Role of NOACs in AF Management. From Evidence to Real World Data Focus on Cardioversion

Transcription

1 Role of NOACs in AF Management. From Evidence to Real World Data Focus on Cardioversion John Rickard MD, MPH Staff Electrophysiologist Cleveland Clinic

2 Agenda NOACs: Update on Real World Data NOAC reversal: DabigatranàPraxbind NOACs and Cardioversion

3 Introduc>on Afib is associated with increased risk of stroke. Warfarin 67% reduction in risk of stroke 26% reduction in total mortality

4 Limitations of Vitamin K Antagonist Unpredictable response Narrow therapeutic window (INR range 2-3) Routine coagulation monitoring Slow onset/offset of action VKA therapy has several limitations that make it difficult to use in practice Frequent dose adjustments Numerous food-drug interactions Numerous drug-drug interactions TTR <70%

5 New Oral An>coagulants: 50 years later NOACs are increasingly used in AF patients Dabigatran Rivaroxaban Apixaban Edoxaban Target Factor IIa Factor Xa Factor Xa Factor Xa Dosing twice daily once daily twice daily once daily Clinical Trial RELY ROCKET-AF ARISTOTLE ENGAGE

6 Clinical Trials vs. Registries Pivotal controlled trials IDEAL setting Practice-based evidence USUAL daily setting Gold Standard Highly controlled environment Comorbidities often excluded selected patient population Good compliance Less controlled environment Represents the real world Not on selected patient population Compliance may be poor Confirms effectiveness and safety in wider patient sample Real-world data can confirm whether the results of an RCT are observed in everyday clinical practice

7 1. Connolly et al. NEJM 2009; 2. Connolly et al. NEJM 2010; 3. Pradaxa : EU SPC, 2015; 4. Graham et al. Circulation 2014l; 5. Connolly S et al. NEJM 2014 Independent FDA study of Medicare patients mirrors the favourable benefit risk profile of dabigatran from RE-LY RE-LY 1 4 Warfarin D150 BID EVENT RATE (% PER YEAR) HR: 0.76 P=0.04 RR: 0.41 P<0.001 RR: 0.94 P=0.41 RR: 1.48 P=0.001 RR: 1.27 P=0.12 RR: 0.88 P=0.05 ISCHAEMIC STROKE ICH MAJOR BLEEDING GI BLEEDING MI MORTALITY MEDICARE *5 Warfarin D150 & D75 BID combined INCIDENCE RATE PER 100 PERSON-YEARS HR: 0.80 P=0.02 HR: 0.34 P<0.001 HR: 0.97 P=0.50 HR: 1.28 P<0.001 HR: 0.92 P=0.29 HR: 0.86 P=

8 Compara>ve Effec>veness and Safety of NOACs and warfarin in pa>ents with AF: propensity weighted na>onwide cohort study Major bleeding Adjusted HR (95% CI) vs warfarin N=61,678 All-cause mortality Adjusted HR (95% CI) vs warfarin Weighted event rate (1 year follow-up)* HR 0.58 ( ) HR 1.06 ( ) HR 0.61 ( ) Weighted event rate (1 year follow-up)* HR 0.63 ( ) HR 0.92 ( ) HR 0.65 ( ) 0 Dabigatran Apixaban Rivaroxaban Warfarin D A R W Dabigatran and apixaban were associated with a statistically significantly lower risk of any bleeding, major bleeding, and death compared with rivaroxaban or warfarin Only standard doses of NOACs were compared in this study. 0 Dabigatran Apixaban Rivaroxaban Warfarin D A R W Larsen et al. BMJ 2016;353:i3189

9 An independent FDA study of > Medicare pa>ents compared Dabigatran 150 mg BID with Rivaroxaban 20 mg OD Graham et al. JAMA Intern Med 2016

10 If warfarin was fighting the battle against the newer agents Lower efficacy Higher bleeding Need for bridging Slow onset and offset Need for INR monitoring Significant food and drug interactions MAY NEVER HAVE BEEN APPROVED BY A REGULATORY AGENCY

11 Pa>ent s Main Concern What if I bleed, have an accident or need urgent surgery? Role of Reversal Agents

12 Schiele et al. Blood 2013; Glund et al. Thromb Haemost 2015 Idarucizumab Reversal agent for Dabigatran Humanized Fab: binds free dabigatran and dabigatran bound to thrombin Binding affinity for dabigatran ~350 higher than dabigatran for thrombin No known off-target effects; does not reverse heparins or any other anticoagulants IV administration, immediate onset of action Short half-life No intrinsic procoagulant or anticoagulant activity

13 Idarucizumab When Do You Need it? Emergency surgery or urgent intervention Open fractures Vascular Surgeries Abdominal surgeries Life-threatening or uncontrolled bleeding Intracranial Hemorrhage GI bleeding

14 Andexanet Alfa

15 Andexanet Alfa

16 Introduc>on Cardioversion for AF First performed in the mid-1950s Increased risk of thromboembolic complications*. 5 7% without adequate anticoagulation Clot/ Atrial Stunning 0.8% by adequate anticoagulation # Guidelines recommend anticoagulation before (3 weeks) and after cardioversion (4 weeks). The Early route TEE as an alternative to 3 week OAC pre DCC Does not Preclude post DCC anticoagualtion *Reneskov et al 1967 Br H J # Bjerkelund et al, AJC 1969)

17 Recommenda>ons for an>coagula>on for CV ESC/EHRA Focused Update 2010

18 NOACs and Cardioversion Dabigatran Rivaroxaban Apixaban Edoxaban Post HOC Analysis Prospective RCT RELY ROCKET-AF ARISTOTLE ENGAGE X-Vert EMANATE ENSURE-AF Questions: Efficacy Safety

19 Thromboembolic Complica>ons During Peri-Cardioversion *** composite of TE and death in CV/ablation Retrospective analysis DCC was a not a predefined variable Small number of patients

20 X-VERT: Rivaroxaban vs. VKA First Prospec3ve Randomized Clinical Trial 1504 pts Cappato R et al, Eur Heart J 2014;35:

21 X-VERT Primary Efficacy & Safety Outcome Efficacy: Composite of stroke, TIA, peripheral embolism, MI,CV death Safety: Major bleeding Cappato R et al, Eur Heart J 2014;35:

22 ENSURE-AF: Primary Efficacy Outcome Edoxaban vs Enoxaparin/Warfarin in Subjects Undergoing Cardioversion of Atrial Fibrillation Composite of : Stroke, SEE, MI, and CV Death

23 EMANATE : Apixaban vs. Warfarin

24 Conclusion Usage of the NOACs is expected to increase as clinicians gain more experience and reassurance with data from the real world studies which are generally consistent with that from clinical trials. The availability of antidote to certain drugs will add more reassurance and acceptance from physicians and patients to use newer anticoagulant therapy. All 4 currently available NOACS appear to be as effective and safe as warfarin in patients with NVAF undergoing DCC.

25 What we do Cardioversion in Pa>ents treated with NOACS In patients with AF of >48 h duration, OACs should be given for 3 weeks before cardioversion It is essential to ask patients about compliance over the past weeks. Document in medical records. If compliance can reliably be confirmed, cardioversion seems acceptably safe If doubts exist about compliance, consider prior TEE Continuous oral anticoagulation for 4 weeks after cardioversion is also mandatory Anticoagulation beyond 4 weeks as clinically indicated (CHADS2VASC2 score)

26 Thank You

27 MAKING A CHOICE Largest RRR of ischemic stroke: dabigatran Largest renal elimination: dabigatran Once daily dosing: Rivaroxaban, edoxaban Most significant reduction in major bleeding: Apixaban Least expensive: Warfarin