Oral Anticoagulants in the Pipeline Tracy Sprunger, Pharm.D., BCPS Assistant Professor, Pharmacy Practice Butler College of Pharmacy and Health Sciences Clinical 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 Drug interactions 1980s LMWH Must transition to warfarin 1990s DTI Limited use to HIT/CV 1990s Xa inhibitors 2010 ORAL DTI/Xa ?????

Clotting Cascade AJHP 2004;61:S7. Currently, the vitamin K antagonist warfarin is the only oral form of anticoagulation for long term use. AJHP 2004;61:S7.

The Ideal Anticoagulant?

Am J Health-Syst Pharm;65:1520 Emerging Therapies Although there are many agents being studied – there are 3 agents very advanced in clinical studies. These agents work by directly inhibiting a single clotting factor – Xa or Iia – Xa is inhibited by____________ Iia inhibited by____________. Am J Health-Syst Pharm;65:1520

Rivaroxaban monograph 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 Xarelto – developed by Beyer/ J& J, and marketed by Ortho-NcNeil and Scios. Currently approved in Canada and ____ for the prevention of VTE in hip and knee surg. Rivaroxaban is a direct thrombin inhibitor – this agent does not require antithrombin as a cofactor like fondaparinux does. Oral bioavailability 80-100% - food does no effect AUC or peak concentration. This agent is highly protein bound (92-95%) Approved in Canada - prodrug of dabigatran Monitoring – dose dependent inhibition of Xa has been observed – may effect PT an dAPTT – but routine monitoring not necessary You m ay remember ximelegatran (Exanta – another oral DTI never marketed bcause of liver damage. www.bayer.ca Rivaroxaban monograph

Rivaroxaban monograph 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.ca Rivaroxaban monograph

Rivaroxaban monograph 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 Child pugh class B and C associated with coagulopathy and clinicallyh sig bleeding risk www.bayer.ca Rivaroxaban monograph

Rivaroxaban Clinical Trials 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 (10-14 days) Riva 2% Enox 9.3% RECORD 3 TKR Riva 9.6% Enox 18.9% p=0.012 (sup) RECORD 4 Enox 30mg bid Riva 6.9% Enox 10.1% RECORD trials were non-inferiority trials except for RECORD 2 which was a superiority trial.

Rivaroxaban Safety RECORD 1 THR 10mg qday Enox 40mg qday TRIAL 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 (10-14 days) Riva 0.1% p=1.00 RECORD 3 TKR Riva 0.6% Enox 0.5% p=0.79 RECORD 4 Enox 30mg bid Riva 0.7% Enox 0.3% p=0.31 Thromb Haemost 2010: 103:572-585

Dabigatran Etexilate MOA Absorption Distribution Direct IIa inhibitor; Pro-drug Absorption Bioavailability ~6% Requires acidic environment Distribution ~35% protein bound T1/2 ~ 14 hrs allowing for once or twice daily administration www.pradaxa.com

Dabigatran Etexilate Metabolism Elimination Rapidly converted to active drug No CYP metabolism Elimination Renal : 80% unchanged t1/2 ~14-17hrs www.pradaxa.com

Dabigatran Dosing in renal impairment Drug interaction studies 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 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 (6-10 days) RE-MOBILIZE (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) For The VTE prevention trials Dabigatran dosed with a half-dose on the day of surgery was compared to enoxaparin. Outcome was venographically detected or symptomatic DVT or PE + all cause mortality. Renovate – exte3nded prophylaxis for 28-35 daysRemodel- dabi started 1-4 hours after surg tx 6-10 days enox started evening prior to surg. RELy_ superior to warf at the 150 dose with a similar amount of major bleeding – an snon-inferior to warfarin at the 110mg BID dose – with significantly less major bleeding.

Dabigatran Safety Trial 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 (6-10 days) 1.5% (220mg) 1.3% RE-MOBILIZE (12-15 days) Enox 30mg bid 0.6% (220mg) 0.6% (150mg) 1.4% STROKE PREVENTION RE-LY AFIB 110 or 150mg bid Warfarin (INR 2-3) 3.11% (150mg) 2.71%(110mg)* 3.36% Primary safety endpoint was major bleeding (fatal bleeding; clinically overt bleeding associated wigh a fall in hemoglobin >= 2mg/dL; clinically overt bleeding requiring 2 units or retroperitoneal, intracrainal, introacular, or intraspinal bleeding.

Apixaban MOA – Direct Xa inhibitor ADME Absorption Metabolism: 3A4 50% bioavailable Peak concentrations 3-4 hrs Metabolism: 3A4 Does not induce or inhibit enzymes Elimination Renal (25%) T1/2 = 10-14 hrs Follow up to razaxaban )development halted due to bleeding concerns Thromb Haemost 2010: 103:572-585 Blood 2010; 115: 15-20

Apixaban Clinical Trials 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 Enox 40mg qday Api 15.1% Enox 24.4% p=0.001 Api 3.5% Enox 4.8% p=0.09 Thromb Haemost 2010: 103:572-585

Ongoing and Future Studies DABIGATRAN 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.gov Thromb Haemost 2010: 103:572-585

DABIGATRAN ETEXILATE RIVAROXABAN APIXABAN Brand Target Pradaxa® Xarelto® ------------ Target IIa Xa Bioavailability (%) ~7% ~90% ~66% T1/2 (hrs) 12-14 9-13 8-15 Renal excretion 90-95% 70% 30% Drug interactions PPI decrease absorption P-glycoprotein substrate Potent 3A4 inhibitors P-glycoprotein inhibitors Monitoring No Antidote Thromb Haemost 2010; 103: 34-39 Thromb Haemost 2010;103: 572-585

Oral Anticoagulants in Development AGENT COMPANY PHASE DTI Dabigatran Beohringer Ingelheim 3 AZD0837 Astra Zeneca 2 MCC977 Mitsubishi Pharma Direct Xa inhibitors Rivaroxaban Bayer, Ortho-McNeil Apixaban Bristol-Myers Squibb – Pfizer Betrixaban Portola YM150 Astellas Edoxaban Daichi Sankyo TAK-442 Takeda 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 Disadvantages – no routine monitoring – can not titrate dose, ? Failuire of therapy vs. non-compliance; no antidote; no monitoring/lab marker available to measure drug activity if needed ; renal/hepatic dosing; 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