Pre-treatment with P2Y12 inhibitors in ACS patients: who ...

Pre-treatment with P2Y12 inhibitors in ACS patients: who, when, why

and which agent

Guerrino Zuin, UOS di UTIC

Dipartimento Cardio-Toraco-Vascolare

Ospedale dell’Angelo Mestre

• The goal of DAPT is to reduce the risk of ischaemic events such as (re)-infarction and, in patients in whom a PCI is performed, the risk of stent thrombosis

• The term ‘pre-treatment’ defines a strategy according to which an antiplatelet drug, usually a P2Y12 inhibitor, is given before coronary angiography is performed. Thus, administration of a P2Y12 inhibitor in the ambulance (pre-hospital setting), in the emergency department, coronary care unit, or even in the catheterization laboratory before coronary angiography is performed can all be appropriately considered to represent pre-treatment. Importantly, the term pretreatment should not be used for administration of P2Y12 inhibitors immediately before a PCI.

EYESHOT

Registry

Pre-Treatment

with DAPT

79.5% (1395/1755)

79.3% (1807/2280)

EYESHOT

Registry

Drugs and Devices

Before Coronary Angio/During Hospit

CURE

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

Cu

mu

lati

ve H

azard

Rate

Clopidogrel

+ ASA*

3 6 9

Placebo

+ ASA*

Months of Follow-Up

11.4%

9.3%

20% RRR

P < 0.001

N = 12,562

0 12

* In combination with standard therapy

The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

Primary End Point - MI/Stroke/CV Death

0.15

0.10

0.05

0.0

0 100 200 300 400

Days of follow-up

12.6%

8.8%

31% RRR

P = 0.002

N = 2658

Clopidogrel

+ ASA*

Placebo

+ ASA*

Cu

mu

lati

ve H

azard

Rate

* In combination with standard therapy

Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001.

Composite of cardiovascular death or MI from randomization to end of follow-up

Overall Long-Term Results

PCI-CURE

CURE

Only 21% of patients undergoing PCI (82% of stents), Evaluated dual antiplatelet therapy in patients managed medically with a minority undergoing delayed catheterization, often several days (6) after admission

NSTEMI

Following the CURE and CREDO studies, clopidogrel pretreatment has been generalized for non-ST elevation ACS management with a Class I-B recommendation in the European (2011) and US guidelines (2012) , with the

paradigm that “sooner is better.”

Prasugrel: The ACCOAST Investigators N Engl J Med 2013

Total population.

Prasugrel: The ACCOAST Investigators N Engl J Med 2013

PCI Cohort.

NSTEMI

the ACTION Study Group: Metanalisi BMJ 2014 All Patients with non-STEMI ACS and patients undergoing PCI : Mortality: Pretreatment with P2Y inhibitors was not associated with a significant reduction in death (any cause) (odds ratio 0.90 e 0.83, P= NS ) Safety: Pretreatment with P2Y12 inhibitors was associated with a significant increase of major bleeding (odds ratio 1.32 e 1.23, P<0.0001 e < 0.48 )

NSTEMI: The ACTION Study Group: Metanalisi BMJ 2014

…with rapid access of patients to the catheterization laboratory (3-4 hrs) and use of modern techniques of revascularization…

…CURRENT study did not confirm the superiority of 600 mg over 300 mg of clopidogrel in the global management of non-ST elevation ACS. Because no data are available for ticagrelor, conclusions cannot be drawn for this drug.

• The concept of systematic and immediate pretreatment with P2Y12 antagonists in patients admitted with non-ST elevation ACS needs to be reconsidered.

• ESC guidelines 2015:

NSTEMI ESC Guidelines 2015

STEMI ESC GUIDELINES 2012

Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction. Gilles Montalescot, M.D. for the ATLANTIC Investigators. N Engl J Med 2014.

Cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding the CHAMPION PHOENIX Investigators*, N Engl J Med, 2013

Stable 56% NSTEMI 25% STEMI 19%

Tabella 6. Pretrattamento farmacologico in pazienti con SCA NSTE a rischio molto alto, candidati a strategia invasiva immediata (< 2 ore).

Raccomandato

Opzionale (SI>no)

Opzionale (NO>si) NO

Anticoagulanti UFH - -

EBPM

Fondaparinux

Bivalirudina

Antiaggreganti per os ASA1

-

Prasugrel2

Ticagrelor2

Clopidogrel2

-

Antiaggreganti e.v. ASA3

- -

Abciximab

Eptifibatide

Tirofiban

EBPM: Eparine a Basso Peso Molecolare

ASA: Acetyl Salicylic Acid (aspirina) 1

in alternativa ad ASA e.v. 2

in aggiunta ad ASA 3

in alternativa ad ASA per os

DOCUMENTO DI CONSENSO ANMCO, SIC, SICI-GISE E SICCH: APPROCCIO CLINICO AL PRETRATTAMENTO FARMACOLOGICO IN PAZIENTI CANDIDATI A PROCEDURE DI RIVASCOLARIZZAZIONE MIOCARDICA: 2016

Tabella 7. Pretrattamento farmacologico in pazienti con SCA NSTE a rischio alto, candidati a strategia invasiva precoce (< 24 ore) e a rischio moderato, candidati a

strategia invasiva elettiva (< 72 ore).

Raccomandato

Opzionale*(SI>no) Opzionale!(NO>si) NO

Anticoagulanti Fondaparinux Enoxaparina) UFH

1

Bivalirudina2

Altre&EBPM

Antiaggreganti)per)os ASA Ticagrelor3 Clopidogrel

3 Prasugrel

Antiaggreganti)e.v. " " " Abciximab!

Eptifibatide!Tirofiban)

Anti"ischemici " Betabloccanti!

NTG Verapamil!Diltiazem

"

Statina Atorvastatina " " "

EBPM: Eparine a Basso Peso Molecolare

ASA: Acetyl Salicylic Acid (aspirina)

NTG: Nitroglicerina 1 in caso di insufficienza renale severa 2 in pazienti con piastrinopenia da eparine 3 in aggiunta ad ASA, in base a fig. 2-3.


Conclusioni

• Nella SCA NSTE del tratto ST, in assenza di trial randomizzati che ne abbiano dimostrato un vantaggio, il pretrattamento con inibitori del recettore P2Y12, pur se molto diffuso, è da considerare opzionale

Conclusioni

• Nella SCA NSTE la probabilità di un vantaggio del pretrattamento va valutata nel singolo paziente e in rapporto alla tempistica di esecuzione della coronarografia. Proponiamo quindi un “pretrattamento selettivo”, guidato dalle condizioni di rischio ischemico, di rischio emorragico e del tempo previsto all’esecuzione della coronarografia.

• Gran parte delle problematiche inerenti questo tema sarebbero risolte da un più precoce accesso alla coronarografia, soprattutto per i pazienti a maggior rischio.

Conclusioni

• Nella SCA STEMI per quanto riguarda il secondo antiaggregante orale, preferenzialmente prasugrel o ticagrelor, pur non essendo dimostrata la superiorità dell’utilizzo in pretrattamento, se ne ritiene consigliabile la somministrazione precoce se l'organizzazione territoriale lo consente e soprattutto se il trasporto del paziente impiega oltre 30 minuti.

Conclusioni

• Nella SCA STEMI la somministrazione di clopidogrel (dose da carico 600 mg, dose di mantenimento 75 mg per os/die) va riservata ai casi in cui prasugrel e ticagrelor sono controindicati o non disponibili.

GRAZIE PER L’ATTENZIONE

Conclusioni

• Nella SCA STEMI è raccomandato pretrattare il paziente con aspirina al primo contatto medico (sul territorio o in ambulanza)

This is a transcript of an online program, which may be found at:

http://www.theheart.org/article/995291.do

In Brief: Optimal Use of Dual Antiplatelet Therapy

Donahoe SM, et al. JAMA. 2007;298:765‐775.Reproduced with permission.

Pooled TIMI Trials: All‐Cause Mortality Through 1 Year After ACS in Patients With Diabetes

11 TIMI trials, N > 62,000 ptsn = 10,613 with diabetes (17.1%)

P < .0001 STEMI

P < .0001 UA/NSTEMI

P < .0001

P < .0001

0 30 90 180 270 360Days After ACS

Cu

mu

lati

ve In

cid

en

ce M

ort

alit

y (

%)

STEMI

Diabetes

UA/NSTEMI

No Diabetes

Diabetes

No Diabetes14

12

10

8

6

4

2

0

Number at Risk

40085141819110,50511,65812,002No Diabetes

92413172339292333133457DiabetesUA/NSTEMI

935112,27615,27416,68537,13639,421No Diabetes161021182653294765087156Diabetes

STEMI

Slide 2 Well, let's start off with understanding some of the characteristics of this patient population. This is an interesting study coming from the TIMI group looking at the overall mortality in patients with diabetes who present with an ACS. As you can see patients with diabetes presenting either with an STEMI [ST-segment elevation myocardial infarction] or a NSTE-ACS (non-ST-elevation acute coronary syndrome) have an increased mortality rate both at 30 days and out up to 1 year.




Overall 12,562 9.3 11.4

Associated MI 3283 11.3 13.7No associated MI 9279 8.6 10.6

Male sex 7726 9.1 11.9Female sex 4836 9.5 10.7

< 65 yr old 6354 5.4 7.6> 65 yr old 6208 13.3 15.3

ST‐segment deviation 6275 11.5 14.3No ST‐segment deviation 6287 7.0 8.6

Enzymes elevated at entry 3176 10.7 13.0Enzymes not elevated at entry 9386 8.8 10.9

Diabetes 2840 14.2 16.7No diabetes 9722 7.9 9.9

Low risk 4187 5.1 6.7Intermediate risk 4185 6.5 9.4High risk 4184 16.3 18.0

History of revascularization 2246 8.4 14.4No history of revascularization 10,316 9.5 10.7

Revascularization after randomization 4577 11.5 13.9No revascularization after randomization 7985 8.1 10.0

Placebo + ASACharacteristic

No. ofPatients

Clopidogrel + ASA

Percentage of Patients With Event

Placebo BetterClopidogrel Better

Relative Risk (95% CI)

1.21.00.80.60.4

CURE: Outcomes With Clopidogrelin Various Subgroups

Yusuf S, et al. N Engl J Med. 2001;345:494‐502.Reproduced with permission.

Slide 8 We know from the CURE [Clopidogrel in Unstable Angina to Prevent Recurrent Events] trial that overall DAPT in high-risk settings is associated with a significant reduction in ischemic events. What do we know about patients with diabetes? Well from this analysis from the CURE trial you can see that the prevalence of events in patients with diabetes is almost double that of patients without diabetes. And overall if you look at the confidence intervals in the diabetic cohort these go across a line of unity suggesting a lower effect of DAPT in diabetic patients.




Days

0

2

4

6

8

10

12

14

16

18

0 30 60 90 180 270 360 450

End

po

int

(%)

CV death/MI/stroke17.0%

12.2%

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.6%

2.5%

Wiviott SD, et al. Circulation. 2008;118:1626‐1636.Adapted with permission.

TIMI major bleeding

TRITON‐TIMI 38: Patients With Diabetes (N = 3146)

P = .81

HR 0.70P < .001

NNT = 21

Slide 10 We currently have available a third generation thienopyridine, which is prasugrel. Prasugrel compared with clopidogrel was evaluated in the TRITON-TIMI 38 [Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction] trial. Here you see the diabetic subgroup analysis from this trial showing how patients with diabetes were the subgroup that benefited the most from more intensive antiplatelet therapy with prasugrel as compared with clopidogrel, with a 30% relative risk reduction in ischemic events without any differences in bleeding.

G Montalescot ACTION Study Group: BMJ 2014, 32.383 patients with NSTEMI

EYESHOT

Registry

STEMI:

Strategies and Timing

HU

B

Coro

Medical

Rx

PCI

CABG

Medical

Rx

1022

(95.9%)

n=1066

44

(4.1%)

919

(86.2%)

13

(1.2%)

90

(8.4%)

134

(12.6%)

SPO

KE

STEMI

Thrombolysis: 54 (5.1%)

followed by PCI in 26 (48.1%)

NSTE-ACS

EYESHOT

Registry

NSTE-ACS:

Strategies and Timing

HU

B

Coro

Medical

Rx

PCI

CABG

Medical

Rx

1258

(82.8%)

n=1519

261

(17.2%)

831

(54.7%)

39

(2.6%)

388

(25.5%)

649

(42.7%)

SPO

KE

The ACCOAST Investigators.

Pretrattamento no Pretrattamento (n=2037) (n=1996)

Pre-treatment with P2Y12 inhibitors in ACS patients: who ...

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