1. Anticoagulants Sara Gordon Sara.Gordon@va.gov
Therapeutics I Study Session
September 25, 2016

2. Patient Case
Mrs. Smith is a 38 year old white female who presents with 2-day history of edema, severe LLE pain, and LLE warmth. Pt returned home 2 days ago from London, England. She reports that these symptoms started on the plane
PMH: tobacco use x18 years, obesity, GERD, HTN
Medications:
HCTZ 25mg daily
Omeprazole 20mg daily
Ortho-Tri-Cyclen daily
Multivitamin daily

3. Patient Case cont. BP 162/98 P 68bpm RR 16
Weight 220lb (100kg) Height 64in
1+ pitting edema; tenderness to palpation in LLE
Venous Duplex Exam Results:
LLE: Evidence of acute nonoccluding thrombus in popliteal vein
RLE: No evidence of thrombus Na
137
BUN 13 Mg
2.1 K
4.4
SCr
0.7
PO4
4.1 Cl
103
Glu
108
Hgb
12.3
CO2 25 Ca
10.1
Hct
37.4

4. What signs and symptoms does Mrs. Smith have for VTE?
Leg swelling, pain, warmth
Unilateral leg edema, tenderness with palpation
Other signs and symptoms patients may present with:
Skin discoloration
Superficial veins may be dilated and “palpable cord” may be felt
Pain in back of the knee during dorsiflexion of the foot while the knee is slightly bent (Homan’s sign)

5. What risk factors does Mrs. Smith have for DVT?
Long flight from London, England
Estrogen-containing oral contraceptive pills + smoking
Obesity
What are some other risk factors for VTE?
Venous stasis
Immobilization, HF, CVA, Age >40, varicose veins, general anesthesia >30 min
Endothelial injury
Major orthopedic surgery, trauma, indwelling catheters, history of VTE
Hypercoagulability
Malignancy, Pregnancy, nephrotic syndrome, inflammatory bowel disease, Protein C or S deficiency
Smokers over the age of 35 who smoke are at an increased risk of VTE
Virchow’s triad

6. What clinical and objective criteria should be used to diagnose DVT?
Duplex ultrasonography is most commonly used
Noninvasive
Measures the rate and direction of blood flow which can visualize clot formation in proximal veins
Cannot reliably detect small blood clots in distal veins
Venography – gold standard
Invasive test that involves the injection of contrast dye which can cause anaphylaxis and nephrotoxicity
D-dimer
Sensitive for clot formation, not very specific
D-dimer can also be elevated for surgery/trauma, pregnancy, increasing age, cancer

7. Why is it important to diagnose and treat patients with VTE?
Postthrombotic Syndrome
Due to destruction or damage to valves in the veins
Blood flow directed to superficial system which leads to edema, calf pain, ulceration
Pulmonary Embolism
Thrombus lodges in the pulmonary artery and causes occlusion of pulmonary blood flow
Dyspnea, tachypnea, tachycardia, chest pain, anxiety
Postthrombotic Syndrome in which valves become incompetent, blood flow directed from deep venous system to superficial system which leads to edema

8. How would you initially treat Mrs. Smith’s DVT?
Heparin
80 units/kg bolus, 18 units/kg/hr infusion
aPTT every 6 hours
Enoxaparin
1 mg/kg SC q12h
1.5 mg/kg SC q24h
Activated partial thromboplastin time

9. Heparin
Binds antithrombin (AT) and causes a conformational change that accelerates AT’s activity
Inhibits thrombin (IIa), Xa, IXa, XIa, and XIIa
IV or SC administration
333 units/kg SC x1, then 250 units/kg SC q12h
Do not give IM due to risk of hematoma
Monitoring: aPTT every 6 hours until therapeutic x12 hours, then check every 24 hours
ADRs: bleeding, HAT, HIT, osteoporosis
Reversal agent: protamine
1 mg protamine per 100 units heparin; max 50 mg

10. Heparin Induced Thrombocytopenia (HITT)
Suspect HIT if platelet count drops by more than 50% from baseline or <120
Thrombosis occurs despite treatment with heparin
Discontinue all forms of heparin
Argatroban, Fondaparinux, Bivalirudin
Do not start warfarin until platelets >150
Warfarin use with a low plt count has been associated with warfarin-induced limb gangrene and necrosis
4Ts: thrombocytopenia – drop in plts
Timing – occurs ~5 days after starting heparin if 1st time, or ~24 hours if received heparin before
Thrombosis
Other causes for thrombocytopenia

11. Low-Molecular Weight Heparins (LMWHs)
Bind AT
have greater affinity for factor Xa than IIa
Enoxaparin (Lovenox)
If CrCl <30 mL/min, 1 mg/kg SC q24h
Dalteparin (Fragmin)
120 units/kg q12h (max 10,000 units)
ADRs: bleeding, anemia, increased LFTs, thrombocytopenia
Do not use in patients with HITT
More predictable anticoagulant response than heparin, does not require monitoring
Largely reversed by protamine
1 mg protamine per 1 mg enoxaparin or 100 units dalteparin

12. Fondaparinux (Arixtra)
Pentasaccharide
Acts by selectively inhibiting factor Xa via AT
Weight–based dosing for VTE treatment
>100 kg: 10 mg SC daily
kg: 7.5 mg SC daily
<50 kg: 5 mg SC daily
Contraindicated in severe renal impairment (CrCl <30 mL/min)
ADRs: bleeding, anemia, injection site reaction, thrombocytopenia
No reversal agent

13. What would you recommend for Mrs
What would you recommend for Mrs. Smith when she is discharged from the hospital?
Direct Thrombin Inhibitor
Dabigatran (Pradaxa)
Factor Xa inhibitors
Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa)
Warfarin

14. Dabigatran
Directly inhibit thrombin (factor IIa); bind to the active thrombin site of free and clot-associated thrombin
Dose: 150mg PO BID after 5-10 days of parenteral anticoagulation
Not recommended in patients with CrCl <30 mL/min
ADRs: dyspepsia, bleeding
Must be kept in original container
Do not crush or chew capsule
Drug interactions: dabigatran is substrate of p-gp; avoid use with rifampin (decreased effect)
Avoid use in patients with CrCl <50 mL/min and p-gp inhibitor
Amiodarone, dronedarone, quinidine, clarithromycin, verapamil
Increases levels of dabigatran
Must be kept in the original containers tightly sealed to protect from moisture, do not put in pill box; desiccant in the lid of the container
Rapid onset, rapid offset
Discontinue 1-2 days (CrCl >/= 50 mL/min) or 3-5 days (CrCl <50 mL/min) before invasive or surgical procedures
Consider longer times for patients undergoing major surgery or spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required; dabigatran has BBW as these patients are at risk of hematomas and subsequent paralysis

15. Rivaroxaban Direct Factor Xa inhibitor Dose for VTE treatment:
15 mg PO BID with food x21 days, then 20 mg PO daily with food
Recurrent VTE: 20 mg PO daily with food
Avoid in CrCl <30 mL/min
3A4 and p-gp substrate
Avoid use with strong inhibitors or inducers
Combination of moderately interacting drugs and impaired renal function
Strong inhibitors: ketoconazole, itraconazole, ritonavir, clarithromycin, erythromycin Strong inducers: rifampicin, carbamazepine, phenytoin, St. John’s wort

16. Apixaban
Dose for VTE treatment: 10 mg PO BID x 7 days, then 5 mg PO BID
3A4 and p-gp substrate
Use 2.5mg BID dosing with concomitant administration of ketoconazole, itraconazole, ritonavir, and clarithromycin

17. Edoxaban
Dosing for VTE: 60 mg after 5-10 days of parenteral anticoagulation
Not recommended in patients with CrCl >90 mL/min OR <15 mL/min
30 mg daily
If CrCl 15-50mL/min
weight </= 60 kg
If using with concomitant p-gp inhibitors (verapamil, quinidine)
Short-term use of azithromycin, clarithromycin, erythromycin, itraconazole, or ketoconazole

18. Warfarin Vitamin K antagonist
Inhibits synthesis of vitamin K dependent clotting factors (II, VII, IX, X) and anticoagulant proteins C and S
Anticoagulant effect depends on the depletion of vitamin K clotting factors
Due to half-life of clotting factors, full anticoagulant effect is not seen for ~5-7 days *must overlap with injectable anticoagulant*
Monitoring: INR
Goal INR: 2-3
ADRs: bleeding, teratogenic effects, warfarin-induced skin necrosis, purple toe syndrome
VII: 4-6 hr
IX 20-24hr
X hr
II >60 hours
HAS-BLED Score: HTN >160 (1), Abnormal renal or liver disease (1pt each), Stroke (1), Bleeding (1), labile INR (1), Age >65 (1), Drug or alcohol use (1), Antiplatelet or NSAID use (1)
Warfarin-induced skin necrosis more common in obese females >50 years old, begins within 10 days of warfarin therapy, patients present with painful, erythematous lesions on breast, thighs, and buttocks which progress to hemorrhagic lesions
Purple toe syndrome usually occurs in men; present with dark, blue-tinged bilateral discoloration of the feet, usually occurs 3-8 weeks after warfarin initiation

19. Initiation of Warfarin therapy
Desire INR increase/day; expect to be therapeutic by day 5-7
Overlab for a minimum of 4-5 days, or until INR therapeutic for at least 24 hours (2 therapeutic INR readings)

20. Warfarin Drug Interactions
S-isomer is metabolized by 2C9
Fluconazole, Amiodarone, Bactrim, Flagyl (FAB-Four) inhibit metabolism of S-isomer, thereby increasing INR
Clarithromycin, quinolones, aspirin, NSAIDs
Possible decreased effect: rifampin, carbamazepine, phenytoin, barbiturates, vitamin K containing foods

21. INR Reversal Vitamin K Fresh-Frozen Plasma
Oral preferred when there is no active bleeding
IV used when prompt reversal required due to active bleed
Fresh-Frozen Plasma
Contains all coagulation proteins
Indicated when immediate reversal of anticoagulation is needed
Prothrombin Complex Concentrate
Contains factors II, VII, IX, X, protein C and S
Recombinant Factor VII

22. How long should Mrs. Smith be anticoagulated?
This is her first provoked DVT by a transient risk factor - 3 months

23. What if Mrs. Smith was in the hospital for an acute medical illness?
Acutely ill hospitalized patients at increased risk of thrombosis should receive thromboprophylaxis with LMWH, UFH, or fondaparinux for duration of hospital stay
Enoxaparin 40mg SC q24h
Heparin 5000 units SC q8h
Fondaparinux 2.5 mg SC daily
Those at low risk of thrombosis should not receive medical thromboprophylaxis
Those at increased risk of thromboprophylaxis but also at high risk of bleed should received graduated compression stockings or intermittent pneumatic compression

24. What if Mrs. Smith came to the hospital for a total knee replacement
What if Mrs. Smith came to the hospital for a total knee replacement? What would you recommend for her as VTE prophylaxis?
Enoxaparin
30 mg SC q12h
Dalteparin
5000 units SC daily
Fondaparinux
2.5 mg SC 6-8 hours after surgery, then q24h
Rivaroxaban
10mg daily without regard to meals at least 6-10 hours after surgery
Total knee replacement: days
Apixaban
2.5mg PO BID starting hours after surgery, continue for 12 days (35 days for total hip)
All: treat for at least days
Rivaroxaban: Total hip replacement: 35 days; contraindicated for CrCl <30mL/min