Νεότερα Αντιπηκτικά: Προοπτικζσ

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1 Νεότερα Αντιπηκτικά: Προοπτικζσ Σταφροσ Β. Κωνςταντινίδησ, MD, PhD, FESC Κακθγθτισ Καρδιολογίασ Δθμοκρίτειο Πανεπιςτιμιο Θράκθσ Professor, Clinical Trials in Antithrombotic Therapy Center for Thrombosis und Hemostasis, University of Mainz, Germany

2 Disclosures Advisory boards / Lecture fees (moderate): Boehringer Ingelheim Bayer HealthCare Pfizer Bristol-Myers Squibb Daiichi Sankyo

3 Νεότερα Αντιπηκτικά Κολπικι Μαρμαρυγι: Το τζλοσ των μεγάλων μελετών και τα πρώτα real world data Συνδυαςμόσ με Aντιαιμοπεταλιακά Aιμορραγικζσ Eπιπλοκζσ Φλεβικι Θρομβοεμβολικι Nόςοσ: Η νζα ζνδειξθ

4 Meta-analysis: NOACs in AF 4 randomized trials patients Rx to a NOAC, to placebo Primary analysis was on high dosages (dabigatran 150mg, rivaroxaban 20 mg, apixaban 5 mg, edoxaban 60 mg) (1) Primary outcome: Stroke or systemic embolic event Stroke or systemic embolism: RR 0.81 ( ) CT Ruff. Lamcet 2014;383:

5 Meta-analysis: NOACs in AF 4 randomized trials patients Rx to a NOAC, to placebo Primary analysis was on high dosages (dabigatran 150mg, rivaroxaban 20 mg, apixaban 5 mg, edoxaban 60 mg) (2) Secondary outcomes Hemorrhagic stroke: RR 0.49 ( ) GI bleeding: RR 1.25 ( ) CT Ruff. Lamcet 2014;383:

6 Meta-analysis: NOACs in AF 4 randomized trials patients Rx to a NOAC, to placebo Primary analysis was on high dosages (dabigatran 150mg, rivaroxaban 20 mg, apixaban 5 mg, edoxaban 60 mg) (3) Major bleeding (4) All-cause mortality: RR 0.90 ( ) CT Ruff. Lamcet 2014;383:

7 European focused recommendations AF (2012) Recommendation Class Level When adjusted-dose VKA cannot be used properly, one of the NOACs is recommended. I B When OAC is recommended, one of the NOACs rather than VKA should be considered for most patients with non-valvular AF based on the net clinical benefit. When patients refuse the use of any OAC, antiplatelet therapy should be considered, using aspirin mg plus clopidogrel 75 mg daily (where there is a low risk of bleeding) or less effectively aspirin mg daily. IIa IIa A B

8 Meta-analysis: Lower-dose NOACs in AF? 4 randomized trials patients Rx to a NOAC, to placebo Primary analysis was on high dosages (dabigatran 150mg, rivaroxaban 20 mg, apixaban 5 mg, edoxaban 60 mg) (3) Major bleeding (4) All-cause mortality: RR 0.90 ( ) (5) Low dosages (dabi 110, edo 30): non-inferior to VKA for primary EP, superior for major bleeding - RR 0.65 ( ), but higher rel. risk of ischemic stroke 1.28 ( ) CT Ruff. Lamcet 2014;383:

9 Use patient s hemorrhagic risk score appropriately! 182,678 patients, 260,000 patient-years 47% received warfarin at some stage Net clinical benefit: annual reduction of thromboembolic events (annual reduction of intracranial hemorrhage) x 1.5 The higher the CHA 2 DS 2 -VASc and the HAS-BLED score, the higher the benefit!! Very few patients did not benefit, mostly those with CHA 2 DS 2 -VASc of 0 L Friberg. Swedish Registry. Circulation 2012;125:

10 Choice of anticoagulant independent of HASBLED? Analysis from ARISTOTLE: Patients who received apixaban had lower rates of major bleeding than did those who received warfarin, with no difference across all score categories (CHADS2, p for interaction=0 4018; CHA2DS2VASc, p for interaction=0 2059; HAS-BLED, p for interaction=0 7127). The relative risk reduction in intracranial bleeding tended to be greater in patients with HAS-BLED scores of 3 or higher (hazard ratio *HR+ 0 22, 95% CI ) than in those with HAS-BLED scores of 0 1 (HR 0 66, ; p for interaction=0 0604). RD Lopes. Lancet 2012;380:

11 Post-marketing data: dabigatran patients in RE-LY and RELY-ABLE Event Dabigatran 110 mg Dabigatran 150 mg Randomized to dabigatran in RE-LY Completed RE-LY alive, still receiving dabigatran 4492 (75%) 4519 (74%) Followed at site participating in RELY-ABLE 3395 (76%) 3397 (75%) Patient enrolled in RELY-ABLE * 2914 (86%) 2937 (87%) Completed RELY-ABLE, still receiving dabigatran Continued in RELY-ABLE beyond month 28 visit 2511 (86%) 2508 (85%) 1082 (44%) 1104 (44%) *Not all dabigatran patients continued into RELY-ABLE. Population can not be considered as randomized any more. Treatment is randomized, population is not SJ Connolly. Circulation 2013;128:

12 Major bleeding: RELY-ABLE SJ Connolly. Circulation 2013;128:

13 Bleeding events: RELY-ABLE Event D150 (%/yr) D110 (%/yr) RELY-ABLE only HR 95% CI Major bleeding Life-threatening GI Intracranial Extracranial Fatal Minor bleeding patients followed for mean of 2.3 years D150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratio SJ Connolly. Circulation 2013;128:

14 Intracranial bleeding: RE-LY + RELY-ABLE SJ Connolly. Circulation 2013;128:

15 FDA Mini-Sentinel Database, Oct 2010 Dec 2011 Published in the N Engl J Med March 13, 2013

16 FDA Mini-Sentinel Database, Oct 2010 Dec 2011 Published in the N Engl J Med March 13, 2013

17 Νεότερα Αντιπηκτικά Κολπικι Μαρμαρυγι: Το τζλοσ των μεγάλων μελετών και τα πρώτα real world data Συνδυαςμόσ με αντιαιμοπεταλιακά αιμορραγικζσ επιπλοκζσ o Σε ςτακερι ςτεφανιαία νόςο o Σε οξζα ςτεφανιαία ςφνδρομα o Τι κάνουμε ςε περίπτωςθ αιμορραγίασ; Φλεβικι κρομβοεμβολικι νόςοσ: Η νζα ζνδειξθ

18 Concomitant antiplatelet therapy in RE-LY : rationale In RE-LY: 38.4% of patients received concomitant ASA or clopidogrel at some time during the trial Use of other antiplatelet agents was very rare Antiplatelets not necessarily taken continuously At any one time only 27% were on concomitant antiplatelets Use of antiplatelet agents was not randomized or stratified Post-hoc analysis: Compare efficacy and safety of dabigatran vs warfarin in relation to concomitant use of antiplatelet therapy (ASA and/or clopidogrel) 6,140 patients (33.9%) received a single antiplatelet agent 812 patients (4.5%) received dual antiplatelet therapy 1. Douketis JD et al. Thromb Res 2011;127:513 7; 2. Johnson SG et al. Chest 2007;131:1500 7; 3. Connolly SJ et al. N Engl J Med 2009; 361: ; 4. Dans AL et al. Circulation 2013;127:634 40

19 Concomitant antiplatelet therapy in RE-LY : baseline characteristics Concomitant antiplatelet therapy No concomitant antiplatelet therapy D110 (n=2322) D150 (n=2304) Warfarin (n=2326) D110 (n=3693) D150 (n=3772) Warfarin (n=3696) Age, yrs Male, % Prior hypertension, % Prior diabetes, % Prior myocardial infarction, % Prior coronary artery disease, % Prior congestive heart failure, % Prior stroke, % CHADS 2 score, % Prior renal disease, % Type of AF, % Persistent Paroxysmal Permanent Duration of antiplatelet use, % of study duration (SD) 67.3 (42.8) 65.2 (43.7) 65.0 (43.8) D110 = dabigatran 110 mg twice daily; D150 = dabigatran 150 mg twice daily; SD = standard deviation AL Dans et al. Circulation 2013;127:634 40

20 Concomitant antiplatelet therapy in RE-LY : time-dependent analysis (1) Rate (%/year) AP No AP HR (95% CI)* Major bleeding D ( ) D ( ) Warfarin ( ) Minor bleeding D ( ) D ( ) Warfarin ( ) Extracranial bleeding D ( ) D ( ) Warfarin ( ) Intracranial bleeding D ( ) D ( ) Warfarin ( ) Favours AP Favours no AP 6,140 patients (33.9%) received a single antiplatelet agent 812 patients (4.5%) received dual antiplatelet therapy 4.0 AL Dans et al. Circulation 2013;127:634 40

21 Concomitant antiplatelet therapy in RE-LY : time-dependent analysis (2); number of antiplatelets Event rate (%/yr) HR (95% CI)* 2 APs 1 AP 0 AP 1 AP vs 0 AP 2 APs vs 0 AP Major bleeding D ( ) 2.39 ( ) D ( ) 2.16 ( ) Warfarin ( ) 2.34 ( ) Minor bleeding D ( ) 1.24 ( ) D ( ) 1.85 ( ) Warfarin ( ) 1.42 ( ) Extracranial bleeding D ( ) 2.31 ( ) D ( ) 2.32 ( ) Warfarin ( ) 2.31 ( ) Intracranial bleeding D ( ) 3.25 ( ) D ( ) 0.00 ( ) Warfarin ( ) 2.02 ( ) 6,140 patients (33.9%) received a single antiplatelet agent 812 patients (4.5%) received dual antiplatelet therapy AL Dans et al. Circulation 2013;127:634 40

22 Comparable data with VKA in WOEST trial Any bleeding Death, MI, stroke, TVR, stent thrombosis WJ Dewilde. Lancet 2013;381:

23 Concomitant antiplatelet therapy in RE-LY : Εditorial Decreasing the dose to 110 mg BID for the duration of antiplatelet use, especially in patients at high bleeding risk, seems reasonable. As both doses were still associated with a lower risk of ICH, the 150 mg BID dose is also a defendable option in patients with a relatively low bleeding risk and a high CHA 2 DS 2 -VASc score. BID = twice daily; ICH = intracranial haemorrhage Sinnaeve PR & Van de Werf F. Circulation 2013;127:566 8

24 AF and CAD in the 2012 Guideline Update Given the non-significant but small numerical increase in MI events with D versus warfarin, the concerned clinician may consider the use of a VKA or another NOAC There is little evidence to support this, as the relative effects of D vs VKA on myocardial ischemia were consistent in patients with or without a baseline history of MI or coronary artery disease. Patients with AF and stable vascular disease, can be managed with OAC alone, whether VKA or, probably, NOAC. There is no need for concomitant aspirin, which would increase the risk of serious hemorrhage including ICH.

25 Overuse of aspirin in the ORBIT-AF registry BA Steinberg. Circulation 2013;128:

26 Overuse of aspirin in the ORBIT-AF registry Unadjusted, 6-month major bleeding rates among high-risk subgroups (absolute numbers of events per group noted above bars) Adjusted major bleeding for OAC+ASA: RR 1.53 ( ) Hx for bleeding for OAC+ASA: RR 1.52 ( ) BA Steinberg. Circulation 2013;128:

27 Νεότερα Αντιπηκτικά Κολπικι Μαρμαρυγι: Το τζλοσ των μεγάλων μελετών και τα πρώτα real world data Συνδυαςμόσ με αντιαιμοπεταλιακά αιμορραγικζσ επιπλοκζσ o Σε ςτακερι ςτεφανιαία νόςο o Σε οξζα ςτεφανιαία ςφνδρομα o Τι κάνουμε ςε περίπτωςθ αιμορραγίασ;

28 And what about AF patients who develop an ACS? Lancet 2013; 381:

29 Bleeding and outcome in WOEST trial Any bleeding Death, MI, stroke, TVR, stent thrombosis WJ Dewilde. Lancet 2013;381:

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31 10% of patients undergoing PCI have concomitant AF Run in period* 0-3 days post-pci (stratified randomization)** Complex patients : initiation of DAT or TAT with Dabigatran 150 or 110 mg BID + P2Y12 inhibitor + ASA vs. TAT with Warfarin (INR ) + P2Y12 inhibitor + ASA Non-Complex patients : initiation of DAT with Dabigatran 150 or 110 mg BID + P2Y12 inhibitor (with d/c of ASA) vs. TAT with Warfarin (INR ) + P2Y12 inhibitor + ASA R Worldwide Event Driven Trial Paroxysmal, persistent or permanent AF (PCI with stenting [BMS or DES] elective or ACS) PRIMARY END POINT T1 DABIGATRAN 110 mg bid DAT vs. WARFARIN TAT Month 1 post-pci Complex patients: Patients that initiated TAT must discontinue Dabigatran 150mg BID + P2Y12 inhibitor Dabigatran 110mg BID + P2Y12 inhibitor TE (Death + MI + SSE) post-stenting for non-inferiority CRB (ISTH major) post-stenting for superiority Warfarin (INR ) + P2Y12 inhibitor + ASA 3M 6M 9M 12M 15M 18/24/30M or EOT DABIGATRAN n = 2818 patients per arm ASA and 150 initiate mg DAT bid regimen DAT in vs. WARFARIN TAT (total = 8454 patients) D110/D150 arms TE (Death + MI + SSE) post-stenting for non-inferiority Non-Complex patients: Maintenance of DAT regimen in D110/D150 arms CRB (ISTH major) post-stenting for non-inferiority TAT: triple antithrombotic therapy DAT: dual antithrombotic therapy * Run in: pre-assessment of the patient complex vs. non-complex characteristics (bridging therapy during the procedure [LMWH, Bivalirudin, UFH, etc.] at the discretion of practicing physician) ** Randomization can be done immediately after PCI and up to 72 hours post-pci; study drug can be started within 12 hours (complex patients) after sheath removal and hemostasis is assured and up to 72 hours post-pci Complex criteria: patient s clinical presentation (ACS vs. non-acs) and lesion/procedure characteristics (e.g. left main, etc.) DAPT Study Complexity Criteria Initiation of DAT or TAT in Complex patients randomized to receive dabigatran is left at the discretion of the practicing physician ASA will be discontinued in the warfarin arm. BMS: Discontinuation of ASA at month 1 ; DES: discontinuation of ASA at month 3 Follow up visits at month 1, 3, 6, 9, 12, 15 and 18, 24 and 30 post-randomization P2Y12 inhibitor (either Clopidogrel or Ticagrelor). The P2Y12 inhibitor can be discontinued after month 12 of follow up at the discretion of the physician 1 EP

32 Νεότερα Αντιπηκτικά Κολπικι Μαρμαρυγι: Το τζλοσ των μεγάλων μελετών και τα πρώτα real world data Συνδυαςμόσ με αντιαιμοπεταλιακά αιμορραγικζσ επιπλοκζσ o Σε ςτακερι ςτεφανιαία νόςο o Σε οξζα ςτεφανιαία ςφνδρομα o Τι κάνουμε ςε περίπτωςθ αιμορραγίασ;

33 For practical help: EHRA

34 Αναςτροφή τησ δράςησ νζων αντιπηκτικϊν και αντιμετϊπιςη αιμορραγίασ Αμορραγία υπό νζα αντιπηκτικά (;) Ήπια Μζτρια-ςοβαρή Απειλητική Καθυςτζρηςη τησ επόμενησ δόςησ ή διακοπή τησ θεραπείασ Συμπτωματική αντιμετϊπιςη Μηχανική ςυμπίεςη Αναπλήρωςη υγρϊν, υποςτήριξη κυκλοφορίασ Μετάγγιςη αίματοσ, FFP Χειρουργική αιμόςταςη PCC U/kg Τρανεξαμικό οξφ mg/kg i.v.* Ενεργόσ άνθρακασ* (αν η τελευταία λήψη <2 ϊρεσ πριν) PCC U/kg Τρανεξαμικό οξφ mg/kg i.v.* Χρήγηςη rfvlla ή FEIBA* Αιμοκάθαρςη* Έλεγχοσ με aptt, Hemoclot Έλεγχοσ με PT, F Xa axtivity

35 Αναςτροφή τησ δράςησ νζων αντιπηκτικϊν και αντιμετϊπιςη αιμορραγίασ: RELY data A Majeed. Circulation 2013;128:

36 Αναςτροφή τησ δράςησ νζων αντιπηκτικϊν και αντιμετϊπιςη αιμορραγίασ: ROCKET-AF data JP Piccini. Eur Heart J 2014;Epub ahead of print

37 Νεότερα Αντιπηκτικά Κολπικι Μαρμαρυγι: Το τζλοσ των μεγάλων μελετών και τα πρώτα real world data Συνδυαςμόσ με αντιαιμοπεταλιακά αιμορραγικζσ επιπλοκζσ Φλεβικι Θρομβοεμβολικι νόςοσ: Η νζα ζνδειξθ

38 NOACs in VTE: Comparison to standard treatment Dabigatran Rivaroxaban Apixaban Edoxaban Study name RE-COVER I+II EINSTEIN DVT+PE AMPLIFY HOKUSAI-VTE Author Schulman, Fatal or symptomatic recurrent VTE Major bleeding Clinically relevant bleeding Bauersachs, 2010; Bueller, 2012 Agnelli, 2013 Bueller, 2013 Non-inferior Non-inferior Non-inferior Non-inferior RRR 40-50% RRR 51% RRR 69% RRR 16% RRR 40-50% RRR 7% RRR 56% RRR 19%

39 Meta-analysis: NOACs in VTE - emphasis on safety 5 randomized trials patients randomized T van der Hulle. J Thromb Haemost 2014;12:

40 New oral anticoagulants: status as of April 2014 Indication Dabigatran Rivaroxaban Apixaban Orthopedics (THR) (EMA) (EMA) Orthopedics (TKR) (EMA) (EMA) Treatment of deep vein thrombosis (FDA EMA pending) pending Treatment of pulmonary embolism (FDA EMA pending) pending Atrial fibrillation Post ACS (EMA)

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42 Does warfarin protect from MI? Patients with AF with RE-LY without RE-LY GYH Lip. Am J Med 2010;123:

43 Does warfarin protect from MI? Patients after MI End point: death, non-fatal re-mi, thromboembolic stroke; FU: 4 years M Hurlen M. N Engl J Med 2002;347:

44 Myocardial infarction in RE-LY: what is relevant? Post hoc end point D110/D150 (rate p.a.) W (rate p.a.) HR for D110/D150 MI, unstable angina, cardiac arrest, cardiac death 3.16%/3.33% 3.41% 0.93 [ ]/ 0.98 [ ] Net clinical benefit (all strokes, systemic embolism, MI, PE, major bleeding, all-cause death) 7.34%/7.11% 7.91% 0.92 [ ]/ 0.90 [ ] SH Hohnloser. Circulation 2012;125:

45 Risk of myocardial infarction?? SH Hohnloser. Circulation 2012;125:

46 Concomitant aspirin and risk of bleeding in AF

47 VKA and coronary artery disease: not everything is clear

48 Dabigatran in AF: Danish prospective nationwide study From Aug 2011 to Dec 2012 Dabigatran: n=4978, propensity matched 1:2 with warfarin (n=8936) Stroke and systemic embolism similar to warfarin Adjusted mortality lower with both D doses versus W Intracranial bleeding lower with both D doses vs W Myocardial infarction lower with both D doses (HR !) GI bleeding lower with D 110 TB Larsen et al. J Am Coll Cardiol 2013; Epub ahead of press

49 The real world : RELY-ABLE goals and design Goals To describe the long-term efficacy and safety of ongoing dabigatran therapy following RE-LY * Methods Patients eligible at completion of RE-LY study if: o Alive and still receiving study dabigatran** o Being followed at centre participating in RELY-ABLE Dabigatran blinded dose continued in RELY-ABLE for 2.3 years # Analysis Two follow-up periods described o RELY-ABLE (post-re-ly ) o RE-LY + RELY-ABLE (beginning of RE-LY to end of RELY-ABLE ## ) * RE-LY -Study: Dabigatran versus Warfarin in patients with atrial fibrillation **Warfarin patients not eligible # Together with RE-LY, this allows for over 4 years of follow-up in total ## Outcome events not adjudicated in RELY-ABLE (in contrast with RE-LY ) Analysis of RE-LY + RELY-ABLE potentially mixes adjudicated and non-adjudicated outcomes

50 Νεότερα Αντιπηκτικά Κολπικι Μαρμαρυγι: Το τζλοσ των μεγάλων μελετών και τα πρώτα real world data Κολπικι Μαρμαρυγι: NOAC και ανάταξθ Συνδυαςμόσ με αντιαιμοπεταλιακά αιμορραγικζσ επιπλοκζσ Φλεβικι κρομβοεμβολικι νόςοσ: Η νζα ζνδειξθ

51 Cardioversion of AF: status 2012 Recommendation Class Level Όταν θ διάρκεια τθσ ΚΜ είναι τουλάχιςτον 48 ώρεσ, ι αν είναι άγνωςτθ, να δίνονται κουμαρινικά ι δαβιγατράνθ τουλάχιςτο 3 εβδομάδεσ πριν και τουλάχιςτο 4 εβδομάδεσ μετά τθν ανάταξθ, ανεξάρτθτα αν ιταν θλεκτρικι ι φαρμακευτικι. Αν υπάρχουν παράγοντεσ κινδφνου για ΑΕΕ ι για υποτροπι τθσ ΚΜ, θ αντιπθκτικι αγωγι να ςυνεχίηεται επ αόριςτο, ανεξάρτθτα αν ο αςκενισ παραμζνει ςε φλεβοκομβικό ρυκμό. I I B B

52 Cardioversion: recent data for rivaroxaban, apixaban N=547 patients, 743 procedures J Am Coll Cardiol 2014;63: N=143 patients, 743 procedures J Am Coll Cardiol 2013;61:

53 Stroke and ischemic events: RELY-ABLE D150 D110 Event (%/yr) (%/yr) HR 95% CI Stroke or SEE All stroke Ischemic Hemorrhagic Myocardial infarction Pulmonary embolism patients followed for mean of 2.3 years D150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratio SEE = systemic embolic event SJ Connolly. Circulation 2013;128: