oral anticoagulants in the pipeline tracy sprunger, pharm.d., bcps assistant professor, pharmacy...
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Oral Anticoagulants in the Pipeline
Tracy Sprunger, Pharm.D., BCPSAssistant Professor, Pharmacy Practice
Butler College of Pharmacy and Health SciencesClinical Pharmacy Specialist, Family Medicine
Disclosure Statement
• I have nothing to disclose
Objectives
• Compare and contrast the mechanism of action, dosing, and significant adverse reactions associated with new agents
• Discuss significant clinical studies with new agents
• Discuss likely place in therapy for new agents
Evolution of Anticoagulation
1930s Heparin•Parenteral•Narrow therapeutic index
•Unpredictable•Monitoring•HIT•Bleeding risk
1950s Warfarin•Narrow therapeutic index
•Unpredictable•Drug interactions•Monitoring •Bleeding risk
1980s LMWH• Parenteral• HIT• Must transition
to warfarin
1990s DTI• Parenteral• Monitoring• Limited use to
HIT/CV• Must transition
to warfarin
1990s Xa inhibitors• Parenteral• Must transition
to warfarin
2010 ORAL DTI/Xa• ?????
Clotting Cascade
AJHP 2004;61:S7.
The Ideal Anticoagulant?
Emerging Therapies
Am J Health-Syst Pharm;65:1520
Rivaroxaban• MOA: Direct Xa inhibitor• Pharmacokinetics
– Absorption• Oral bioavailability ~100%• Peak plasma conc. 2-4 hrs• May take with or w/out food
– Distribution• Highly protein bound
– Metabolism• CYP 3A4, 2J2, CYP independent mechanism
www.bayer.caRivaroxaban monograph
Rivaroxaban
– Elimination• 1/3 unchanged in urine• 1/3 inactive metabolites excreted in urine• 1/3 inactive metabolites fecal• T ½
– 5-9 hrs (young patients)– 11-13 hrs (elderly)
www.bayer.caRivaroxaban monograph
Rivaroxaban• Contraindications
• Hepatic disease• Bleeding• Concomitant strong CYP3A4, P-gp inhibitors
– Caution with inducers
• Pregnancy• Breastfeeding
• Not recommended ClCr <30ml/min• Routine monitoring not recommended
– Some clotting tests prolonged
www.bayer.caRivaroxaban monograph
Rivaroxaban Clinical TrialsTRIAL PATIENT DOSING COMPARATOR OUTCOME RESULTS
RECORD 1 THR 10mg qday(31-39 days)
Enox 40mg qday
Composite VTE and all cause mortality
Riva 1.1%Enox 3.7%p<0.001 (sup)
RECORD 2 THR 10mg qday(31-39 days)
Enox 40mg qday (10-14 days)
Riva 2%Enox 9.3%p<0.001 (sup)
RECORD 3 TKR 10mg qday(10-14 days)
Enox 40mg qday
Riva 9.6%Enox 18.9%p=0.012 (sup)
RECORD 4 TKR 10mg qday(10-14 days)
Enox 30mg bid Riva 6.9%Enox 10.1%p<0.001 (sup)
Rivaroxaban SafetyTRIAL PATIENT DOSING COMPARATOR OUTCOME RESULTS
RECORD 1 THR 10mg qday(31-39 days)
Enox 40mg qday
Major Bleeding
Riva 0.3%Enox 0.1%
p=0.18
RECORD 2 THR 10mg qday(31-39 days)
Enox 40mg qday (10-14 days)
Riva 0.1%Enox 0.1%
p=1.00
RECORD 3 TKR 10mg qday(10-14 days)
Enox 40mg qday
Riva 0.6%Enox 0.5%
p=0.79
RECORD 4 TKR 10mg qday(10-14 days)
Enox 30mg bid Riva 0.7%Enox 0.3%
p=0.31
Thromb Haemost 2010: 103:572-585
Dabigatran Etexilate
• MOA– Direct IIa inhibitor; Pro-drug
• Absorption– Bioavailability ~6%– Requires acidic environment
• Distribution– ~35% protein bound
www.pradaxa.com
Dabigatran Etexilate
• Metabolism– Rapidly converted to active drug– No CYP metabolism
• Elimination• Renal : 80% unchanged• t1/2 ~14-17hrs
www.pradaxa.com
Dabigatran
• Dosing in renal impairment– ClCr 30-50ml/min – 150mg/day– Contraindicated ClCr < 30ml/min
• Drug interaction studies– No effect – Atorvastatin (3A4 P-gp substrate);
diclofenac (2C9 substrate), digoxin (P-gp substrate)– Amiodarone (P-gp inhibitor) increased dabigatran 50-
60%– Pantoprazole decreased bioavailability 20-30%
Thromb Haemost 2010: 103:572-585
Dabigatran Etexilate Clinical Trials
TRIAL PATIENT POPULATION DOSING COMPARATOR OUTCOME RESULTS
VTE PREVENTION
RE-NOVATE
THR 150 or 220mg qday(28-35 days)
Enox 40mg qday
VTE + all cause mortality
Non-inferior
RE-MODEL
TKR 150 or 220mg qday(6-10 days)
Enox 40mg qday
Non-inferior
RE-MOBILIZE
TKR 150 or 220mg qday(12-15 days)
Enox 30mg bid Failed to achieve noninferiority
STROKE PREVENTION
RE-LY AFIB 110 or 150mg bid
Warfarin (INR 2-3)
Stroke or systemic embolism
150mg (superior)110mg (non-inferior)
Dabigatran SafetyTrial
Patient population
Dosing Comparator Outcome Results
VTE PREVENTION
RE-NOVATE THR 150 or 220mg qday(28-35 days)
Enox 40mg qday
Major Bleeding
2.0% (220mg)1.3% (150mg)
vs.1.6%
RE-MODEL TKR 150 or 220mg qday(6-10 days)
Enox 40mg qday
1.5% (220mg)1.3% (150mg)
vs.1.3%
RE-MOBILIZE
TKR 150 or 220mg qday(12-15 days)
Enox 30mg bid
0.6% (220mg)0.6% (150mg)
vs.1.4%
STROKE PREVENTION
RE-LY AFIB 110 or 150mg bid
Warfarin (INR 2-3) Major
Bleeding
3.11% (150mg)2.71%(110mg)*
vs.3.36%
Apixaban• MOA – Direct Xa inhibitor• ADME
– Absorption• 50% bioavailable• Peak concentrations 3-4 hrs
– Metabolism: 3A4• Does not induce or inhibit enzymes
– Elimination• Renal (25%)• T1/2 = 10-14 hrs
Thromb Haemost 2010: 103:572-585Blood 2010; 115: 15-20
Apixaban Clinical TrialsTrial Patients Dosing Comparator Outcome Results
ADVANCE-1 TKR 2.5mg BID(10-14 days)
Enox 30mg bid
Total VTE + all cause mortality
API 9.0%Enox 8.8%
Non-Inferiority not met
Bleeding API 5.3%Enox 6.6%
ADVANCE-2 TKR 2.5mg BID(10-14 days)
Enox 40mg qday
Total VTE + all cause mortality
Api 15.1%Enox 24.4%
p=0.001
BleedingApi 3.5%Enox 4.8%
p=0.09
Thromb Haemost 2010: 103:572-585
Ongoing and Future StudiesDABIGATRAN RIVAROXABAN APIXABAN
PCI ACS VTE prevention(medical patients (ADOPT)
Long term VTE Stroke prevention (atrial fibrillation
Atrial fibrillation (ARISTOTLE, AVERROES)
TKA/THA renal dosing DVT treatment with concomitant 3A4 inducers
Prophylaxis of recurrent PE/DVT (AMPLIFY)
ACS (APPRAISE 2)
www.clinicaltrials.govThromb Haemost 2010: 103:572-585
DABIGATRAN ETEXILATE
RIVAROXABAN APIXABAN
Brand Pradaxa® Xarelto® ------------
Target IIa Xa Xa
Bioavailability (%)
~7% ~90% ~66%
T1/2 (hrs) 12-14 9-13 8-15
Renal excretion 90-95% 70% 30%
Drug interactions
PPI decrease absorptionP-glycoprotein substrate
Potent 3A4 inhibitorsP-glycoprotein inhibitors
Potent 3A4 inhibitors
Monitoring No No No
Antidote No No No
Thromb Haemost 2010; 103: 34-39Thromb Haemost 2010;103: 572-585
Oral Anticoagulants in Development
AGENT COMPANY PHASEDTI
Dabigatran Beohringer Ingelheim 3
AZD0837 Astra Zeneca 2
MCC977 Mitsubishi Pharma 2
Direct Xa inhibitors
Rivaroxaban Bayer, Ortho-McNeil 3
Apixaban Bristol-Myers Squibb – Pfizer 3
Betrixaban Portola 2
YM150 Astellas 2
Edoxaban Daichi Sankyo 3
TAK-442 Takeda 2
Novel VKA
ATI-5923 Aryx Therapeucis 2b
Blood 2010; 115: 15-20
The Ideal Anticoagulant? • Oral• Once daily dosing• Quick onset• Limited monitoring (available)• Limited or no drug interactions• Available and effective antidote• Wide therapeutic index• Low cost
Limitations of New Agents• No monitoring
– Unable to titrate dose– Failure of therapy vs. poor compliance
• Short t1/2
– Poor compliance may affect efficacy more than VKA
• No antidote• Renal/hepatic dose adjustments likely
required• Cost
Conclusions• 3 new oral agents with direct Xa or IIa activity• VTE prevention
– Superior data for rivaroxaban– Non-inferior for dabigatran– ? Apixaban– Generally, risk of bleeding no different than enoxaparin
• Dabigatran promising data for atrial fibrillation• Still no “perfect” oral anticoagulant….. But
making strides