Antithrombotische Therapie bei Koronarer Herzerkrankung

Antithrombotische Therapie bei Koronarer Herzerkrankung The never ending story Triple, duo, mono

Meinrad Gawaz Innere Medizin III, Kardiologie und Kreislauferkrankungen Eberhard Karls Universität Tübingen

Rückgang der Todesfälle aufgrund kardiovaskulärer Erkrankungen in Relation zum Wissenschaftlichen Fortschritt

600

1958 Koronarangiografie entwickelt (Jones)

1969 Erste Beschreibung einer Bypass-Operation (Favolo)

Tote auf 100.000 Einwohner

500

400

300

200

100

1954 Erste Prozedur am offenen Herzen (Gibbon)

1961 Risikofaktoren definiert (Julian) 1967 Herztransplanta tion (Barnard)

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

• Diagnostik • Prävention 0 1940 1950 1960 1970 • Pharmakologische Therapie • Interventionelle Therapie • Operationen

1980 Erster 1992 implantierbarer Reinfarktprophylaxe Kardiovertermit Captopril Defibrillator erfolgreich (SAVE) (Mirowski) 1976 Register zum 2007 Erster Herzinfarkt in Kardiale Cholesterinsenker Deutschland Resynchronisation (HMGCoA(Ludwigshafen) bei Herzinsuffizienz Reduktasehemmer) beschrieben 2009 1985 (Endo) Linksventrikuläres TIMI-1 Studie Assistsystem bei (bis heute 60 TIMIfortgeschrittener Studien) Herzinsuffizienz 2002 National Cholesterol ALLHAT: Education Programm Identifizierung früher Blutdrucksenkung (NECP) in den USA Infarktrisiken durch und Lipidsenkung 1979 genomweite zur Vermeidung KoronarAssoziationsstudien eines Herzinfarkts angioplastie entwickelt Gensequenzierung zur 1986 (Grüntzig) Validierung der Erster CoronarWirksamkeit Stent in Lausanne kardiovaskulärer (Sigwart) 1983 Medikation Coronary GISSI und ISIS-2: 2002 Wertigkeit von ASS Artery MedikamentenSurgery und Streptokinase freisetzende Study Stents (CASS)

1980

1990

2000 1993 Primär-PCI ist besser als Fibrinolyse

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

2010

2020

2012 SHEPLangzeitdaten: Lebensverlängerung durch Blutdrucksenkung nachgewiesen

Jahr

Duale Antiplättchen Therapie (DAPT) ACS/PCI

TAVI

DAPT

PCI/Stent

MitralClip

Okkluder (PFO/LAA)

Duale Antiplättchen Therapie (DAPT) ACS/PCI

TAVI

DAPT

PCI/Stent

MitralClip

Okkluder (PFO/LAA)

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

DAPT 12 Monate bei ACS

EHJ 2014

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

DAPT 6 Monate bei stabiler KHK/PCI

EHJ 2014

EPICOR Background 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 Inclusion

Index event

Pre-hospital

In-hospital

Post-discharge Phone call FU at 6 w and quarterly

Day 0 Admission

24 months after index event

Discharge

Acute phase

• Basline data • Short-term medical management from symptoms onset: antithrombotics (dose + timing), invasive procedure • Early clinical outcomes • Economic evalutation

Bueno H et al., AHA 2014 Modified after: Bueno H et al., Am Heart J 2013;165:8-14

Long-term FU • • • •

Long-term medical management Post-discharge clinical outcomes QoL-assessment Persistence on antithrombotic treatment: planned + unplanned interruptions • Economic evaluation

8

EPICOR

Results – changes in DAPT over time in patients discharged on DAPT 8000

Number of patients

6000

4000

2000

0 0

2

4

6

8

10

12

16

14

18

20

22

Months since discharge DAPT

Bueno H et al., AHA 2014

Aspirin only

Other antiplatelet only

None

Died

Lost to FU

9

EPICOR

Results – persistence on DAPT at the end of FU by country in patients discharged on DAPT Eastern Europe P<0.001

Latin America P<0.001

Northern Europe P<0.001

Southern Europe P<0.001

Percentage of patients remaining on DAPT

%

62.9%

Bueno H et al., AHA 2014

66.6%

63.0% 55.5%

10

Duale Antiplättchen Therapie (DAPT) Stentthrombose?

DAPT <6 Monate

6-12 Monate

Blutungsrisiko?

>12 Monate

CREDO: Long-Term (1 Year) Benefits of Clopidogrel in PCI Patients MI, Stroke, or Death – ITT Population 15

Combined Endpoint Occurrence (%)

Placebo* (28d Clp) Clopidogrel* (1a Clp) 11.5%

27% RRR 10

P=0.02 8.5%

5

0 0

3

6

9

Months From Randomization * Plus ASA and other standard therapies

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

12

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

Clopidogrel* (n=1,053)

Placebo* (n=1,063)

P-value

Any

93 (8.8%)

71 (6.7%)

0.07

Non-procedural

13 (1.2%)

8 (0.8%)

0.28

Procedural

81 (7.7%)†

63 (5.9%)‡

0.12

CABG

64

Non-CABG

17

55 8

Major Bleeding

* 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.

Blutung erhöht die Mortalität!

CURE: 12.559 patients 25,0

Life threatening bleeding

Mortality (%)

20,0 15,0 Severe bleeding

10,0 Moderate bleeding

5,0

No bleeding

0,0

0

30

60

90

120

150

180

days

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

Stent-Thrombose 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

1.8% 1.5%

1.5%

1.4%

0.9% 0.7%

Randomisierte Studien Langzeit vs. Kurzzeit DAPT bei elektiver PCI

Ischemic Endpoints By DAPT Duration In Randomized Trials

EXCELLENT t 6 mos (n=957) 12 mos (n=970)

*Cardiac death / MI / TVR **Death / MI, CVA, Revasc ***Death/MI/Revasc

PRODIGY tt

REAL-LATE/ ZEST-LATE ttt

6 mos (n=1546) 24 mos (n=1500)

12 mos (n=1344) 24 mos (n=1357)

Adapted from

OPTIMIZE tttt 3 mos (n=1563) 12 mos (n=1556)

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

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

Index stent procedure

0-12 months: all subjects on open-label DAPT

DES treated subjects 22,866


At month 12: 1:1 randomization occurs

12-30 months: blinded treatment occurs

5,020 receive thienopyridine + ASA 9,961 4,941 receive placebo + ASA

12 vs 30

Follow-up 30 months: primary endpoint

9,499 (95.4%)

33 months:

9,390 (94.3%)

DAPT Primary endpoint Major adverse cardiovascular and cerebrovascular events

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

Cumulative incidence (%)

100

8

90 80 70

6

60

4

50 40 30 20

Thienopyridine Placebo

2 0

10 0 0

0

12

12

15

15

18

18

21

21

24

27

24

27

30

33

30

3 3

Months since enrollment No. at risk Thienopyridine Placebo

5020 4941

4934 4845

4870 4775

4828 4721


4765 4651

4686 4603

4642 4556

3110 3105


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=0.02 100 8 Thienopyridine 90 Placebo 6 80 70 4

60 50 40 30 20

2 0

10 0 0

0

12

12

15

15

18

18

21

21

24

27

30

33

27

30

3 3

4611 4476

4554 4412

3029 2997

24

Months since enrollment No. at risk Thienopyridine Placebo

5020 4941

4917 4799

4840 4715

4778 4635

4702 4542

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


P<0.001

P<0.001

P=0.052 P<0.001

P<0.001

P=0.16 P=0.55


P=0.68

DAPT Safety (bleeding) Bleeding endpoint during month 12 to month 30 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 complications

•

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)


DAPT Conclusion and clinical relevance • 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


ISAR-SAFE Study flow

DES Continuous clopidogrel therapy for 6 months

6

Randomization N=4005

Months after index PCI

0

15

6 months placebo N=1998 Study therapy not initiated, N=1 • Immediate withdawal of consent, N=1

6 months clopidogrel N=2007 Study therapy not initiated, N=4 • Immediate withdawal of consent, N=2 • Physician decision due to erroneous enrolment, N=2

Incomplete 9-month FU, N=127 Premature study drug discontinuation, N=255

Incomplete 9-month FU, N=135 Premature study drug discontinuation, N=277

Included for analysis N=1997

Included for analysis N=2003

Schulz-Schuepke S et al., AHA 2014

6 vs 12

ISAR-SAFE Primary endpoint 5

Composite od death, MI, stent thrombosis, stroke or TIMI major bleeding (%)

 -0.1%, 1-sided 95% CI 0.5%, P Noninferiority <0.001 4

3

12 months of clopidogrel

2

1.6% 1.5%

1

6 months of clopidogrel 0 0

1

2

3

4

5

6

Months after randomization


6 vs 12

7

8

9

ISAR-SAFE Ischemic endpoint vs. bleeding Composite of death, MI, stent thrombosis, stroke)

TIMI major or minor bleeding

5

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

4

4

3

3

2

12 months of clopidogrel 1.5%

Incidence

Incidence

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

2

1.3% 1


1


0 0

1

2

3

4

5

6

7



8

9

0.7% 0.3% 6 months of clopidogrel

0 0

1

2

3

4

5

6

7


8

9

ITALIC Study flow

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

Patient with Xience V implantation N=2031

Aspirin resistant

Good aspirin responders

With or without dose adjustment N=137

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

Gilard M et al., AHA 2014

6 vs 24

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

ITALIC

Cumulative death, MI, TVR, stroke, major bleeding rate (%)

Primary endpoint – 12 months

24 months DAPT 6 months DAPT

1.6% 1.5% 0

910 912

2

4

910 912

6

910 912

8

910 911

10

905 905

 Non-inferiority was established for 6 month vs. 24 month DAPT Gilard M et al., AHA 2014

12 months

901 900

896 897

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

DAPT 6 Monate bei stabiler KHK/PCI

EHJ 2014

Duale Antiplättchen Therapie (DAPT) Risikoadjustierte DAPT Frühes und spätes ischämisches Risiko und Blutungsrisiko

Stentthrombose

Tod und Myokardinfarkt

3-6 Monate Komplikationen nach PCI

>6 Monate Komplikationen der Koronaren Herzerkrankung/Atherosklerose

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 “CAPRIElike Cohort” Primary outcome event rate (%)

10

N=9,478

Placebo + ASA 8.8%

8

Clopidogrel + ASA 7.3%

6

4

RRR: 17.1 % [95% CI: 4.4%, 28.1%] p=0.01

2

0 0

6

12

18

24

30

Months since randomization Bhatt DL et al. JACC 2007;49:1982

CHARISMA

Primary Efficacy Evaluation Prior MI Cohort CV Death, MI, or Stroke 12%

N = 17,779 Mean f/u: 2.5 years

Event Rate (%)

10%

Placebo

9.7% Hazard Ratio 0.80; 95% CI 0.72 - 0.89 p < 0.001

8%

8.1% Vorapaxar

6%

4%

2%

0% 0

180

360

540

720

Days since Randomization

900

1080

>1 Jahr Therapiedauer

Komponenten des primären Wirksamkeitsendpunkts Rivaroxaban 2,5 mg 2x/d, beide Strata CV-Tod/MI/Schlaganfall 13

Kardiovaskulärer Tod 5

HR = 0,84

Kumulative Inzidenz (%)

mITT p = 0,02 Plazebo 10,7% ITT p = 0,007

5

HR = 0,66 mITT p = 0,002 ITT p = 0,005

Gesamtmortalität HR = 0,68

Plazebo

mITT p = 0,002 ITT p = 0,004

4,1%

Plazebo 4,5%

9,1% 2,9%

2,7%

Rivaroxaban 2,5 mg 2x/d

Rivaroxaban

Rivaroxaban

2,5 mg 2x/d

2,5 mg 2x/d

NNT = 63 0

NNT = 71 0

0

6

12 18 Monate

24

NNT = 63 0

0

6

12 18 Monate

24

0

6

12 18 Monate

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

24

Longterm DAPT beyond 1 year after MI PEGASUS TIMI 54: Trial design N=~21,000

History of MI 1-3 years prior + ≥ 1 additional atherothrombosis risk factor * Planned treatment with aspirin 75-150mg and standard background care

RANDOMIZE DOUBLE BLIND

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 * Age ≥ 65 years, diabetes, second prior MI, multivessel CAD or chronic non-end-stage renal dysfunction clinicaltrials.gov NCT01225562

Art und Dauer der DAPT • Krankheitsbild (stabile KHK, ACS)

• Intervention (BMS, DES) • Begleiterkrankungen (Vorhofflimmern) •

Blutungsrisiko

•

Individuelles Stent-Thromboserisiko

•

Begleitfaktoren (Diabetes)

•

Individuelle Arztentscheidung

•

Patienten-Compliance

Stroke: 2-20%/Jahr (Dauer) Stent-Thrombose: 0.2-3% (Zeit) Blutung: 0.5-15%/Jahr (Antithrombot.Therapie)

Stroke

Modified according to Seyffarth et al., Heart 2010

Antithrombotische Therapie bei PCI und Vorhofflimmern

Evidenz für Triple-Therapie?

Randomisierte Studien zur Triple-Therapie

WOEST ISAR-Triple (MUSICA-2)

WOEST

Primary Endpoint: Total number of TIMI bleeding events

Triple therapy group Double therapy group

Cumulative incidence of bleeding

50 %

44.9%

40 %

30 %

19.5% 20 %

10 %

p<0.001 HR=0.36 95%CI[0.26-0.50]

0% 0

30

60

90

120

180

270

365

159 226

140 208

Days n at risk: |

284 210 194 186 181 279 253 244 241 241

173 236

WOEST

Secondary Endpoint (Death, MI,TVR, Stroke, ST) Triple therapy group Double therapy group

Cumulative incidence

20 %

17.7%

15 %

11.3% 10 %

5%

p=0.025 HR=0.60 95%CI[0.38-0.94] 0% 0

30

60

90

120

180

270

365

242 258

223 234

Days n at risk:

284 272 270 266 261 279 276 273 270 266

252 263

ISAR-Triple

ISAR-Triple

TCT 2014

Aktuelle Empfehlungen zur Triple-Therapie der europäischen Fachgesellschaften

Current Opinion der Fachgesellschaften EHRA, EAPCI, ACCA

Lip et al. EHJ 2014

Nicht-valvuläres Vorhofflimmern + PCI

ASS Clp

1. Schlaganfallrisiko

Niedrig (CHADS-Vasc)

2. Blutungsrisiko

Niedrig (HASBLED)

3. Klinik

SAP/PCI

AK

4. Antithrombotische Therapie

0

6 Monate

12


ASS Clp



2. Blutungsrisiko

Hoch (HASBLED)

3. Klinik

SAP/PCI

AK


0

6 Monate

12


ASS Clp



2. Blutungsrisiko

Niedrig (HASBLED)

3. Klinik

ACS/PCI

AK


0

6 Monate

12


ASS Clp



2. Blutungsrisiko

Hoch (HASBLED)

3. Klinik

ACS/PCI

AK


0

6 Monate

12

Current Opinion der Fachgesellschaften EHRA, EAPCI, ACCA

Lip et al. EHJ 2014

Antithrombotische Therapie bei Koronarer Herzerkrankung The never ending story Triple, duo, mono


Orale Antithrombotische Therapie Antikoagulation

Marcumar

Antithrombozytäre Therapie

Aspirin Clopidogrel

2008

2014

Rivaroxaban Dabigatran Apixaban

Prasugrel Ticagrelor

Edoxaban

Vorapaxar

Vielen Dank für die Aufmerksamkeit!


Antithrombotische Therapie bei Koronarer Herzerkrankung

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