1. How to Switch from Clopidogrel to Prasugrel or Ticagrelor
Jorge F. Saucedo M.D, MBA Professor of Medicine Director, Cardiac Catheterization Laboratories OU Medical Center Vice Chief, Section Of Cardiology OU Health Science Center

2. Jorge F. Saucedo, MD Honoraria: Merck and Company, Inc.
Eli Lilly and Company
Stocks, Stock Options, other ownership interest: Vascular Solutions

3. How to Switch from Clopidogrel to Prasugrel or Ticagrelor
Clinical Data
No studies published with clinical endpoints evaluating switching from clopidogrel to prasugrel or ticagrelor

4. Trials Comparing IPA Following the Switch from Clopidogrel to Prasugrel or to Ticagrelor
TABF (healthy volunteers)
PRINCIPLE-TIMI 44 (elective PCI)
ACAPULCO (NSTE-ACS patients undergoing PCI)
SWAP (recent ACS history)
TRIPLET (ACS patients undergoing PCI)
RESPOND
PLATO (pre specified subgroup analysis)★

5. Switching from Clopidogrel to Prasugrel in Healthy Volunteers: Study Design (TABF)
Subjects Enrolled
(N=40)
Aspirin 81 mg/day x 7 days
(N=39)
Clopidogrel 600 mg LD x 1 day
+ 75 mg/day MD x 10 days
+ Aspirin 81 mg/day
(N=39) R
(N=35)
Prasugrel 60 mg LD x 1 day
+10 mg/day MD x 10 days
+ Aspirin 81 mg/day
(N=16)
Prasugrel
10 mg/day MD x 11 days
+ Aspirin 81 mg/day
(N=19)
ADP=Adenosine Diphosphate; LD=Loading Dose; MD=Maintenance Dose
Payne CD et al. Platelets 2008;19:

6. Figure found on page 3, bottom of page; Text taken from page 3, column 1, last paragraph & column 2, paragraphs 1 & 2:
This figure depicts the average MPA response to the aspirin, clopidogrel, and prasugrel dosing regimens.
Daily aspirin reduced mean MPA by about 9% points from drug-free baseline (p<0.001).
The clopidogrel 600 mg LD further reduced MPA at one, two, four and 24 hours, respectively, with the maximal effect (mean MPA ~32%) achieved at four hours after the 600 mg LD.
During Day 11 of the clopidogrel 75 mg MD phase, the mean MPA (37%) at 24 hours post-MD was modestly increased compared to post-LD levels.
On Day 12, in subjects switched directly to the prasugrel 60 mg LD, MPA was substantially reduced within 30 minutes, with a maximal effect (mean MPA ~4%) observed at two hours after the prasugrel LD (p<0.001 versus clopidogrel MD).
During subsequent daily prasugrel 10 mg MD, MPA levels increased gradually from the post-LD nadir and achieved a new steady state at about four days after the prasugrel 60 mg LD.
Additional text from page 3, column 2, last paragraph and page 4, column 1, first paragraph:
During prasugrel MD, a new pharmacodynamic steady state MPA of ~24% (p<0.01 versus clopidogrel MD) was achieved within four to five days of switching directly from clopidogrel MD regardless of whether a subject received a prasugrel LD or was switched directly to the prasugrel MD regimen.

7. LD Phase MD Phase No PCI Planned elective PCI
Prasugrel Compared with High Loading- and Maintenance-Dose Clopidogrel
in Patients with Planned Percutaneous Coronary Intervention
PRINCIPLE TIMI 44
LD Phase
Clopidogrel Naïve No planned GP IIb/IIIa
Planned elective PCI
Baseline laboratory measures
Clopidogrel
600 mg
Prasugrel
60 mg
0.5 hour post-LD labs;
coronary angiography and post-angiography labs
PCI
No PCI
6 hoursa labs,
15 day events
6 hoursa, hours labs
MD Phase
Clopidogrel
150 mg x 14 day
15 day clinical events, labb, crossover
29 day clinical events, labb
Prasugrel
10 mg x 14 day
Study Design The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation Thrombolysis in Myocardial Infarction (PRINCIPLE-TIMI) 44 was a multicenter, randomized, double-blind, double-dummy, active comparator-controlled, two-phase trial with crossover design. There were 201 patients randomized to prasugrel 60 mg or clopidogrel 600 mg loading dose (LD). After randomization and prior to administration of study drug, patients had baseline laboratory measures that included light transmission aggregometry, vasodilator-stimulated phosphoprotein phosphorylation status, and the VerifyNow™ P2Y12 assay. For the LD phase, study drug was given blinded as a pretreatment approximately 1 hour (no less than 30 minutes) prior to the time that cardiac catheterization was expected to begin. Subjects were then to undergo percutaneous coronary intervention (PCI) if coronary anatomy was suitable. After PCI, patients received a daily maintenance dose for 14 days (± 2 days) of either prasugrel 10 mg or clopidogrel 150 mg, which correlated with the LD assignment. At 15 days, clinical events were assessed, labs were collected, and patients were switched in a crossover fashion directly to the alternate maintenance therapy, without any washout period. At Day 29 (± 4 days), assessments were made for clinical events and final platelet measures were performed.
Primary end points: aLD phase 6 hours IPA (20 µM ADP); bMD phase 15 day and 29 day IPA (20 µM ADP). ADP=Adenosine Diphosphate; GP=Glycoprotein; IPA=Inhibition of Platelet Aggregation; LD=Loading Dose; MD=Maintenance Dose; PCI=Percutaneous Coronary Intervention
Wiviott SD et al. Circulation 2007;116:
Wiviott SD et al. Circulation 2007;116:

8. PRINCIPLE-TIMI 44 Crossover Trial: Loading & Maintenance Dose Phases IPA (20 µM ADP)
Key Points
The relationship between IPA and clinical activity has not been established.
Prasugrel had a significantly greater percent inhibition of platelet aggregation (IPA) than clopidogrel at all time points during the loading dose (LD) phase.
IPA with 20 µM ADP at 6 hours after loading dose was significantly greater after prasugrel 60 mg (mean, 74.8 ± 13.0%) compared with clopidogrel 600 mg (31.8 ± 21.1%), with an LS (least square) mean difference of 43.2% (95% CI, 38.0 to 48.4; p< ).
The greater antiplatelet effect (higher mean IPA) of the prasugrel LD measured by IPA with 20 µM ADP was apparent after 30 minutes (30.8 ± 29.0% versus 4.9 ± 13.2%; p< ) and maintained through 18 to 24 hours.
Significantly greater levels of platelet inhibition (IPA) with prasugrel compared with clopidogrel extended from the LD phase to the maintenance dose phase.
IPA with 20 µM ADP after days of MD therapy (ie, day 15 and 29 data combined) was significantly greater in patients receiving prasugrel 10 mg daily (mean 61.3 ± 17.8%) compared with clopidogrel 150 mg daily (46.1 ± 21.3%). The LS (least square) mean difference was 14.9% (95% CI, 10.6 to 19.3; p< ).
Background
The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 (PRINCIPLE TIMI 44) trial was a 2-phase crossover study comparing prasugrel with high-dose clopidogrel in patients with planned percutaneous coronary intervention.
Phase 1 investigated the LD of prasugrel 60 mg compared with clopidogrel 600 mg using Light Transmission Aggregometry (LTA), with the primary end point of IPA with 20 μmol/L ADP at 6 hours.
The formula to calculate IPA follows: IPA% = {1-[(MPA at time t after LD)/(MPA at baseline)]} x 100.
Following PCI, patients entered the 28-day maintenance phase (phase 2) of the trial and were randomized to receive a once-daily MD for 14 ± 2 days of either prasugrel 10 mg or clopidogrel 150 mg corresponding to the phase 1 (LD) assignment. Following a collection of end points at days 15±2, patients crossed-over directly to the alternate maintenance therapy for the rest of the treatment period. A second collection of end points was scheduled at days 29±4.
The primary end point of the MD phase was IPA with 20 μmol/L ADP following 2 weeks of therapy.
ADP=Adenosine Diphosphate; CI=Confidence Interval; MD=Maintenance Dose
Note Section Reference Only:
Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in
patients with planned percutaneous coronary intervention. Circulation. 2007;116:
Primary efficacy end point was IPA at 6 hours. Any difference in the pharmacokinetics of prasugrel compared with other antiplatelet agents has not been correlated to clinical outcomes.
ADP=Adenosine Diphosphate; IPA=Inhibition of Platelet Aggregation; PRINCIPLE=The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation; TIMI=Thrombolysis In Myocardial Infarction
Wiviott SD et al. Circulation 2007;116:

9. Primary End Point: MD Phase IPA (20 µM ADP)
PRINCIPLE TIMI 44
Primary End Point: Maintenance Dose Phase Inhibition of Platelet Aggregation (20 µM ADP) The primary efficacy end point of IPA with 20 µM adenosine diphosphate (ADP) after days of MD therapy (ie, Day 15 and 29 data combined) was significantly greater in patients receiving prasugrel 10 mg daily (mean ± 17.8%) compared with clopidogrel 150 mg daily (46.1 ± 21.3%). The least square (LS) mean difference was 14.9% (95% CI, ; P < ). Importantly, similar results with highly significant differences between groups were seen for IPA with 20 µM ADP at Day 14 visit and following crossover to alternate therapy at Day 29. LS mean difference at 15 and 29 days was 14.9 (95% CI ); P <
CI=Confidence Interval; IPA=Inhibition of Platelet Aggregation; MD=Maintenance Dose
Note Section Reference Only:
Wiviott SD et al. Circulation 2007;116:
ADP=Adenosine Diphosphate; CV=Cardiovascular; IPA=Inhibition of Platelet Aggregation; MD=Maintenance Dose; MI=Myocardial Infarction; NF=Nonfatal
lWiviott SD et al. Circulation 2007;116:

10. Open-label Loading Dose Phase
ACAPULCO
Prasugrel Compared With High-Dose Clopidogrel in Acute Coronary Syndrome
Clopidogrel 900 mg LD (cumulative) and mg of aspirin LD
Open-label Loading Dose Phase
Daily Maintenance Dose (MD) Phase (1st MD at 16 to 28 hours after the Loading Dose [LD]) R*
Visit 1
Visit 2
Optional coronary angiography/
Percutaneous coronary intervention
Informed consent
Visit 3
Visit 4
Prasugrel 10 mg MD + ≤100 mg aspirin
Clopidogrel 150 mg MD + ≤100 mg aspirin
Day 1
Day 2
Day 15 ± 2
Day 29 ± 4
Crossover
Clopidogrel 900 mg LD (cumulative) and mg of aspirin LD
The first blood sample for platelet-function measures was collected irrespective of whether subjects were on chronic clopidogrel treatment or had previously received a clopidogrel loading dose for the acute coronary syndrome event.
True pre-loading dose baseline platelet aggregation is available only in clopidogrel-naive subjects.
Additional blood samples were collected 6-18 h after the 900-mg loading dose and h after the last maintenance dose at Visit 3 and Visit 4
Source: Montelescot G, et al. Thromb Haemost 2010;103(1):214, Figure 1 (p. 215)
*Randomization ≤48 hours from onset of ischemic symptoms
Montelescot G, et al. Thromb Haemost 2010;103(1):

11. MPA Combined Data of Both MD Periods
ACAPULCO
Primary End Point:
MPA Combined Data of Both MD Periods
LS Means
p<0.001
39.1
Maximal Platelet Aggregation (%) (20 µM ADP)
26.2
Comparison of Study Treatments in the MD Phase (combined data from both MD periods)
This slide shows the change in MPA for 20 μM ADP for the combined data from Visits 3 and 4. The primary end point analysis demonstrated that the LS mean MPA to 20 µM ADP was statistically significantly lower following the prasugrel 10-mg MD compared with the clopidogrel 150 mg MD (26.2% for prasugrel vs. 39.1% for clopidogrel; p<0.001; data for Visits 3 and 4 combined).
ADP=Adenosine Diphosphate; LS=Least Squares; MD=Maintenance Dose; MPA=Maximal Platelet Inhibition
Reference:
Montalescot G, Sideris G, Cohen R, Meuleman C, Bal dit Sollier C, Barthélémy O, Henry P, Lim P, Beygui F, Collet JP, Marshall D, Luo J, Petitjean H, Drouet L. Prasugrel compared with high-dose clopidogrel in acute coronary syndrome. The randomised, double-blind ACAPULCO study. Thromb Haemost 2010;103(1):
n=47
n=49
Clopidogrel 150 mg
Prasugrel 10 mg
Montelescot G et al. Thromb Haemost 2010;103:
ADP=Adenosine Diphosphate; LS=Least Squares; MD=Maintenance Dose; MPA=Maximal Platelet Aggregation
Pras

12. Maximum Platelet Aggregation by Treatment Sequence
ACAPULCO
Maximal Platelet Aggregation (%) 20 µM ADP
Pre-LD
Post-LD
Visit 3 (Day 15)
Visit 4 (Day 29)
Pre-Loading Dose
Clopidogrel 900 mg
Clopidogrel 150 mg
Prasugrel 10 mg † ‡ * 10 20 30 40 50 60 70 80 90
Source: Montelescot G, et al. Thromb Haemost 2010;103(1):Figure 3, p. 218
*Comparison of prasugrel 10 mg at day 15 vs. the clopidogrel 900 mg loading dose, p=0.011 †Comparison of clopidogrel 150 mg versus prasugrel 10 mg at day 15, p=0.008; ‡Comparison of clopidogrel 150 mg vs. prasugrel 10 mg at day 29, p<0.001; ADP=adenosine diphosphate
Montelescot G, et al. Thromb Haemost 2010;103(1):

13. Increased Platelet Inhibition After Switching From Maintenance Clopidogrel to Prasugrel in Patients with Acute Coronary Syndromes: Results of the SWAP (SWitching Anti Platelet) Study
The SWAP Study

14. Study Design Patient eligible for enrollment 30-330 days post ACS
SWAP
Patient eligible for enrollment days post ACS
(Must be prescribed clopidogrel 75 mg)
Daily aspirin mg to continue throughout study
Clopidogrel 75 mg MD x days
Baseline platelet function studies at end of clopidogrel run-in
(139 patients randomized)
Platelet function studies at Baseline (end of 2 week clopidogrel run-in), 2 hours, 24 hours, 7 and 14 days
Prasugrel 60 mg LD,
10 mg MD x days
N=31
Clopidogrel 75 mg MD
x days
N=33
Prasugrel 10 mg MD
N=36
Angiolillo DJ et al. J Am Coll Cardiol 2010;56:
ACS=Acute Coronary Syndrome; LD=Loading Dose; MD=Maintenance Dose

15. Results: MPA at Various Time Points Following Loading Dose of Study Drug
SWAP
Similar pharmacodynamic profiles were observed regardless of platelet function assay conducted (LTA, VerifyNow®, and VASP).
LTA=Light Transmittance Aggregometry; VASP=Vasodilator-stimulated Phosphoprotein Phosphorylation
Note Section Reference Only:
Angiolillo DJ et al. JACC 2010;56:
20 µM ADP
Mean ± SD
ADP=Adenosine Diphosphate; LD=Loading Dose; MD=Maintenance Dose; MPA=Maximal Platelet Aggregation; SD=Standard Deviation
*p < vs clopidogrel 75 mg MD; †p < vs prasugrel 10 mg MD
Angiolillo DJ et al. JACC 2010;56:

16. Results: VerifyNow® P2Y12 Assay Following Loading Dose of Study Drug
SWAP
Similar pharmacodynamic profiles were observed regardless of platelet function assay conducted (LTA, VerifyNow®, and VASP). Time 0 is baseline value obtained after 2 weeks of open-label clopidogrel and before administration of first dose of study drug.
LTA=Light Transmittance Aggregometry; VASP=Vasodilator-stimulated Phosphoprotein Phosphorylation
Note Section Reference Only:
Angiolillo DJ et al. JACC 2010;56:
Mean ± SD
LD=Loading Dose; MD=Maintenance Dose; PRU=P2Y12 Reaction Units
*P< vs clopidogrel 75 mg MD; †P< vs prasugrel 10 mg MD
Angiolillo DJ et al. JACC 2010;56:

17. Time Since 1st Dose of Randomized Study Drug
SWAP: Poor Response Rates
SWAP
Placebo LD/Clopidogrel 75 mg MD (N=33)
Placebo LD/Prasugrel 10 mg MD (N=36)
P = 0.014
Prasugrel 60 mg LD/Prasugrel 10 mg MD (N=31) 21 20 16 16 15
Poor Response Rate (%) 5 6
Poor response rate was defined as patients with maximal platelet aggregation (MPA) > 65% to 20 M ADP assessed by light transmission aggregometry performed prior to randomization and at 2 hr, 24 hr and 7 days following the start of study drug. At the end of the 7 day MD period, the poor response rate was significantly lower with prasugrel (both groups combined) compared with clopidogrel (5% vs. 21%; p=0.014). 3
Time Since 1st Dose of Randomized Study Drug
Poor response was defined as patients with MPA > 65% to 20 µM ADP assessed by light transmission aggregometry
LD=Loading Dose; MD=Maintenance Dose; MPA=Maximal Platelet Aggregation
Angiolillo DJ et al. Manuscript Submitted 2009

18. J Am Coll Cardiol Intv. 2011;4(4):403-410
Prasugrel Overcomes High On-Clopidogrel Platelet Reactivity Post-Stenting More Effectively Than High-Dose (150-mg) Clopidogrel: The Importance of CYP2C19*2 Genotyping
J Am Coll Cardiol Intv. 2011;4(4): doi: /j.jcin
J Am Coll Cardiol Intv. 2011;4(4):

19. PR by Treatment Sequence Data for the Pre-crossover and Post-crossover
Data for the pre-crossover and post-crossover. Lines represent medians, and error bars represent interquartile range. Patients' platelet reactivity (PR) in the upper quartile (asterisks) and lower quartiles (open circles) on day 30 are shown. The majority of patients in the upper and lower quartiles under prasugrel (solid green circles) on day 30 remained in the same quartiles under clopidogrel (solid black circles) on day 60. Patients in the upper and lower quartiles under clopidogrel on day 30 dispersed across all 4 quartiles under prasugrel on day 60. HTPR = high on-treatment platelet reactivity; PRU = platelet reactivity unit(s).
J Am Coll Cardiol Intv. 2011;4(4):

20. J Am Coll Cardiol Intv. 2011;4(4):403-410
PR by Treatment Sequence in Noncarriers and Carriers of CYP2C19*2 Allele During the Pre- and Post-Crossover Periods
J Am Coll Cardiol Intv. 2011;4(4):

21. TRIPLET (H7T-CR-TAEH) Study
Comparison of Platelet Inhibition Following a Prasugrel 60 mg or Prasugrel 30 mg LD with or without Pretreatment with a Clopidogrel LD in ACS Subjects undergoing PCI
TRIPLET (H7T-CR-TAEH) Study 25

22. If proceeding to PCI  VN-P2Y12 PRU Baseline, Genomics sample
Study Design
ACS-PCI Patient
ASA
Clopidogrel Placebo
Clopidogrel 600 mg
Clopidogrel 600 mg
Diagnostic Angiogram
If proceeding to PCI  VN-P2Y12 PRU Baseline, Genomics sample
Prasugrel 60 mg
Prasugrel 60 mg
Prasugrel 30 mg
VN-P2Y12 PRU: 2 ± 1 hr, 6 ± 1 hr, 24 ± 4 hr
Prasugrel 10 mg qd
Prasugrel 10 mg qd
Prasugrel 10 mg qd
VN-P2Y12 PRU: 72 ± 24 hr
IPA=Inhibition of Platelet Aggregation; LD=Loading Dose; PRU=P2Y12 Reaction Units
Adapted from trial number NCT

23. Pharmacodynamic Endpoints (PD Population): Primary Endpoint
TRIPLET Study
Pharmacodynamic Endpoints (PD Population): Primary Endpoint
PRU at 6 hrs
P=0.188
Median
P=0.809
VN-P2Y12, PRU
[Source: TRIPLET for EuroPCR oral_ FINAL: Slide 11]
REFERENCE:
European Society of Cardiology-PCR
Placebo/ Pras 60 mg n = 43
Clop 600 mg/ Pras 60 mg
n = 38
Clop 600 mg/ Pras 30 mg n = 45
LS mean* (SE)
(11.86)
35.61
(12.36)
53.92
(11.74)
LS mean difference (CI)
22.24
(-10.98, 55.47)
3.93
(-28.20, 36.07)
*MMRM specification: response variable = treatment + visit + treatment by visit + country
Euro PCR. 2012
Clop=Clopidogrel, CI=Confidence Interval, LS=Least square, MMRM=Mixed-Effect Model Repeated Measure, Pras=Prasugrel, PRU=P2Y12 Reaction Units, PD=Pharmacodynamic, SE=Standard Error, VN=VerifyNow

24. Pharmacodynamic Endpoints (PD Population): Secondary Endpoint
TRIPLET Study
Pharmacodynamic Endpoints (PD Population): Secondary Endpoint
% Inhibition at 6 hrs
Median
VN-P2Y12, % Inhibition
[Source: TRIPLET for EuroPCR oral_ FINAL: Slide 11]
REFERENCE:
European Society of Cardiology-PCR
Placebo/ Pras 60 mg n = 43
Clop 600 mg/ Pras 60 mg
n = 38
Clop 600 mg/ Pras 30 mg n = 45
LS mean* (SE)
79.87 (3.95)
86.77
(4.13)
78.55
(3.93)
LS mean difference (CI)
-6.89
(-18.02, 4.24)
1.33
(-9.44, 12.10)
*MMRM specification: response variable = treatment + visit + treatment by visit + country
Euro PCR. 2012
Clop=Clopidogrel, CI=Confidence Interval, LS=Least square, MMRM=Mixed-Effect Model Repeated Measure, Pras=Prasugrel, PRU=P2Y12 Reaction Units, PD=Pharmacodynamic, SE=Standard Error, VN=VerifyNow

25. Time Course: Pharmacodynamic Population
TRIPLET Study
Time Course: Pharmacodynamic Population
PRU (LS mean), PD population
% Inhibition (LS mean), PD population * * ** * * * * * * *
[Source: TRIPLET for EuroPCR oral_ FINAL: Slide 12]
At 24 hours, inhibition of platelet aggregation there was a modest difference (P=0.049) between the placebo/prasugrel 60 mg group and the clopidogrel 600 mg/prasugrel 60 mg group
REFERENCE:
European Society of Cardiology-PCR
Post LD
Post LD
*P=NS at each time point vs. placebo/prasugrel 60 mg, **P=0.049 between the placebo/prasugrel 60 mg group and the clopidogrel 600 mg/prasugrel 60 mg group
Euro PCR. 2012
LD=Loading Dose, LS=Least Square, PD=Pharmacodynamic, PRU= P2Y12 Reaction Units

26. Safety: Bleeding 106 TEAEs in 276 patients
TRIPLET Study
Safety: Bleeding
106 TEAEs in 276 patients
14 hemorrhagic events in 12 patients were reported
3: placebo LD/prasugrel 60 mg LD
3: clopidogrel 600 mg LD/prasugrel 60 mg LD
6: clopidogrel 600 mg LD/prasugrel 30 mg LD
2 patients experienced a Hgb change from baseline (decrease of ≥3g/dL)
Neither of these patients received a prasugrel LD as both were discontinued and referred for CABG surgery
3 bleeding SAEs in 2 patients, one of which was related to study drug (hematemesis)
[Source: TRIPLET for EuroPCR oral_ FINAL: Slide 13]
REFERENCE:
European Society of Cardiology-PCR
Euro PCR. 2012
CABG=Coronary Artery Bypass Surgery, TEAES=Treatment Emergent Adverse Events, LD=Loading Dose, SAEs=Severe Adverse Events

27. Gurbel P A et al. Circulation 2010;121:1188-1199
RESPOND
Study flow diagram demonstrating treatment in nonresponders and responders.
Figure 1. Study flow diagram demonstrating treatment in A, nonresponders and B, responders. PK/PD indicates pharmacokinetic/pharmacodynamic.
Gurbel P A et al. Circulation 2010;121:

28. Gurbel P A et al. Circulation 2010;121:1188-1199
RESPOND
IPA in response to ADP (20 μmol/L) in clopidogrel-responsive patients before and after crossover
IPA in response to ADP
(20 μmol/L) in clopidogrel-responsive patients maintained on constant therapy
Figure 5. A, Inhibition of platelet aggregation in response to ADP (20 μmol/L, maximum extent) in clopidogrel-responsive patients before and after crossover. *P<0.0001, †P<0.001, ‡P<0.05. B, IPA in response to ADP (20 μmol/L, maximum extent) in clopidogrel-responsive patients maintained on constant therapy. *P<0.0001, †P<0.001, ‡P<0.05.
*P<0.0001, †P<0.001, ‡P<0.05.
Gurbel P A et al. Circulation 2010;121:

29. RESPOND Inhibition of platelet aggregation in response to ADP
(20 μmol/L) in clopidogrel-nonresponsive patients
Figure 2. Inhibition of platelet aggregation in response to ADP (20 μmol/L, maximum extent) in clopidogrel-nonresponsive patients. *P<0.0001, †P<0.001, ‡P<0.05.
*P<0.0001, †P<0.001, ‡P<0.05.
Gurbel P A et al. Circulation 2010;121:

30. RESPOND Nonresponders Cohort:
The proportion of clopidogrel nonresponders who achieved >10% final extent IPA on ticagrelor and clopidogrel was similar
A greater proportion of clopidogrel nonresponders achieved >10% maximum extent IPA on ticagrelor compared with clopidogrel (100% vs. 75% of patients, respectively; p=0.005)

31. RESPOND
A greater proportion of clopidogrel nonresponders achieved >30% and >50% maximum extent IPA on ticagrelor (75% and 13% of patients, respectively; p<0.001) versus clopidogrel (13% and 0% of patients, respectively; p=0.046)
When switched from clopidogrel to ticagrelor, platelet aggregation decreased from 59±9% to 35±11% (p<0.0001)
When switched from ticagrelor to clopidogrel, platelet aggregation increased from 36±14% to 56±9% (p <0.0001).

32. PLATO Clopidogrel Received Prior to Index Event
Clopidogrel-exposed patients, both those on maintenance treatment with clopidogrel and those who received an open-label loading dose of clopidogrel prior to randomization, were eligible for inclusion into the PLATO trial
PLATO was not designed or powered to demonstrate the efficacy or safety of ticagrelor compared with clopidogrel specifically in those patients who received clopidogrel prior to randomization into the PLATO trial.

33. PLATO Clopidogrel Received Prior to Index Event
Prior use of clopidogrel was allowed in PLATO . The percent of patients who were receiving clopidogrel therapy prior to the index event was 7.9% in the ticagrelor group and 7.8% in the clopidogrel group
In a prespecified subgroup analysis, the type of antiplatelet therapy received prior to the index event did not significantly affect the primary efficacy or safety composite endpoint.

34. PLATO Primary Efficacy Endpoint Clopidogrel Received Prior to Index Event
P value interaction= 0.43
Clopidogrel+/-ASA
N=1397
ASA
N=5024
None
N=12 147

35. Ticagrelor Versus Prasugrel in Acute Coronary Syndrome Patients With High On-Clopidogrel Platelet Reactivity Following Percutaneous Coronary Intervention: A Pharmacodynamic Study
Of 139 patients with platelet reactivity assessment, 44 (31.7%) were identified to have high on-treatment platelet reactivity and were all randomized. Until day 15, side effects leading to study drug discontinuation occurred in 1 patient, leaving 43 patients available to test the study hypothesis. PRU = platelet reactivity unit(s).
J Am Coll Cardiol. 2012;60(3):

36. Ticagrelor Versus Prasugrel in ACS in Patients With High On-Clopidogrel PR Following PCI
Least squares estimates and 95% confidence intervals are presented. PRU = platelet reactivity unit(s).
Combined data for the pre- and post-crossover periods are depicted. Lines represent medians, and error bars represent interquartile range. Patients' PR at baseline in the upper quartile and the lower quartile are marked with asterisks and open circles, respectively. Solid circles represent intermediate quartiles. Only a minority of patients (2 of 11, 18.2%) remained in the upper quartile following ticagrelor, compared with 6 of 11 (50.0%) following prasugrel. HTPR = high on-treatment platelet reactivity; PRU = platelet reactivity unit(s).
Platelet reactivity is significantly lower in patients receiving ticagrelor compared with prasugrel
J Am Coll Cardiol. 2012;60(3):

37. How to Switch from Clopidogrel to Ticagrelor
Patients can be transitioned from clopidogrel to ticagrelor without interruption of antiplatelet effect
Patients with ACS who have received a LD of clopidogrel may be started on ticagrelor ( 180 mg LD and continue treatment with 90 mg twice daily)
Transitioning from clopidogrel to ticagrelor resulted in an absolute IPA increase of 26.4% and from ticagrelor to clopidogrel resulted in an absolute IPA decrease of 24.5%
In ACS patients with HTPR on clopidogrel post PCI, ticagrelor produces higher platelet inhibition when compared to prasugrel

38. How to Switch from Clopidogrel to Prasugrel
Patients can be transitioned from MD clopidogrel to MD prasugrel without interruption of antiplatelet effect
Transitioning from MD clopidogrel to LD prasugrel results in profound IPA and “acute abolition” of poor clopidogrel responders
Platelet reactivity with Prasugrel 60 mg LD added to clopidogrel 600 mg LD was no different than Prasugrel 60 mg alone in patients with ACS undergoing PCI
In patients with HTPR after PCI, prasugrel is more effective compared to high clopidogrel in reducing PR, particularly in CYP2C119*2