New Insights from the Effective

Transcription

1 New Insights from the Effective anticoagulation with factor xa next GEneration in Atrial Fibrillation TIMI 48 (ENGAGE AF-TIMI 48 Trial) Robert P. Giugliano, MD, SM Senior Investigator, TIMI Study Group Physician, Cardiovascular Medicine Brigham and Women s Hospital Associate Professor in Medicine Harvard Medical School Boston, Mass

2 MY CONFLICTS OF INTEREST ARE: Research Grants: Daiichi-Sankyo, Merck Honoraria/Consulting: Bristol-Myers Squibb, Daiichi- Sankyo, Janssen, Merck, Pfizer, Portola, Sanofi

3 Study Design 21,105 PATIENTS AF documented within last 12 m CHADS 2 2 RANDOMIZATION 1:1:1 Double-blind, Double-dummy Warfarin (N=7036) (INR ) Median TTR 68.4% Higher-dose Edoxaban 60* mg QD (N=7035) Lower-dose Edoxaban 30* mg QD (N=7034) Median follow-up 2.8 yrs (~60,000 patient-years) *Edoxaban dose reduced by 50% if: - CrCl ml/min - weight 60 kg - strong P-gp inhibitor 1º Efficacy EP = Stroke or SEE 1º Safety EP = Major Bleeding (ISTH criteria) CrCl, creatinine clearance; ISTH, International Society on Thrombosis and Haemostasis; P-gp, P-glycoprotein; SEE, systemic embolic event Ruff CR et al. Am Heart J 2010; 160: Giugliano RP. NEJM 2013; 369:

4 21,105 Patients, 1393 Centers, 46 Countries Key Trial Metrics UNITED STATES (3907) CHINA (469) DENMARK (219) CROATIA (127) E. Antman; R. Giugliano Y. Yang P. Grande M. Bergovec POLAND (1278) HUNGARY (464) ESTONIA (191) PHILIPPINES (125) W. Ruzyllo R. Kiss J. Voitk N. Babilonia Received drug / enrolled 99.6% CZECH REPUBLIC (1173) ROMANIA (410) MEXICO (190) THAILAND (115) J. Spinar M. Dorobantu A. García-Castillo P. Sritara Completeness of follow-up 99.5% RUSSIAN FEDERATION (1151) SLOVAKIA (405) PORTUGAL (180) TURKEY (111) M. Ruda T. Duris J. Morais A. Oto Final visit or died / enrolled 99.1% UKRAINE (1148) UNITED KINGDOM (400) PERU (173) FRANCE (110) A. Parkhomenko J. Camm M. Horna J.J. Blanc ARGENTINA (1059) ISRAEL (283) ITALY (169) AUSTRALIA (102) Off drug (patients per yr) 8.8% E. Paolasso B. Lewis P. Merlini; M. Metra P. Aylward JAPAN (1010) SERBIA (277) SPAIN (166) GREECE (51) Y. Koretsune; T. Yamashita M. Ostojic J.L. Zamorano D. Alexopoulos Withdrew consent, no data 0.9% GERMANY (913) SOUTH AFRICA (277) NETHERLANDS (153) FINLAND (42) V. Mitrovic A. Dalby T. Oude Ophuis M. Nieminen CANADA (774) CHILE (254) BELGIUM (149) NORWAY (34) D. Roy R. Corbalan H. Heidbuchel D. Atar Lost to follow-up n=1 BRAZIL (707) SWEDEN (252) COLOMBIA (141) SWITZERLAND (5) J.C. Nicolau S. Juul-Möller R. Botero T. Moccetti Median time in therapeutic range [Interquartile range] INDIA (690) TAIWAN (234) GUATEMALA (136) B. SomaRaju S. Chen G. Sotomora 68.4% [ ] BULGARIA (520) SOUTH KOREA (230) NEW ZEALAND (131) A. Goudev N. Chung H. White Giugliano RP. NEJM 2013; 369:

5 Primary Efficacy and Safety Results (2.8 years median f/u) Stroke/SEE: Noninferiority Analysis (mitt, On Treatment) Warfarin TTR 68.4% Hazard ratio (97.5% CI) P Values Non-inferiority Superiority Edoxaban 60* mg QD vs warfarin 0.79 P< P=0.017 *Dose reduced by 50% in selected patients edoxaban noninferior ISTH Major Bleeding: (Safety Cohort, On Treatment) Edoxaban 60* mg QD vs warfarin 0.80 P<0.001% Giugliano RP. et al. NEJM 2013;369: % 0.5% 1.0% 2.0% edoxaban superior edoxaban inferior Safety'cohort=all'pa/ents'who'received'at'least'1'dose'by'treatment'actually'received'

6 DRAFT Risk Differences for 1000 Patients per 10 Yrs: Edoxaban 60/30 mg vs Warfarin Secondary End Points ITT Overall CE-6 0 Events/10,000 patients/year * Stroke SEE death -51 * -36 CV death All death Myocardial infarction -5 * p < 0.05

7 DRAFT Risk Differences for 1000 Patients per 10 Yrs: Edoxaban 60/30 mg vs Warfarin Safety Endpoints Safety Cohort, On-Treatment CE-7 40 * 28 Events/10,000 patients/year *** Major bleed LT = life-threatening. * p < 0.05; ** p 0.01; *** p *** LT or fatal bleed -46 *** ICH -17 ** Fatal bleed -12 * Fatal ICH -4 Major GI bleed

8 Top 4 Types of CV Death # pts Sudden Cardiac Death (45%) # pts P = NS for each pairwise comparisons Warfarin HD Edox LD Edox # pts Fatal Ischemic Stroke (8.8%) P = NS for each pairwise comparisons Warfarin HD Edox LD Edox Giugliano RP. ESC 2014, Barcelona, Spain 50 0 # pts Fatal CHF /Shock (23%) P = NS for each pairwise comparisons Warfarin HD Edox LD Edox Fatal Bleeding (7.5%) 65 P= P< Warfarin HD Edox LD Edox 8

9 Bleeding Related to Death # pts Bleeding contributed to death (16% ICH) P = Fatal (79% ICH) P < Warfarin HD Edox LD Edox ICH=Intracranial hemorrhage Giugliano RP. ESC 2014, Barcelona, Spain 9

10 Risk Differences for 1000 Patients per 10 yrs: Edox 60/30 mg vs. Warfarin Net Outcomes Net Outcomes 0 Events/10,000 Patients/Year * -59* -85* * p < Stroke/SEE Major Bleed Death Stroke/SEE Life-threatening bleed Death Disabling stroke Life-threatening bleed Death 10

11 Transition Period Outcomes All pts transitioned! VKA or NOAC If VKA: Frequent INRs, overlapped VKA + edox (30 or 15 mg) for 2 wks until INR 2.0 If NOAC: start when INR < 2.0 Events After Transition to Open-label Anticoagulant Warfarin (n=4503) High-dose Edoxaban (n=4526) Low-dose Edoxaban (n=4613) Stroke or SEE* through 30d 7 (0.16%) 7 (0.15%) 7 (0.15%) Major Bleeds through 14d 6 (0.13%) 4 (0.09%) 5 (0.11%) Data shown include all patients on blinded study drug at the end of the treatment period SEE=systemic embolic event. No SEEs occurred during the 30-day transition period. 11

12 Summary: Main Trial Compared to well-managed warfarin (TTR 68.4%) oncedaily edoxaban: Non-inferior for stroke/see (both regimens) High dose stroke/see on Rx (trend ITT) Both regimens significantly reduced: Major bleeding ICH Hemorrhagic stroke CV death Superior net clinical outcomes No excess in stroke or bleeding during transition! oral anticoagulant at end of trial Giugliano RP. NEJM 2013; 369:

13 High Risk Subgroups Requiring dose adjustment Elderly Women History of stroke/tia Concomitant antiplatelet Prior heart failure

14 ng / ml Edoxaban Concentration & Anti-FXa Activity Mean Edoxaban Trough Concentration (N=6,780) 48.5 ± 45.8 No DR 60 mg 34.6 ± 30.9 DR 30 mg High Dose Edoxaban 24.5 ± ± 14.5 No DR 30 mg Low Dose Edoxaban DR = Dose Reduction DR 15 mg IU / ml 1,00 0,80 0,60 0,40 0,20 0,00 Mean Trough Anti-FXa Activity (N=2,865) 0.85 ± 0.76 No DR 60 mg 0.64 ± 0.54 DR 30 mg High Dose Edoxaban 0.44 ± 0.37 No DR 30 mg 0.35 ± 0.28 DR 15 mg Low Dose Edoxaban Ruff CT, Lancet 2015 Published Online March 11,

15 2,5 Stroke/SEE in Patients With and Without Dose Reduction High Dose Edoxaban vs. Warfarin No Dose Reduction: HR 0.78 ( ) Dose Reduction: HR 0.81 ( ) P interaction = 0.85 HD = High Dose LD = Low Dose Edox = Edoxaban 2, ,0 1,5 1,0 Low Dose Edoxaban vs. Warfarin No Dose Reduction: HR 1.07 ( ) Dose Reduction: HR 1.07 ( ) 1, P interaction = ,38 1,79 0,5 0,0 Edox Conc (ng/ml) Anti-Fxa (IU/mL) Ruff CT, Lancet 2015 Warfarin HD Edox LD Edox 60 mg 30 mg No Edoxaban Dose Reduction NA NA Warfarin HD Edox LD Edox 30 mg 15 mg Edoxaban Dose Reduced NA NA

16 6,0 5,0 4,0 3,0 Major Bleeding in Patients With and Without Dose Reduction High Dose Edoxaban vs. Warfarin No Dose Reduction: HR 0.88 ( ) Dose Reduction: HR 0.63 ( ) 3, P interaction = 0.02 Low Dose Edoxaban vs. Warfarin No Dose Reduction: HR 0.55 ( ) Dose Reduction: HR 0.31 ( ) P interaction = HD = High Dose LD = Low Dose Edox = Edoxaban 4,85 3,05 2,0 1, ,0 0,0 Edox Conc (ng/ml) Anti-Fxa (IU/mL) Ruff CT, Lancet 2015 Warfarin HD Edox 60 mg LD Edox 30 mg No Edoxaban Dose Reduction NA NA Warfarin HD Edox 30 mg LD Edox 15 mg Edoxaban Dose Reduced NA NA

17 Edoxaban Trough Concentration & Outcomes Probability of Event Over 3 Years ICH Major Bleed Stroke or SEE Trough Edoxaban Concentration [ng/ml] Ruff CT, Lancet 2015 Published Online March 11,

18 Efficacy and Safety of Edox in Elderly No Evidence of Effect Modification Stroke/ SEE Ischemic Stroke Major Bleeding HD Edoxaban vs Warfarin HR, 95% CI <65 yr yr 75 yr <65 yr yr 75 yr <65 yr yr 75 yr HDE W LDE Event rate (%/ pt-yr) P- 0.9 interaction: all > LD Edoxaban vs Warfarin HR, 95% CI ICH <65 yr yr 75 yr Kato E, AHA 2014, Chicago, USA Favors Edoxaban Favors Warfarin Favors Edoxaban Favors Warfarin

19 Primary Efficacy Outcome by Gender Stroke/SEE: mitt cohort, On Treatment Women Men Warfarin TTR 68.4% Edoxaban 60* mg QD vs warfarin Hazard ratio (95% CI) 0.78% 0.80% Annual rate Edox Warf 1.21 vs vs 1.46 P -int 0.91 Edoxaban 30* mg QD vs warfarin 1.16% 1.02% 1.80 vs vs Giugliano RP WHITH 2015, Berlin, Germany

20 Primary Safety Outcome by Gender Major Bleeding: Safety cohort, On Treatment Women Warfarin TTR 68.4% Edoxaban 60* mg QD vs warfarin Men Hazard ratio (95% CI) 0.74% 0.84% Annual rate Edox Warf 2.48 vs vs 3.47 P -int 0.34 Edoxaban 30* mg QD vs warfarin 0.46% 0.48% 1.54 vs vs Giugliano RP WHITH 2015, Berlin, Germany 0.25% 0.5% 1.0% 2.0%

21 %/yr 4' 3' 2' 1' 2.9% 0,2% 0,6% Primary Efficacy Events Stratified by History of Stroke/TIA HR 0.86 ( ) 2.4% 0,1% 0,3% 2,1% 2,0% HR 1.10 ( ) 3.2% 0,1% 0,2% 2,9% Interaction P-values HD Edox: 0.86 LD Edox: 0.84 Systemic'embolic'event' Hemorrhagic'stroke' Ischemic'stroke' HR 0.88 ( ) 1.4% 0,1% 1.2% 0,4% 0,1% 0,2% 0,9% 1,0% HR 1.14 ( ) 1.6% 0,2% 0,1% 1,3% 0' Warfarin' (N=1991)' HD'Edox' (N=1976)' LD'Edox' (N=2006)' Yes, Prior Stroke/TIA (N=5973) Warfarin' (N=5045)' HD'Edox' (N=5059)' LD'Edox' (N=5028)' No Prior Stroke/TIA (N=15,132) Rost NS, World Stroke Congress Oct 2014, Istanbul, Turkey

22 The event rate in patients by APT (%/y) KM rate of Bleeding of Edoxaban and Warfarin by Concomitant Antiplatelet Use P interaction>0.05 HR 0.80, P=0.01 HR 0.56, P<0.001 HR 0.82, P=0.10 HR 0.51, P<0.001 No APT APT No APT APT HD edoxaban LD edoxaban Warfarin P interaction=0.046, LD Edox vs Warf HR 0.60, P<0.001 HR 0.50, P<0.001 HR 0.50, P=0.001 HR 0.27, P<0.001 Major Bleeding Fatal/life-threatening Bleeding Xu H et al, AHA 2014

23 Efficacy in Patients with Prior CHF Stroke/SEE HDE W LDE No.HF HF,7NYHA7I.II HF,7NYHA7III.IV Ischemic Stroke No.HF HF,7NYHA7I.II HF,7NYHA7III.IV Hemorrhagic stroke Higher Dose Edoxaban vs. Warfarin HR 95% CI Annualized Event Rate (%/yr) No.HF HF,7NYHA7I.II HF,7NYHA7III.IV Lower Dose Edoxaban vs. Warfarin HR 95% CI Favors7HDE Magnani G, AHA 2014, Chicago, USA Favors77W P"int&>&0.05&for&all& Favors7LDE Favors77W 23

24 Major Advances in Direct Oral Anticoagulants (NOACs) in AF 1989$1993 Yr: Trial'Comple/on' FDA'Approval' Nov'2010' Nov'2011' Jun'28,'2012?' 2013' N, RCT: EMEA'Approval' 2900 Aug'2011' 18,113 Dec'2011' 14,266 18,201 21,105

25 PK/PD of 4 NOACs in AF Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) Target IIa (thrombin) Xa Xa Xa Hrs to Cmax CYP metabolism None 32% 15% <4% Bioavailability 7% 80% 66% 62% Transporters P-gp P-gp/BCRP P-gp P-gp Protein binding 35% >90% 87% 55% Half-life 12-14h 9-13h 8-15h 10-14h Renal elimination 80% 66%* 27% 50% *Approximately half of which s excreted unchanged in the urine BCRP = breast cancer resistance protein; CYP = cytochrome P450; NR = not reported; P-gp = P-glycoprotein Gonzalez-Quesada CJ. Am J Cardiovasc Drugs 2014 ;14: Grip LT. Hot Topics 2013:31:7-18 Plitt A. JCPT 2014 (on-line doi: / ) Ericksson BI. Clin Pharmacokinet 2009; 48: 1-22

26 Drug-drug Interactions with NOACs Kovacs RJ, et al. JACC 2015;65: Avoid Reduce dose

27 Pointers* towards which NOAC to Choose Renal impairment Consider agent least dependent on renal function Apix, Edox 30 Riva 15 High risk of bleeding, e.g. HAS-BLED 3; very old Consider agent / dose with the lowest incidence of bleeding Apixa, Edox. Dabi 110 Specific patient characteristics Previous GI bleeding or high-risk or GI upset Concomitant CYP inhib. High risk of ischemic stroke, low bleeding risk Previous stroke (secondary prevention) CAD, previous MI or highrisk for ACS/MI Consider agents with the lowest reported incidence of GI bleed Consider agents with no/little metabolism via CYP system Consider agent / dose with the best reduction of ischemic stroke Consider best investigated agent or greatest reduction of 2 0 stroke Consider agent with a positive effect in ACS Apix, LD Edox Dabi, Edox Dabigatran 150 Riva, Apix, HD Edox Riva, HD Edox Patient preference Consider once daily formulation Riva, Edox Savelieva I and Camm AJ. Clinical Cardiology 2013 Gonzalez-Quesada CJ and Giugliano RP. JTT 2014 (in press) * All of these pointers are debatable