AMERICAN JOURNAL OF CARDIOLOGYJULY 2015,116:339-43

BACKGROUND

The current non-ST-elevation acute coronary syndrome(NSTE-ACS) guidelines advocate either a ticagrelor loadingdose (LD) as soon as possible and before percutaneouscoronary intervention (PCI) or a prasugrel LD at the time ofintervention

However, to date no study has compared these 2 strategies

ESC GUIDELINES 2014 –UA/NSTEMI

ESC GUIDELINES 2014 -STEMI

ESC GUIDELINES 2014 -SIHD

Clopidogrel Prasugrel Ticagrelor

Mechanism of Action Irreversible Irreversible reversible

Dosing route oral oral oral

Onset of action 3-8 h (prodrug) 1-4 h (prodrug) min – hours (oral, direct)

Inhibition irreversible irreversible Reversible in 24-

48 hrs of discontinuation

Maximum Inhibition ~40% Full Full

Variability +++ ++ +

Selectivity +++ +++ +*

P2Y12 Inhibitors

*off-target (adenosine receptor) adverse events: hypotension, dyspnea, heart block, etc

TRITON TIMI-38: Study Design

Double-blind

ACS (STEMI or UA/NSTEMI) & Planned PCIASA

PRASUGREL60 mg LD/ 10 mg

MD

CLOPIDOGREL300 mg LD/ 75 mg

MD

1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, UTVR Stent Thrombosis (ARC definite/probable) Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic

Median duration of therapy - 12 months

N= 13,600

Wiviott SD et al. Am Heart J 2006;152:627-35

Net Clinical BenefitDeath, MI, Stroke, Major Bleed (non CABG)

0

5

10

15

0 30 60 90 180 270 360 450Days

Endp

oint

(%

)

HR 0.87P=0.004

13.9

12.2

Prasugrel

ClopidogrelITT= 13,608

-23

6

-25

-20

-15

-10

-5

0

5

10

Events per 1000 pts

MI Major Bleed(non CABG)

+ All CauseMortalityClop 3.2%Pras 3.0 %

P=0.64

0

2

4

6

8

0 1 2 3

1

0 3060 90 180 270 360 450

HR 0.82P=0.01

HR 0.80P=0.003

5.6

4.7

6.9

5.6

Days

Pri

mar

y En

dpoi

nt (

%)

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel

Loading Dose Maintenance Dose

Timing of Benefit

SafetySignificant increase in serious bleeding(32% increase)

Avoid in pts with prior CVA/TIA

Efficacy1. A significant reduction in:

CV Death/MI/Stroke 19% Stent Thrombosis 52% uTVR 34%

MI 24%2. An early and sustained benefit3. Across ACS spectrum

Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD

ConclusionsHigher IPA to Support PCI

Net clinical benefit significantly favored Prasugrel

Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit : risk balance

BACKGROUND

The current non-ST-elevation acute coronary syndrome(NSTE-ACS) guidelines advocate either a ticagrelor loadingdose (LD) as soon as possible and before percutaneouscoronary intervention (PCI) or a prasugrel LD at the time ofintervention

However, to date no study has compared these 2 strategies

observational studies have clearly demonstratedthat efficient P2Y12-ADP receptor blockade during PCI is associated with a significant reduction in peri-procedural myonecrosis

“DATA HAS SHOWN THAT PERIPROCEDURAL MYONECROSIS HAS BEEN ASSOCIATED WITH SHORT- AND LONG-TERM CLINICALOUTCOME”

• Of importance, despite their fast onset of action, ticagrelor and prasugrel require 1 to 6 hours to achieve optimal PR inhibition in ACS.

• Therefore, this difference in the timing of LD between the 2 drugs may have an impact on periprocedural myonecrosis

METHODS

• A prospective, monocenter, open-label randomized study

• January 2014 to September 2014.• Patients between 18 and 75 years old who

underwent PCI for an intermediate or high-risk NSTE-ACS and agreeing to participate in the study were eligible

• Patients were randomized according to a sequence generated using R software (blockrand package with block size randomly varying among 2, 4, and 6) to ticagrelor or prasugrel therapy.

• Ticagrelor and prasugrel were given according to the protocol recommended in the 2014 ESC guidelines for revascularization.

• In the ticagrelor group, patients received a 180 mg LD as soon as possible after the diagnosis of NSTEACS followed by 90 mg twice daily as maintenance dose.

• All patients received their LD at least 4 hours before PCI (13.4 + 8.3 hours).

• In the prasugrel group, patients who underwent PCI received a 60 mg LD as soon as the coronary anatomy was known and the decision to proceed to PCI taken.

• They received prasugrel 10 mg daily as maintenance dose.

Exclusion criteria• ST-elevation ACS• NSTEACS medically managed or intended for surgery after PCI, • cardiogenic shock, • cardiac arrest, • contraindication to antiplatelet therapy, • treatment with a P2Y12-ADP antagonist <1 month, • a platelet count <100 G/L, • history of bleeding diathesis, • history of hemorrhagic stroke, stroke,• recent surgery (<1 month), • age >75 years old, • hemodialysis,• weight <60 kg, • treatment with a P2Y12-ADP receptor during the previous month, oral

anticoagulant therapy, and use of medication with known interference with ticagrelor or prasugrel and bradycardia.

• PCI was performed using the radial route in all cases but 4 (2 patients in each group).

• All patients received either a bolus of heparin (100 IU/kg) during the procedure followed by ACT-adjusted additional bolus or standard bivalirudin infusion.

• All patients received an LD of 150 mg of aspirin at the time of PCI.

• Drug-eluting stents were used in all patients.• Blood samples were collected and drawn by

atraumatic venipuncture of the antecubital vein on admission, before PCI, 6, 12, and 24 hours after PCI and at any other time if clinically required.

PRIMARY END POINT

• The primary end point was the rate of periprocedural myonecrosis defined by an increase of >5 times the ninety ninth percentiles of the assay in troponin-negative patients before PCI or a 20% increase compared with pre-PCI value in case of elevated baseline value within 24 hours after intervention.

SECONDARY END POINTS• Secondary end points included myocardial insults,

which were defined as any troponin elevation more than the ninety-ninth percentiles in troponin-negative patients before PCI and any troponin increase in those with elevated baseline troponin levels within 24 hours after intervention.

• MACE (major adverse cardiovascular Events) and bleedings events at 1 month post PCI were noted.

• MACE comprised cardiovascular death, myocardial infarction, urgent revascularization, and stroke.

• Bleeding events upto 1 month follow up were recorded.

RESULTS

DISCUSSION

• The present study demonstrated that pretreatment with a ticagrelor LD before PCI significantly reduced the occurrence of periprocedural myonecrosis in patients with NSTE-ACS who underwent PCI compared with prasugrel given at the time of PCI.

• Because periprocedural myonecrosis has been associated with short- and long-term clinical outcome, the present pilot study supports pretreatment with ticagrelor in intermediate and high-risk NSTE-ACS to improve the outcome.

• Platelet-rich thrombus plays a key role in the pathophysiology of ACS. PR inhibition is, therefore, critical to prevent complications and ischemic recurrences.

• In particular, P2Y12-ADP receptor antagonists are critical as demonstrated by the PCI Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) and the Clopidogrel for the Reduction of Events During Observation (CREDO) trials.

• Following these findings, several studies have confirmed the link between the level of PR inhibition and periprocedural myonecrosis.

• They suggested that an optimal blockade of the P2Y12-ADP receptor is required to prevent both periprocedural complications and myonecrosis.

• This was further confirmed in the Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) study where optimal PR inhibition with cangrelor reduced intraprocedural events and periprocedural myocardial infarctions.

• The present findings support the use of pretreatment with a ticagrelor LD in intermediate and high-risk PCI to prevent periprocedural myonecrosis.

• There are 2 main explanations for this benefit of ticagrelor pretreatment compared with periprocedural loading with prasugrel in our study.

• First, the difference in the timing of the LD results in suboptimal PR inhibition during PCI in patients who received prasugrel.

• Suboptimal PR during intervention may favor an increase in periprocedural myonecrosis in the setting of NSTE-ACS where platelet-rich thrombi are common.

• Second, it was demonstrated that ticagrelor has pleiotropic properties compared with thienopyridines including vascular properties through the adenosine metabolism.

• These specific properties of ticagrelor could also be involved in this protective effect against periprocedural myonecrosis that has a complex and multifactorial pathophysiology.

LIMITTIONS1. Study was not powered to compare clinical end points

between the 2 protocols. However, a surrogate end point was used, which was shown to be an independent prognostic factor of mortality and was fully validated before.

2. Small single center study3. Only patients treated with PCI were included in our study.4. Finally, because of the methodology of the present study,

we cannot differentiate between a benefit related to the timing of loading between the 2 groups or specific drug properties to explain the difference in periprocedural myonecrosis.

TAKE-HOME MESSAGE• Periprocedural myonecrosis has been associated with

poor long and short term outcome.• Achieving an optimal PR inhibition at the time of PCI is

critical to prevent adverse events.• Clopidogrel has a high interpersonal variability response• Latest guidelines recommend use of ticagrelor or

prasugrel in ACS patients undergoing PCI ahead of clopidogrel.

• Preloading with ticagrelor seems to be the best modality available for preloading the ACS patients undergoing PCI

THANKYOU

statistics• The rate of periprocedural myonecrosis was assumed to be 40% in

the prasugrel group. A sample size of 103 patients per group was required based on the ability to detect a relative reduction of 45% for the primary end point in the ticagrelor group, with a power of 80% and a p <0.05.

• The number of participants was increased to 106 per group to allow for 3% of loss to follow-up.

• Statistical analyses were performed with IBM SPSS Statistics 20.0 (IBM Inc., New York, New York). All tests were 2 sided and considered significant if <0.05. Categorical data are expressed as counts (%) and were compared using the chi-square or Fisher’s exact tests. Continuous variables are expressed as mean SD and were compared using Student’s t tests

Prasugrel pretreatment

• In the Comparison of prasugrel at the time of percutaneous Coronary intervention Or as pretreatment At the time of diagnosis in patients with non-ST-elevation MI (ACCOAST) trial, prasugrel pretreatment in the setting of an NSTE-ACS did not reduce ischemic events compared with periprocedural intake of the drug.

• Following this study, the use of pretreatment is debated