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New & Novel Anticoagulants

Hamid Al-Mondhiry, MD Professor of Medicine The Pennsylvania State University College of Medicine Hershey, PA

VTE: Incidence and Impact in the United States

Approximately 2 million VTEs occur every year1 Each year 1 person in 1000 will experience his/her first VTE in the US2 One third manifest pulmonary embolism (PE, with or without deep vein thrombosis [DVT]) Death within 1 month of diagnosis2: 6% of DVT cases 12% of PE cases Recurrent DVT: 17% of DVT patients 2 years after initial treatment3* 30% of DVT patients 8 to 10 years after initial treatment*3,4
*High dose standard heparin or LMWH for at least 10 days; oral anticoagulant therapy was initiated during the first week and continued for at least 3 months; Unfractionated heparin was given as an initial IV bolus followed by IV infusion; oral anticoagulant therapy was initiated after the first week and continued for at least 6 months. 1. Hirsh J, Hoak J. Circulation. 1996;93:2212-2245. 2. American Heart Association. Heart Disease and Stroke Statistics 2004 Update. 3. Prandoni P et al. Haematologica. 1997;82:423-428. 4. Pengo V et al. N Engl J Med. 2004;350:2257-2264.

Consequences of VTE
Recurrent VTE Post-thrombotic syndrome (PTS)1
Presence of leg symptoms (pain, cramps, heaviness, pruritus, and paresthesia) and signs (pretibial edema, skin induration, hyperpigmentation, new venous ectasia, redness and pain during calf compression)
High systolic and mean pulmonary artery pressures Normal pulmonary-capillary wedge pressure Angiographic abnormalities

Chronic thromboembolic pulmonary hypertension (CTPH)2


1. Prandoni P et al. Haematologica. 1997;82:423-428. 2. Pengo V et al. N Engl J Med. 2004;350:2257-2264.

AF and Stroke
AF increases stroke risk 4- to 5-fold Stroke is the most common and devastating complication of AF Incidence of all-cause stroke in patients with AF is 5% AF is an independent risk factor for stroke

Annual Stroke Rate (%)


Permanent AF Intermittent AF

Approximately 15% of all strokes in the United States caused by AF

Risk for stroke increases with age Stroke risk persists even in asymptomatic AF Stroke risk persists in patients with a highrisk profile despite a strategy of rhythm control (AFFIRM study, RACE study)

Low Risk

Moderate High Risk Risk

RACE II = Rate Control Efficacy in Permanent Atrial Fibrillation. Fuster V, et al. J Am Coll Cardiol. 2006;48(4):e149-e246. Kannel WB, et al. Med Clin North Am. 2008;92(1):17-42. Page RL, et al. Circulation. 2003;107(8):1141-1145. Hart RG, et al. J Am Coll Cardiol. 2000; 35(1):183-187. Dulli DA, et al. Neuroepidemiology. 2003;22(2):118-123.

Anticoagulant Drugs
Anticoagulants are among the most frequently used drugs to prevent and treat venous and arterial thromboembolism. Highest incidence of adverse effects, second only to cytotoxic drug Problem with dosing, monitoring, compliance

The Ideal Anticoagulant

Bioavailable, predictable dose response High efficacy to safety index Administered parenteral or oral Rapid onset of action Available antidote Minimal interactions with other drugs

Limitations of Vit K Antagonists

Limitations: Slow onset & offset of action Individual variability in anticoagulant effect Narrow therapeutic index Same dose for treatment and prophylaxis Clinical Implication: Need to bridge Variable dosing Need to monitor Over anticoagulation

Food and drug interaction

Reduced synthesis of natural anticoagulants: PC, PS

Restrictions, frequent monitoring

Risk of skin necrosis with PC deficiency

New & Novel Anticoagulants


X Xa Va PL Xa

Factor Xa Inhibitors Indirect (via AT): Fondaparinux (subQ) Direct: Oral Rivaroxaban Apixaban Betrixaban



Direct Thrombin Inhibitors (DTI)

Oral: Dabigatran IV: Argatroban Lepirudin



Indirect F Xa Inhibitors
Synthetic Pentasaccharide Binds AT with high affinity T 17 h, given subQ daily Binds weakly to PF4: 3 cases of HIT reported 2007-2010 Excreted unchanged in the urine, contraindicated in renal failure. No antidote

Fondaparinux: Indications & Dosing

Prophylaxis of DVT and PE 2.5 mg sub Q daily Treatment of DVT and PE 50 kg: 5 mg sub Q daily 50-99 kg: 7.5 mg sub Q daily 100 kg: 10 mg sub Q daily

Dabigatran Etexilate
Oral Direct Thrombin Inhibitor (DTI) Prodrug of Dabigatran Bioavailability ~ 6%, Time to peak 2-3 h Half life 14-17 h: qd or bid dosing 80% excreted unchanged in the urine Predictable pharmacokinetics No drug interactions Approved by FDA for A-fib 10/10

Mechanism of Action

Lee CJ, Ansell JE. Br J Clin Pharmacol. Accepted article; doi:1111/1365-2125.2011.03916.x.

Dabigatran Etexilate (DE) vs Warfarin Prevention of Stroke in Atrial Fibrillation

18,113 pt. with A-fib, F/U 2 years DE, 110 mg bid was non inferior to Warfarin in the primary end point 150 mg bid was superior to Warfarin The cumulative incidence of bleeding 0.38% Warfarin, 0.12% with DE The incidence of dyspepsia was higher in DE leading to higher rate of discontinuation ____________________
Moia M et al N Eng J Med 2009, 361: 3672

Dabigatran Etexilate 150-220 mg vs Enoxaparin 40-60 mg in Major Orthopedic Surgery

Study Population: n Efficacy Safety
Major Bleeding


TKR 2,076
6-10 days

Non-Inferior Enox. 30 mg bid Superior


Equivalent Equivalent

TKR 2,615
12-15 days


THR 3,494
28-351 days



Ansell J Hematology 2010, p 221

Dabigatran Treatment of VTE: RECOVER-1

* Randomized trial, 2564 pts comparing Dabigatran 150 mg bid vs Warfarin in the treatment of VTE for 6M after initial Rx with parenteral anticoagulant (9D) * Primary Efficacy: Non-Inferior * Safety: Lower rate of any bleeding: 16.1% vs 21.9% (P<0.001) Major bleed: comparable * Death, ACS and LFTs: comparable

Schulman S. et al. NEJ Med 2009, 361:2342

Oral direct Xa Inhibitor Bioavailability ~80%, Time to peak 2-3 h Half life 7-11 h, od or bid dosing One third excreted unchanged by the kidney, one third metabolized then excreted by the kidney, one third metabolized by the liver and excreted in the bowel Inhibitors of CyP3A4 and Pgp e.g. Ketoconazole and Ritonavir increase drug level in the circulation

Rivaroxaban 10 mg/D Vs Enoxaparin 40 mg/D In Major Orthopedic Surgery

Study RECORD-1 Population: n THR 4,541
31-39 days

Efficacy Riv. Superior


Major Bleeding



THR 2,509
31-39 days Enox 10-14 d

Riv. Superior



TKR 2,531
13-17 days

Riv. Superior



TKR 3,148
13-17 days

Riv. Superior


Ansell J Hematology 2010, p 221

Rivaroxaban in Atrial Fibrillation (a Fib)

ROCKET-AF multisite, worldwide trial 14,000 pts at high risk of stroke randomized: Riv 20/15 mg/day vs warfarin Complex study population, high CHADs score Riv non-inferior Risk of hemorrhagic stroke with Riv: 0.26% vs 0.44% Warfin Major bleeding similar: 3.6% vs 3.45%
Cabral KP et al J Thromb Hemost 2011, 9:44

Rivaroxaban: Treatment of VTE and Acute Coronary Syndrome (ACS)

Phase III trials: EINSTEIN DVT and EINSTEIN PE: Rivaroxaban 15 mg bid for 3 weeks then 20 mg daily for periods of 3, 6 or 12 m ACS pts: Phase III trial adding Rivaroxaban 2.5/5 mg bid to dual antiplatelet drugs

Oral direct, reversible Xa inhibitor 50% bioavailability, time to peak 3 h Half life 8-14 h, od or bid dosing Multiple pathways of elimination: oxidative metabolism, renal (25%) and intestinal Advantage in pts with renal impairment

Apixaban 2.5 mg bid vs Enoxaparin 40-60 mg/D in Major Orthopedic Surgery


TKR 3,195
12 days

9.0% vs 8.9%

Major Bleeding

Apix - Safer
P 0.053


TKR 1,973
12 days

Apix - Superior



THR 5,407
35 days

Apix - Superior


Ansell J Hematology 2010, p 221

Apixaban in Patients with A-Fib

Double blind randomized trail of 5599 pts with A-fib at increased risk of stroke for whom warfarin was unsuitable Apixaban 5 mg bid vs ASA 81-325mg/day Trial stopped: Apixaban clearly superior
* Stroke or systemic embolism in 1.6% pts on Apixaban vs 3.47% ASA (P<0.001) * Major bleeding 1.4% vs 1.2% P=0.57

Conolly SJ et al N Eng J Med 2011, 364: 806

Ongoing Phase III Trials

Dabigatran, Rivaroxiban, Apixaban, Other Xa inhibitors

Acute & maintenance treatment of venous thromboembolism Prophylaxis, other indications