Novel Anticoagulants : Bleeding and Bridging

Transcription

1 Novel Anticoagulants : Bleeding and Bridging Michael D. Ezekowitz, MBChB, DPhil, FACC, FAHA, FRCP, MA Professor, Thomas Jefferson Medical School Director Atrial Fibrillation Research and Education The Cardiovascular Research Foundation NY Lankenau, Bryn Mawr and Paoli Hospitals

2 Disclosures Consultant: ARYx Therapeutics, AstraZeneca, Boehringer Ingelheim, BMS, Daiichi Sankyo, Medtronic, Portola, sanofi-aventis, Merck, Pfizer, J&J, Bayer Coherex Gilead, St Jude Medical Grants: ARYx Therapeutics, Boehringer Ingelheim, Daiichi Sankyo, Portola, sanofi-aventis Trials : Co-PI Petro and RELY: Executive committee Engage AF: Co-PI Explore Xa : Co-PI X-Vert

3 SCOPE OF PRESENTATION Cardioversion AF ablation Interruption Long term Data

4 Periprocedural Anticoagulation Options Uninterrupted Hold evening and morning dose before procedure Hold for 24 hours Hold from between 12 and 48 hours If renal function impared or critical organ involved 2 to 5 days Providência R, Albenque JP, Combes S, et al. Heart E-published July

5 Peri-procedural clinical outcomes subgroup analysis Healey... Ezekowitz Circ 2012 Disclaimer: Dabigatran etexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details

6 Peri-procedural outcome Analysis Aim: To assess outcomes in patients undergoing surgery/invasive procedure during RE-LY Approach: Bleeding and thromboembolic events assessed Primary analysis limited to the first surgery/procedure per patient Peri-procedural period: 7 days before to day 30 post-procedure 4591 patients included in the subanalysis Even distribution of patients and surgery types across treatment arms Common surgeries/procedures included dental, pacemaker/icd, cataract removal (all ~10%) ICD = implantable cardioverter defibrillator; Healey JS et al. Circulation 2012 doi: / CIRCULATIONAHA

7 Periprocedural anticoagulation management Healey JS et al. Circulation 2012 doi: / CIRCULATIONAHA Warfarin managed according to local practice Dabigatran withheld prior to procedure: Dec 2005 Aug 2008: 24 hours for all patients Aug 2008 Mar 2009: 2 5 days (based on CrCl) for high-risk procedures Dabigatran restarted post-procedure after achieving adequate haemostasis Time from last anticoagulant dose to procedure: Dabigatran: 49 (35 85) hours Warfarin: 114 (87 144) hours Peri-procedural bridging with heparin used in 15.3% (D110), 17.0% (D150), and 28.5% (warfarin) of patients (P<0.001) CrCl = creatinine clearance; D110 = dabigatran 110 mg twice daily; D150 = dabigatran 150 twice daily

8 Peri-procedural bleeding outcomes No significant difference in risk of bleeding for either dose vs warfarin % patients D110 vs warfarin D150 vs warfarin D110 n=1487 D150 n=1546 Warfarin n=1558 RR (95% CI) P value RR (95% CI) P value Major bleeding ( ) ( ) 0.58 Fatal bleeding ( ) ( ) 0.99 Re-operation ( ) ( ) 0.32 RBC transfusion ( ) ( ) 0.42 Minor bleeding ( ) ( ) 0.24 D110 = dabigatran 110 mg twice daily; D150 = dabigatran 150 mg twice daily; RBC = red blood cell; RR = relative risk Healey JS et al. Circulation 2012 doi: / CIRCULATIONAHA

9 Peri-procedural thromboembolic events Low incidence of thromboembolic events across all treatment groups % patients D110 vs warfarin D150 vs warfarin D110 n=1487 D150 n=1546 Warfarin n=1558 RR (95% CI) P value RR (95% CI) P value Ischaemic stroke or SE ( ) ( ) 0.99 Stroke (all cause) ( ) ( ) 0.48 SE ( ) CV death ( ) ( ) ( ) CV cardiovascular; D110 = dabigatran 110 mg twice daily; D150 = dabigatran 150 mg twice daily; RR = relative risk; SE =systemic embolism Healey JS et al. Circulation 2012 doi: / CIRCULATIONAHA

10 Healey JS et al. Circulation 2012 doi: / CIRCULATIONAHA Peri-procedural outcomes subgroup analysis: major bleeding by timing of anticoagulation interruption Significantly lower rate of bleeding with dabigatran (both doses) for patients undergoing surgery within 48 hours of anticoagulation interruption <24 hrs 2.8 (5/180) % patients (n/n) D110 vs warfarin D150 vs warfarin D110 D150 Warfarin 6.8 (13/192) 15.4 (12/78) RR (95% CI) 0.18 ( ) P value RR (95% CI) < ( ) P value hrs 3.2 (16/505) 3.3 (17/520) 9.0 (8/89) 0.35 ( ) ( ) hrs 4.5 (14/310) 4.5 (14/309) 5.7 (7/122) 0.79 ( ) ( ) 0.60 >72 hrs 4.7 (21/451) 6.2 (29/468) 3.6 (45/1237) 1.28 ( ) ( ) P-Trend D110 = dabigatran 110 mg twice daily; D150 = dabigatran 150 mg twice daily; RR = relative risk

11 Rocket :Discontinuing Rivaroxiban vs warfarin (Patel et al JACC 2013 ) 26 AIM : Post hoc Analysis.Strokes /SE within 30days of discontinuing anticoagulation of >3 days Results :Strokes / SE Rivaroxiban VS warfarin (6.2 vs 5.05 ) P=0.62. Major Bleeds Similar Warfarin vs Rivaroxiban : 16.7 vs 17.2

12 Summary Elective procedure for patients receiving Rivaroxiban, Apixaban, Dabigatran ( if Cr Cl > 50 ) and Endoxiban stop 24 hrs. before procedure For Dabigatran only if Cr Cl between 30 and 49 stop 2 to 5 days procedure If critical organ then use judgement Restart as soon as possible after procedure 27

13 Background: FDA Mini-Sentinel Data 1 GI major bleeding Intracranial bleeding No. of events/ No. of patients Dabigatran FDA Postmarketing Surveillance * Incidence (No. of events per 100,000 days at risk) No. of events/ No. of patients Warfarin Incidence (No. of events per 100,000 days at risk) 16/10, /43, /10, /43, *New users of dabigatran and warfarin from the Mini-Sentinel distributed database, October 2010 through December Events were assessed during drug exposure, from inpatient or emergency department settings only. Analysis with required diagnosis of atrial fibrillation. FDA`s conclusion: Bleeding rates associated with new use of dabigatran do not appear to be higher than bleeding rates associated with new use of warfarin FDA = Food and Drug Administration; GI = gastrointestinal. 1. Southworth MR, Reichman ME, Unger EF. NEJM 2013;14:

14 Background Patients completing RELY and taking Dabigatran were eligible to continue in RELY-ABLE, the Long-term Multi-center Extension of Dabigatran Treatment in Patients with Atrial Fibrillation, providing further long term follow up in 5851 patients 1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. NEJM 2009;361: Connolly SJ, Wallentin L, Ezekowitz MD, et al. Circulation 2013;128:

15 Patient Flow Through RE-LY and RELY-ABLE Dabigatran 150 mg, n Dabigatran 110 mg, n Start of RE-LY Randomized in RE-LY Completed RE-LY (alive and receiving study drug) Enrolled in RELY-ABLE ab Receiving study drug at RELY-ABLE 28-month visit Continued in RELY-ABLE beyond 28-month visit Remained in RELY-ABLE for 6 years (maximum of 6.7 years) a Patients randomized to warfarin in RE-LY were not eligible for RELY-ABLE ; b Excluding 40 patients who did not receive study drug or for whom there were serious protocol violations at their center. Median follow- up 4.6 years 6.7 years (maximum follow-up) 30

16 Proportion Remaining on Study Medication (%) Patients Remaining on Dabigatran During Follow-up in RE-LY and RELY-ABLE Dabigatran 110 mg Dabigatran 150 mg Time from Randomization (Years) No at risk: D D Proportion of patients (in %) not permanently discontinuing study medication during the 6 years of combined RE-LY and RELY-ABLE follow-up Median follow-up 4.6 years; Maximum follow-up 6.7 years D110 = Dabigatran 110 mg; D150 = Dabigatran 150 mg. Ezekowitz et al AHA

17 Cumulative Risk Stroke or Systemic Embolism Dabigatran 110 mg Dabigatran 150 mg Time from Randomization (Years) No at risk: D D Annual rate of stroke or systemic embolization: Dabigatran 150 mg, 1.25% per year; 110 mg, 1.54% per year HR 0.81 (95% CI 0.68, 0.96) D110 = Dabigatran 110 mg; D150 = Dabigatran 150 mg; HR: hazard ratio; CI = confidence interval.ezekowitz et al AHA

18 Cumulative Risk Hemorrhagic Stroke Dabigatran 110 mg Dabigatran 150 mg Time from Randomization (Years) No at risk: D D Annual rate hemorrhagic stroke: Dabigatran 150 mg, 0.11% per year; 110 mg, 0.13% per year HR 0.91 (95% CI 0.51, 1.62) D110 = Dabigatran 110 mg; D150 = Dabigatran 150 mg; HR: hazard ratio; CI = confidence interval.ezekowitz et al AHA

19 Cumulative Risk All-cause Mortality Dabigatran 110 mg Dabigatran 150 mg Time from Randomization (Years) No at risk: D D Annual mortality rate: Dabigatran 150 mg, 3.43% per year; 110 mg, 3.55% per year HR 0.97 (95% CI 0.87, 1.08) D110 = Dabigatran 110 mg; D150 = Dabigatran 150 mg; HR: hazard ratio; CI = confidence interval. Ezekowitz et al AHA

20 Embolic and Thrombotic Outcomes and Hospitalizations Dabigatran 150 mg n (%/year) Dabigatran 110 mg n (%/year) Hazard Ratio (Dabigatran 150 mg versus 110 mg) 95% CI Stroke or systemic embolism 243 (1.25) 296 (1.54) , 0.96 All stroke 217 (1.12) 270 (1.41) , 0.95 Ischemic or type uncertain 199 (1.03) 248 (1.29) , 0.95 Hemorrhagic 22 (0.11) 24 (0.13) , 1.62 Myocardial infarction 134 (0.69) 138 (0.72) , 1.22 Cardiovascular hospitalization 1484 (7.66) 1401 (7.30) , 1.14 Any hospitalization 3133 (16.18) 3045 (15.87) , 1.10 Total mortality 665 (3.43) 681 (3.55) , 1.08 Vascular mortality 397 (2.05) 407 (2.12) , 1.11 n = number of events, %/year = rate per 100 patient years of follow-up. Ezekowitz et al AHA

21 Cumulative Risk Major Bleeding Dabigatran 110 mg Dabigatran 150 mg Time from Randomization (Years) No at risk: D D Annual rate of major bleeding: Dabigatran 150 mg, 3.34% per year; 110 mg, 2.76% per year HR 1.22 (95% CI 1.08, 1.37) D110 = Dabigatran 110 mg; D150 = Dabigatran 150 mg; HR: hazard ratio; CI = confidence interval. Ezekowitz AHA

22 Cumulative Risk Major Gastrointestinal Bleeding Dabigatran 110 mg Dabigatran 150 mg Time from Randomization (Years) No at risk: D D Annual rate of major GI bleeding: Dabigatran 150 mg, 1.50% per year; 110 mg, 1.26% per year HR 1.19 (95% CI 1.01, 1.42) D110 = Dabigatran 110 mg; D150 = Dabigatran 150 mg; GI = gastrointestinal; HR: hazard ratio; CI = confidence interval.ezekowitz 2013 AHA 37

23 Bleeding Outcomes [ Dabigatran 150 mg n (%/year) Dabigatran 110 mg n (%/year) Hazard Ratio (Dabigatran 150 mg versus 110 mg) 95% CI Major Bleeding 646 (3.34) 529 (2.76) , 1.37 Life-threatening 300 (1.55) 261 ( 1.36) , 1.35 Gastrointestinal 291 (1.50) 242 (1.26) , 1.42 Intracranial 62 (0.32) 45 (0.23) , 2.01 Extra-cranial 589 (3.04) 495 (2.58) , 1.33 Fatal 45 (0.23) 42 (0.22) , 1.62 Minor Bleeding 2127 (10.98) 1884 (9.82) , 1.22 n = number of events, %/year = rate per 100 patient years of follow-up.ezekowitz AHA

24 Major bleeding Rate (% per year) D110 D150 WAR Dabigatran110 vs. warfarin P (inter) Dabigatran150 vs. warfarin P (inter) Age < Age Age CCLEAR CCLEAR CLEAR > DAB better WAR better DAB better WAR better 39

25 Major bleeding D110 vs. WARFARIN D150 vs. WARFARIN CHADS2 0-1 Annual rate, % D110 D150 WARFARIN P = 0.4 P = Dabigatran better Warfarin better Dabigatran better Warfarin better 40

26 ARISTOTLE: Benefits of Apixaban vs. Warfarin Were Consistent Regardless of Age Apixaban (%/year) Warfarin (%/year) Interaction P value All bleeding (n=18,140) 0.94* <65 65 to < Intracranial bleeding (n=18,140) 0.20* <65 65 to < Fatal bleeding or fatal hemorrhagic stroke (n=18,140) 0.23* <65 65 to < Net benefit (n=18201) 0.18* <65 65 to < APIXABAN BETTER WARFARIN BETTER * Cox proportional hazards model was fit using restricted cubic splines for age to allow non-linear relationship Halvorsen S, Wallentin L, Yang H, et al. J Am Coll Cardiol. 2013;61(10_S). E-published 12 March Doi: /S (13)

27 NEW DAWN Millions of patients world wide with AF will benefit from significant stroke reduction Challenge :Translating Clinical Trials into practice must minimize temporary and permanent discontinuation