, or

VKA therapy

No need to change the choice of anticoagulant after the first 3 months of therapy (Grade 2C)

NOAC > VKA > LMWH

Cancer = LMWH

NOAC evidence 4 new RCTs and extensive clinical experience

Risk reduction similar between NOACs and VKA Risk reduction greater with LMWH than VKA in patients with cancer Risk reduction seems to be similar between all NOACs

No direct comparison Risk of bleeding less with NOACs than VKA

GI bleeding may be higher, though Risk may be less with apixaban

Risk of fatal bleeding similar between VKA and NOACs Conclusion, less bleeding and greater convenience with NOACs

Parenteral Anticoagulation Dosing

UFH 80 U/kg IV bolus followed by 18

U/kg/hr 5000U IV bolus followed by 1000 U/hr

Enoxaparin 1 mg/kg SQ Q12H 1.5 mg/kg SQ QD CrCl < 30: 1 mg/kg SQ Q24H

Fondaparinux < 50kg: 5mg SQ QD 50-100kg: 7.5mg SQ QD > 100kg: 10mg SQ QD

Tinzaparin 175 U/kg SQ QD CrCl < 30: use with caution

Nadroparin 171 U/kg SQ QD CrCl 30-50: reduce dose by 25-

33% CrCl < 30: CI

Dalteparin – off-label

Oral Anticoagulation Therapy Vitamin K Antagonist - warfarin

Started on day 1 or 2 of parenteral anticoagulation Maintain overlap for at least 5 days and INR therapeutic for 48 hours

INR goal = 2-3 Many diet, drug, and disease interactions

OR NOAC – rivaroxaban, apixaban, edoxaban, dabigatran

Preferred VTE treatment

Rivaroxaban (Xarelto)Dosing DVT/PE treatment: 15mg BID x 21 days followed by 20mg

QD Take with food Extremes in weight do not influence Does not require parenteral anticoagulation prior to initiation

Reduction in risk of recurrence: 20mg QD Renal and hepatic impairment

CrCl < 30: avoid use Moderate-severe hepatic impairment: avoid use

Rivaroxaban (Xarelto)Characteristics ADR

Bleeding/thrombosis Spinal/epidural hematoma

DDI CYP 3A4 (major) CYP 2J2 (minor) P-gp

Pregnancy C D/c 24 hours prior to surgery

CrCl < 50: consider d/c 3-5 days prior

Apixaban (Eliquis)Dosing DVT treatment: 10mg BID x 7 days followed by 5mg BID

Does not require parenteral anticoagulation prior to initiation Reduction in risk of recurrence: 2.5mg BID after at least 6 months of

DVT treatment Renal impairment

CrCl < 30: use with caution Under nonvalvular atrial fibrillation

≥ 80 yoa AND weighs ≤ 60kg or SCR ≥ 1.5 reduce dose by 50% Hepatic impairment

Moderate: use with caution Severe: not recommended

Apixaban (Eliquis)Characteristics ADR

Bleeding/thrombosis Spinal/epidural hematoma

DDI CYP 3A4 (major)

Reduce dose by 50% CYP 1A2, 2C19, 2C8, 2C9 (minor) P-gp

Pregnancy B D/c 24-48 hours prior to surgery

Edoxaban (Savaysa)Dosing DVT/PE treatment: 60mg QD

Requires 5-10 days of parenteral anticoagulation prior to initiation Weight dose adjustment

≤ 60kg: reduce dose by 50% Renal impairment

CrCl > 95: avoid CrCl 15-50: reduce dose by 50% CrCl < 15: avoid

Hepatic impairment Moderate-severe: avoid

Edoxaban (Savaysa)Characteristics ADR

Bleeding/thrombosis Spinal/epidural hematoma Abnormal LFTs

DDI with specific P-gp inhibitors Verapamil, quinidine, macrolides, oral itraconazole, oral ketoconazole Reduce dose by 50%

Pregnancy C D/c 24 hours prior to surgery

Edoxaban (Savaysa)

CrCl > 95 CrCl 95-51 CrCl 50-15 CrCl < 15

> 61kg Avoid 60mg 30mg Avoid

P-gp Avoid 30mg 15mg Avoid

≤ 61kg Avoid 30mg 15mg Avoid

P-gp Avoid 15mg avoid Avoid

Dabigatran (Pradaxa)Dosing DVT/PE treatment/prevention: 150mg BID

After 5-10 days of parenteral anticoagulation Take with full glass of water Dispense in original container

Discard 4 months after opening Renal

CrCl < 50 and concomitant P-gp: 75mg BID CrCl ≤ 30: dose not provided

Non-valvular a fib with CrCl 15-30: 75mg BID If with P-gp, avoid

CrCl < 15: not studied, CI per CHEST Hepatic

Severe impairment: avoid

Dabigatran (Pradaxa)

Characteristics ADR

Bleeding/thrombosis Spinal/epidural hematoma GI upset

DDI P-gp inhibitor

Pregnancy C d/c 1-2 days or 3-5 days (CrCl <

50) before surgery

Reversal Idarucizumab (Praxbind)

5g dose (2 2.5g vials) Give within 15 mins

Dialyzable

NOAC ComparisonNOAC Parenteral

neededWeight adj DDI Reversal Unique

Rivaroxaban No No 3A4, P-gp No Take with food

Apixaban No ~ No 3A4, P-gp No Pregnancy B

Edoxaban Yes Yes P-gp No CrCl > 95: avoid

Dabigatran Yes No P-gp Praxbind, dialyzable

GI upset

Thrombophilia Recommended treatment: UFH or LMWH followed by VKA

Sufficient data not available regarding safety and efficacy of NOACs in patients with thrombophilia

RAPS: rivaroxaban vs enoxaparin with warfarin in APS

Antithrombin deficiency Heparin resistance – need larger doses

Not as much AT for heparin to reduce Protein C deficiency

Warfarin-induced skin necrosis

Duration of Anticoagulant Therapy Active treatment = 3-6 months

Secondary prophylaxis Primary risk factor – provoked vs unprovoked

Provoked by transient/reversible risk factor = lowest risk of recurrence 3 months

Unprovoked/unidentifiable = moderately high risk of recurrence Base duration of therapy on secondary risk factors and bleeding risk

Provoked by progressive/persistent factor = highest risk of recurrence Indefinite therapy

Secondary risk factors – location and history Second episode = indefinite therapy UE or isolated distal (unprovoked or transient provoked) = 3 months

Indefinite therapy only recommend in low-moderate bleeding risk!

Management of Recurrent VTE on Anticoagulant Therapy

Unusual occurrence so reevaluate: Diagnosis Compliance Underlying malignancy

If occurs while on therapeutic VKA or NOAC therapy, suggest switching to LMWH therapy at least temporarily At least 1 month

If occurs while on long-term LMWH, suggest increasing dose by 1/4 -1/3

Aspirin for Extended Treatment of VTE

“In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, we suggest aspirin over no aspirin to prevent recurrent VTE (Grade 2B).” Not a reasonable alternative

80% reduction vs 30% Additional indications

Systemic Thrombolytic Therapy for PE

Suggested indications for thrombolytic use PE associated with hypotension Acute PE that deteriorates after starting anticoagulant therapy

Suggest using a peripheral vein over catheter-directed thrombolysis

Only use if low risk of bleeding!

If massive PE with high bleeding risk, failed systemic thrombolysis, or shock, suggest catheter-assisted thrombus removal Only if appropriate expertise and resources available

Compression Stockings to Prevent PTS

“In patients with acute DVT of the leg, we suggest not using compression stockings routinely to prevent PTS (Grade 2B)” Post-thrombotic syndrome: chronic complication of DVT resulting in

chronic venous insufficiency Larger RCT showed no benefit A trial of compression stockings may be tried for s/s associated with

PTS

Whether to Anticoagulate Subsegmental PE

Subsegmental PE: no involvement of the more proximal pulmonary arteries Low risk of recurrent VTE clinical surveillance

As long as no DVT also present More likely a false positive or arose from a small DVT

High risk of recurrent VTE anticoagulation Evaluate bleeding risk

Treatment of Acute PE Out of the Hospital

“In patients with low-risk PE and whose home circumstances are adequate, we suggest treatment at home or early discharge over standard discharge (Grade 2B).” Standard discharge: after first 5 days of treatment

Summary

Non-Cancer: NOAC > VKA > LMWH Cancer: LMWH Recurrent: Switch to LMWH or increase LMWH dose ASA: consider upon anticoagulant d/c Thrombolytic: only in massive or deteriorating PE Compression stockings: do not routinely use Subsegmental: base therapy on risk

References DiPiro JT, Talbert RL, Yee GC, et. al. Pharmacotherapy: A Pathophysiologic

Approach, Ninth Edition. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE

disease: Antithrombotic Therapy and Prevention of Thrombosis, 10th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2016;149(2):315-352.

Kearon C, Akl EA. Duration of anticoagulant therapy for deep vein thrombosis and pulmonary embolism. Blood 2014; 123(12):1794-1801.

Lexi-Drugs. Lexicomp Online. Wolters Kluwer Health, Inc. Hudson, OH. Available at: http://online.lexi.com. Accessed February 4, 2016.

Bauer KA. Management of inherited thrombophilia. UpToDate. Wolters Kluwer Health, Inc. Hudson, OH. Available at: http://www,uptodate.com/contents/management-of-inherited-thrombophilia

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