Fibrillazione Atriale Non Valvolare: Come Orientare La Scelta Dei Nuovi Anticoagulanti Orali Gianluca Botto, MD, FAAC, FESC Divisione di Cardiologia Ospedale Sant Anna, Como
The Promise of NOAs
Antithrombotic Treatments in non valvular AF (4.845 pts) OAC Other ATT Courtesy of Di Pasquale G. None
Desirable Qualities of a New Anticoagulant 5 Oral Fixed dosing Rapid onset and offset of action Predictable anticoagulant response (no monitoring) Minimal food and drug interactions Reversible As or more effective than current agents As or safer than current agents More cost-effective than current Rxs
Efficacy
Trials on New Oral Anticoagulants in AFIB Trial Drug Company Dose Design RE-LY Dabigatran Boeringer 110 mg and 150 mg bid PROBE ROCKET-AF Rivaroxaban Bayer 20 mg daily ARISTOTLE Apixaban Bristol MS / Pfizer 5 mg bid double-dummy, double-blind double-dummy, double-blind ENGAGE-AF Edoxaban Daiichi Sankyo EXPLORE-Xa Betrixaban Merck OPAL-2 YM150 Astrellas 30 mg and 60 mg daily 40,60,80 mg daily six regimens double-dummy, double-blind double-blind, open label W double-blind, open label W
NOAs vs Warfarin in Pts with AF ALL-CAUSE STROKE or SE ISCHEMIC STROKE HEMORRHAGIC STROKE Miller CS. Am J Cardiol 2012; 110: 453-460
Recent NOA Trials: Ischemic Stroke RELY Dabigatran 110 mg Dabigatran 150 mg Warfarin ROCKET Rivaroxaban 20 mg Warfarin ARISTOTLE Apixaban 5 mg Warfarin 1.34% / yr 1.20 0.35 0.92% / yr 0.76 0.03 1.20% / yr HR P-value (ITT) 1.62% / yr 0.99 0.92 1.64% / yr 0.97% / yr 0.92 0.42 1.05% / yr Patel MR. N Engl J Med 2011; Connolly SJ. N Engl J Med 2009; Granger C. N Eng J Med 2011
Efficacy and TTR in 3 SPAF Studies
Safety
NOAs vs Warfarin in Pts with AF MAJOR BLEEDING INTRACRANIAL BLEEDING GE BLEEDING Miller CS. Am J Cardiol 2012; 110: 453-460
Indirect Comparison of NOAs in Pts with AF A Network Meta-analisys Harenberg J. Int Angiol 2012; 31: 330-9
Net Clinical Benefit for Warfarin and NOAs by CHA 2 DS 2 -VASc Score Banerjee A. Thrombosis Haemost 2012
Cost-Efficacy
Anticoagulation Rx in Pts With NV-AF Projected Costs, Cost-Efficacy and Cost-Benefit Harrington AR. Stroke 2013 in press
Who is NOT a Candidate For NOAs? Mechanical valve Creat-Cl < 30 ml/min Severe hepatic dysfunction Non-compliant with W
Fibrillazione Atriale Non Valvolare: Come Orientare La Scelta Dei Nuovi Anticoagulanti Orali Gianluca Botto, MD, FAAC, FESC Divisione di Cardiologia Ospedale Sant Anna, Como
Putting it All Togeteher What Should We Do Now in Clinical Practice? Daily dosage (OD vs BID) Effect of renal funcion Perioperative managem Drug Interaction Elderly and fragile pts ACS/MI GI bleeding
Patients Preferences For Type 2 Diabetes Treatment Dosing Schedules Hauber AB. Patient Preference and Adherence 2013:7 937 949
Summary Of The RCTs Involving Novel Anticoagulants vs Warfarin For Stroke Prevention In Non-Valvular AF
Apr 2012
Anticoagulants: PK Parameters AVK a-iia a-xa Poulsen BK et al, Drugs 2011
Clin Pharmacokinet 2010; 49: 259-68.
Time Course of Effect of Dabigatran on aptt Weitz JI. Circulation 2012; 126: 2428-2432
Renal disease Hepatic disease Kreutz R, Fundamental Clin Pharmacol 2011
Estimated Drug Half-lives And Effect On AUC NOA Plasma Concentrations @ Different Stages Of CKD Compared To Healthy Controls Apr 2012
Noacs In Renal Dysfunction Approved European Labels And Dosing In CKD Apr 2012
NOAs Last Intake Of Drug Before Elective Surgical Intervention Apr 2012
Effect on NOAs plasma levels (area under the curve, AUC) from drug drug interactions and clinical factors. Recommendations towards NOAC dosing EHRA Practical Guidelines Europace 2013; 15: 625-651
Dabigatran Etexilate And Dronedarone Effect of dronedarone (P-gp inhibitor) on pharmacokinetics and pharmacodynamics of dabigatran was studied 1 Sponsored by sanofi-aventis Dronedarone 400 mg BID increased steady-state dabigatran exposures by 1.7- to 2.0-fold 1 Due to increased absorption through P-gp inhibition Similar level of interaction to that observed for dabigatran in the presence of other P-gp inhibitors, such as amiodarone and verapamil No effect of dronedarone on renal clearance of dabigatran 1 EU SmPC: co-administration of dabigatran and dronedarone not recommended because inadequate clinical data are available (Pradaxa : EU SmPC, 2012) 1. Brunet A. Eur Heart J 2011; 32: 618 9
Circulation. 2012; 125: 669-676
ATLAS ACS 2 TIMI 51 N=15,526* Physician's decision to add thienopyridine or not Stratum 1: ASA alone (7%) ASA dose = 75 100 mg/day Stratum 2: ASA + thienopyridine (93%) Placebo n=355 Rivaroxaban 2.5 mg bid n=349 Rivaroxaban 5 mg bid n=349 Placebo n=4821 Rivaroxaban 2.5 mg bid n=4825 Rivaroxaban 5 mg bid n=4827 Event-driven study 1002 events *184 patients were excluded from the efficacy analyses prior to unblinding because of trial misconduct at three sites Mega JL et al. N Engl J Med 2011. 13 November 2011
NEJMed 2013
RE-LY Cardioversion Subgroup Stroke or Systemic Embolism with/without TEE Stroke/systemic embolism (%) 2.5 2.0 1.5 1.0 0.5 0.0 With TEE prior to cardioversion (24.8% of pts) 0.61 Dabigatran 110 mg BID P=0.65 0.0 Dabigatran 150 mg BID P=0.17 1.14 Warfarin Without TEE prior to cardioversion (13.3% of pts) 0.83 Dabigatran 110 mg BID P=0.54 0.39 Dabigatran 150 mg BID P=0.75 0.52 Warfarin Similar rates of stroke or systemic embolism with/without TEE before cardioversion Nagarakanti R. Circulation 2011;123:131 6
Kirchhof P. EHRA-Europace Meeting, Athens 2013 Apr 2012
NOAs Global Market Share June 2013 RIVAROXABAN DABIGATRAN APIXABAN IMS MIDAS Database Monthly Sales
Humanity greatest advance are not in its discoveries, but in how those discoveries are applied Bill Gates, June 7, 2007 Harvard Commencement Address
Novel Oral Anticoagulants NOAs all provide important advantage over W, including convenience, at least as effective prevention of stroke, and less intracranial hemorrhage Until head-to-head trials or large scale observational studies that reflects routine use of these agents are available, indirect comparison are just one tool for hypothesis generating The new agents provide an important opportunity to improve the care of pts with AFIB including for pts with indications but not currently treated with any OAC.