1. Is There a Role for Antiplatelet or Genetic Testing to Tailor Antiplatelet Therapy in 2017?
Paul A. Gurbel, M.D.
Inova Center for Thrombosis Research and Drug Development
Inova Heart and Vascular Institute
Falls Church, Virginia 1 1

2. Disclosures Honoraria/Consulting Astra Zeneca Boehringer Merck Janssen
Bayer
Research Grants/Support
Haemonetics
DCRI
NIH
Merck
MedImmune
Coramed
Dr. Gurbel has patents in the field of platelet function testing 2

3. Indisputable Evidence: Coronary Thrombotic Events are “Platelet-Centric”
Mechanism of ACS- A “Platelet-Centric” View
“Vulnerable
Plaque”
“Plaque Rupture”
Endothelium”
“Plaque Erosion”
Platelet Activation- Upstream Mediator
Basic evidence:
Platelets mediate
- Adhesion molecule expression1
- Adhesion/internalization of monocytes  initiation of atherogenesis2-4
- oxLDL formation - Development of vulnerable plaque5
Gawaz M et al. Circulation. 1998;98:
Schulz C et al. Circulation. 2007;116:764-73
Gawaz M et al. J Thromb Haemost. 2008;6: 235-42
Afek A et al. Microvasc Res. 2009;77:364-9
Navarese EP et al. Ann Intern Med ;164:600-7.
Angiographic evidence (IVUS):
HPR associated with
- Coronary atherosclerosis burden, periprocedural MI6 and calcification7
- Culprit lesion atherosclerotic burden and adverse plaque morphology8
6. Mangiacapra F et a. J Am Coll Cardiol Intv 2013;3:35-40
7. Chirumamilla AP et al. J Am Coll Cardiol Img 2012;5:540-9
Yun KH et al. J Am Call Cardiol Img 2016;

4. THE PARADOX in CV Medicine
Platelet - mediated thrombosis: leading cause of death in patients CVD
In current practice, nothing is done to: assess intrinsic thrombogenicity confirm adequate antiplatelet effects non selective “one-size-fits-all” depersonalized therapy
In many pts clopidogrel has no PD effect- should you give your high risk pt a placebo? 4

5. No Other Better Mechanism to Explain Clinical Outcomes
Of TRITON and PLATO
P2Y12 Inhibition = Clinical Efficacy
TRITON TIMI 38
PLATO
Wiviott SD et al. N Engl J Med 2007;357:
Wallentin L. et al. N Engl J Med. 2009;361:
Wiviott SD. et al. Circulation. 2007;116:
Gurbel PA, et al. Circulation. 2009;120: =

6. Link of HPR to Thrombosis is Solid and Indisputable
With Event s n=38
p<0.02
? Threshold
20 uM ADP Aggregation (%)
Cumulative Frequency (%) 10 20 30 40 50 60 70 80 90
100
Without Events n=154
Evidence for the Link Between Poor Platelet Inhibition and Post-PCI Thrombotic Events
The PREPARE POST-STENTING Study
Gurbel PA et al. J Am Coll Cardiol. 2005; 46:1820-6

7. HPR (Unblocked P2Y12 Signaling/Poor Response to Clopidogrel) is an Independent Risk Factor for Post-PCI Events
ADAPT-DES Registry:
- 8,349 patients undergoing PCI
- Multicenter study
Kirtane AJ et al. J Am Coll Cardiol Intv 2015;8:1978–87
2-Year Rates of Definite/Probable ST Clinically Relevant Bleeding
Quantifying P2Y12 Blockade As a Clinical Tool
Tantry US, Gurbel PA et al. J Am Coll Cardiol. 2013;62:
Therapeutic Window Concept for P2Y12 Receptor Reactivity

8. Efficacy of PFT-Guided Antiplatelet Therapy in PCI Patients: Systematic review and meta-analysis (10 studies)
Aradi D et al. Int J Cardiol. 2013;167:
Discordance Between These Studies and Personalized Antiplatelet Therapy Studies
Study (n)
PFT
Patients
Therapy for HPR
Outcome (%)
GRAVITAS
(2,214)
VerifyNow P2Y12 Assay
Stable CAD (60%) NSTE-ACS (10%)
75mg CLP vs
ReLD 600mg LD/150mg MD
MACE: 2.3 vs. 2.3 Major bleeding:1.4 vs. 2.3
ARCTIC
(2,440)
Stable CAD (63%) NSTE-ACS (27%)
Baseline: 600mg LD/75mg MD CLP ( 97%) or 60mg LD/10mg MD PRS (3%)
At 14 – 30d: Add 75mg CLP (90%) or PRS (<10%)
MACE : 34.6 vs. 31.1
ST : 1 vs. 0.7
Major bleeding: 2.3 vs. 2.3
ANTARCTIC (1,312)
>75 yrs ACS/PCI
“Adjusting” - de-intensification to clopidogrel in an attempt to reduce bleeding
MACE : 28% vs. 28%
BARC (types 1, 2, 3, 4, or 5): 39% vs. 38%
Price MJ et al. JAMA. 2011;305: Collet J-P et al. N Engl J Med 2012;367:
Cayla G et al. Lancet. 2016;388:

9. Reasons for Discordant Observations
- Patients: Stable CAD patients vs. High risk ACS patients
- PFT to measure HPR: VerifyNow vs. Multiplate/VASP/TEG
- Drug to Over come HPR: High dose CLP vs. PRS or TIG
- All underpowered studies: Need ~17,000 patients needed to prove or disprove personalized antiplatelet therapy strategy
De Caterina R et al. N Engl J Med. 2013;368:871
Incomplete monitoring
Treatment with low-dose prs resulted in need to Rx HPR in only 4%
Randomization was initiated 14 days after PCI: missing potential beneficial effect of PFM on early outcomes
Nat Rev Cardiol. 2016;13:

10. The Ongoing PFT Based Personalized Trial: TROPICAL -ACS
15 Europecenters, open label, prospective, randomized trial
Multiplate Analyzer
ACS patients undergoing successful PCI, N=2,600
Monitoring Arm
Control Arm
7d prasugrel 5/10mg qd
7d clopidogrel 75mg qd
14d prasugrel 5/10mg qd
PFT: ADPtest
11.5m prasugrel 5/10mg qd
11.5m prasugrel 5/10mg qd
11.5m clopidogrel 75mg qd
Uniform Antiplatelet therapy with prasugrel
Personalized Antiplatelet therapy with prasugrel
Primary Endpoint:
1 y MI, stroke, CV death and bleeding
Secondary Endpoints:
Individual incidences of bleeding, stent thrombosis, all-cause mortality
Cost-effective analysis
NCT

11. PFT to Guide Timing of Surgery: TARGET-CABG Study
500
1000
1500
2000
2500
3000
3500 mL
Clopidogrel naïve
On Clopidogrel
4 hrs
12 hrs
24 hrs
p = NS
Post-Surgery
Primary Endpoint: 24 Hr Chest Output
Clopidogrel naïve (n=95)
TEG MAADP
On clopidogrel (n=96)
Wait 5 d
Wait 3-5 d
< 1 d
35-50mm
>50mm
Primary Endpoint: hrs chest output
Secondary Endpoint: Hospital duration
<35mm
CATHETERIZATION
Thrombelastography (TEG)
Better preoperative balance than intra- and postoperative correction which is not measurable
50% - > Ischemic events – surrogate marker for clotting
> 50%: normal values in ASPECT (CAD + aspirin) and association with ischemic events – assumption that surrogate marker for clotting
< 30%: responder – wait 5 days (biological half life)
N = 139
Cutoff: 60: pts
50: /139 = 23%
< 30: 46/139 = 33%
30-50%: 63/139 = 46%
Secondary Endpoint:
~ 50% shorter waiting time than recommended in the current guidelines.
Mahla E, Gurbel PA et al. Circ Cardiovasc Interv. 2012;5:

12. Genetic Testing

13. Sinai Hospital of Baltimore Study Platelet Aggregation, %
13 SNP’s
Sinai Hospital of Baltimore Study
Platelet Aggregation, %
100 80 60 40 20 1 2
No. of CYP2C19*2 Alleles
P=.92
Pre-clopidogrel
P=.02
Post-clopidogrel
HR=2.42; 95% CI, 1.18–4.99; P=0.02 50 90
Days 40 30 20 10
180
270
360
No. of CYP2C19*2 Alleles 1
% Experiencing Event

14. Presented at AHA 2016 at New Orleans

15. Study Design
MACE: Death, MI, or stroke within 12 months following index PCI
In patients with CYP2C19 LOF, CV outcomes can be improved when clinical genotype made available and alternative therapy prescribed early after PCI

16. The Ongoing Genotyping Based Personalized Trial (TAILOR PCI)
Multicenter, open label, prospective, randomized trial (n=5,270)
CYP2C19 genotyping by Spartan-TM Bioscience assay
Clopidogrel 75 mg /d
Genotyping at the end of 1 year for LoF or wild type allele
Conventional Arm
Wild type
Clopidogrel 75mg/d
Active Arm Prospective Genotyping
LoF carriers
Ticagrelor 90 mg/bid
ACS/Stable patients undergoing PCI
Primary Endpoint:
1 y non-fatal MI, non-fatal stroke, CV death, severe recurrent ischemia, and stent thrombosis
Secondary Endpoints:
Number of LoF carriers with major or minor bleeding
NCT

17. PFT and Genetic Testing in 2017?
#1 We don’t have a definitive prospective study to dispute its utility
#2 But, we do have totality of evidence: huge biologic plausibility huge observational database: ex vivo high reactivity = risk huge prospective randomized trial data:
less thrombosis with more P2Y12 inhibition
- intriguing new IVUS studies- link of HPR to: atherosclerotic burden/adverse plaque morphology
#3 Platelet function testing to guide timing of surgery

18. At IHVI, phenotyping and genotyping will be done in all cath pts