antithrombotische therapie bei koronarer herzerkrankung münch… · • begleitfaktoren (diabetes)...
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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)
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
Duale Antiplättchen Therapie (DAPT)
>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
Duale Antiplättchen Therapie (DAPT)
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
Mauri L et al., Hotline Session AHA 2014
Mauri L et al., NEJM 2014
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
Mauri L et al., Hotline Session AHA 2014
Mauri L et al., NEJM 2014
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
Mauri L et al., Hotline Session AHA 2014
Mauri L et al., NEJM 2014
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)
Mauri L et al., Hotline Session AHA 2014
Mauri L et al., NEJM 2014
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
Mauri L et al., Hotline Session AHA 2014
Mauri L et al., NEJM 2014
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
Schulz-Schuepke S et al., AHA 2014
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 months of clopidogrel
6 vs 12
ISAR-SAFE Ischemic endpoint vs. bleeding
Schulz-Schuepke S et al., AHA 2014
0
Months after randomization
0
1
2
3
4
5
1 2 3 4 5 6 7 8 9
12 months of clopidogrel
HR 0.87 (95% CI 0.51-1.47), P=0.59
1.5%
1.3%
6 months of clopidogrel
Composite of death, MI, stent thrombosis, stroke)
Incid
en
ce
0
Months after randomization
0
1
2
3
4
5
1 2 3 4 5 6 7 8 9
12 months of clopidogrel
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
Duale Antiplättchen Therapie (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
Rivaroxaban 2,5 mg 2x/d
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%
Rivaroxaban 2,5 mg 2x/d
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
Nicht-valvuläres Vorhofflimmern + PCI
1. Schlaganfallrisiko Niedrig (CHADS-Vasc)
2. Blutungsrisiko Hoch (HASBLED)
3. Klinik SAP/PCI
ASS
Clp
AK
4. Antithrombotische Therapie
Monate 0 12 6
Nicht-valvuläres Vorhofflimmern + PCI
1. Schlaganfallrisiko Niedrig (CHADS-Vasc)
2. Blutungsrisiko Niedrig (HASBLED)
3. Klinik ACS/PCI
ASS
Clp
AK
4. Antithrombotische Therapie
Monate 0 12 6
Nicht-valvuläres Vorhofflimmern + PCI
1. Schlaganfallrisiko Niedrig (CHADS-Vasc)
2. Blutungsrisiko Hoch (HASBLED)
3. Klinik ACS/PCI
ASS
Clp
AK
4. Antithrombotische Therapie
Lip et al. EHJ 2014
Current Opinion der Fachgesellschaften
EHRA, EAPCI, ACCA
Antithrombotische Therapie bei Koronarer Herzerkrankung
Meinrad Gawaz Innere Medizin III, Kardiologie und Kreislauferkrankungen
Eberhard Karls Universität Tübingen
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
Meinrad Gawaz Innere Medizin III, Kardiologie und Kreislauferkrankungen
Eberhard Karls Universität Tübingen
Vielen Dank für die Aufmerksamkeit!