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: Nikolaus.Sarafoff@med.uni-muenchen.de