WAS HAT SICH GEÄNDERT: DAPT UND OAK BEI PCI PATIENTEN MIT VORHOFFLIMMERN

Transkript

1 CAMPUS GROSSHADERN CAMPUS INNENSTADT MEDIZINISCHE KLINIK UND POLIKLINIK I WAS HAT SICH GEÄNDERT: DAPT UND OAK BEI PCI PATIENTEN MIT VORHOFFLIMMERN Kardiologie Update Priv.-Doz. Dr. med. Nikolaus Sarafoff

2 Disclosure Information Vortragshonorare und Reisekosten von Lilly/Daichi Sankyo, BMS/Pfizer, Boehringer Ingelheim, Bayer Healthcare, Biotronik

3 Hintergrund Coronary stent implantation + Atrial fibrillation Oral Anticoagulation Dual Antiplatelet Dual Antiplatelet Oral Anticoagulation ISAR, NEJM 1996 ACTIVE-W Lancet 2006 = Orale Antikoagulation + duale antithrombozytärer Therapie (N)OAC + ASS + Clopidogrel TRIPLE Therapie

4 Risiko: Blutungen Lamberts Circulation 2012

5 Fragen zur Triple Therapie 1. Welcher Stent (BMS, DES?) 2. Triple Therapie wie und wie lange? 3. Welche Medikamentenkombinationen und in welchen Dosierungen? Marcumar, Rivaroxaban, Dabigatran, Apixaban, Edoxaban Aspirin Clopidogrel, Prasugrel, Ticagrelor

6 Drug-Eluting Stents (DES) vs. Bare Metal Stents (BMS) Vorhofflimmerleitlinien 2010 the duration of antiplatelet therapy should be minimized Camm et al. EurHJ 2010

7 Drug-Eluting Stents (DES), ZEUS n=1606 Patienten mit hohem Risiko für Blutung oder Thrombose Randomisierte Studie BMS vs DES (zotarolimus) DAPT Dauer: median 32 Tage [IQR Tage) Death, MI, TVR Myocardial infarction Valgimigli et al. JACC 2015

8 Drug-Eluting Stents (DES), LEADERS-FREE n=2466 Patienten mit hohem Risiko für Blutung oder Thrombose Randomisierte Studie BMS vs DES (biolimus, polymer frei) DAPT Dauer: 1 Monat, dann einfache Plättchenhemmung (meist Aspirin) Cardiac Death, MI, Stent thrombosis TLR Urban et al. NEJM2015

9 Drug-Eluting Stents (DES) Windecker et al. EurHJ 2014 Guidelines on myocardial revascularization

10 Dauer der Therapie ISAR TRIPLE ISAR TRIPLE Studie n=614 DES und Indikation für OAC PCI Randomization Stop clopidogrel Group A Stop clopidogrel Group B A: 6-week group Clopidogrel Aspirin and oral anticoagulation B: 6-month group Clopidogrel Aspirin and oral anticoagulation 0 6-week Follow-up 6-month Follow-up 9-month Follow-up Time (months) Fiedler.et Sarafoff, JACC 2015

11 Dauer der Therapie ISAR TRIPLE Cardiacdeath, myocardialinfarction, stent thrombosis or ischemic stroke TIMI major bleeding Months 6-month group 6-week group Fiedler, et Sarafoff JACC 2015

12 Dauer der Therapie ISAR TRIPLE Cardiacdeath, myocardialinfarction, stent thrombosis or ischemic stroke Landmark analysis of anybarc Bleedingafter 6 weeks(6w) Months 6-month group 6-week group Fiedler, et Sarafoff JACC 2015

13 NOACs: Dabigatran vs. Warfarin (RE-LY Studie) Re-Ly n=18113 No Antiplatelet n=11161 (62%) + ASS oder Clopidogrel n=6140 (34%) TRIPLE: + ASS + Clopidogrel n=812 (4.5%) Dans et al. Circ 2013

14 Dabigatran vs. Warfarin (RE-LY Studie) Major Blutung Minor Blutung 10,0% 8,0% 6,0% 4,0% 2,0% 6,3% 2,8% 2,6% 5,5% 5,4% 2,2% 30,0% 25,0% 20,0% 15,0% 10,0% 5,0% 24,0% 14,4% 20,9% 13,4% 15,7% 11,7% 0,0% Warfarin Dabigatran 150mg Dabigatran 110mg 0,0% Warfarin Dabigatran 150mg Dabigatran 110mg Triple Therapie No antiplatelet Dans et al. Circ 2013

15 Prasugrel bei Triple Therapie n=377 Patienten mit DES und Triple Therapie für 6 Monate n=21 (6%) Prasugrel + Aspirin + Marcumar Register Timimajorandminorbleeding VKA + Aspirin+ Death, MI, IschemicStroke, Stentthrombosis p = 0.61 VKA + Aspirin+ VKA + Aspirin + + VKA + Aspirin Sarafoff et al., JACC 2013

16 Prasugrel bei Triple Therapie TRANSLATE-ACS: 233 Zentren USA % Any BARC Bleeding MACE: Death, MI, Revascularization or Stroke Jackson et al., JACC Cardiovasc Interv Windecker et al. EurHJ 2014

17 Aspirin bei Triple Therapie (WOEST) PCI und orale Antikoagulation n = 573 Randomisiert 1:1 DUAL Clopidogrel OAC TRIPLE Aspirin Clopidogrel OAC Dewilde et al. Lancet 2013

18 Aspirin bei Triple Therapie (WOEST) TIMI major, minor or minimal bleeding Aspirin + Clopidogrel + OAC Clopidogrel + OAC Dewilde et al. Lancet 2013

19 Aspirin bei Triple Therapie (WOEST) Death, MI, Stroke, TVR, Stentthrombosis Aspirin + Clopidogrel + OAC Clopidogrel + OAC Dewilde et al. Lancet 2013

20 PIONEER-AF-PCI (AHA NEW ORLEANS ) Vorhofflimmern und PCI 2100 Patienten (431 Zentren) Rivaroxaban 15mg Clopidogrel* Rivaroxaban 2,5mg Clopidogrel* ASS Vit K Antagonist Clopidogrel* ASS WOEST-ähnlich ATLAS-ähnlich TRIPLE Therapie Primärer Endpunkt: TIMI major, minor or bleeding requiring medical attention (12 Monate) * ~5%Ticagrelor oder Prasugrel Gibson et al. NEJM 2016

21 Kaplan-Meier Estimates of First Occurrence of Clinically Significant Bleeding Events TIMI Major, TIMI Minor, or Bleeding Requiring Medical Attention (%) VKA VKA + DAPT + DAPT Riva + DAPT Riva + P2Y 12 v. VKA + DAPT HR=0.59 (95% CI: ) p < ARR=9.9 NNT=11 p< p< Riva + P2Y 12 HR = 0.63 (95% CI ) HR ARR = 0.59 = (95% 8.7 Riva + CI DAPT ) v. VKA + DAPT ARR NNT = 9.9 = 12HR=0.63 (95% CI: ) NNT = 11 p < ARR=8.7 NNT= % 18.0% 16.8% No. at risk Riva VKA + DAPT P2Y 12 VKA Riva + DAPT VKA + DAPT Days Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. Clinically significant bleeding is the composite of TIMI major, TIMI minor, and BRMA. Hazard ratios as compared to the VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model. Log-Rank P-values as compared to VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) two-sided log rank test. Gibson et al. AHA 2016

22 Bleeding Endpoints Using TIMI Criteria (Primary Analysis) Kaplan-Meier Estimates Hazard Ratio (95% CI) Overall Riva + P2Y 12 (N=696) Riva + DAPT (N=706) Comb. Riva (N=1402) VKA + DAPT (N=697) Riva + P2Y 12 vs. VKA + DAPT Riva + DAPT vs. VKA + DAPT Combined vs. VKA + DAPT Clinically significant bleeding 109 (16.8%) 117 (18.0%) 226 (17.4%) 167 (26.7%) 0.59 ( ) p< ( ) p< ( ) p<0.001 TIMI Major 14 (2.1%) 12 (1.9%) 26 (2.0%) 20 (3.3%) 0.66 ( ) p= ( ) p= ( ) p=0.093 TIMI minor 7 (1.1%) 7 (1.1%) 14 (1.1%) 13 (2.2%) 0.51 ( ) p= ( ) p= ( ) p=0.071 BRMA 93 (14.6%) 102 (15.8%) 195 (15.2%) 139 (22.6%) 0.61 ( ) p< ( ) p= ( ) p<0.001 Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. Clinically significant bleeding is the composite of TIMI major, TIMI minor, and BRMA events. A subject could have more than component event. n = number of subjects with events, N = number of subjects at risk, % = KM estimate at the end of study. Hazard ratios as compared to VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model. Log-Rank p-values as compared to VKA group are based on the (stratified, only for Overall 2.5 mg BID/15 mg QD comparing VKA) two-sided log rank test. BRMA = Bleeding requiring medical attention, TIMI = Thrombolysis in myocardial infarction, CI = confidence interval, DAPT = dual antiplatelet therapy, HR = hazard ratio, VKA = vitamin K antagonist Gibson et al. AHA 2016

23 Kaplan-Meier Estimates of First Occurrence of CV Death, MI or Stroke Cardiovascular Death, Myocardial Infarction, or Stroke (%) VKA + DAPT Riva + P2Y 12 Riva + DAPT 6.5% 6.0% 5.6% Riva + P2Y 12 v. VKA + DAPT HR=1.08 (95% CI: ) p=0.750 Riva + DAPT v. VKA + DAPT HR=0.93 (95% CI: ) p=0.765 No. at risk Riva + P2Y 12 Riva + DAPT VKA + DAPT Days Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. Composite of adverse CV events is composite of CV death, MI, and stroke. Hazard ratios as compared to VKA group are based on the (stratified, only for the Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model. Log-Rank P-values as compared to the VKA group are based on the (stratified, only for Overall, 2.5 mg BID/115 mg QD comparing VKA) two-sided log rank test. 6 Subjects were excluded from all efficacy analyses because of violations in Good Clinical Practice guidelines Gibson et al. AHA 2016

24 Major Adverse Cardiac Events All Strata Kaplan-Meier Estimates Hazard Ratio (95% CI) Overall Riva + P2Y 12 (N=694) Riva + DAPT (N=704) VKA + DAPT (N=695) Riva + P2Y 12 vs. VKA + DAPT Riva + DAPT vs. VKA + DAPT Adverse CV Event 41 (6.5%) 36 (5.6%) 36 (6.0%) CV Death 15 (2.4%) 14 (2.2%) 11 (1.9%) MI 19 (3.0%) 17 (2.7%) 21 (3.5%) Stroke 8 (1.3%) 10 (1.5%) 7 (1.2%) Stent Thrombosis 5 (0.8%) 6 (0.9%) 4 (0.7%) Adverse CV Events + Stent Thrombosis 41 (6.5%) 36 (5.6%) 36 (6.0%) 1.08 ( ) p= ( ) p= ( ) p= ( ) p= ( ) p= ( ) P= ( ) p= ( ) p= ( ) p= ( ) p= ( ) p= ( ) p=0.765 Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. A subject could have more than component event. n = number of subjects with events, N = number of subjects at risk, % = KM estimate at the end of study. Hazard ratios as compared to VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model. Log-Rank p-values as compared to VKA group are based on the (stratified, only for Overall 2.5 mg BID/15 mg QD comparing VKA) two-sided log rank test. CI = confidence interval, DAPT = dual antiplatelet therapy, HR = hazard ratio, VKA = vitamin K antagonist 6 Subjects were excluded from all efficacy analyses because of violations in Good Clinical Practice guidelines. Gibson et al. AHA 2016

25 All Cause Hospitalization for an Adverse Event All Cause Rehospitalization (%) VKA + DAPT Riva + P2Y 12 v. VKA + DAPT HR=0.77 (95% CI: ) p=0.005 ARR=7.4 NNT=14 Riva + P2Y 12 Riva + DAPT Riva + DAPT v. VKA + DAPT HR=0.74 (95% CI: ) p=0.001 ARR=10.3 NNT= % 34.1% 31.2% No. at risk Riva + P2Y 12 Riva + DAPT VKA + DAPT Days Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. Rehospitalizations do not include the index event and include the first rehospitalization after the index event. Hazard ratios as compared to the VKA group are based on the Cox proportional hazards model. Log-Rank P-values as compared to VKA group are based on the two-sided log rank test Gibson et al. AHA 2016

26 Stabile Angina DES + Indikation für OAC TRIPLE THERAPIE SOP PIONEER AF-PCI Akutes Koronarsyndrom DES + Indikation für OAC HAS-BLED 3 HAS-BLED 3 Nein Ja Nein Ja 3 Monate Aspirin Clopidogrel (N)OAC 1 Monat Aspirin Clopidogrel (N)OAC 6 Monate Aspirin Clopidogrel (N)OAC 1 Monat Aspirin Clopidogrel (N)OAC IIa IIa IIa IIa Selected patients Clopidogrel + N(OAC) IIb Clopidogrel + (N)OAC bis Monat 12 Aspirin und (N)OAC auf Dauer Aspirin und (N)OAC auf Dauer adaptiert nach Revaskularisationsleitlinien Windecker et al. EurHJ 2014 Stand 12/2014 PD Dr. Sarafoff

27 Aktuelle NOAC Triple Studien Dabigatran (n=2727) Apixaban (n=4600) Apixaban-ACS (n=400) Results 2017? 2018? 2018/2019? Atrial fibrillation and PCI / ACS NOAC (different dosages) P2Y12 inhibitors (Clopidogrel / Prasugrel / Ticagrelor) With or without Aspirin Vit K Antagonist Clopidogrel (C/P/T) With /without aspirin

28 Zusammenfassung Triple Therapie DES der neuen Generation sind den BMS vorzuziehen. NOAC können alternativ zu VKA verwendet werden. Ticagrelor oder Prasugrel ist im Rahmen einer Triple Therapie nicht empfohlen. Die Ergebnisse der 3 randomisierten Studien (WOEST, ISAR-TRIPLE, PIONEER) zeigen Weniger ist mehr (Weniger Substanzen, niedrigere Dosierung, kürzere Therapie) Cave: Nicht für ischämische Endpunkte gepowered

29 Zusammenfassung Triple Therapie Aktuelle Leitlinien empfehlen (noch) Initial (für mind. 1 Monat) eine Triple Therapie bestehend aus Aspirin, Clopidogrel und OAC (VKA oder NOAC). IIa Bei ausgewählten Patienten kann eine duale Therapie mit Clopidogrel und OAC (ohne Aspirin) als Alternative zu einer initialen Triple Therapie erwogen werden. IIb Laufende Studien evaluieren weiter, ob duale Therapien aus Clopidogrel und OAC ausreichende Sicherheit und Effektivität bieten.

30 VIELEN DANK FÜR IHRE AUFMERKSAMKEIT Priv.-Doz. Dr. med. Nikolaus Sarafoff Klinikum der Universität München Medizinische Klinik und Poliklinik I Nikolaus.Sarafoff@med.uni-muenchen.de KLINIKUM DER UNIVERSITÄT MÜNCHEN MEDIZINISCHE KLINIK UND POLIKLINIK I