TICAGRELOR LOADING VS PRASUGREL

1. AMERICAN JOURNAL OF CARDIOLOGY
JULY 2015,116:339-43

2. BACKGROUND
The current non-ST-elevation acute coronary syndrome
(NSTE-ACS) guidelines advocate either a ticagrelor loading
dose (LD) as soon as possible and before percutaneous
coronary intervention (PCI) or a prasugrel LD at the time of
intervention
However, to date no study has compared these 2 strategies

3. ESC GUIDELINES 2014 –UA/NSTEMI

4. ESC GUIDELINES 2014 -STEMI

5. ESC GUIDELINES 2014 -SIHD

8. 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

9. TRITON TIMI-38: Study Design
Double-blind
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
PRASUGREL
60 mg LD/ 10 mg MD
CLOPIDOGREL
300 mg LD/ 75 mg MD
1o endpoint: CV death, MI, Stroke
2o endpoints: CV death, MI, UTVR
StentThrombosis (ARC definite/probable)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
Median duration of therapy - 12 months
N= 13,600
Wiviott SD et al. Am HeartJ 2006;152:627-35

10. Net Clinical Benefit
Death, MI, Stroke,
Major Bleed (non CABG)
0
5
10
15
0 30 60 90 180 270 360 450
Days
Endpoint(%)
HR 0.87
P=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
(nonCABG)
+
All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64

11. 0
2
4
6
8
0 1 2 3
1
0
306090 180 270 360 450
HR 0.82
P=0.01
HR 0.80
P=0.003
5.6
4.7
6.9
5.6
Days
PrimaryEndpoint(%)
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel
Loading Dose Maintenance Dose
Timing of Benefit

12. Safety
Significant
increase in
serious bleeding
(32% increase)
Avoid in pts with
prior CVA/TIA
Efficacy
1. A significant reduction in:
CV Death/MI/Stroke 19%
Stent Thrombosis 52%
uTVR 34%
MI 24%
2. An early and sustained benefit
3. Across ACS spectrum
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Conclusions
Higher IPAto 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

16. BACKGROUND
The current non-ST-elevation acute coronary syndrome
(NSTE-ACS) guidelines advocate either a ticagrelor loading
dose (LD) as soon as possible and before percutaneous
coronary intervention (PCI) or a prasugrel LD at the time of
intervention
However, to date no study has compared these 2 strategies

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

18. “DATA HAS SHOWN THAT
PERIPROCEDURAL MYONECROSIS HAS
BEEN ASSOCIATED WITH SHORT- AND
LONG-TERM CLINICAL
OUTCOME”

21. • 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

22. METHODS

23. • 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

24. • 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.

25. • 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.

27. 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.

28. • 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.

29. 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.

30. 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.

31. RESULTS

36. DISCUSSION

37. • 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.

38. • 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.

39. • 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.

40. LIMITTIONS
1. 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 study
3. 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.

41. 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

42. 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

43. 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