Ontstolling in de dagelijkse praktijk casuïstiek · • AF en CVA 1990 • Ischemische...

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Alles wat u wilt weten over ontstolling en plaatjesremming bij CAD, hartfalen, AF en stents (VKA,

NOAC, aspirine, clopidogrel, prasugrel en ticagrelor)

Ontstolling in de dagelijkse praktijkcasuïstiek

Jur ten Berg, cardioloog

2016

Disclosures

• Advisory / consulting fees: AstraZeneca, Eli Lilly,

Daiichi Sankyo, the Medicines Company,

Accumetrics, Boehringer-Ingelheim, BMS

• Research grants: ZonMw, AstraZeneca

• Patiënt 65 jaar• Asymptomatisch. “Krijg ik ook een hartinfarct, fam

belast voor HVZ”• Hypertensie sinds 50e, ACE-remmer• Rookt, hypercholesterolemie (TCh 6; LDL 3,5 mmol/l)• Vader 55 AMI en 70 colon ca

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Casus I

• ASA?

1. Ja2. nee

Eerste 6 studies meta-analyse ATT Antithrombotic Trialist Collaboration 2009

• Per 10.000 treated for 10 years

• 72 events (CV death, MI, or stroke) prevented• 51 cancer deaths prevented• 47 major bleedings (149 GI bleeds) incurred• 9 hemorrhagic strokes incurred

• Effect man=woman• DM not sufficient risk

• Bleeding as severe as MI?

Casus I

6

Tailoring therapy according to baseline risk

• Framingham coronary heart disease risk score: 10-jr MI/death

• ESC’s SCORE: 10-jr fatal atherosclerotic event 5% fatal ~ 15% (x3) total

events

• Patient 17% risk (ESC’s SCORE): antwoord 1: ja aspirine

• Patiënt 50 jr

• Hypertensie, ACE-remmer

• Gedilateerde cardiomyopathie, geen CAD

• Echo: EF 30%, atria gedilateerd

Casus II HF en SR

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Vraag: 1. OAC

2. ASA

3. Nix

Hartfalen en SR

No placebo

• Death, non-fatal MI, non-fatal stroke: Warfarin = aspirin

• Major bleeding: warfarin higher

• Stroke: warfarin lower

• Wash studie: no medication similar to ASA or warfarin

ASA vs warfarin

ASA vs warfarin vs No

1212

Very low EF

Wel indicatie!

• Patiënt 60 jr

• Hypertensie, ACE-remmer

• AF en CVA 1990

• Ischemische cardiomyopathie

• Stabiel AP II CCS, PCI DES 2013

• Echo: EF 30%, murale trombus, atria gedilateerd

• ECG: SR, lichte ST-T afw

Casus III Hf en coronairlijden

11

1. OAC2. ASA3. OAC en ASA

NOAC = VKA. When combined NOAC plus APT use lower dose NOAC

1212

Casus IV

13

• Man 55 jaar, DM II, in 2012 OWI, hypertensie met GFR = 48 ml/min, rookt.

• STEMI 4 oktober 2016 DES proximale LAD, 9 oktober PCI Cx en diffuus RCA

• Geen recidief, geen bloeding

• 4 oktober 2017 polikliniek

a) P2Y12 remmer (ticagrelor) had al gestopt moeten zijn

b) Nu stop

c) Nog jaren continueren

BMS versus 1st and 2nd generation DES

Results from a registry of 18,334 unselected patients*

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Jaren na procedure

% 3

0

2

Jaren na procedure

% 3

0

1

Tada T, et al. JACC Cardiovasc Interv 2013

Stent thrombosis Stent thrombosis; 1st year and for the period

after the 1st year (separately)

1

0 1 32 0 1 32

2

HR adj.

2,05

0,82

n

18.334

BMS

o-DES

n-DES

95% CI

1,47 – 2,86

0,56 – 1,19

P value

<0,001

0,30

HR adj.

4,72

1,01

n

18.334

BMS

o-DES

n-DES

95% CI

2,01 – 11,1

0,32 – 3,25

P value

<0,001

0,98

* patients undergoing coronary stenting

Meta-analysis

Trial EXCELLENT PRODIGY REAL/ZEST-LATE

RESET

Primary endpoint Composite of cardiac death, MI, or ID-TVR

Composite of all-cause death, MI or CVAs

MI or cardiac death Composite of cardiac death, MI, ST, ID-TVR and TIMI major

or minor bleeding

Time to randomization At index PCI 1 month after index PCI 12 months after index PCI

At index PCI

DAPT duration

Extended DAPT Group

12 months 24 months 24 months 12 months

Control DAPT Group 6 months 6 months 12 months 3 months

Longest FU 12 months 24 months 24 months 12 months

Kort DAPT even veilig als lang DAPT

12,536 pts randomized to stop DAPT at 3, 6 or 12 months vs. 12 or 24 months

Collet J et al. Lancet. 2014 Jul 15. pii: S0140-6736(14)60612-7. doi: 10.1016/S0140-6736(14)60612-7

I A

DAPT duration in Stable Coronary Artery Disease

According to ESC Guidelines (not our patient!)

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DAPT is indicated for at least 1 month after BMS implantation

Recommendations for antithrombotic treatment in patients with SCAD undergoing PCI

I A

DAPT is indicated for 6 months after DES implantation I B

Myocardial revascularization Guidelines (2014)

Shorter DAPT duration (<6 months) may be considered after DES implantation in patients at high

bleeding riskIIb A

Life-long single antiplatelet therapy, usually ASA, is recommended

Instruction of patients about the importance of complying with antiplatelet therapy is recommended I C

DAPT may be used for more than 6 months in patients at high ischemic risk and low bleeding risk IIb C

Windecker et al. Eur Heart J 2014;35(37):2541-619

Pas op:

• Studies merendeel low risk patienten

• Geen power om een verschil in stent trombose aan te tonen

DAPT N=9000

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12 month observational

period: Open-label

Thienopyridine + Aspririn

requiredPlacebo + Aspirin

Thienopyridines + Aspirin3 month observational

period:

Off Thienopyridine +

On Aspririn

Time in months after index stent

procedure (not scale)

Previous studies underpowered

Designed in response to FDA-request

R Study drug

treatment ends

Free from MI, stroke, repeat revascularization and bleeding, adherent to P2Y12

0 12 30 33

Mauri et al. NEJM DOI:10.1056/NEJMoa1409312

DAPT

Primary endpoint

19

Maanden na randomisatie

5,6

6,5

0 12 15 18 21 30 33

% 8

6

4

0


Death, MI, Stroke

24 27

2

HR

0,29

P value

<0,001

n

9.961

12 months

30 months

4,3

5,9

95% CI

0,59 – 0,85

DAPT

Primary endpoint

20


0,7

1,4

0 12 15 18 21 30 33

% 8

6

4

0

Stent Thrombosis

24 27

2

0,4

1,4

HR

1,03

95% CI

0,17 – 0,48

P value

0,03

n

9.961

12 months

30 months


DAPT

Primary endpoint

21


0 12 15 18 21 30 33

% 10

8

6

0

Not-Stent Thrombosis Myocardial Infarction

24 27

4

HR

0,59

95% CI

0,45 – 0,78

P value

<0,001

n

9.961

12 months

30 months


1,8

2,955% of the MI

benefit is NOT

related to stent

thrombosis

DAPT

Bleedings

22

TIMI

Moderate or

Severe

% 4

3

2

0

2,5

1,61,7

1,0

0,80,6

3,1

1,5

2,6

1,5

0,1 0,1

0,001

0,004

0,15

<0,001

<0,001

0,38

Moderate Severe BARC

Type 2

BARC

Type 3

BARC

Type 5

12 months

30 months

1

DAPT

Cause for difference in mortality?

23

12-30 M mortality

All cause mortality

Cardiac

Vascular

Non-cardiovascular

(bleeding, trauma, cancer)


Thienopyridine

N=5.020

98 (2,0%)

45 (0,9%)

5 (0,1%)

48 (1,0%)

Placebo

N=4.941

74 (1,5%)

47 (1,0%)

5 (0,1%)

22 (0,5%)

P value

0,052

0,98

0,98

0,002

Absolute

Difference

24 (0,5%)

-2 (-0,1%)

0 (-)

26 (0,5%)

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School



N= 21.000

age of 65 years or older, diabetes mellitus requiring medication, a second prior spontaneous myocardial infarction, multivessel coronary artery

disease, or chronic renal dysfunction, defined as an estimated creatinine clearance of less than 60 ml per minute.

Reduction in CV death, MI or stroke with ticagrelor by time from P2Y12 inhibitor withdrawal

27Bonaca MP et al. Eur Heart J 2016; 37(14): 1133-42

0.70 (0.57, 0.87)

0.75 (0.61, 0.92)

0.73 (0.61, 0.87) <0.001

0.90 (0.72, 1.12)

0.82 (0.65, 1.02)

0.86 (0.71, 1.04) 0.11

0.96 (0.73, 1.26)

1.06 (0.81, 1.38)

1.01 (0.80, 1.27) 0.96

Ticagrelor 90 mg

Ticagrelor 60 mg

PooledPlacebo betterTicagrelor better 1.0

HR (95% CI) P value

≤30 days

n=7181

>30 days

to 1 year

n=6501

>1 year

n=5079

Time from P2Y12 inhibitor withdrawal to

randomization

P-interaction 0.0097

27% RRR

14% RRR

RRR

0.7 0.9 1.1

Casus IV

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• Man 40 jaar, DM I, hypertensie met GFR = 48 ml/min, rookt, fam HVZ

• STEMI 4 oktober 2016 DES proximale LAD, 9 oktober PCI Cx en diffuus RCA

• Geen recidief, geen bloeding

• 4 oktober 2017 polikliniek

a) P2Y12 remmer (ticagrelor) had al gestopt moeten zijn

b) Nu stop

c) Nog jaren continueren

PEGASUS: age of 65 years or older, diabetes mellitus requiring medication, a

second prior spontaneous myocardial infarction, multivessel coronary artery

disease, or chronic renal dysfunction, defined as an estimated creatinine

clearance of less than 60 ml per minute.

DAPT: no event first year

Casus V

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• Vrouw 87 jaar, 57 kg, hypertensie, maag bloeding ulcus 2013

• NSTEMI en PCI DES prox LAD succesvol 21 sept 2016

a) 1 jaar DAPT

b) 6 maanden DAPT

c) 3 maanden DAPT

I A

DAPT is indicated for at least 1 month after BMS implantation I A

DAPT is indicated for 6 months after DES implantation I B

Shorter DAPT duration (<6 months) may be considered after DES implantation in patients at high

bleeding riskIIb A

Life-long single antiplatelet therapy, usually ASA, is recommended

I C

Personal Information

Sex Male

Age 83

Blood pressure 161/89 mmHg

Pulse 69 bpm

Oxygen saturation 97%

Patient: Paul*

Patient History

Medical History

• Hypertension (diagnosed 2004)

• Type 2 diabetes mellitus

• Paroxysmal NVAF (diagnosed 2012;

CHA2DS2-VASc: 5)

• Peripheral artery disease

• Renal insufficiency (GFR = 38 ml/min)

Medications

• β-blocker

• Statin

• ACE inhibitor

• Antidiabetics

• NOAC since 2013 (because of labile INR/low TTR)

Presentation • Heavy chest pain (40 min, previous night)

• Pain-free at presentation

• Nonstemi

Case VI

Study Design: Multicenter, randomized, open-label trial following a PROBE design

R

Randomization

≤120 hours

post-PCI* 6-month minimum treatment duration with visits every 3 months for the first year, then visits

and telephone contact alternating every 3 months and a 1-month post-treatment visit

Patients with AF

undergoing PCI

with stenting

no recent Stroke

CrCl <30mL/min

Dabigatran 150 mg BID + P2Y12 inhibitor

Dabigatran 110 mg BID + P2Y12 inhibitor

Warfarin (INR 2.0–3.0) + P2Y12 inhibitor + ASA

Dabigatran (110 or 150 mg)

Warfarin

1 month of ASA (BMS)3 months of ASA (DES)

N=2725

Mean duration of

follow-up:

~14 months

P2Y12 inhibitor

P2Y12 inhibitor

Time to first major bleeding event or clinically relevant non-major bleeding event

Pro

ba

bil

ity o

f e

ve

nt

(%)

0

0 90 180 270 360 450 540 630 720

Time to first event (days)

40

35

30

25

20

15

10

5

Warfarin

triple therapy

Dabigatran 110 mg

dual therapy

HR: 0.52 (95% CI: 0.42–0.63)

Non-inferiority P<0.0001

P<0.0001

0 90 180 270 360 450 540 630 720


40

35

30

25

20

15

10

5

0

Dabigatran 150 mg

dual therapy

Warfarin

triple therapy

HR: 0.72 (95% CI: 0.58–0.88)

Non-inferiority P<0.0001

P=0.002

Time to death or thromboembolic event, orunplanned revascularization

35

30

25

20

15

10

5

0

Pro

bab

ilit

y o

f ev

en

t (%

)

0 90 180 270 360 450 540 630 720


Dabigatran (combined doses)

dual therapy

Warfarin

triple therapy

• Dual therapy:

– Discharge on NOAC, clopidogrel (12 months), pantoprazole,

β-blocker, statin, ACE inhibitor

Case VI

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