Oral Anticoagulation For Deep Venous Thrombosis and Pulmonary Embolism

Robby FerranteWNE Pharmacy Candidate

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.

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

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

Prophylactic Treatment2

Generally, parenteral heparins or warfarin are used prophylactically.

NOAC are becoming more commonly used as warfarin use is decreasing

Clotting Cascade

Intrinsic Pathway: Trauma inside the

vascular system Factors XII, XI, IX,

VIII Slower

Extrinsic Pathway: External trauma Factor VII Quicker

http://mrcpandme.blogspot.com/2010/09/mrcp-revision-battle-142-clotting.html

Warfarin

http://journal.publications.chestnet.org/data/Journals/CHEST/22073/zcb1060816760001.jpeg

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

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

Dabigatran4

Dose for DVT/PE prophylaxis: CrCl > 30 mL/min▪ 150 mg Orally, twice a day

CrCl 15-30 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)

Dabigatran ADME

Absorption 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 = 12-17 hours

Dabigatran

Black Box Warning: Premature discontinuation increases risk

of thrombotic event. Epidural or spinal hematomas may occur

in patients undergoing neuraxial anesthesia.

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

Factor Xa Inhibitors

Oral Options: Rivaroxaban (Xarelto) Apixaban (Apixaban) Edoxaban (Only in Japan)▪ Will not discuss edoxaban

Factor Xa Inhibitors

RIVAROXABAN

A: Tmax 2-4 hours

D: 92%-95% protein bound

M: Hepatic

E: Renal 66% Non dialyzable T ½ - 5 - 11.7 hours

APIXABAN

A: Tmax 3-4 hours

D: 87% Protein Bound

M: Hepatic (Mainly 3A4)

E: Fecal (majority) Renal 27% Non dialyzable T ½ - 6.8 hours (2.5 mg) T ½ - 15.2 hours (5 mg)

Factor Xa Inhibitors

RIVAROXABAN6

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

APIXABAN7

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 12-24

hours after surgery for 35 days

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

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%)

Thank You Nadine!

  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 Once daily BID

Dosing Adjustments Based on INR Renal dose adjust 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 Hepatic Hepatic Hepatic

Monitoring INR Not required Not required Not required

Pregnancy X C C B

DDI 3A4/ 2C9 No dose adjustment 3A4 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 None None

ADE Dyspesia, GI bleeding

Meta-Analysis (NOAC vs VKA)3

Meta-Analysis Efficacy

Meta-Analysis Safety

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.

References

1.) Deep Vein Thrombosis (DVT) / Pulmonary Embolism (PE) Data and Statistics. Atlanta Georgia. Center of Disease Control and Prevention. Published 8 June, 2012. www.cdc.gov/ncbddd/dvt/data.html

2.) Kirley K, Oato DM, Kornfield R, et al. National trends in oral anticoagulant use in the United States, 2007 to 2011. Circ Cardiovasc Qual Outcomes 2012; 5(5): 615-21

3.) 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: 320-8

4.) 1. Product Information: PRADAXA(R) oral capsules, dabigatran etexilate mesylate oral capsules. Boehringer Ingelheim Pharmaceuticals, Inc. (Per FDA), Ridgefield, CT, 2012.

5.) 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; 361:2342-2352

References

6.) Product Information: XARELTO(R) oral tablets, rivaroxaban oral tablets. Janssen Pharmaceuticals, Inc. (per manufacturer), Titusville, NJ, 2012.

7). Product Information: ELIQUIS(R) oral tablets , apixaban oral tablets. Bristol-Myers Squibb Company (per FDA), Princeton, NJ, 2014

8.) The EINSTEIN Investigators. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. N Engl J Med 2010; 363:2499-2510

9.) The EINSTEIN–PE Investigators. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism.N Engl J Med 2012; 366:1287-1297

10.) 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; 369:799-808

Questions?