Novel OAC s : How should we use them?

Transcription

1 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

2 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

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

4 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:

5 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: ; Nutescu EA, et al. Cardiol Clin 2008; 26:

6 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

7 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

8 NOACs : Pharmacology AcJon Apixaban Dabigatran Rivaroxaban Direct factor Xa inhibitor Direct thrombin inhibitor Direct factor Xa inhibitor T max (hours) Half- life (hours) ~ 12 h ~ 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, Bristol- Myers Squibb/Pfizer Canada. PRADAX TM (dabigatran). PM, Boehringer Ingelheim Canada Ltd. XARELTO (rivaroxaban). PM, Bayer Canada.

9 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:

10 NOACs : Evidence- Based Medicine Apixaban Dabigatran Rivaroxaban Trials ARISTOTLE RE- LY ROCKET AF Number of parjcipants CHADS 2 score 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 ml/min ELIQUIS TM (apixaban). PM, Bristol- Myers Squibb/Pfizer Canada. PRADAX TM (dabigatran). PM, Boehringer Ingelheim Canada Ltd. XARELTO (rivaroxaban). PM, Bayer Canada.

11 RE- LY Stroke or Systemic Embolism (n=18 113) 0.06 CumulaJve incidence HR = 0.90 (95% CI ) p = 0.29 (superiority) p < (non- inferiority) (TTR = 64%) Dabigatran 110 mg Dabigatran 150 mg HR = 0.65 (95% CI ) p < (superiority) Follow- up (months) Connolly SJ, et al. N Engl J Med. 2009; 361: Connolly SJ, et al. N Engl J Med 2010; 363(19):

12 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 ( ) ( ) < Major Bleed 0.80 ( ) ( ) 0.31 IC Bleed 0.31 ( ) < ( ) < Total Death 0.91 ( ) ( ) Green : Statistically significant Connolly SJ, et al. for the RE- LY Steering CommiQee and InvesJgators. N Engl J Med. 2009; 361: Patel MR, et al. and the ROCKET AF Steering CommiQee for the ROCKET AF InvesJgators. N Engl J Med. 2011; 365: Granger CB, et al. for the ARISTOTLE CommiQees and InvesJgators. N Engl J Med. 2011; 365:

13 ROCKET AF Stroke or systemic embolism (n=14 264) CumulaJve incidence ITT Analysis HR = 0.88 (95% CI ) p = 0.12 (superiority) p < (non- inferiority) Follow- up (months) OT Analysis HR = 0.79 (95% CI ) p = 0.02 (superiority) p < (non- inferiority) (TTR = 58%) Rivaroxaban Patel MR, et al. N Engl J Med. 2011; 365:

14 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 ( ) ( ) < ( ) 0.12 Major Bleed 0.80 ( ) ( ) ( ) 0.58 IC Bleed 0.31 ( ) < ( ) < ( ) 0.02 Total Death 0.91 ( ) ( ) ( ) 0.15 Green : Statistically significant Connolly SJ, et al. for the RE- LY Steering CommiQee and InvesJgators. N Engl J Med. 2009; 361: Patel MR, et al. and the ROCKET AF Steering CommiQee for the ROCKET AF InvesJgators. N Engl J Med. 2011; 365: Granger CB, et al. for the ARISTOTLE CommiQees and InvesJgators. N Engl J Med. 2011; 365:

15 ARISTOTLE Stroke or Systemic Embolism (n=18 201) CumulaJve incidence ITT Analysis HR = 0.79 (95% CI ) p = 0.01 (superiority) p < (non- inferiority) (TTR = 62%) Apixaban Follow- up (months) Granger CB et al. N Engl J Med. 2011; 365:

16 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 ( ) ( ) < ( ) ( ) < 0.01 Major Bleed 0.80 ( ) ( ) ( ) ( ) < IC Bleed 0.31 ( ) < ( ) < ( ) ( ) < Total Death 0.91 ( ) ( ) ( ) ( ) Green : Statistically significant Connolly SJ, et al. for the RE- LY Steering CommiQee and InvesJgators. N Engl J Med. 2009; 361: Patel MR, et al. and the ROCKET AF Steering CommiQee for the ROCKET AF InvesJgators. N Engl J Med. 2011; 365: Granger CB, et al. for the ARISTOTLE CommiQees and InvesJgators. N Engl J Med. 2011; 365:

17 AVERROES CumulaJve risk Stroke or systemic embolism HR 0.45 (95% CI, ) p<0.001 Aspirin 3.7 % Apixaban 1.6% CumulaJve risk HR 1.13 (95% CI, ) p=0.57 Major bleeding Apixaban 1.46% Aspirin 1.2% Months Months Mean CHADS 2 score at baseline: 0 1: 36%; 2: 36%; 3+: 28% Connolly SJ, et al. N Engl J Med. 2011; 364:

18 2012 CCS AF Guidelines When OAC therapy is indicated, most pa>ents should receive dabigatran, rivaroxaban, or apixaban in preference to warfarin CCS AF Guidelines. Can J Cardiol. 2012; 28:

19 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: Patel MR, et al. N Engl J Med. 2011; 365: Granger C, et al. N Eng J Med. 2011; 365:

20 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 > Monitoring (serum creajnin and egfr) Yearly + with clinical deteriorajon Every 6 months* + with clinical deteriorajon *Expert opinion CCS AF Guidelines. Can J Cardiol. 2012; 28:

21 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: Alberts M, et al. Lancet Neuro. 2012; 11:

22 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:

23 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 > While on concomitant therapy, test INR just prior to the next dose of the NOAC Schulman S, Crowther MA. Blood 2012; 119: ELIQUIS TM (apixaban). PM, Bristol- Myers Squibb/Pfizer Canada. PRADAX TM (dabigatran). PM, Boehringer Ingelheim Canada Ltd. XARELTO (rivaroxaban). PM, Bayer Canada.

24 Current LimitaJons of OACs Dabigatran and rivaroxaban CrCl < 30 ml/min Apixaban Very limited data in CrCl 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)