Antithrombotische Therapie bei Koronarer Herzerkrankung Münch… · • Begleitfaktoren (Diabetes)...

Antithrombotische Therapie bei Koronarer Herzerkrankung

Meinrad Gawaz Innere Medizin III, Kardiologie und Kreislauferkrankungen

Eberhard Karls Universität Tübingen

The never ending story - Triple, duo, mono

Tote

au

f 1

00

.00

0 E

inw

oh

ner

1940 1950 1960 1970 1980 1990 2000 2010 2020

0

100

200

300

400

500

600

Jahr

Rückgang der Todesfälle aufgrund kardiovaskulärer Erkrankungen in Relation zum Wissenschaftlichen Fortschritt

1954 Erste Prozedur am offenen Herzen (Gibbon)

1958 Koronarangiografie entwickelt (Jones)

1961 Risikofaktoren definiert (Julian)

1969 Erste Beschreibung einer Bypass-Operation (Favolo)

1972 National High Blood Pressure Education Programm (NHBPEP) in den USA

1976 Erster Cholesterinsenker (HMGCoA- Reduktasehemmer) beschrieben (Endo)

1979 Koronar- angioplastie entwickelt (Grüntzig)

1980 Erster implantierbarer Kardioverter- Defibrillator (Mirowski)

1983 Coronary Artery Surgery Study (CASS)

1985 TIMI-1 Studie (bis heute 60 TIMI-Studien) National Cholesterol Education Programm (NECP) in den USA

1986 Erster Coronar-Stent in Lausanne (Sigwart) GISSI und ISIS-2: Wertigkeit von ASS und Streptokinase

1992 Reinfarktprophylaxe mit Captopril erfolgreich (SAVE) Register zum Herzinfarkt in Deutschland (Ludwigshafen)

1993 Primär-PCI ist besser als Fibrinolyse

2002 ALLHAT: Blutdrucksenkung und Lipidsenkung zur Vermeidung eines Herzinfarkts

2002 Medikamenten- freisetzende Stents

2007 Kardiale Resynchronisation bei Herzinsuffizienz

2009 Linksventrikuläres Assistsystem bei fortgeschrittener Herzinsuffizienz Identifizierung früher Infarktrisiken durch genomweite Assoziationsstudien Gensequenzierung zur Validierung der Wirksamkeit kardiovaskulärer Medikation

2012 SHEP-Langzeitdaten: Lebensverlängerung durch Blutdrucksenkung nachgewiesen

GISSI – Gruppo Italiano zum Studium des Überlebens nach Myokardinfarkt TIMI – Thrombolysis in Myocaridal Infarction (Organisation, Studienklaster, Klassifikation des Durchfluss) ISIS – International Studies of Infarct Survival (ISIS-1 bis -4) Quelle: Eugene Braunwald, NEJM 2012/Cardio News Mai 2012

1967 Herztransplantation (Barnard)

• Diagnostik

• Prävention

• Pharmakologische Therapie

• Interventionelle Therapie

• Operationen

DAPT

PCI/Stent

ACS/PCI TAVI

MitralClip

Okkluder

(PFO/LAA)

Duale Antiplättchen Therapie (DAPT)

Art und Dauer der DAPT

• Krankheitsbild (stabile KHK, ACS)

• Intervention (BMS, DES)

• Begleiterkrankungen (Vorhofflimmern)

• Blutungsrisiko

• Individuelles Stent-Thromboserisiko

• Begleitfaktoren (Diabetes)

• Individuelle Arztentscheidung

• Patienten-Compliance

DAPT-Leitlinien bei ACS (ESC/EACTS) - 2014

EHJ 2014

DAPT 12 Monate bei ACS

DAPT-Leitlinien bei PCI/stabile KHK (ESC/EACTS) - 2014

EHJ 2014

DAPT 6 Monate bei stabiler KHK/PCI

EPICOR

Aim: to describe current international patterns of the use of DAPT after discharge

in patients surviving hospitalization for ACS using data from the EPICOR study

Background

Bueno H et al., AHA 2014

Modified after: Bueno H et al., Am Heart J 2013;165:8-14

8

Index event Inclusion

Pre-hospital In-hospital Post-discharge

Day 0 Phone call FU at 6 w and quarterly

24 months

after index event

Acute phase Long-term FU

• Basline data

• Short-term medical management from

symptoms onset: antithrombotics (dose

+ timing), invasive procedure

• Early clinical outcomes

• Economic evalutation

• Long-term medical management

• Post-discharge clinical outcomes

• QoL-assessment

• Persistence on antithrombotic treatment:

planned + unplanned interruptions

• Economic evaluation

Admission Discharge

EPICOR Results – changes in DAPT over time in patients

discharged on DAPT

Bueno H et al., AHA 2014 9

0 6

Months since discharge

10 14 22

8000

6000

4000

2000

0

Num

ber

of patients

20 18 16 12 8 4 2

DAPT Aspirin only Other antiplatelet only None Died Lost to FU

EPICOR Results – persistence on DAPT at the end of FU by

country in patients discharged on DAPT

Bueno H et al., AHA 2014 10

Eastern Europe

P<0.001

Latin America

P<0.001

Northern Europe

P<0.001

Southern Europe

P<0.001

Pe

rcen

tage o

f p

atie

nts

rem

ain

ing o

n D

AP

T

%

62.9% 66.6% 63.0%

55.5%

DAPT

6-12 Monate


>12 Monate <6 Monate

Stentthrombose?

Blutungsrisiko?

MI, Stroke, or Death – ITT Population

* Plus ASA and other standard therapies

Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420.

Co

mb

ine

d E

nd

po

int

Occu

rren

ce (

%)

Months From Randomization

27% RRR P=0.02

Placebo* (28d Clp)

Clopidogrel* (1a Clp)

0

5

10

15

8.5%

11.5%

0 3 6 9 12

CREDO: Long-Term (1 Year) Benefits of Clopidogrel in PCI Patients

* Plus ASA and other standard therapies † 101 patients underwent CABG in the clopidogrel group ‡ 99 patients underwent CABG in the placebo group

ITT=Intent-To-Treat population

Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420.

8 17 Non-CABG

55 64 CABG

0.12 63 (5.9%)‡ 81 (7.7%)† Procedural

0.28 8 (0.8%) 13 (1.2%) Non-procedural

0.07 71 (6.7%) 93 (8.8%) Any

P-value Placebo* (n=1,063)

Clopidogrel* (n=1,053)

Major Bleeding

CREDO: Safety Outcomes: Major Bleeding Events One-Year Results ITT

Blutung erhöht die Mortalität! M

ort

ality

(%

)

No bleeding

Moderate bleeding

Severe bleeding

Life threatening bleeding

days

25,0

20,0

15,0

10,0

5,0

0,0

0 30 60 90 120 150 180

CURE: 12.559 patients

Modified according to Eikelboom JW et al. Circulation 2006; 114: 774-782

Off-label/Real-world DES thrombosis

Rotterdam/Bern Registry

• 8,146 consecutive (ALL) DES cases in Bern/Rotterdam 2002 - 2005

• Angiographically proven ST

• 90% of all DES patients complete clinical follow-up

Wenaweser

FDA Hearing 12/06

Lancet in press

Stent-Thrombose

ARC Definition patient level meta-analyses

Definite or probable

1.5%

0.9%

1.5%

1.8%

0.7%

1.4%

Stent-Thrombose

Randomisierte Studien Langzeit vs. Kurzzeit DAPT bei elektiver

PCI

Ischemic Endpoints By DAPT Duration In Randomized Trials

Adapted from t Gwon et al. ACC 2011

tt Valgimigli et al. ESC 2011

ttt Park et al. NEJM 2010;362:1374

tttt Feres et al. TCT 2013 LBCT

*Cardiac death / MI / TVR

**Death / MI, CVA, Revasc

***Death/MI/Revasc

EXCELLENT t PRODIGY tt REAL-LATE/ OPTIMIZE tttt ZEST-LATE ttt

6 mos (n=957) 6 mos (n=1546) 12 mos (n=1344) 3 mos (n=1563)

12 mos (n=970) 24 mos (n=1500) 24 mos (n=1357) 12 mos (n=1556)

Ischemic events

Bleeding events


Aktuelle Daten?

DAPT Dual antiplatelet therapy beyond one year after drug-eluting corornary stent procedures

Mauri L et al., Hotline Session AHA 2014

Mauri L et al., NEJM 2014

DAPT Study flow



Index stent

procedure

0-12

months: all

subjects on

open-label

DAPT

At month 12:

1:1

randomization

occurs

12-30

months:

blinded

treatment

occurs

30 months:

primary

endpoint

33 months:

Follow-up

DES treated

subjects 22,866 9,961

5,020 receive

thienopyridine + ASA

4,941 receive

placebo + ASA

9,499

(95.4%)

9,390

(94.3%)

12 vs 30

DAPT Primary endpoint



Months since enrollment

Stent thrombosis 12-30 mo Thienopyridine vs. placebo, 0.4% vs 1.4%;

hazard ratio, 0.29; P<0.001

12-33 mo Thienopyridine vs. placebo, 0.7% vs 1.4%; hazard ratio, 0.45; P<0.001

10 Cu

mu

lati

ve in

cid

en

ce (

%)

20

30

40

50

60

70

80

90

100

0 0 12 15 18 21 24 27 30 3

3

12 15 18 21 24 27 30 33

0

2

4

6

8

0

5020

4941

4934

4845

4870

4775

4828

4721

4765

4651

4686

4603

4642

4556

Thienopyridine

Placebo

3110

3105

No. at risk

Thienopyridine

Placebo

Months since enrollment

Major adverse cardiovascular and

cerebrovascular events 12-30 mo Thienopyridine vs placebo, 4.3% vs. 5.9%;

hazard ratio, 0.71; P<0.001

. 12-33 mo Thienopyridine vs placebo, 5.6% vs 6.5%; hazard ratio, 0.82; P=0.02

10 Cu

mu

lati

ve in

cid

en

ce (

%)

20

30

40

50

60

70

80

90

100

0 0 12 15 18 21 24 27 30 3

3

12 15 18 21 24 27 30 33

0

2

4

6

8

0

5020

4941

4917

4799

4840

4715

4778

4635

4702

4542

4611

4476

4554

4412

Thienopyridine

Placebo

3029

2997

No. at risk

Thienopyridine

Placebo

DAPT Co-primary effectiveness endpoints & components: 12-30 months



P<0.001 P<0.001

P=0.55

P<0.001

P=0.052

P<0.001

P=0.16

P=0.68

Cu

mu

lative

in

cid

en

ce

(%

)

%

DAPT

• Continued treatment with thienopyridine did not meet the prespecified safety criterion for

non-inferiority to placebo

• There was no significant difference between the randomized treatments with respect to

severe bleeding according to the GUSTO criteria (0.81% versus 0.56%) or with respect

to fatal bleeding (type 5 bleeding) according to the BARC criteria (0.15% and 0.09%,

respectively; P=0.38)

Safety (bleeding)



Bleeding complications

Continued

thienopyridine

N=4710

Placebo

N=4649

Difference

%-points

(95% CI)

Two-sided

P-value for

difference

GUSTO severe or moderate

Severe

Moderate

119 (2.5)

38 (0.8)

81 (1.7)

73 (1.6)

26 (0.6)

48 (1.0)

1.0 (0.4-1.5)

0.2 (-0.1-0.6)

0.7 (0.2-1.2)

0.001

0.15

0.004

BARC type 2, 3 or 5

Type 2

Type 3

Type 5

263 (5.6)

145 (3.1)

122 (2.6)

7 (0.1)

137 (2.9)

72 (1.5)

68 (1.5)

4 (0.1)

2.6 (1.8-3.5)

1.5 (0.9-2.1)

1.1 (0.6-1.7)

0.1 (-0.1-0.2)

<0.001

<0.001

<0.001

0.38

Bleeding endpoint during month 12 to month 30

DAPT

• Following drug-eluting stent treatment, continuation of thienopyridine plus

aspirin beyond one year reduces the risk of stent thrombosis and MACCE

compared with aspirin alone

– Relative reductions of 71% for ST, 29% for MACCE and 53% for MI

– Myocardial infarction were reduced, both in the stent and in other locations

– Treatment benefit on ST and MI consistent across drugs, for newer and older stents, and across subjects

with higher or lower risk of events

• The benefit of extended thienopyridine treatment was tempered by an

increase in bleeding events (relative increase 61%). Severe and/or fatal

bleeding was uncommon

• Non-cardiovascular mortality during treatment period was higher with

continued thienopyridine therapy

• Continued thienopyridine therapy markedly reduces both stent-related and

other ischemic events beyond the stent-treated region in patients who have

tolerated one year of DAPT after drug-eluting coronary stent treatment

Conclusion and clinical relevance



Included for analysis

N=2003

ISAR-SAFE Study flow

Schulz-Schuepke S et al., AHA 2014

DES

Continuous clopidogrel therapy for 6 months

Randomization

N=4005

6 months placebo

N=1998

6 months clopidogrel

N=2007

Included for analysis

N=1997

Study therapy not initiated, N=4

• Immediate withdawal of consent,

N=2

• Physician decision due to

erroneous enrolment, N=2

Study therapy not initiated, N=1

• Immediate withdawal of consent,

N=1

Incomplete 9-month FU, N=127

Premature study drug discontinuation, N=255

Incomplete 9-month FU, N=135

Premature study drug discontinuation, N=277 Mo

nth

s a

fte

r in

de

x P

CI

15

6

0

6 vs 12

ISAR-SAFE Primary endpoint


0

Months after randomization

Co

mp

osit

e o

d d

eath

, M

I, s

ten

t th

rom

bo

sis

,

str

oke o

r T

IMI m

ajo

r b

leed

ing

(%

)

0

1

2

3

4

5

1 2 3 4 5 6 7 8 9

12 months of clopidogrel

-0.1%, 1-sided 95% CI 0.5%, P Noninferiority <0.001

1.6%

1.5%


6 vs 12

ISAR-SAFE Ischemic endpoint vs. bleeding


0


0

1

2

3

4

5

1 2 3 4 5 6 7 8 9


HR 0.87 (95% CI 0.51-1.47), P=0.59

1.5%

1.3%


Composite of death, MI, stent thrombosis, stroke)

Incid

en

ce

0


0

1

2

3

4

5

1 2 3 4 5 6 7 8 9


HR 0.46 (95% CI 0.18-1.21), P=0.12

0.7%

0.3% 6 months of clopidogrel

Incid

en

ce

TIMI major or minor bleeding

ITALIC Major inclusion criteria

1. Patients > 18 years

2. At least 1 Xience V DES implanted

3. Not pretreated with abciximab

4. Exclusion of aspirin resistance

Study flow

Gilard M et al., AHA 2014

Patient with Xience V implantation

N=2031

Aspirin resistant With or without dose adjustment

N=137

Good aspirin responders Randomization

N=1894

Randomization applied No events during first 6 months

N=1850

Resistant group Clopidogrel (Prasugrel or ticagrelor) +

aspirin duration decided by the team

FU: 131 at 1 y

Group 1 DAPT for another 18 months

followed by aspirin alone

N=924

FU: 910 at 1 y

Group 2 aspirin alone

N=926

FU: 912 at 1 y

6 vs 24

ITALIC

Non-inferiority was established for 6 month vs. 24 month DAPT

Primary endpoint – 12 months

Gilard M et al., AHA 2014

1.6% 1.5%

0 2 4 6 8 10 12 months

24 months DAPT 910 910 910 910 905 901 896

6 months DAPT 912 912 912 911 905 900 897

Cum

ula

tive

de

ath

, M

I, T

VR

, str

oke

, m

ajo

r

ble

ed

ing r

ate

(%

)

DAPT-Leitlinien bei PCI/stabile KHK (ESC/EACTS) - 2014

EHJ 2014

DAPT 6 Monate bei stabiler KHK/PCI

Stentthrombose

Komplikationen nach PCI

Komplikationen der Koronaren Herzerkrankung/Atherosklerose

Frühes und spätes ischämisches Risiko und Blutungsrisiko

Risikoadjustierte DAPT


Tod und Myokardinfarkt

3-6 Monate

>6 Monate

Risikoprädiktoren im REACH Register 1

1 Bhatt et al. JAMA 2010; 304 (12):1350-1357

Risikoraten im REACH Register 1

1 Bhatt et al. JAMA 2010; 304 (12):1350-1357

Primary Endpoint (CV Death, MI, or Stroke) in

Patients with Previous MI, IS, or PAD “CAPRIE-

like Cohort”

RRR: 17.1 %

[95% CI: 4.4%, 28.1%]

p=0.01

Pri

mary

ou

tco

me e

ven

t ra

te (

%)

0

2

4

6

8

10

Months since randomization

0 6 12 18 24 30

Clopidogrel + ASA

7.3%

Placebo + ASA

8.8% N=9,478

Bhatt DL et al. JACC 2007;49:1982 CHARISMA

0%

2%

4%

6%

8%

10%

12%

0 180 360 540 720 900 1080

Ev

en

t R

ate

(%

)

Days since Randomization

Primary Efficacy Evaluation

Prior MI Cohort

CV Death, MI, or Stroke

8.1%

9.7%

Hazard Ratio 0.80;

95% CI 0.72 - 0.89

p < 0.001

Placebo

Vorapaxar

N = 17,779

Mean f/u: 2.5 years

>1 Jahr

Therapiedauer

Komponenten des primären

Wirksamkeitsendpunkts

Rivaroxaban 2,5 mg 2x/d, beide Strata

0

Monate

Kardiovaskulärer Tod

NNT = 71

5

0 24

4,1%

2,7%

Plazebo

Rivaroxaban 2,5 mg 2x/d

HR = 0,66

mITT p = 0,002

ITT p = 0,005

18 12 6 0

5

Gesamtmortalität

Monate

4,5%

2,9%

24 0

Plazebo


HR = 0,68

mITT p = 0,002

ITT p = 0,004

18 12 6

NNT = 63

Monate

CV-Tod/MI/Schlaganfall

Ku

mu

lati

ve

In

zid

en

z (

%)

HR = 0,84

mITT p = 0,02

ITT p = 0,007 10,7%

9,1%


Plazebo

13

0 24 0 18 12 6

NNT = 63

CV = Kardiovaskulär; HR = Hazard Ratio; MI = Myokardinfarkt; NNT = Number needed to treat

Mega JL et al. N Engl J Med 2011. DOI: 10.1056/NEJMoa1112277; Gibson CM et al. Presented at AHA Scientific Sessions 2011

History of MI 1-3 years prior + ≥ 1 additional

atherothrombosis risk factor *

Longterm DAPT beyond 1 year after MI

PEGASUS TIMI 54: Trial design

Ticagrelor

90mg bid Ticagrelor

60mg bid Placebo

Follow-Up visits Q4 months for first year, then Q6

months

Primary efficacy endpoint: CV death, MI, or stroke

N=~21,000

* Age ≥ 65 years, diabetes, second prior MI, multivessel CAD or chronic non-end-stage renal

dysfunction clinicaltrials.gov NCT01225562

RANDOMIZE

DOUBLE BLIND

Planned treatment with aspirin 75-150mg

and standard background care

Art und Dauer der DAPT

• Krankheitsbild (stabile KHK, ACS)

• Intervention (BMS, DES)

• Begleiterkrankungen (Vorhofflimmern)

• Blutungsrisiko

• Individuelles Stent-Thromboserisiko

• Begleitfaktoren (Diabetes)

• Individuelle Arztentscheidung

• Patienten-Compliance

Modified according to Seyffarth et al., Heart 2010

Stroke

Stroke: 2-20%/Jahr (Dauer)

Stent-Thrombose: 0.2-3% (Zeit)

Blutung: 0.5-15%/Jahr (Antithrombot.Therapie)

Antithrombotische Therapie

bei PCI und Vorhofflimmern

Evidenz für Triple-Therapie?

Randomisierte Studien zur

Triple-Therapie

WOEST

ISAR-Triple

(MUSICA-2)

|

Primary Endpoint: Total number of TIMI bleeding events

WOEST

Days

Cu

mu

lati

ve

in

cid

en

ce

of

ble

ed

ing

0 30 60 90 120 180 270 365

0 %

10 %

20 %

30 %

40 %

50 %

284 210 194 186 181 173 159 140 n at risk:

279 253 244 241 241 236 226 208

Triple therapy group Double therapy group 44.9%

19.5%

p<0.001

HR=0.36 95%CI[0.26-0.50]

Secondary Endpoint (Death, MI,TVR, Stroke, ST)

WOEST

Days

Cu

mu

lati

ve

in

cid

en

ce

0 30 60 90 120 180 270 365

0 %

5 %

10 %

15 %

20 %

284 272 270 266 261 252 242 223 n at risk:

279 276 273 270 266 263 258 234

17.7%

11.3%

p=0.025

HR=0.60 95%CI[0.38-0.94]

Triple therapy group Double therapy group

ISAR-Triple

ISAR-Triple

TCT 2014

Aktuelle Empfehlungen zur Triple-Therapie der europäischen Fachgesellschaften

Lip et al. EHJ 2014

Current Opinion der Fachgesellschaften

EHRA, EAPCI, ACCA

Monate 0 12 6

Nicht-valvuläres Vorhofflimmern + PCI

1. Schlaganfallrisiko Niedrig (CHADS-Vasc)

2. Blutungsrisiko Niedrig (HASBLED)

3. Klinik SAP/PCI

ASS

Clp

AK

4. Antithrombotische Therapie

Monate 0 12 6



2. Blutungsrisiko Hoch (HASBLED)

3. Klinik SAP/PCI

ASS

Clp

AK


Monate 0 12 6



2. Blutungsrisiko Niedrig (HASBLED)

3. Klinik ACS/PCI

ASS

Clp

AK


Monate 0 12 6



2. Blutungsrisiko Hoch (HASBLED)

3. Klinik ACS/PCI

ASS

Clp

AK


Lip et al. EHJ 2014

Current Opinion der Fachgesellschaften

EHRA, EAPCI, ACCA

Antithrombotische Therapie bei Koronarer Herzerkrankung



The never ending story - Triple, duo, mono

Orale Antithrombotische Therapie

Antikoagulation Antithrombozytäre Therapie

2008

Marcumar

2014

Aspirin

Clopidogrel

Rivaroxaban

Dabigatran

Apixaban

Edoxaban

Prasugrel

Ticagrelor

Vorapaxar



Vielen Dank für die Aufmerksamkeit!

Antithrombotische Therapie bei Koronarer Herzerkrankung Münch… · • Begleitfaktoren (Diabetes)...

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Transcript of Antithrombotische Therapie bei Koronarer Herzerkrankung Münch… · • Begleitfaktoren (Diabetes)...