Trombosprevention hos patienter med förmaksflimmer och Akuta Koronara Syndrom. Joakim Alfredsson Ischemisektionsansvarig US, Linköping

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1 Trombosprevention hos patienter med förmaksflimmer och Akuta Koronara Syndrom Joakim Alfredsson Ischemisektionsansvarig US, Linköping

2 RATIONAL för att kombinera antikoagulantia med trombocythämmare

3 Stars trial 1653 pat. Primär EP: död/tvr/st/mi Leon NEJM 1998

4 PCI med stent Dubbel trombocythämning bättre än enkel avseende stenttrombos, ny MI. Dubbel trombocythämning bättre än waran+ ASA

5 Stenttrombos Reellt hot Potentiellt livshotande tillstånd Dock mycket färre idag

6 Annan indikation för OAC Andra tillstånd med ökad risk för trombemboli Förmaksflimmer: En stor andel (20-45%) av patienter med FF behöver ngn gång revaskulariserande behandling (Kralev PloS One 2011) Ca 7% av MI-populationen har FF (Swedeheart)

7 Primär EP: Stroke, artäremboli, MI, CV död ACTIVE-W, Lancet 2006

8 Annan indikation för OAC Förmaksflimmer: Waran bättre än kombinationen ASA+Clopidogrel

9 Andra orala antikoagulantia NOAC lika effektivt som waran och med bättre säkerhetsprofil vid FF Dabigatran--RE-LY Rivaroxaban--ROCKET-AF Apixaban--ARISTOTLE Edoxaban ENGAGE AF

10 Stroke Stroke är också ett tillstånd förenat med stor mortalitet och morbiditet

11 Rational för trippelbehandling Två tillstånd Olika optimal behandling

12 Blödningskomplikationer

13 Blödningskomplikationer Tillägg av Clopidogrel till ASA ökar risken för Major bleeding med 1,4 (CURE) Waran+ASA vs Waran RR ICH 2,0 (Rev Hart Stroke 2005) Waran + DAPT vs Waran+ SAPT RR major bleeding 2,0 (dewilde Lancet 2012)

14 Eikelboom Circ 2009

15 Influence of recurrent MI, major bleed, and non-cabg related blood transfusion on mortality to 1 year [three Cox model with MIs, bleeds, and transfusions as time-updated covariates (pre-/post-event) adjusted for baseline predictors]. Mehran R et al. Eur Heart J 2009;30: Published on behalf of the European Society of Cardiology. All rights reserved. The Author For permissions please journals.permissions@oxfordjournals.org

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17 WOEST ESC, Hotline III, Munchen, August 28th, 2012 The WOEST Trial: First randomised trial comparing two regimens with and without aspirin in patients on oral anticoagulant therapy undergoing coronary stenting Willem Dewilde, Tom Oirbans, Freek Verheugt, Johannes Kelder, Bart De Smet, Jean-Paul Herrman, Tom Adriaenssens, Mathias Vrolix, Antonius Heestermans, Marije Vis, Saman Rasoul, Kaioum Sheikjoesoef, Tom Vandendriessche, Carlos Van Mieghem, Kristoff Cornelis, Jeroen Vos, Guus Brueren, Nicolien Breet and Jurriën ten Berg The WOEST Trial= What is the Optimal antiplatelet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing (clinicaltrials.gov NCT )

18 WOEST Study Design-2 1:1 Randomisation: Double therapy group: OAC + 75mg Clopidogrel qd Triple therapy group OAC + 75mg Clopidogrel qd + 80mg Aspirin qd 1 month minimum after BMS 1 year after DES 1 month minimum after BMS 1 year after DES Follow up: 1 year Primary Endpoint: The occurence of all bleeding events (TIMI criteria) Secondary Endpoints: - Combination of stroke, death, myocardial infarction, stent thrombosis and target vessel revascularisation - All individual components of primary and secondary endpoints

19 Cumulative incidence (%) Cumulative incidence (%) The WOEST trial: Is ASA Necessary in Triple Therapy? Small-scale, open-label WOEST study (N=573) compared safety outcomes with triple therapy (VKA plus clopidogrel plus ASA) vs dual therapy (VKA plus clopidogrel): 69% of WOEST patients had AF Safety outcomes Efficacy outcomes VKA plus clopidogrel (dual therapy) (n=279) VKA plus clopidogrel plus ASA (triple therapy) (n=284) * * Power 23% 14% 31% * 0 Any bleeding TIMI major TIMI major + minor 0 Death MI Stroke *p<0.05 Dewilde WJ et al, Lancet 2013;381:

20 Rivaroxaban is the First & Currently Only NOAC to Provide Data From a Dedicated RCT in AF-PCI Design: An open-label, randomized, controlled phase IIIb safety study Population: patients with paroxysmal, persistent or permanent NVAF undergoing PCI (with stent placement) N=2,124 Decision for DAPT duration: 1, 6 or 12 months 1:1:1 R Rivaroxaban 15 mg OD* # plus single antiplatelet Rivaroxaban 2.5 mg BID # plus DAPT VKA (INR ) plus DAPT Rivaroxaban 15 mg OD* plus low-dose ASA VKA plus low-dose ASA DAPT duration (1 or 6 months) End of treatment (12 months) *CrCl ml/min: 10 mg OD; # first dose hours after sheath removal; clopidogrel (75 mg daily) (alternative use of prasugrel or ticagrelor allowed, but capped at 15%); ASA ( mg daily) plus clopidogrel (75 mg daily) (alternative use of prasugrel or ticagrelor allowed, but capped at 15%); first dose hours after sheath removal 1. Janssen Scientific Affairs, LLC [accessed 10 Oct 2016]; 2. Gibson CM et al, Am Heart J 2015;169: e5; 3. Gibson CM et al, New Engl J Med 2016; doi: /NEJMoa

21 PIONEER AF-PCI Key Inclusion and Exclusion Criteria Key inclusion criteria Medical history of paroxysmal, persistent or permanent NVAF Undergone PCI with stent placement for primary atherosclerotic disease INR 2.5 at randomization Key exclusion criteria Contraindication for anticoagulant or antiplatelet therapy or unacceptable risk of bleeding* History of stroke or TIA CrCl <30 ml/min at screening *Including, but not limited to, platelet count <90,000/µl at screening, history of ICH, 12-month history of clinically significant GI bleeding, non-vka-induced elevated PT at screening, anaemia of unknown cause with a haemoglobin level <10 g/dl (<6.21 mmol/l) or significant liver disease or liver function test abnormalities Janssen Scientific Affairs, LLC [accessed 14 Oct 2016]

22 PIONEER AF-PCI Study Flow 2,236 screened 112 not eligible 2,124 enrolled 709 randomized to Group randomized to Group randomized to Group 3 ITT analysis set 696 received 1 dose No DAPT stratification 706 received 1 dose 1 month DAPT: months DAPT: months DAPT: received 1 dose 1 month DAPT: months DAPT: months DAPT: 341 Safety analysis set 696 in safety analysis 694 in in efficacy analysis* 706 in safety analysis 704 in in efficacy analysis* 697 in safety analysis 695 in in efficacy analysis* *Some patients excluded due to site violation of GCP guideline; no patients were lost to follow-up Gibson CM et al, New Engl J Med 2016; doi: /NEJMoa

23 Baseline Demographics Were Similar Between Groups (1) Characteristic Group 1 Rivaroxaban 15 mg OD plus single antiplatelet (N=709) Group 2 Rivaroxaban 2.5 mg BID plus DAPT (N=709) Group 3 VKA plus DAPT (N=706) Age, years, mean ± SD 70.4± ± ±8.7 Female sex, n (%) 181 (25.5) 174 (24.5) 188 (26.6) CrCl, ml/min, mean ± SD 78.3± ± ± <60 ml/min, n (%) 194 (28.8) 196 (28.8) 175 (26.2) <30 ml/min, n (%) 8 (1.2) 7 (1.0) 2 (0.3) CHA 2 DS 2 -VASc score, mean ± SD* 3.73± ± ± , n (%) 77 (10.9) 75 (10.6) 51 (7.2) 2, n (%) 632 (89.1) 634 (89.4) 655 (92.8) HAS-BLED score, mean ± SD* 3.00± ± ± , n (%) 196 (27.6) 227 (32.0) 208 (29.3) 3, n (%) 513 (72.4) 482 (68.0) 498 (70.5) Type of AF, n (%) Persistent 146 (20.6) 146 (20.6) 149 (21.1) Permanent 262 (37.0) 238 (33.6) 243 (34.5) Paroxysmal 300 (42.4) 325 (45.8) 313 (44.4) *Values calculated from data in published manuscript (not explicitly stated) Gibson CM et al, New Engl J Med 2016; doi: /NEJMoa

24 Baseline Demographics Were Similar Between Groups (2) Characteristic Group 1 Rivaroxaban 15 mg OD plus single antiplatelet (N=709) P2Y 12 inhibitor at baseline, n (%) Group 2 Rivaroxaban 2.5 mg BID plus DAPT (N=709) Group 3 VKA plus DAPT (N=706) Clopidogrel 660 (93.1) 664 (93.7) 680 (96.3) Prasugrel 12 (1.7) 11 (1.6) 5 (0.7) Ticagrelor 37 (5.2) 34 (4.8) 21 (3.0) Urgency of revascularization, n (%) Elective 428 (60.4) 430 (60.6) 449 (63.6) Urgent 281 (39.6) 279 (39.4) 257 (36.4) Type of index event, n (%) NSTEMI 130 (18.5) 129 (18.4) 123 (17.8) STEMI 86 (12.3) 97 (13.8) 74 (10.7) Unstable angina 145 (20.7) 148 (21.1) 164 (23.7) Type of stent, n (%) Drug-eluting stent 464 (65.4) 471 (66.8) 468 (66.5) Bare metal stent 231 (32.6) 220 (31.2) 224 (31.8) Both 14 (2.0) 14 (2.0) 12 (1.7) Gibson CM et al, New Engl J Med 2016; doi: /NEJMoa ]

25 TIMI major, TIMI minor or bleeding requiring medical attention (%) Both Rivaroxaban Strategies was Associated With Significantly Improved Safety Rivaroxaban 15 mg OD plus single antiplatelet vs VKA plus DAPT: HR=0.59; (95% CI ); p<0.001 Rivaroxaban 2.5 mg BID plus DAPT vs VKA plus DAPT: HR=0.63 (95% CI ); p< % 18.0% 16.8% ARR 8.7% NNT= 12 ARR 9.9% NNT= Time (days) Group 3 (VKA plus DAPT) Group 2 (Rivaroxaban 2.5 mg BID plus DAPT) Group 1 (Rivaroxaban 15 mg OD plus single antiplatelet) Gibson CM et al, New Engl J Med 2016; doi: /NEJMoa ]

26 360-day Kaplan Meier estimate (%) Comparable Efficacy with Rivaroxaban Strategies vs VKA plus DAPT 7 Group 3 (VKA plus DAPT) (n=695) Group 2 (rivaroxaban 2.5 mg BID plus DAPT) (n=704) Group 1 (rivaroxaban 15 mg OD plus single antiplatelet) (n=694) Major adverse CV events* Composite endpoint CV death MI Stroke Stent thrombosis Components of composite endpoint and stent thrombosis Incidence of major adverse CV events was comparable between all three treatment strategies; however, the trial was not powered for efficacy *Composite of CV death, MI and stroke Gibson CM et al, New Engl J Med 2016; doi: /NEJMoa ]

27 Ytterligare studier för NOAK

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33 Ytterligare studier för NOAK AUGUSTUS (Apixaban) ENTRUST-AF-PCI (Edoxaban) Ingen har power för effekt Väldigt få med ticagrelor

34 2016 ESC GL for management of AF

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37 Sammanfattning Evidens för OAC+ DAPT är mycket gammal och har tveksam relevans idag. OAC+SAPT ger (inte förvånande) färre blödningar vs TT OAC+SAPT har inte utvärderats avseende effekt men ingen tendens till ökade ischemiska händelser har setts. Några har baserat på dessa data börjat med OAC+SAPT Pga oro för clopidogrels stora variation i effekt används ticagrelor Någon randomiserad studie stor nog att besvara frågan om effekt kommer sannolikt inte att bli av

38 Om inte randomiserad studie: Observationella data mycket bättre om ett center går över till en viss strategi än om behandlingen har getts baserat på individuell risk Region Skåne (Kalmar län) har gått över till OAC+SAP För få hittills för att kunna analysera data på ett bra sätt Om två-tre regioner går över till OAC-tica kan vi se om det är en säker behandling och möjligen få svar på effekt. Flera analyser: Pat som behandlats med OAC+tica vs matchad pop med OAC+DAPT Center som haft denna strategi vs center som haft dominerande OAC+DAPT strategi Center som ändrar strategi vs historiska kontroller samma center OAC+tica vs OAC+clop

39 Tack!

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