Optimal antithrombotic treatment after acute coronary syndrome: the - - PowerPoint PPT Presentation

Optimal antithrombotic treatment after acute coronary syndrome: the (complicated) near future

Jur ten Berg

Associate Professor, PhD, MSc, FESC, FACC

• St. Antonius Hospital, Nieuwegein, the Netherlands;

University Hospital Groningen, the Netherlands

Research Grants: ZonMw, AstraZeneca Advisory/consulting/speakers fees: Accu-Metrics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Ferrer, Idorsia, Pfizer, The Medicines Company

Disclosures

Optimal antithrombotic treatment after acute coronary syndrome: the near future

• Duale therapie: aspirine plus clopidogrel, prasugrel of ticagrelor
• 1, 3, 6, 12, >12 maanden
• Keuze P2Y12 remmer obv gentyping?
• Ticagrelor monotherapy na 3 maanden DAPT?

Roffi et al. Eur Heart J. 2015;doi:10.1093/eurheartj/ehv320;

Recommendation Class Level Oral antiplatelet therapy

A P2Y12 inhibitor is recommended in addition to aspirin, for 12 months unless there are contraindications such as excessive risk of bleeds. I A

• Ticagrelor (180 mg loading dose, 90 mg twice daily) is recommended in the absence of

contraindications, for all patients at moderate-to-high risk of ischaemic events (e.g. elevated cardiac troponins), regardless of initial treatment strategy and including those pretreated with clopidogrel (which should be discontinued when ticagrelor is started). I B

• Prasugrel (60 mg loading dose, 10 mg daily dose) is recommended in patients who are

proceeding to PCI if no contraindications. I B

• Clopidogrel (300-600 mg loading dose, 75 mg daily dose) is recommended for patients who

cannot receive ticagrelor or prasugrel or who require oral anticoagulation. I B

Casus I-duur DAPT

• Vrouw 78 jaar, 57 kg, hypertensie
• Opname ivm NONSTEMI, trop T pos, Hb 6,9 mmol/l , GFR=58, L 5.6,
• PCI DES prox LAD succesvol

a)1 jaar DAPT b)6 maanden DAPT c) 3 maanden DAPT

Casus I-welke P2Y12 remmer

• Vrouw 78 jaar, 57 kg, hypertensie
• Opname ivm NONSTEMI, trop T pos, Hb 6,9 mmol/l, GFR=58, L 5.6,
• PCI DES prox LAD succesvol

a) ticagrelor b) prasugrel c) clopidogrel

Reasons for dual antiplatelet therapy (DAPT): prevention of ST

44 yr female STEMI due to ST after discontinuing ticagrelor after 2 months

Reasons for DAPT: prevention of spontaneous MI

DAPT Trial (N=10,000)

* Free from MI, stroke, repeat revascularization and bleeeding, adherent to P2Y12 12-month

• bservational period:
• pen label

Thienopyridine + Aspirin required 3-month

• bservational period:

Off Thienopyridine, On Aspirin Thienopyridine + Aspirin Placebo + Aspirin Randomization* Study drug treatment ends 12 30 33

Time in months after index stent procedure (not to scale)

Mauri L, et al. Am Heart J 2010;160:1035-1041.e1

Both ST related and spontaneous MI

Months post randomisation 12 15 18 21 30 33 % 10 8 6 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 2,9 55% of the MI benefit is NOT related to stent thrombosis

Mauri L, et al. Am Heart J 2010;160:1035-1041.e1

Clopidogrel + ASA (N=6259) Placebo + ASA (N=6303)

DAPT is not innocent!

CURE: Major Bleeding at 1 year clopidogrel + ASA

<100 mg (N=5320) 1.9% 3.0% 100-199 mg (N=3109) 2.8% 3.4% >200 mg (N=4110) 3.7% 4.9% P value for trend .0001 .0009

Adapted from Peters RJG, et al. Circulation. 2003;108:1682-1687.

ASA Dose

One-year mortality (%) Relative risk (95% CI) compared with no bleed P value No bleed 2.54 – – Access site only 6.16 2.33 (1.53–3.53) <0.001 All nonaccess site 14.4 5.40 (4.32–6.74) <0.0001 Nonaccess only 14.1 5.52 (3.62–8.40) <0.001 Both access and nonaccess 14.5 5.70 (3.78–8.61) <0.001 Indeterminate 14.6 5.18 (3.82–7.03) <0.001 Unadjusted one-year mortality rates and relative risks associated with experiencing a 30-day TIMI bleed. Verheugt et al. JACC 2001

Especially spontaneous bleeding increased mortality

Analysis in 17 393 patients who underwent PCI as part of the REPLACE-2, ACUITY, and HORIZONS-AMI trials

• Predominantly

conservative treatment

• BMS, first generation DES
• Clopidogrel: weaker and

variable response

ASA plus P2Y12 inhibitor clopidogrel for 12 months

N Engl J Med 2001; 345:494-502

Stronger P2Y12 inhibitors: prasugrel and ticagrelor

• Stronger P2Y12

inhibition

• Rapid onset
• Very few low

responders

Wiviott, et al. N Engl J Med 2007; 357:2001-2015 Wallentin, et al. N Engl J Med 2009; 361:1045-1057

Prasugrel and ticagrelor superior in large outcome trials

• All comers ACS treated at admittance
• Post PCI

Wiviott, et al. N Engl J Med 2007; 357:2001-2015 Wallentin, et al. N Engl J Med 2009; 361:1045-1057

Roffi et al. Eur Heart J. 2015;doi:10.1093/eurheartj/ehv320;

Adapted from Roffi et al. 20151

Recommendation Class Level Oral antiplatelet therapy

A P2Y12 inhibitor is recommended in addition to aspirin, for 12 months unless there are contraindications such as excessive risk of bleeds. I A

• Ticagrelor (180 mg loading dose, 90 mg twice daily) is recommended in the absence of contraindications, for all

patients at moderate-to-high risk of ischaemic events (e.g. elevated cardiac troponins), regardless of initial treatment strategy and including those pretreated with clopidogrel (which should be discontinued when ticagrelor is started). I B

• Prasugrel (60 mg loading dose, 10 mg daily dose) is recommended in patients who are proceeding to PCI if no

contraindications. I B

• Clopidogrel (300-600 mg loading dose, 75 mg daily dose) is recommended for patients who cannot receive ticagrelor
• r prasugrel or who require oral anticoagulation.

I B

Stronger P2Y12 preferred in all patients?

• 1. Roffi et al. Eur Heart J. 2015;doi:10.1093/eurheartj/ehv320;
• 2. Lip et al. Eur Heart J.2014;35:3155–3179;

Adapted from Roffi et al. 20151

Class Level Oral antiplatelet therapy

A P2Y12 inhibitor is recommended in addition to aspirin, for 12 months I A

• Ticagrelor (180 mg loading dose, 90 mg twice daily) is recommended in the absence of high bleeding

risk, for all patients at moderate-to-high risk of ischaemic events (e.g. elevated cardiac

troponins), regardless of initial treatment strategy and including those pretreated with clopidogrel (which should be discontinued when ticagrelor is started). I B

• Prasugrel (60 mg loading dose, 10 mg daily dose) is recommended in patients who are proceeding to PCI if no

contraindications. I B

• Clopidogrel (300-600 mg loading dose, 75 mg daily dose) is recommended for patients who cannot receive ticagrelor
• r prasugrel or who require oral anticoagulation.

I B

Need to individualise

Who are these patients?

Can we rely on gut feeling?

Aggressive and long DAPT ticagrelor or prasugrel Peacefully and shorter DAPT clopidogrel Highly activated platelets Old, fragile platelets

Randomised comparison of clopidogrel versus ticagrelor or prasugrel in patients of 70 years or older with non-ST

• elevation

acute coronary syndrome

POPular AGE trial (N=1000)

Marieke E. Gimbel MD

• St. Antonius hospital, Nieuwegein, the Netherlands

Jurriën ten Berg, Vera Deneer (PIs)

Choice of P2Y12 inhibition based on age

Primary safety outcome

Clopidogrel Ticagrelor/prasugrel

23.1% 17.6%

HR 0.74 (95%CI 0.56-0.97) P=0.03

Secondary efficacy outcome

Ticagrelor/prasugrel Clopidogrel

12.8% 12.5%

HR 1.02 (95% CI 0.72-1.45) P=0.91

Can we rely on gut feeling?

Aggressive and long DAPT ticagrelor or prasugrel Peacefully and shorter DAPT clopidogrel Risk for bleeding? Risk for thrombosis? Highly activated platelets Old, fragile platelet Average patients

Introductie

Ticagrelor 60 mg BID

Valgimigli, et all. European Heart Journal, Volume 39, Issue 3, 14 January 2018, Pages 213–260,

Individualise DAPT duration

Valgimigli, et all. European Heart Journal, Volume 39, Issue 3, 14 January 2018, Pages 213–260,

Valgimigli, et all. European Heart Journal, Volume 39, Issue 3, 14 January 2018, Pages 213–260,

Antwoord Casus 1- DAPT 6 maanden

Casus II

28

• Man 55 jaar, DM II, hypertensie met GFR = 48 ml/min, rookt nog
• 2015- 1 PCI RCA voor OWI DAPT 12 maanden
• 2016-12 PCI DES proximale LAD, PCI Cx en diffuus RCA herstart DAPT
• 2018-1 geen AP, geen bloeding

a) P2Y12 remmer had al gestopt moeten zijn b) Nog jaren continueren

Casus II

29

• Man 55 jaar, DM II, hypertensie met GFR = 48 ml/min, rookt nog
• 2015-1 PCI RCA voor OWI DAPT 12 maanden
• 2016-12 PCI DES proximale LAD, PCI Cx en diffuus RCA herstart DAPT
• 2018-1 geen AP, geen bloeding

a) P2Y12 remmer had al gestopt moeten zijn b) Nog jaren continueren DAPT score: no event first year, score 3 (DM, prior MI or PCI, smoking) PEGASUS: age of 65 years or older, diabetes mellitus, a second prior spontaneous MI, multivessel CAD, or GFR < 60 ml/min

30

• Woman 78 yrs, 57 kg,

hypertension, no prior bleeding

• Hb 11.1 g/dl, L 5.6, GFR=58
• NON-STEMI, PCI DES LAD

successful

• PRECISE-DAPT score ≧25,

prolonged DAPT was associated with no ischemic benefit but increased bleeding with NNH = 38

• DAPT duration 6 months

Costa F, at all Lancet. 2017 Mar 11;389(10073):1025-1034.

Genotype-guided oral P2Y12 inhibition in patients with ST- segment elevation myocardial infarction undergoing primary PCI

POPular Genetics

Daniel M.F. Claassens MD

• St. Antonius hospital, Nieuwegein, The Netherlands

Jurriën M. ten Berg, Vera H.M. Deneer (PIs)

ESC Hot Line Session NEJM 2019

Reduce bleeding by de-escalation P2Y12 inhibition (ticagrelor to clopidogrel) with the use of genotyping (point-of-care)

May 2012 – April 2018 99.9% complete follow-up available

STEMI undergoing Primary PCI N= 2488

T = 14H

No genetic testing (N = 1246) Genetic testing (N= 1242)

Ticagrelor/prasugrel 12 months

35% Carrier of LOF CYP2C19 *2 or *3 Ticagrelor/prasu 12 months

65% No LOF CYP2C19 *1/*1 Clopidogrel 12 months

Rate of adherence 84.5% Rate of adherence 82.0% R* (1:1)

T = 0 Genetic results: +3H T = 365 days

Results

0% 2% 4% 6% 45 90 135 180 225 270 315 360

Time since index PCI (days) primary thrombotic & bleeding outcome Standard treatment Genotype-guided

1246 1218 1202 1198 1193 1185 1179 1178 1173 1242 1213 1203 1201 1197 1191 1187 1184 1177

Genotype-guided Standard treatment

N at risk

5.9% 5.1%

HR (95%CI) = 0.86 (0.62 – 1.21) Pnon-inf = 0.0002

All-cause death, MI, definite stent thrombosis, stroke, PLATO major bleeding

Standard treatment

Time since index PCI (days) PLATO major & minor bleeding

1246 1193 1168 1155 1141 1130 1113 1106 1094 1242 1208 1193 1175 1162 1153 1145 1134 1121

Genotype-guided

N at risk

45 90 135 180 225 270 315 360

0% 5% 10%

Standard-treatment Genotype-guided 12.5% 9.8%

HR (95%CI) = 0.78 (0.61 – 0.98)

PLATO Major & minor bleeding

P=0.04

Conclusions DAPT post ACS

• Standard DAPT (ASA and a strong P2Y12 inhibitor) for 12 months for all ACS

patients, is not the way to go

• Individualise which P2Y12 inhibitor based on ischemic and bleeding risk,

especially elderly with high bleeding risk clopidogrel

• Individualise DAPT duration based on ischemic and bleeding risk
• PRECISE DAPT (≧25) to shorten DAPT (6 months)
• DAPT score (≧2, previous MI) to prolong DAPT (ticagrelor 60 mg BID)
• De-escalation of P2Y12 inhibition based on CYP2C19 genotyping (POC) to reduce

the risk of bleeding may be an option

• Ticagrelor monotherapy at 3 months after stenting may be an option