Drugs

Timeline of Anticoagulation Options

1916
Heparin
1950s
1990s
2002
1970s
Warfarin
LMWH
Selective factor Xa inhibitor Direct thrombin inhibitors
Weitz J, Hirsh J. Chest. 2001;119:95S.

Current Anticoagulants

Route of Administration
Laboratory Monitoring
Heparin
Parenteral
Yes
Low molecular weight heparins
Parenteral
No
Fondaparinux
Parenteral
No
Direct thrombin inhibitors
Parenteral
Yes
Vitamin K antagonists (warfarin)
Oral
Yes

Current antithrombotic agents: multi-targeted

Vitamin K antagonists
TM
VIIa
Xa
Cellular tissue factor
Ca2+
II
X
IX
PS
PC
PCa
XIIIa
XI
XII
Soluble fibrin
Fibrinogen
Fibrin (clot)
Heparins
Xa
Va
PL
Ca2+
IXa
VIIIa
Ca2+
PL
IIa
XIa
VII
Intrinsic system
Extrinsic system
XIIa

Advantages of LMWH (low molecular weight heparin) over UFH (unfractionated heparin)

Better bioavailability and predictable pharmacokinetics VTE treatment using weight-based dosing with no need for laboratory monitoringLonger half-life twice or once daily subcutaneous dosingLower rate of heparin-induced thrombocytopenia

VIIa

Xa
IXa
XIa
XIIa
Selective Indirect Factor Xa inhibition
Tissue factor
Antithrombin
Fondaparinux
Fibrinogen
Fibrin clot
Factor II(prothrombin)

Fondaparinux

Synthetic pentasaccharide Longer half-life than LMWH No laboratory monitoring required No reactivity with HIT antibodies Approved for prophylaxis of VTE following major orthopedic and abdominal surgery and for treatment of VTE



Limitations of Warfarin (Vitamin K Antagonists)
LIMITATION CONSEQUENCE
Slow onset of action Genetic variation in metabolism Multiple food and drug interactions Narrow therapeutic index
Overlap with a parenteral anticoagulant Variable dose requirements Frequent coagulation monitoring (INR) Frequent coagulation monitoring (INR)

VIIa

Xa
IXa
XIa
XIIa
Direct Factor Xa Inhibition
Tissue factor
Fibrinogen
Fibrin clot
Factor II(prothrombin)

Rivaroxaban (BAY 59-7939) (oral) LY517717 (oral)

Factor II(Prothrombin)
Fibrinogen
XII
VII
X
XI
IX
Direct Thrombin Inhibition
XIIa
Thrombin
VIIa
XIa
Fibrin
IXa
Xa
Tissue Factor
LepirudinBivalirudinArgatroban Ximelagatran (oral) Dabigatran (oral)

Anticoagulant Treatment of Venous Thromboembolism

1.Initial treatment with adequate doses of heparin is important.2.Warfarin can be initiated early. Antithrombotic effect of warfarin requires reduction ofprothrombin levels: this effect requires at least 4 daysof treatment and the need for overlap with heparin.4.DVT can be treated at home with LMWH/fondaparinux.5.Unprovoked (“idiopathic”) VTE is a chronic disease.6.What is the optimal duration of initial treatment? Which patients require long term anticoagulant therapy and what should the INR intensity be?

* The Importance of DVT Prophylaxis in Patients With Cancer

VTE is one of the leading causes of death in cancer patients, occurring in 4% to 20% of patients Hospitalized patients with cancer and cancer patients receiving active therapy are at greatest risk for VTE Cancer increased the risk of VTE 4.1-fold Chemotherapy increased the risk 6.5-fold Major risk factors include older age, comorbid conditions, recent surgery or hospitalization, active chemotherapy or hormonal therapy All hospitalized cancer patients should be considered for prophylaxis Patients with cancer undergoing surgery should be considered for prophylaxis LMWH is the preferred drug

Recurrent Venous Thrombosis is CommonFollowing a First Episode of Symptomatic DVT

Cumulative Incidence (%)
Years
Prandoni et al, Ann Intern Med 1996;125:1-7

Duration of Anticoagulant Therapy

First event with reversible or time limited risk factor 3-6 months at INR 2-3 Unprovoked VTE, first or second event 6-12 months at INR 2-3, then consider indefinite anticoagulation at INR 2-3 weighing recurrence versus bleeding risk (? INR 1.5-2) Special Situations - indefinite anticoagulation First event with Cancer until resolved (consider chronic LMWH) Antiphospholipid antibody syndrome Antithrombin deficiency or multiple genetic defects, ? deficiencies of protein C or protein S

ANTICOAGULANT DOSING

Subcutaneous Heparin Dosing for Treatment of Acute Venous Thromboembolism General Considerations 1. Round weight-based dose to nearest prefilled syringe size. 2. Consider monitoring anti-Xa heparin levels for weight >120 kg or <60 kg. 3. Repeat CBC day 7 to assess for heparin-induced thrombocytopenia. a. If heparin exposed in prior 6 months, CBC on day 3. 4. LMWH not recommended if creatinine clearance (CrCl) <30 ml/min.

Dosing

Enoxaparin: 1 mg/kg every 12 hours or 1.5 mg/kg daily For cancer patients and those at high bleeding or thrombosis risk, favor twice-daily dosing Dalteparin: 200 IU/kg daily In cancer patients for long-term treatment: 200 IU/kg daily for 4 weeks (cap at 18,000 IU), then: a. <56kg: 7,500 IU daily b. 57-68 kg: 10,000 IU daily e. >98 kg: 18,000 IU daily c. 69-82 kg: 12,500 IU daily d. 83-98 kg: 15,000 IU daily Tinzaparin: 175 IU/kg daily Fondaparinux: Daily dose: <50 kg: 5 mg. 50-100 kg: 7.5 mg. >100 kg:10 mg Unfractionated heparin: 333 IU/kg x 1, then 250 IU/kg every 12 hours

Initial Warfarin Dosing for Venous Thromboembolism or Atrial Fibrillation in Ambulatory Outpatients, Target INR 2.0-3.0
General Considerations 1. Obtain baseline PT/INR and investigate if abnormal. 2. Determine use of potential warfarin interacting medications. 3. Document target INR and prescribed warfarin tablet strength. 4. Provide patient education on safety, monitoring, drug and food interactions. 5. For acute thrombosis, overlap with heparin/LMWH/fondaparinux for 5+ days until INR therapeutic. 6. Recommend first INR check on day 3-4.


DAY
INR
DAILY DOSE
1-3

3 or 4

7& 10 day
--------1.3-1.41.4-1.51.6-1.8>1.9>2≤ 1.51.6-1.9 2-33.1-3.53.6-4.0>4.1≥6.0 *5 mg

7.5 mg 5 mg 2.5/5 mg alternating 2.5 mg Hold one day ,then 2.5 mg# Increase by 15% of ADD(ADD = average daily dose) Increase by 10% of ADD No change Decrease by 10% of ADD Decrease by 15% of ADD Hold one day , decrrease by 10% or more # C ONSIDER VITAMINE K#

Warfarin dosing (cont ) * 2.5 mg for frailty, liver disease, malnutrition, drugs that enhance warfarin activity, or Asian ethnicity; 5-7.5 mg for young healthy patients #Check INR more frequently

ANTICOAGULANT REVERSAL

A. General Principles of Management of Anticoagulant-Associated Bleeding HASHTI 1. Hold further doses of anticoagulant 2. Consider Antidote 3. Supportive treatment: volume resuscitation, inotropes as needed 4. Local or surgical Hemostatic measures: topical agents (aminocaproic acid, tranexamic acid) 5. Transfusion (red cells, platelets, FFP as indicated) 6. Investigate for bleeding source Definitions Used for Reversal Situations Non-urgent: Reversal is elective (procedures >7 days away) Urgent (without bleeding): Reversal needed within hours Urgent (with bleeding): Emergency reversal

AGENT

DOSE
COMMENT
Vitamin K
1-10 mg IV/PO, not SQ or IM
Infusion reactions rare; administer over 20-30min• Takes 6 (IV) to 24 (PO) hours to reverse warfarin• Large doses can cause warfarin resistance on resumption Protamine sulfate
12.5-50 mg IV
Full reversal of unfractionated heparin• 60%-80% reversal of LMWH• No reversal of fondaparinux Platelets
1 apheresis unit 5-8 whole blood units
Raise platelet count by 30 x 109/L• Goal platelet count 50 - 100 x 109/L(indication dependent) Frozen plasma (FFP)
10-30 mL/kg (1 unit = ~250ml)
Replaces all coagulation factors, but cannotfully correct° Hemostasis usually requires factor levels~30%° Factor IX may only reach 20%• May need repeat dose after 6 hours• Large volume, takes hours to thaw and infuse Recombinant factor VIIa (rFVIIa)
15-90 units/kg (lower doses studied
Rapid infusion of small volume• Rapid INR correction of warfarin, but may notcorrect bleeding because only restores FVIIa• Risk of thrombosis 5-10%• May need repeat dose after 2 hours Prothrombin complex concentrates (PCC)
25-50 units/kg IV (lower doses studied)
Rapid INR correction in warfarin patients• Small volume infusion over 10-30 minutes• Risk of thrombosis 1.4%• Contraindicated with history of HIT• May need repeat dose after 6 hours• Consider adding FFP if 3-factor PCC used


Reversal of Antiplatelet Agents
Non-Urgent
Urgent (Not Bleeding)
Urgent (Bleeding)
Discontinue agent 5-10 days prior to procedure
Consider platelet transfusion prior to high risk bleeding procedures
HASHTI• Platelet transfusion