1. Oral Anticoagulation For Deep Venous Thrombosis and Pulmonary Embolism
Robby Ferrante
WNE Pharmacy Candidate
Oral Anticoagulation For Deep Venous Thrombosis and Pulmonary Embolism

2. Objectives
Review the clotting cascade and the effect of various anticoagulants on this cascade
Discuss oral anticoagulants that are used to treat DVT/PE.
Analyze the use of these agents and their place in DVT/PE therapy.

3. Deep Venous Thrombosis
Deep vein thrombosis (DVT) occurs when a blood clot forms in one or more deep veins
Symptoms usually occur in legs
Can cause leg pain or swelling
May occur without any symptoms.
Common causes:
Immobility
Traumatic Injury
Surgery
Obesity
Prolonged travel
Pregnancy
Thrombophilia
May be excluded by a D-dimer test before imaging is performed.
D-dimer is a fibrin degradation product, fibrinolysis product

4. Pulmonary Embolism1
Blockage of 1+ pulmonary arteries by a substance that has traveled from elsewhere in the body
Causes impaired blood flow
Increased pressure in the right ventricle
Symptoms
Dyspnea
Acute chest pain
Increased heart rate
Cough
Abnormal breathing sounds
Low blood pressure
Cardiac arrest
00,000 to 600,000 (1 to 2 per 1,000, and in those over 80 years of age, as high as 1 in 100) each year in the United States.
Estimates suggest that 60, ,000 Americans die of DVT/PE (also called venous thromboembolism).
According to CDC

5. Prophylactic Treatment2
Generally, parenteral heparins or warfarin are used prophylactically.
NOAC are becoming more commonly used as warfarin use is decreasing
Prophaylactically for:
Atrial Fibrillation CHADS2 score
Previous DVT
Prior to surgery in elderly patients

6. Clotting Cascade Intrinsic Pathway: Extrinsic Pathway:
Trauma inside the vascular system
Factors XII, XI, IX, VIII
Slower
Extrinsic Pathway:
External trauma
Factor VII
Quicker

7. Warfarin
Warfarin sodium is an anticoagulant that works by blocking the regeneration of vitamin K(1) epoxide, thus inhibiting synthesis of vitamin K-dependent clotting factors which include factors 2, 7, 9 and 10, and the anticoagulant proteins C and S 
-S 4-6 hrs N 24 hours O hours T 60 hours (3 days)

8. Warfarin3 Vitamin K antagonists are the standard treatment therapy.
Relative risk reduction of ~85% vs placebo
Recurrence risk of ~3%
Major bleeding risk ~2.1% during first 6 months
There are critiques of warfarin therapy:
Monitoring
Small therapeutic window
Effect of diet
Multiple drug interactions

9. Direct Thrombin Inhibitor
MOA:
Potent, competitive, and reversible direct inhibitor of free and clot- associated thrombin
Only one oral agent
Dabigatran (Pradaxa)
Indicated for DVT
treatment and prophylaxis

10. Dabigatran4 Dose for DVT/PE prophylaxis: Administration:
CrCl > 30 mL/min
150 mg Orally, twice a day
CrCl mL/min
75 mg Orally, twice a day
Administration:
Must be swallowed whole
Not to be used in NG tube
Keep in original container (120 days)
For

11. Dabigatran ADME Absorption Distribution Metabolism Excretion
Tmax = 1-6 hours
Food does not effect bioavailability
Distribution
~ 35% protein bound
Metabolism
Prodrug hydrolyzed by the liver
Hepatic metabolism and PGP substrate
Excretion
Renal excretion (80%)
Dialyzable
T ½ = hours

12. Dabigatran Black Box Warning:
Premature discontinuation increases risk of thrombotic event.
Epidural or spinal hematomas may occur in patients undergoing neuraxial anesthesia.

13. Re-Cover Trial5
2539 patients in randomized double blind noninferiority trial
150 mg Dabigatran BID
30/1274 (2.4%) had recurrent VT
20 patients had major bleed
Warfarin; INR 2-3
27/1265 (2.1%) had recurrent VT
24 patients with major bleed
Interesting observation: INR randomization
D/C 9.0% dabi, 6.8% warfarin

14. Factor Xa Inhibitors Oral Options: Rivaroxaban (Xarelto)
Apixaban (Apixaban)
Edoxaban (Only in Japan)
Will not discuss edoxaban

15. Factor Xa Inhibitors A: Tmax 2-4 hours D: 92%-95% protein bound
Rivaroxaban
Apixaban
A: Tmax 2-4 hours
D: 92%-95% protein bound
M: Hepatic
E: Renal 66%
Non dialyzable
T ½ hours
A: Tmax 3-4 hours
D: 87% Protein Bound
M: Hepatic (Mainly 3A4)
E: Fecal (majority)
Renal 27%
Non dialyzable
T ½ hours (2.5 mg)
T ½ hours (5 mg)

16. Factor Xa Inhibitors DVT/PE Treatment Post operative Prophylaxis
Rivaroxaban6
Apixaban7
DVT/PE Treatment
15 mg PO BID for 21 days
Then 20 mg PO Daily
Take With food
Post operative Prophylaxis
Hip Repair
10 mg PO Daily 6-10 hours after surgery for 35 days
DVT/PE Treatment
10 mg PO BID for 7 days
Then 5 mg PO BID
DVT/PE Prophylaxis
2.5 PO BID
Post Operative Prophylaxis
2.5 mg PO BID hours after surgery for 35 days

17. EINSTEIN VT8 and DVT9 3449 and 4832 Patients with acute DVT
Rivaroxaban 15 mg BID for 3 weeks, then 20 mg PO QD
Neither study displayed significant primary outcomes
DVT study: 36 events vs 51 events
Slight increase in nonfatal bleed
PE study: 50 events vs 44 events
Increase in major bleed in the standard therapy
Double blind randomized event driven
PE: 26 vs 52

18. Amplify Study10 5395 patients involved in the study with acute VT
Apixaban 10 mg BID for 7 days, then 5 mg BID
Primary Endpoiont – recurrent VT or VT related death.
59 events vs 71 events (2.3% vs 2.7%)
Clinically relevant
Major Bleeding
1.8% vs 0.6%
All Bleeds
4.3% vs 9.7%

19. Thank You Nadine! Warfarin Dabigatran Rivaroxaban Apixaban
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Indication
Prophylaxis and treatment of VTE, Cardiac valve replacement, Prevention of stroke in atrial fibrillation
Prevention and treatment of VTE, Prevention of stroke in nonvalvular atrial fibrillation
Prevention and treatment of VTE, Nonvalvular atrial fibrillation
Prevention and treatment of venous thromboembolism, Nonvalvular atrial fibrillation
Dosing frequency
Once daily
BID
Dosing Adjustments
Based on INR
Renal dose adjust
Reduce dose if 2 or more factors: >80y/o, Weight < 60kg, Scr >1.5
Onset
3-5 days
2-3 hours
2.5-4 hours
3-4 hours
Metabolism
Hepatic
Monitoring
INR
Not required
Pregnancy X C B
DDI
3A4/ 2C9
No dose adjustment
3A4
Contraindication
Bleeding
Creatinine clearance <15 mL/min , Hemodialysis dependent
Contraindicated in those with a creatinine clearance <15 mL/min
N/A
Antidote
Vitamin K
None
ADE
Dyspesia, GI bleeding
Thank you!
A couple things I didn’t mention, Preg cat
apix = B

20. Meta-Analysis (NOAC vs VKA)3
International Society in Thrombosis and Haemostasis
24455 patients with accute VTE
All Phase iii trials, met Cochrane Collaboration’s tool for assessing risk of bias.
Einstein studies showed most bias risk

21. Meta-Analysis Efficacy
Recurrent VTE had best RR with 88%

22. Meta-Analysis Safety
NNT for non-major bleed - 56

23. Conclusion
Almost all comparisons between NOACs and VKAs were relatively similar
Few significant differences
Depending on patient factors, NOACs are a viable option and have proven to be non-inferior while also potentially reducing bleeding risk.

24. References
1.) Deep Vein Thrombosis (DVT) / Pulmonary Embolism (PE) Data and Statistics. Atlanta Georgia. Center of Disease Control and Prevention. Published 8 June, ) Kirley K, Oato DM, Kornfield R, et al. National trends in oral anticoagulant use in the United States, 2007 to Circ Cardiovasc Qual Outcomes 2012; 5(5): ) Van Der Hulle J, Koolman J, Den Exter PL, et al. Effectiveness and Safety of Novel Oral Anticoagulants as Compared With Vitamin K Antagonists in the Treatment of Acute Symptomatic Venous Thromboembolism: A Systematic review and Meta-Analysis. J Thromb Haemost 2014; 12: ) 1. Product Information: PRADAXA(R) oral capsules, dabigatran etexilate mesylate oral capsules. Boehringer Ingelheim Pharmaceuticals, Inc. (Per FDA), Ridgefield, CT, ) Sam Schulman, M.D., Clive Kearon, M.D., Ajay K. Kakkar, M.D., et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. N Engl J Med 2009; 361:

25. References
6.) Product Information: XARELTO(R) oral tablets, rivaroxaban oral tablets. Janssen Pharmaceuticals, Inc. (per manufacturer), Titusville, NJ, ). Product Information: ELIQUIS(R) oral tablets , apixaban oral tablets. Bristol-Myers Squibb Company (per FDA), Princeton, NJ, ) The EINSTEIN Investigators. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. N Engl J Med 2010; 363: ) The EINSTEIN–PE Investigators. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism.N Engl J Med 2012; 366: ) Giancarlo Agnelli, M.D., Harry R. Buller, M.D., Ph.D., Alexander Cohen, M.D., et al. Oral Apixaban for the Treatment of Acute Venous Thromboembolism. N Engl J Med 2013; 369:

26. Questions?