0106-New and Novel Anticoagulants - (Short) Version May 2011

New & Novel AnticoagulantsNew & Novel Anticoagulants

Hamid Al-Mondhiry, MDHamid Al-Mondhiry, MDProfessor of MedicineProfessor of Medicine

The Pennsylvania State UniversityThe Pennsylvania State UniversityCollege of MedicineCollege of Medicine

Hershey, PAHershey, PA

VTE: Incidence and Impact in the United States

• Approximately 2 million VTEs occur every yearApproximately 2 million VTEs occur every year11

• Each year 1 person in 1000 will experience his/her first VTE in the USEach year 1 person in 1000 will experience his/her first VTE in the US22

– One third manifest pulmonary embolism (PE, with or without deep One third manifest pulmonary embolism (PE, with or without deep vein thrombosis [DVT])vein thrombosis [DVT])

• Death within 1 month of diagnosisDeath within 1 month of diagnosis22::– 6% of DVT cases6% of DVT cases– 12% of PE cases12% of PE cases

• Recurrent DVT:Recurrent DVT:– 17% of DVT patients 2 years after initial treatment17% of DVT patients 2 years after initial treatment3*3*

– 30% of DVT patients 8 to 10 years after initial treatment30% of DVT patients 8 to 10 years after initial treatment**††3,43,4

1. Hirsh J, Hoak J. 1. Hirsh J, Hoak J. Circulation. Circulation. 1996;93:2212-2245.1996;93:2212-2245.2. American Heart Association. 2. American Heart Association. Heart Disease and Stroke Statistics – 2004 Update.Heart Disease and Stroke Statistics – 2004 Update. 3. Prandoni P et al. 3. Prandoni P et al. Haematologica. Haematologica. 1997;82:423-428.1997;82:423-428.4. Pengo V et al. 4. Pengo V et al. N Engl J Med. N Engl J Med. 2004;350:2257-2264.2004;350:2257-2264.

*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.

Consequences of VTEConsequences of VTE• Recurrent VTERecurrent VTE• Post-thrombotic syndrome (PTS)Post-thrombotic syndrome (PTS)11

– Presence of leg symptoms (pain, cramps, heaviness, pruritus, and Presence of leg symptoms (pain, cramps, heaviness, pruritus, and paresthesia) and signs (pretibial edema, skin induration, paresthesia) and signs (pretibial edema, skin induration, hyperpigmentation, new venous ectasia, redness and pain during hyperpigmentation, new venous ectasia, redness and pain during calf compression)calf compression)

• Chronic thromboembolic pulmonary hypertension (CTPH)Chronic thromboembolic pulmonary hypertension (CTPH)22

– High systolic and mean pulmonary artery pressuresHigh systolic and mean pulmonary artery pressures– Normal pulmonary-capillary wedge pressureNormal pulmonary-capillary wedge pressure– Angiographic abnormalitiesAngiographic abnormalities

• MortalityMortality

1. Prandoni P et al. 1. Prandoni P et al. Haematologica. Haematologica. 1997;82:423-428.1997;82:423-428.2. Pengo V et al. 2. Pengo V et al. N Engl J Med. N Engl J Med. 2004;350:2257-2264.2004;350:2257-2264.

Intermittent AFPermanent AF

Annual Stroke Rate (%)

AF and StrokeAF and Stroke• AF increases stroke risk 4- to 5-foldAF increases stroke risk 4- to 5-fold

• Stroke is the most common and devastating Stroke is the most common and devastating complication of AFcomplication of AF

– Incidence of all-cause stroke in Incidence of all-cause stroke in patients with AF is 5%patients with AF is 5%

• AF is an independent risk factor AF is an independent risk factor for strokefor stroke

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

– Risk for stroke increases with ageRisk for stroke increases with age

• Stroke risk persists even in asymptomatic AFStroke risk persists even in asymptomatic AF

• Stroke risk persists in patients with a “high-Stroke risk persists in patients with a “high-risk” profile despite a strategy of rhythm risk” profile despite a strategy of rhythm control (AFFIRM study, RACE study)control (AFFIRM study, RACE study)

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.

LowRisk

ModerateRisk

HighRisk

10

8

6

4

2

0

Anticoagulant DrugsAnticoagulant Drugs

• Anticoagulants are among the most frequently used Anticoagulants are among the most frequently used drugs to prevent and treat venous and arterial drugs to prevent and treat venous and arterial thromboembolism.thromboembolism.

• Highest incidence of adverse effects, second only to Highest incidence of adverse effects, second only to cytotoxic drugcytotoxic drug

• Problem with dosing, monitoring, complianceProblem with dosing, monitoring, compliance

The Ideal AnticoagulantThe Ideal Anticoagulant

• Bioavailable, predictable dose responseBioavailable, predictable dose response• High efficacy to safety indexHigh efficacy to safety index• Administered parenteral or oralAdministered parenteral or oral• Rapid onset of actionRapid onset of action• Available antidoteAvailable antidote• Minimal interactions with other drugsMinimal interactions with other drugs

Limitations of Vit K AntagonistsLimitations of Vit K Antagonists Limitations:Limitations:

• Slow onset & offset of actionSlow onset & offset of action

• Individual variability in Individual variability in anticoagulant effectanticoagulant effect

• Narrow therapeutic indexNarrow therapeutic index

• Same dose for treatment and Same dose for treatment and prophylaxisprophylaxis

• Food and drug interactionFood and drug interaction

• Reduced synthesis of natural Reduced synthesis of natural anticoagulants: PC, PSanticoagulants: PC, PS

Clinical ImplicationClinical Implication::

• Need to bridgeNeed to bridge

• Variable dosingVariable dosing

• Need to monitorNeed to monitor

• Over anticoagulationOver anticoagulation

• Restrictions, frequent monitoringRestrictions, frequent monitoring

• Risk of skin necrosis with Risk of skin necrosis with PC deficiencyPC deficiency

TF-VIIa

XaVaPL

X Xa

Fibrinogen Fibrin

ThrombinII

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

Direct Thrombin Inhibitors (DTI) Oral: Dabigatran IV: Argatroban Lepirudin

IXaVIII

New & Novel Anticoagulants

Indirect F Xa InhibitorsIndirect F Xa Inhibitors

FondaparinuxFondaparinux• Synthetic PentasaccharideSynthetic Pentasaccharide• Binds AT with high affinityBinds AT with high affinity• T ½ 17 h, given subQ dailyT ½ 17 h, given subQ daily• Binds weakly to PF4: 3 cases of HIT Binds weakly to PF4: 3 cases of HIT

reported 2007-2010reported 2007-2010• Excreted unchanged in the urine, Excreted unchanged in the urine,

contraindicated in renal failure.contraindicated in renal failure.• No antidoteNo antidote

Fondaparinux: Fondaparinux: Indications & DosingIndications & Dosing

• Prophylaxis of DVT and PE Prophylaxis of DVT and PE 2.5 mg sub Q daily2.5 mg sub Q daily

• Treatment of DVT and PETreatment of DVT and PE50 kg: 5 mg sub Q daily50 kg: 5 mg sub Q daily

50-99 kg: 7.5 mg sub Q daily50-99 kg: 7.5 mg sub Q daily≥≥100 kg: 10 mg sub Q daily100 kg: 10 mg sub Q daily

Dabigatran EtexilateDabigatran Etexilate

• Oral Direct Thrombin Inhibitor (DTI)Oral Direct Thrombin Inhibitor (DTI)• Prodrug of DabigatranProdrug of Dabigatran• Bioavailability ~ 6%, Time to peak 2-3 hBioavailability ~ 6%, Time to peak 2-3 h• Half life 14-17 h: qd or bid dosingHalf life 14-17 h: qd or bid dosing• 80% excreted unchanged in the urine80% excreted unchanged in the urine• Predictable pharmacokineticsPredictable pharmacokinetics• No drug interactionsNo drug interactions• Approved by FDA for A-fib 10/10Approved by FDA for A-fib 10/10

Mechanism of ActionMechanism of Action

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

Dabigatran Etexilate (DE) vs WarfarinDabigatran Etexilate (DE) vs WarfarinPrevention of Stroke in Atrial FibrillationPrevention of Stroke in Atrial Fibrillation

• 18,113 pt. with A-fib, F/U 2 years18,113 pt. with A-fib, F/U 2 years• DE, 110 mg bid was non inferior to Warfarin in DE, 110 mg bid was non inferior to Warfarin in

the primary end pointthe primary end point• 150 mg bid was superior to Warfarin150 mg bid was superior to Warfarin• The cumulative incidence of bleeding 0.38% The cumulative incidence of bleeding 0.38%

Warfarin, 0.12% with DEWarfarin, 0.12% with DE• The incidence of dyspepsia was higher in DE The incidence of dyspepsia was higher in DE

leading to higher rate of discontinuationleading to higher rate of discontinuation____________________ ____________________ Moia M et al N Eng J Med 2009, 361: 3672Moia M et al N Eng J Med 2009, 361: 3672

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

Study Population: n Efficacy SafetyMajor Bleeding

RE-MODEL TKR 2,0766-10 days

Non-Inferior Equivalent

RE-MOBILIZE TKR 2,61512-15 days

Enox. 30 mg bid Superior

p=0.02

Equivalent

RE-NOVATE THR 3,49428-351 days

Non-Inferior Equivalent

Ansell J Hematology 2010, p 221

Dabigatran Treatment of VTE: Dabigatran Treatment of VTE: RECOVER-1RECOVER-1

* Randomized trial, 2564 pts comparing Randomized trial, 2564 pts comparing Dabigatran 150 mg bid vs Warfarin in the treatment of Dabigatran 150 mg bid vs Warfarin in the treatment of VTE for 6M after initial Rx with parenteral anticoagulant VTE for 6M after initial Rx with parenteral anticoagulant (9D)(9D)

* Primary Efficacy: Non-InferiorPrimary Efficacy: Non-Inferior* Safety: Lower rate of any bleeding: Safety: Lower rate of any bleeding: 16.1% vs 21.9% (P<0.001)16.1% vs 21.9% (P<0.001)

Major bleed: comparableMajor bleed: comparable* Death, ACS and LFTs: comparableDeath, ACS and LFTs: comparable

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

RivaroxabanRivaroxaban

• Oral direct Xa InhibitorOral direct Xa Inhibitor• Bioavailability ~80%, Time to peak 2-3 hBioavailability ~80%, Time to peak 2-3 h• Half life 7-11 h, od or bid dosingHalf life 7-11 h, od or bid dosing• One third excreted unchanged by the kidney, One third excreted unchanged by the kidney,

one third metabolized then excreted by the one third metabolized then excreted by the kidney, one third metabolized by the liver and kidney, one third metabolized by the liver and excreted in the bowelexcreted in the bowel

• Inhibitors of CyP3A4 and Pgp e.g. Inhibitors of CyP3A4 and Pgp e.g. Ketoconazole and Ritonavir increase drug level Ketoconazole and Ritonavir increase drug level in the circulationin the circulation

Rivaroxaban 10 mg/D Vs Enoxaparin Rivaroxaban 10 mg/D Vs Enoxaparin 40 mg/D In Major Orthopedic Surgery40 mg/D In Major Orthopedic Surgery

Study Population: n Efficacy SafetyMajor Bleeding

RECORD-1 THR 4,54131-39 days

Riv. Superiorp<0.001

Equivalent

RECORD-2 THR 2,50931-39 days

Enox 10-14 d

Riv. Superiorp<0.0001

Equivalent

RECORD-3 TKR 2,53113-17 days

Riv. Superiorp,<0.001

Equivalent

RECORD-4 TKR 3,14813-17 days

Riv. Superiorp=0.012

Equivalent

Ansell J Hematology 2010, p 221

Rivaroxaban in Atrial Fibrillation (a Fib)Rivaroxaban in Atrial Fibrillation (a Fib)

• ROCKET-AF multisite, worldwide trialROCKET-AF multisite, worldwide trial• 14,000 pts at high risk of stroke randomized: 14,000 pts at high risk of stroke randomized:

Riv 20/15 mg/day vs warfarinRiv 20/15 mg/day vs warfarin• Complex study population, high CHADs scoreComplex study population, high CHADs score• Riv non-inferiorRiv non-inferior• Risk of hemorrhagic stroke Risk of hemorrhagic stroke with Riv: with Riv:

0.26% vs 0.44% Warfin0.26% vs 0.44% Warfin• Major bleeding similar: 3.6% vs 3.45%Major bleeding similar: 3.6% vs 3.45%

Cabral KP et al J Thromb Hemost 2011, 9:44

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

• Phase III trials: EINSTEIN DVT and Phase III trials: EINSTEIN DVT and EINSTEIN PE: Rivaroxaban 15 mg bid for 3 EINSTEIN PE: Rivaroxaban 15 mg bid for 3 weeks then 20 mg daily for periods of 3, 6 or weeks then 20 mg daily for periods of 3, 6 or 12 m12 m

• ACS pts: Phase III trial adding Rivaroxaban ACS pts: Phase III trial adding Rivaroxaban 2.5/5 mg bid to dual antiplatelet drugs2.5/5 mg bid to dual antiplatelet drugs

ApixabanApixaban

• Oral direct, reversible Xa inhibitorOral direct, reversible Xa inhibitor• 50% bioavailability, time to peak 3 h50% bioavailability, time to peak 3 h• Half life 8-14 h, od or bid dosingHalf life 8-14 h, od or bid dosing• Multiple pathways of elimination: oxidative Multiple pathways of elimination: oxidative

metabolism, renal (25%) and intestinalmetabolism, renal (25%) and intestinal• Advantage in pts with renal impairmentAdvantage in pts with renal impairment

Apixaban 2.5 mg bid vs EnoxaparinApixaban 2.5 mg bid vs Enoxaparin40-60 mg/D in Major Orthopedic Surgery40-60 mg/D in Major Orthopedic Surgery

Study Population Efficacy SafetyMajor Bleeding

ADVANCE-1 TKR 3,19512 days

9.0% vs 8.9% Apix - SaferP 0.053

ADVANCE-2 TKR 1,97312 days

Apix - SuperiorP<0.0001

Equivalent

ADVANCE-3 THR 5,40735 days

Apix - SuperiorP<0.0001

Equivalent

Ansell J Hematology 2010, p 221

Apixaban in Patients with A-FibApixaban in Patients with A-Fib

• Double blind randomized trail of 5599 pts with Double blind randomized trail of 5599 pts with A-fib at increased risk of stroke for whom A-fib at increased risk of stroke for whom warfarin was unsuitablewarfarin was unsuitable

• Apixaban 5 mg bid vs ASA 81-325mg/dayApixaban 5 mg bid vs ASA 81-325mg/day• Trial stopped: Apixaban clearly superiorTrial stopped: Apixaban clearly superior

* Stroke or systemic embolism in 1.6% pts on Stroke or systemic embolism in 1.6% pts on Apixaban vs 3.47% ASA (P<0.001)Apixaban vs 3.47% ASA (P<0.001)

* Major bleeding 1.4% vs 1.2% P=0.57Major bleeding 1.4% vs 1.2% P=0.57

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

Ongoing Phase III TrialsDabigatran, Rivaroxiban, Apixaban, Other Xa inhibitors

• Acute & maintenance treatment of venous thromboembolism

• Prophylaxis, other indications