Novel OAC s : How should we use them?

Novel OAC s : How should we use them? Jean C. Grégoire MD, FRCP(c), FACC, FACP Associate Professor, Université de Montréal, IntervenJonal Cardiologist, InsJtut de cardiologie de Montréal

Disclosures Speaker s Bureau/Honoraria : AbboQ, Amgen, AstraZeneca, Bayer, Bristol- Myers Squibb, Boehringer- ingelheim, Eli Lilly, Forest, Merck, NovarJs, Pfizer, Servier, Sunovion, Valeant ConsulJng Fees : Amgen, AstraZeneca, Bristol- Myers Squibb, Eli Lilly, Forest, Janssen, NovarJs, Roche, Sunovion, Valeant

ObjecJves Who should get them and who shouldn t? How to switch from e to NOAC? What to monitor? Drug interacjons?

2012 CCS AF Guidelines Assess Thromboembolic Risk (CHADS 2 ) CHADS 2 = 0 CHADS 2 = 1 CHADS 2 > 2 Increasing Stroke Risk No anjthrombojc ASA OAC* OAC* OAC No addijonal risk factors for stroke Either female sex or vascular disease Age > 65 or combinajon of female sex and vascular disease *ASA is a reasonable alternajve in selected pajents as indicated by risk/benefit 2012 CCS AF Guidelines. Can J Cardiol. 2012; 28:125-136.

Challenges Unpredictable response Frequent dose adjustments Narrow therapeujc window (INR range 2-3) RouJne coagulajon monitoring therapy has several limitajons that make it difficult to use in pracjce Numerous food- drug interacjons Numerous drug- drug interacjons Slow onset/offset of acjon resistance Ansell J, et al. Chest 2008;133:160S- 198S; Umer Ushman MH, et al. J Interv Card Electrophysiol 2008; 22:129-137; Nutescu EA, et al. Cardiol Clin 2008; 26:169-187

CoagulaJon Cascade Contact AcJvaJon (Intrinsic) Pathway XII XI Tissue Factor (Extrinsic) Pathway Tissue Factor IX UFH VIII VII X LMWH V Common Pathway II Fibrinogen Fibrin

NOACs and CoagulaJon Cascade Contact AcJvaJon (Intrinsic) Pathway XII XI Tissue Factor (Extrinsic) Pathway Tissue Factor IX VIII VII X Direct Factor Xa Inhibitor Rivaroxaban Apixaban Common Pathway V II Direct Thrombin Inhibitor Dabigatran Fibrinogen Fibrin

NOACs : Pharmacology AcJon Apixaban Dabigatran Rivaroxaban Direct factor Xa inhibitor Direct thrombin inhibitor Direct factor Xa inhibitor T max (hours) 3 2 2-4 Half- life (hours) ~ 12 h ~ 12 14 h ~ 5 13 h Renal excrejon ~ 27% ~ 85% ~ 33% Dosing BID BID ID INR monitoring Not required Not required Not required Drug interacjons CYP3A4 P- glycoproteine CYP3A4 AnJdote None None None Trials Averroes, Aristotle Re- Ly Rocket- AF ELIQUIS TM (apixaban). PM, 2012. Bristol- Myers Squibb/Pfizer Canada. PRADAX TM (dabigatran). PM, 2012. Boehringer Ingelheim Canada Ltd. XARELTO (rivaroxaban). PM, 2012. Bayer Canada.

NOACs : Drug InteracJons DABIGATRAN RIVAROXABAN APIXABAN P- gp inhibitors (verapamil, quinidine, amiodarone ) CYP3A4 and P- gp inhibitors (ketoconazole, itraconazole, voriconazole, posaconazole and HIV protease inhibitors) CYP3A4 and P- gp inhibitors (ketoconazole, itraconazole, voriconazole, posaconazole, and HIV protease inhibitors) P- gp inductors (carbamazepine, millepertuis ) CYP3A4 and P- gp inductors (rifampicin, phenytoin, carbamazepine, phenobarbitone) CYP3A4 and P- gp inductors (rifampicin, phenytoin, carbamazepine, phenobarbitone) Monographie de Pradaxs MC 2012, Boehringer Ingelheim (Canada) Ltée Monographie de Xarelto MC, février 2012, Bayer Inc Granger C, et al. N Engl J Med 2011;365:981-992

NOACs : Evidence- Based Medicine Apixaban Dabigatran Rivaroxaban Trials ARISTOTLE RE- LY ROCKET AF Number of parjcipants 18 201 18 113 14 262 CHADS 2 score 2.1 2.2 3.5 Dose 5 mg BID 150 mg BID 20 mg OD 2.5 mg BID 110 mg BID 15 mg OD Dose adjustment 2.5 mg BID if 2/3 criteria: age 80, weight 60 kg, or creajnine 133 μmol/l 110 mg BID if age 80 or age 75 with a risk factor for bleeding 15 mg OD if CrCl 30 49 ml/min ELIQUIS TM (apixaban). PM, 2012. Bristol- Myers Squibb/Pfizer Canada. PRADAX TM (dabigatran). PM, 2012. Boehringer Ingelheim Canada Ltd. XARELTO (rivaroxaban). PM, 2012. Bayer Canada.

RE- LY Stroke or Systemic Embolism (n=18 113) 0.06 CumulaJve incidence 0.05 0.04 0.03 0.02 0.01 HR = 0.90 (95% CI 0.74 1.10) p = 0.29 (superiority) p < 0.001 (non- inferiority) (TTR = 64%) Dabigatran 110 mg Dabigatran 150 mg HR = 0.65 (95% CI 0.52 0.81) p < 0.001 (superiority) 0.00 0 6 12 18 Follow- up (months) 24 30 Connolly SJ, et al. N Engl J Med. 2009; 361:1139 1151. Connolly SJ, et al. N Engl J Med 2010; 363(19):1875-1876.

NOACs Compared to Dabigatran 110 vs. Dabigatran 150 vs. Rivaroxaban vs. Apixaban vs. RR (95% CI) p RR (95% CI) p RR (95% CI) p RR (95% CI) p Stroke/SE 0.91 (0.74 1.11) 0.34 0.66 (0.53 0.82) < 0.001 Major Bleed 0.80 (0.69 0.93) 0.003 0.93 (0.81 1.07) 0.31 IC Bleed 0.31 (0.20 0.47) < 0.001 0.40 (0.27 0.60) < 0.001 Total Death 0.91 (0.80 1.03) 0.13 0.88 (0.77 1.00) 0.051 Green : Statistically significant Connolly SJ, et al. for the RE- LY Steering CommiQee and InvesJgators. N Engl J Med. 2009; 361:1139 51. Patel MR, et al. and the ROCKET AF Steering CommiQee for the ROCKET AF InvesJgators. N Engl J Med. 2011; 365:883 91. Granger CB, et al. for the ARISTOTLE CommiQees and InvesJgators. N Engl J Med. 2011; 365:981 92.

ROCKET AF Stroke or systemic embolism (n=14 264) CumulaJve incidence 0.06 0.05 0.04 0.03 0.02 0.01 0.00 ITT Analysis HR = 0.88 (95% CI 0.75 1.03) p = 0.12 (superiority) p < 0.001 (non- inferiority) 0 6 12 18 Follow- up (months) OT Analysis HR = 0.79 (95% CI 0.66 0.96) p = 0.02 (superiority) p < 0.001 (non- inferiority) 24 30 (TTR = 58%) Rivaroxaban Patel MR, et al. N Engl J Med. 2011; 365:883 91.

NOACs Compared to Dabigatran 110 vs. Dabigatran 150 vs. Rivaroxaban vs. Apixaban vs. RR (95% CI) p RR (95% CI) p RR (95% CI) p RR (95% CI) p Stroke/SE 0.91 (0.74 1.11) 0.34 0.66 (0.53 0.82) < 0.001 0.88 (0.74 1.03) 0.12 Major Bleed 0.80 (0.69 0.93) 0.003 0.93 (0.81 1.07) 0.31 1.04 (0.90 1.20) 0.58 IC Bleed 0.31 (0.20 0.47) < 0.001 0.40 (0.27 0.60) < 0.001 0.67 (0.47 0.93) 0.02 Total Death 0.91 (0.80 1.03) 0.13 0.88 (0.77 1.00) 0.051 0.92 (0.82 1.03) 0.15 Green : Statistically significant Connolly SJ, et al. for the RE- LY Steering CommiQee and InvesJgators. N Engl J Med. 2009; 361:1139 51. Patel MR, et al. and the ROCKET AF Steering CommiQee for the ROCKET AF InvesJgators. N Engl J Med. 2011; 365:883 91. Granger CB, et al. for the ARISTOTLE CommiQees and InvesJgators. N Engl J Med. 2011; 365:981 92.

ARISTOTLE Stroke or Systemic Embolism (n=18 201) CumulaJve incidence 0.06 0.05 0.04 0.03 0.02 0.01 ITT Analysis HR = 0.79 (95% CI 0.66 0.95) p = 0.01 (superiority) p < 0.001 (non- inferiority) (TTR = 62%) Apixaban 0.00 0 6 12 18 24 30 Follow- up (months) Granger CB et al. N Engl J Med. 2011; 365:981 92.

NOACs Compared to Dabigatran 110 vs. Dabigatran 150 vs. Rivaroxaban vs. Apixaban vs. RR (95% CI) p RR (95% CI) p RR (95% CI) p RR (95% CI) p Stroke/SE 0.91 (0.74 1.11) 0.34 0.66 (0.53 0.82) < 0.001 0.88 (0.74 1.03) 0.12 0.79 (0.66 0.95) < 0.01 Major Bleed 0.80 (0.69 0.93) 0.003 0.93 (0.81 1.07) 0.31 1.04 (0.90 1.20) 0.58 0.69 (0.60 0.80) < 0.001 IC Bleed 0.31 (0.20 0.47) < 0.001 0.40 (0.27 0.60) < 0.001 0.67 (0.47 0.93) 0.02 0.42 (0.30 0.58) < 0.001 Total Death 0.91 (0.80 1.03) 0.13 0.88 (0.77 1.00) 0.051 0.92 (0.82 1.03) 0.15 0.89 (0.80 0.99) 0.048 Green : Statistically significant Connolly SJ, et al. for the RE- LY Steering CommiQee and InvesJgators. N Engl J Med. 2009; 361:1139 51. Patel MR, et al. and the ROCKET AF Steering CommiQee for the ROCKET AF InvesJgators. N Engl J Med. 2011; 365:883 91. Granger CB, et al. for the ARISTOTLE CommiQees and InvesJgators. N Engl J Med. 2011; 365:981 92.

AVERROES CumulaJve risk 0.0 0.01 0.03 0.05 Stroke or systemic embolism HR 0.45 (95% CI, 0.32 0.62) p<0.001 Aspirin 3.7 % Apixaban 1.6% CumulaJve risk 0.0 0.005 0.010 0.015 0.020 HR 1.13 (95% CI, 0.74 1.75) p=0.57 Major bleeding Apixaban 1.46% Aspirin 1.2% 0 3 6 9 12 18 21 Months 0 3 6 9 12 18 21 Months Mean CHADS 2 score at baseline: 0 1: 36%; 2: 36%; 3+: 28% Connolly SJ, et al. N Engl J Med. 2011; 364:806 817.

2012 CCS AF Guidelines When OAC therapy is indicated, most pa>ents should receive dabigatran, rivaroxaban, or apixaban in preference to warfarin. 2012 CCS AF Guidelines. Can J Cardiol. 2012; 28:125-136.

NOAC Compared to e Stroke prevenjon Major bleeding Intracranial hemorrhage Mortality Apixaban Dabigatran 110 mg Dabigatran 150 mg Rivaroxaban Connolly SJ, et al. N Engl J Med. 2009; 361:1139 1151. Patel MR, et al. N Engl J Med. 2011; 365:883 891. Granger C, et al. N Eng J Med. 2011; 365:981 992.

Renal FuncJon Monitoring Depends on age, pre- exisjng renal funcjon, co- morbidijes, medicajons, and new OAC Renal funcjon should be assessed prior new OACs CrCl ml/min > 50 30-50 Monitoring (serum creajnin and egfr) Yearly + with clinical deteriorajon Every 6 months* + with clinical deteriorajon *Expert opinion. 2012 CCS AF Guidelines. Can J Cardiol. 2012; 28:125 136.

PaJents Likely to Benefit From Severe renal impairment (CrCl < 30 ml/min) ProstheJc or significant valvular heart disease Stable INRs? PaJent preference 2012 CCS AF Guidelines. Can J Cardiol. 2012; 28:125 136. Alberts M, et al. Lancet Neuro. 2012; 11:1066 81.

Switching: to a New OAC Stop warfarin 2-3 days before Monitor INR daily IniJate new OAC when: - INR < 2 : start apixaban or dabigatran - INR 2.5 : start rivaroxaban StarJng new OAC will depend on renal funcjon and prescribing informajon for new OAC Schulman S, Crowther MA. Blood. 2012; 119:3016 3023.

TransiJoning NOAC to Bridging essenjal To balance onset of warfarin (~ 5 days) and half- life of NOAC 1. IniJate warfarin, conjnue NOAC for at least 2 days 2. DisconJnue NOAC once INR is > 2.0 3. While on concomitant therapy, test INR just prior to the next dose of the NOAC Schulman S, Crowther MA. Blood 2012; 119:3016 3023. ELIQUIS TM (apixaban). PM, 2012. Bristol- Myers Squibb/Pfizer Canada. PRADAX TM (dabigatran). PM, 2012. Boehringer Ingelheim Canada Ltd. XARELTO (rivaroxaban). PM, 2012. Bayer Canada.

Current LimitaJons of OACs Dabigatran and rivaroxaban CrCl < 30 ml/min Apixaban Very limited data in CrCl 15 24 ml/min CrCl < 15 ml/min No accurate monitoring available No specific anjdote (ongoing research) Long- term safety Less clinical experience in some groups (e.g., IHD)