New & Novel Anticoagulants Hamid Al-Mondhiry, MD Professor of Medicine The Pennsylvania State University Col ege of Medicine Hershey, PA
VTE: Incidence and Impact in the United States • Approximately 2 mil ion 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) • Chronic thromboembolic pulmonary hypertension (CTPH)2 – High systolic and mean pulmonary artery pressures – Normal pulmonary-capillary wedge pressure – Angiographic abnormalities • Mortality 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 Annual Stroke Rate (%) • Stroke is the most common and devastating complication of AF 10 – Incidence of all-cause stroke in Permanent AF patients with AF is 5% 8 Intermittent AF • AF is an independent risk factor for stroke 6 – Approximately 15% of all strokes in the United States caused by AF 4 – Risk for stroke increases with age • Stroke risk persists even in asymptomatic AF 2 • Stroke risk persists in patients with a “high-risk” profile despite a strategy of rhythm control (AFFIRM study, RACE study) 0 Low Moderate High Risk 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: Clinical Implication: • Slow onset & offset of action • Need to bridge • Individual variability in • Variable dosing anticoagulant effect • Narrow therapeutic index • Need to monitor • Same dose for treatment and • Over anticoagulation prophylaxis • Food and drug interaction • Restrictions, frequent monitoring • Reduced synthesis of natural • Risk of skin necrosis with anticoagulants: PC, PS PC deficiency
New & Novel Anticoagulants TF-VIIa Factor Xa Inhibitors IXa Indirect (via AT): VIII Fondaparinux (subQ) X Xa Direct: Oral Rivaroxaban Apixaban Xa Betrixaban Va PL Direct Thrombin II Inhibitors (DTI) Thrombin Oral: Dabigatran IV: Argatroban Lepirudin Fibrinogen Fibrin
Indirect F Xa Inhibitors Fondaparinux • Synthetic Pentasaccharide• Binds AT with high affinity• T ½ 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 RE-MODEL TKR 2,076 Non-Inferior Equivalent 6-10 days RE-MOBILIZE TKR 2,615 Enox. 30 mg bid Equivalent 12-15 days Superior p=0.02 RE-NOVATE THR 3,494 Non-Inferior Equivalent 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
Rivaroxaban • 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 Population: n Efficacy Safety Major Bleeding RECORD-1 THR 4,541 Riv. Superior Equivalent 31-39 days p<0.001 RECORD-2 THR 2,509 Riv. Superior Equivalent 31-39 days p<0.0001 Enox 10-14 d RECORD-3 TKR 2,531 Riv. Superior Equivalent 13-17 days p,<0.001 RECORD-4 TKR 3,148 Riv. Superior Equivalent 13-17 days p=0.012 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
Apixaban • 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 Study Population Efficacy Safety Major Bleeding ADVANCE-1 TKR 3,195 9.0% vs 8.9% Apix – Safer 12 days P 0.053 ADVANCE-2 TKR 1,973 Apix – Superior Equivalent 12 days P<0.0001 ADVANCE-3 THR 5,407 Apix – Superior Equivalent 35 days P<0.0001 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