1. Ticagrelor versus clopidogrel in African-American patients with stable coronary artery disease: a randomized, open-label, multiple-dose, crossover study
Ron Waksman, MD Washington Hospital Center, Washington DC
On behalf of
J Maya AstraZeneca LP, Wilmington, DE
DJ Angiolillo University of Florida, Jacksonville, FL
G Carlson AstraZeneca LP, Wilmington, DE
R Teng AstraZeneca LP, Wilmington, DE
R Caplan AstraZeneca LP, Wilmington, DE
K Ferdinand Tulane University, New Orleans, LA

2. Ron Waksman, MD
Consulting: Abbott Laboratories, AstraZeneca, Biotronik Inc., Boston Scientific Corporation, Medtronic Inc.
Grant Support: Volcano Therapeutics, Inc.
Honoraria: Abbott Laboratories, AstraZeneca, Boston Scientific Corporation, Medtronic Inc.

3. Disclosure Statement of Financial Interest
Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below
Affiliation/Financial Relationship
Company
Grant/Research Support
Consulting Fees/Honoraria
Boston Scientific
Biotronik
Astra Zeneka
Lilly Dahichi
Medtronic
Abbott Vascular
Astra Zeneca

4. Rationale: pharmacodynamic study of ticagrelor in African-American patients
Ticagrelor is an oral, reversibly binding ADP receptor antagonist acting via the P2Y12 receptor
The PLATelet inhibition and patient Outcomes (PLATO) phase III study evaluated ticagrelor vs clopidogrel in patients with ACS1
at 12 months, composite endpoint of death from vascular causes, MI, or stroke was significantly lower with ticagrelor versus clopidogrel: 9.8% vs. 11.7%; HR = 0.84 (95% CI: 0.77−0.92); p<0.0011
Few African-American patients were enrolled in the PLATO trial
Ticagrelor
1. Wallentin et al. N Engl J Med. 2009;361:

5. Variability in clopidogrel response in African-American patients
High post-treatment platelet reactivity (HPR) is an independent risk factor for 12-month cardiovascular death and non-fatal MI1
Clopidogrel hyporesponse has been reported in up to 30% of patients1,2  
CYP2C19 is the primary enzyme involved in converting the clopidogrel prodrug into an active metabolite1,3
African-Americans have a high prevalence of the loss-of-function allele CYP2C19*2, which could contribute to their higher rate of clopidogrel non-response2
1. Smith SC Jr et al. Circulation. 2006; 113: e166–e Pendyala LK et al. Am Heart J. 2013; 166:266– FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug. Available at: Accessed: 12 February

6. Randomized, open-label, crossover study of the antiplatelet effects of ticagrelor versus clopidogrel in African-American patients with stable CAD
We evaluated platelet reactivity during the onset and repeated dose administration of ticagrelor compared with clopidogrel
in African American patients with stable coronary artery disease (CAD)
receiving chronic low-dose acetylsalicylic acid (ASA; 75 to 100 mg) as background therapy

7. Study sites and investigators
DE, MD, DC
Ron Waksman
Washington DC
Michael Main
Kansas City MO
Alberto Yataco
Towson MD
Michael Stillabower
Newark DE
Rodolfo Sotolongo
Beaumont TX
Dominick Angiolillo
Jacksonville FL
Keith Ferdinand
Atlanta GA
Anthony Alfieri
Wilmington
Luis Tami
Hollywood

8. Study design Treatment Period 1 Treatment Period 2 7–9 days 7–9 days
Randomization
Treatment A: clopidogrel 600mg/75mg OD
Treatment B: ticagrelor 180mg/90mg BID
Platelet tests
Platelet tests
Platelet tests
Platelet tests
Screening Visit 1
10–14 day washout period
Treatment B: ticagrelor 180mg/90mg BID
Treatment A: clopidogrel 600mg/75mg OD
Platelet tests
Platelet tests
Platelet tests
Platelet tests
Visit 2
Visits 3 & 4
Visit 5
Visits 6 & 7
Study D5130L00013; ClinicalTrials.gov Identifier: NCT

9. Patient population Target patient population Key exclusion criteria
African-American patients with stable CAD taking mg acetylsalicylic acid (ASA) daily
Stable angina pectoris (current or history of)
Objective evidence of CAD
Previous myocardial infarction (MI) or previous revascularisation, i.e. percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG)
Key exclusion criteria
Any indication for oral anticoagulant or dual antiplatelet treatment during study period
Concomitant therapy with strong CYP3A inhibitors, CYP3A substrates with narrow therapeutic index, or strong CYP3A inducers
Increased bleeding risk
Diabetic patients with HbA1c ≥10%

10. Primary and secondary objectives
Primary objective
Compare on-treatment platelet reactivity 2 hours after a loading dose of ticagrelor or clopidogrel
P2Y12 Reaction Units (PRU) using VerifyNow™; least squares means and 2-sided 95% confidence intervals (CIs)
Secondary objectives
Compare on-treatment platelet reactivity with ticagrelor vs clopidogrel
at 0.5 and 8 hours after loading dose; at 2 hours and 8 hours on Day 7; end of dosing on Day 8 (12 hours after last evening dose of ticagrelor; 24 hours after the last morning dose of clopidogrel)
P2Y12 Reaction Units (least squares means; 95% CI)
inhibition of P2Y12 receptor at 2 hours after loading dose = 1−{PRU after study drug/PRU at baseline} X 100 %
Evaluate plasma concentration of ticagrelor and its active metabolite AR–C124910XX
Assess safety of ticagrelor by AEs, physical examination and vital signs

11. Study population (n=34) Treatment and characteristics
Randomized and dosed: n (%)
34 (100.0)
Completed 14 days’ treatment: n (%)1
30 (88.2)
Completed follow-up period: n (%)
31 (91.2)
Median age: years (range)
62.5 (50–75)
Age ≥65: n (%)
12 (35.3)
Male: n (%)
23 (67.6)
Black or African American: n (%)
Median weight: kg (range)
91 (49-177)
Hypertension: n (%)
Dyslipidemia: n (%)2
34 (100)
Type II diabetes: n (%)
17 (50.0)
Coronary artery disease history
Stable angina pectoris: n (%)
6 (17.6)
Past MI: n (%)
Median time since last MI: years (range)
15 (44.1)
4.8 (1.1–25.6)
Previous PCI: n (%)
22 (64.7)
Previous CABG: n (%)
16 (47.1)
Congestive heart failure: n (%) Past
Current (not symptomatic)
2 (5.9)
Valvular heart disease: n (%)
Current peripheral arterial occlusive disease: n (%)
Past pulmonary embolism: n (%)
1 (2.9)
1Patients who completed 7, 8, or 9 days of both sequences were identified as Completed 14 days of treatment
2Including hypercholesterolemia

12. Primary outcome: platelet reactivity 2 hours after loading dose
Difference in least squares mean −183.6 (95% CI: −213.9, −153.3) p<0.001
P2Y12 reaction units: values expressed as the least-squares means with 2-sided confidence intervals (CI)

13. Time course of platelet reactivity
350
Clopidogrel
Ticagrelor
300
250
200
***
P2Y12 reaction units
150
100 50
***
***
***
***
***
***
–50
Baseline
0.5 2 8
Baseline 2 8
12–24
Hours post loading dose
Hours post maintenance dose
Values are expressed as the least-squares mean and 95% confidence intervals. ***p<0.001 for ticagrelor versus clopidogrel
Note: patients with low baseline PRU values (indicating an incomplete washout from anti-platelet therapy) are excluded from this analysis during the period corresponding to the low baseline value

14. Inhibition of platelet reactivity over time
12–24
0.5 8
100 90 80 70 60 50 20
–20 2
Reduction from baseline (%)
Clopidogrel
Ticagrelor
***
Hours post loading dose
Baseline
Hours post maintenance dose 40 30 10
–10
***p<0.001
Inhibition of P2Y12 receptor after loading dose = 1−{PRU after study drug/PRU at baseline} X 100 % Note: Patients with low baseline PRU values (indicating an incomplete washout from anti-platelet therapy) excluded during the period corresponding to the low baseline value.

15. High on-treatment platelet reactivity: % patients with PRU ≥208
Ticagrelor
Clopidogrel
p<
Percent of patients
p<0.0001
p<0.001
p<0.01
p=0.0102
Hours post loading dose
Hours post maintenance dose
Baseline (BL); P2Y12 reaction units (PRU); p = Fisher’s Exact Test p value (2-tail)

16. Plasma concentration-time profiles: ticagrelor
Mean ticagrelor plasma concentration (ng/mL)
ONSET-OFFSET (n = 52–57)
RESPOND non-responders Tic  Clop (n = 15–20)
RESPOND responders Tic  Clop (n = 11–14)
RESPOND responders Tic  Tic (n = 10–13)
Time (hours) 1
100
10,000 4 8 12 16 20 24 10
1,000
Mean ticagrelor plasma concentration (ng/mL)
3000
2000
1500
1000
500 70 10
0.5 2 8 12
Hours post loading dose
Hours post maintenance dose
Left hand plot: geometric mean (± standard deviation) ticagrelor plasma concentrations in African-American patients following a loading dose (180mg) and subsequent maintenance dose (90mg) of ticagrelor; patients with low baseline PRU values (indicating an incomplete washout from anti-platelet therapy) are excluded from this analysis during the period corresponding to the low baseline value.
Right hand plot: similar geometric mean ticagrelor plasma concentrations following a ticagrelor loading dose (180mg) in patients with coronary artery disease (Husted et al. Clin Pharmacokinet 2012;51:397–409).
Baseline (BL); clopidogrel (Clop); P2Y12 reaction units (PRU); ticagrelor (Tic)

17. Plasma concentration-time profiles: AR-C124910XX
Mean AR-C124910XX plasma concentration (ng/mL)
700
500
300
200
100 10 1
0.5 2 8 12
Hours post loading dose
Hours post maintenance dose
Mean AR-C124910XX plasma concentration (ng/mL)
Time (hours) 1 10
1,000 4 8 24
100 16 20 12
ONSET-OFFSET (n = 34–57)
RESPOND non-responders Tic  Clop (n = 10–20)
RESPOND responders Tic  Clop (n = 9–14)
RESPOND responders Tic  Tic (n = 5–13)
Left hand plot: geometric mean (± standard deviation) AR-C124910XX plasma concentrations in African-American patients following a loading dose (180mg) and subsequent maintenance dose (90mg) of ticagrelor; patients with low baseline PRU values (indicating an incomplete washout from anti-platelet therapy) are excluded from this analysis during the period corresponding to the low baseline value.
Right hand plot: similar AR-C124910XX geometric mean plasma concentrations following a ticagrelor loading dose (180mg) in patients with coronary artery disease (Husted et al. Clin Pharmacokinet 2012;51:397–409).
Baseline (BL); clopidogrel (Clop); P2Y12 reaction units (PRU); ticagrelor (Tic)

18. Safety: patients with at least one adverse event
Preferred term, n (%)
Ticagrelor (n=34)
Clopidogrel (n=31)
Hemorrhoidal hemorrhage
1 ( 2.9%)
0 ( 0.0%)
Epistaxis
Dyspnea
2 ( 5.9%)
Application site bruise
1 ( 3.2%)
Vessel puncture site bruise
Blood glucose decreased
Contusion
Musculoskeletal pain
Acute MI
Vaginal hemorrhage
One patient experienced a serious AE (moderate intensity acute MI) but this was not considered to be treatment-related (the last dose of ticagrelor was taken 14 days earlier)
No deaths were reported during the study
No other notable safety findings occurred in terms of adverse events, vital signs or physical examinations

19. Conclusions
In African-American patients with stable CAD on low-dose daily aspirin, ticagrelor compared with clopidogrel provided faster onset and greater extent of platelet inhibition
Plasma concentrations of ticagrelor and AR-C124910XX were consistent with those observed in previous studies of ticagrelor
There were no unexpected safety findings with ticagrelor
These findings suggest that the benefit/risk profile seen with ticagrelor in PLATO may be extrapolated to African-American patients with ACS