CAMPUS GROSSHADERNCAMPUS INNENSTADT
MEDIZINISCHE KLINIK UND POLIKLINIK I
WAS HAT SICH GEÄNDERT: DAPT UND OAKBEI PCI PATIENTEN MIT VORHOFFLIMMERN
Kardiologie Update 2016 – 20.11.2016
Priv.-Doz. Dr. med. Nikolaus Sarafoff
Disclosure Information
� Vortragshonorare und Reisekosten von Lilly/Daichi Sankyo, BMS/Pfizer, Boehringer Ingelheim, Bayer Healthcare, Biotronik
Hintergrund
ISAR, NEJM 1996
Dual Antiplatelet
Oral Anticoagulation
Coronary stent implantation
ACTIVE-W Lancet 2006
Atrial fibrillation
Oral Anticoagulation
Dual Antiplatelet
+
=Orale Antikoagulation + duale antithrombozytärer Therapie
(N)OAC + ASS + Clopidogrel� TRIPLE Therapie
Risiko: Blutungen
Lamberts Circulation 2012
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
Drug-Eluting Stents (DES) vs. Bare Metal Stents (BMS)
Vorhofflimmerleitlinien 2010
Camm et al. EurHJ 2010
…… the duration of antiplatelet therapy should be minimized…
Drug-Eluting Stents (DES), ZEUS
n=1606 Patienten mit hohem Risiko für Blutung oder ThromboseRandomisierte StudieBMS vs DES (zotarolimus)
DAPT Dauer: median 32 Tage [IQR 30 - 180 Tage)
Valgimigli et al. JACC 2015
Death, MI, TVR Myocardial infarction
Drug-Eluting Stents (DES), LEADERS-FREE
n=2466 Patienten mit hohem Risiko für Blutung oder ThromboseRandomisierte StudieBMS vs DES (biolimus, polymer frei)DAPT Dauer: 1 Monat, dann einfache Plättchenhemmung (meist Aspirin)
Urban et al. NEJM2015
Cardiac Death, MI, Stent thrombosis TLR
Drug-Eluting Stents (DES)
Windecker et al. EurHJ 2014Guidelines on myocardial revascularization
Dauer der Therapie – ISAR TRIPLE
PCI
Randomi-
zation
Aspirin and oral anticoagulation
Stop
clopidogrel
Group A
Aspirin and oral anticoagulation
Clopidogrel
0 6-week
Follow-up
6-month
Follow-up
9-month
Follow-up
Time
(months)
Stop
clopidogrel
Group B
A: 6-week
group
B: 6-month
group
Clopidogrel
ISAR TRIPLE Studien=614DES und Indikation für OAC
Fiedler….et Sarafoff, JACC 2015
Dauer der Therapie – ISAR TRIPLE
Cardiac death, myocardial infarction,
stent thrombosis or ischemic strokeTIMI major bleeding
6-month group
6-week groupFiedler,… et Sarafoff JACC 2015
Months
Dauer der Therapie – ISAR TRIPLE
Cardiac death, myocardial infarction,
stent thrombosis or ischemic stroke
6-month group
6-week groupFiedler,… et Sarafoff JACC 2015
Landmark analysis of
any BARC Bleeding after 6 weeks (6w)
Months
NOACs: Dabigatran vs. Warfarin (RE-LY Studie)
Dans et al. Circ 2013
Re-Ly
n=18113
n=6140
(34%)
n=812
(4.5%)
+ ASS oder Clopidogrel
TRIPLE:
+ ASS + Clopidogrel
No
Antiplatelet
n=11161
(62%)
Dabigatran vs. Warfarin(RE-LY Studie)
Major Blutung Minor Blutung
Triple Therapie No antiplatelet
6,3%5,5% 5,4%
2,8% 2,6%2,2%
0,0%
2,0%
4,0%
6,0%
8,0%
10,0%
Warfarin Dabigatran
150mg
Dabigatran
110mg
24,0%
20,9%
15,7%14,4% 13,4%
11,7%
0,0%
5,0%
10,0%
15,0%
20,0%
25,0%
30,0%
Warfarin Dabigatran
150mg
Dabigatran
110mg
Dans et al. Circ 2013
Prasugrel bei Triple Therapie
Sarafoff et al., JACC 2013
Timi major and minor bleeding Death, MI, Ischemic Stroke,
Stentthrombosis
p = 0.61
VKA + Aspirin+
VKA + Aspirin +
VKA + Aspirin+
+ VKA + Aspirin
n=377 Patienten mit DES und Triple Therapie für 6 Monaten=21 (6%) Prasugrel + Aspirin + MarcumarRegister
Prasugrel bei Triple Therapie
Jackson et al., JACC Cardiovasc Interv. 2015
Windecker et al. EurHJ 2014
Any BARC Bleeding MACE: Death, MI, Revascularization or Stroke
TRANSLATE-ACS:233 Zentren USA2010-2012
15%
Aspirin bei Triple Therapie (WOEST)
PCI und orale
Antikoagulation
n = 573
DUAL
Clopidogrel
OAC
TRIPLE
Aspirin
Clopidogrel
OACDewilde et al. Lancet 2013
Randomisiert 1:1
Aspirin bei Triple Therapie (WOEST)
Aspirin + Clopidogrel + OAC
Clopidogrel + OAC
TIMI major, minor or minimal bleeding
Dewilde et al. Lancet 2013
Aspirin bei Triple Therapie (WOEST)
Death, MI, Stroke, TVR, Stentthrombosis
Aspirin + Clopidogrel + OAC
Clopidogrel + OAC
Dewilde et al. Lancet 2013
PIONEER-AF-PCI (AHA NEW ORLEANS 14.11.2016)
Gibson et al. NEJM 2016
Vorhofflimmern und PCI
2100 Patienten (431 Zentren)
• Rivaroxaban 15mg 1-0-0
• Clopidogrel*
• Rivaroxaban 2,5mg 1-0-1
• Clopidogrel*
• ASS
• Vit K Antagonist
• Clopidogrel*
• ASS
Primärer Endpunkt: TIMI major, minor or bleeding requiring medical attention (12 Monate)
WOEST-ähnlich ATLAS-ähnlich TRIPLE Therapie
* ~5%Ticagrelor oder Prasugrel
Kaplan-Meier Estimates of First Occurrence of Clinically Significant Bleeding Events
TIM
I Maj
or, T
IMI M
inor
, or
Ble
edin
g R
equi
ring
Med
ical
Atte
ntio
n (%
)
697
Days
593 555 521 461 426 329VKA + DAPTNo. at risk
VKA + DAPT
26.7%
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
VKA + DAPT
Riva + DAPT
18.0%
p<0.00018
HR = 0.63 (95% CI 0.50-0.80)ARR = 8.7NNT = 12
706697
636593
600555
579521
543461
509426
409329
Riva + DAPTVKA + DAPT
VKA + DAPT
Riva + P2Y12
16.8%
p<0.000013
HR = 0.59 (95% CI 0.47-0.76)ARR = 9.9NNT = 11
696697
628593
606555
585521
543461
510426
383329
Riva + P2Y12VKA + DAPT
Riva + P2Y12
VKA + DAPT
Riva + DAPT
Riva + P2Y12 v. VKA + DAPT
HR=0.59 (95% CI: 0.47-0.76)p <0.000013ARR=9.9NNT=11
Riva + DAPT v. VKA + DAPTHR=0.63 (95% CI: 0.50-0.80)p <0.00018ARR=8.7NNT=12
696706697
628636593
606600555
585579521
543543461
510509426
383409329
Riva + P2Y12Riva + DAPTVKA + DAPT
Bleeding Endpoints Using TIMI Criteria(Primary Analysis)
Kaplan-Meier Estimates Hazard Ratio (95% CI)
OverallRiva +P2Y12
(N=696)
Riva +DAPT
(N=706)
Comb.Riva
(N=1402)
VKA +DAPT
(N=697)
Riva + P2Y12vs. VKA + DAPT
Riva + DAPT vs. VKA + DAPT
Combined vs. VKA + DAPT
Clinically significantbleeding
109 (16.8%)
117 (18.0%)
226(17.4%)
167 (26.7%)
0.59 (0.47-0.76) p<0.001
0.63 (0.50-0.80)p<0.001
0.61 (0.50-0.75)p<0.001
TIMI Major14
(2.1%)12
(1.9%)26
(2.0%)20
(3.3%)0.66 (0.33-1.31)
p=0.2340.57 (0.28-1.16)
p=0.1140.61 (0.34-1.09)
p=0.093
TIMI minor7
(1.1%)7
(1.1%)14
(1.1%)13
(2.2%)0.51 (0.20-1.28)
p=0.1440.50 (0.20-1.26)
p=0.1340.51 (0.24-1.08)
p=0.071
BRMA93
(14.6%)102
(15.8%)195
(15.2%)139
(22.6%)0.61 (0.47-0.80)
p<0.0010.67 (0.52-0.86)
p=0.0020.64 (0.51-0.80)
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
Kaplan-Meier Estimates of First Occurrence of CV Death, MI or Stroke
Car
dio
vasc
ula
r D
eath
, Myo
card
ial
Infa
rcti
on
, or
Str
oke
(%
)
DaysRiva + P2Y12Riva + DAPTVKA + DAPT
694704695
648662635
633640607
621628579
590596543
562570514
430457408
VKA + DAPT
Riva + DAPT
Riva + P2Y12
Riva + P2Y12 v. VKA + DAPTHR=1.08 (95% CI: 0.69-1.68)p=0.750
Riva + DAPT v. VKA + DAPTHR=0.93 (95% CI: 0.59-1.48)p=0.765
6.5%
5.6%6.0%
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
No. at risk
Gibson et al. AHA 2016
Major Adverse Cardiac EventsAll Strata
Kaplan-Meier Estimates Hazard Ratio (95% CI)
OverallRiva +P2Y12
(N=694)
Riva +DAPT
(N=704)
VKA +DAPT
(N=695)
Riva + P2Y12 vs. VKA + DAPT
Riva + DAPT vs. VKA + DAPT
Adverse CV Event 41 (6.5%) 36 (5.6%) 36 (6.0%)1.08 (0.69-1.68)
p=0.7500.93 (0.59-1.48)
p=0.765
CV Death 15 (2.4%) 14 (2.2%) 11 (1.9%)1.29 (0.59-2.80)
p=0.5231.19 (0.54-2.62)
p=0.664
MI 19 (3.0%) 17 (2.7%) 21 (3.5%)0.86 (0.46-1.59)
p=0.6250.75 (0.40-1.42)
p=0.374
Stroke 8 (1.3%) 10 (1.5%) 7 (1.2%)1.07 (0.39-2.96)
p=0.8911.36 (0.52-3.58)
p=0.530
Stent Thrombosis 5 (0.8%) 6 (0.9%) 4 (0.7%)1.20 (0.32-4.45)
p=0.7901.44 (0.40-5.09)
p=0.574
Adverse CV Events + Stent Thrombosis
41 (6.5%) 36 (5.6%) 36 (6.0%)1.08 (0.69-1.68)
P=0.7500.93 (0.59-1.48)
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
All
Cau
se R
ehos
pita
lizat
ion
(%)
696706697
Days609607592
582570540
559548490
496493422
437454369
322367272
Riva + P2Y12Riva + DAPTVKA + DAPT
No. at risk
Riva + P2Y12VKA + DAPT
Riva + DAPT
34.1%
31.2%
41.5%
Riva + P2Y12 v. VKA + DAPT
HR=0.77 (95% CI: 0.65-0.92)p=0.005ARR=7.4NNT=14
Riva + DAPT v. VKA + DAPTHR=0.74 (95% CI: 0.61-0.88)p=0.001ARR=10.3NNT=10
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.
All Cause Hospitalization for an Adverse Event
Gibson et al. AHA 2016
Stabile Angina
DES + Indikation für OAC
Aspirin und (N)OAC auf Dauer
HAS-BLED ≥ 3
JaNein
3 Monate
Aspirin
Clopidogrel
(N)OAC
1 Monat
Aspirin
Clopidogrel
(N)OAC
TRIPLE THERAPIE SOP
Akutes Koronarsyndrom
DES + Indikation für OAC
HAS-BLED ≥ 3
JaNein
6 Monate
Aspirin
Clopidogrel
(N)OAC
1 Monat
Aspirin
Clopidogrel
(N)OAC
Aspirin und (N)OAC auf Dauer
Clopidogrel + (N)OAC bis Monat 12
IIa IIa IIa IIa
„Selected
patients“
Clopidogrel +
N(OAC)
IIb
adaptiert nach RevaskularisationsleitlinienWindecker et al. EurHJ 2014
Stand 12/2014 PD Dr. Sarafoff
�PIONEER AF-PCI
Aktuelle NOAC Triple Studien
Atrial fibrillation and PCI / ACS
• Vit K Antagonist
• Clopidogrel (C/P/T)
• With /without aspirin
Dabigatran (n=2727)
Apixaban (n=4600)
Apixaban-ACS (n=400)
• NOAC (different dosages)
• P2Y12 inhibitors (Clopidogrel / Prasugrel / Ticagrelor)
• With or without Aspirin
Results
2017?
2018?
2018/2019?
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
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.
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
MEDIZINISCHE KLINIK UND POLIKLINIK I
VIELEN DANK FÜR IHRE AUFMERKSAMKEIT
Priv.-Doz. Dr. med. Nikolaus Sarafoff
Klinikum der Universität München Medizinische Klinik und Poliklinik I
E-Mail: [email protected]
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