Antiplatelet drug resistance: Definitions, diagnosis, and implications for personalized medicine

1
Antiplatelet drug resistance Definitions,
diagnosis, and implications for personalized
medicine

• Peter Berger, MD
• Interventional Cardiologist
• Director, Center for Clinical Studies
• Geisinger Clinic

2
Potential Conflicts of Interest

• I have spoken at CME approved scientific symposia
  supported by BMS, Sanofi-Aventis, the Medicines
  Company, AstraZenica, Medtronic, Sheering Plough,
  Lilly/Daiichi Sankyo (all for less than 10,000).
  
• I have served as a consultant to PlaCor,
  Lilly/Daiichi Sankyo, Molecular Insight
  Pharmaceuticals, CV Therapeutics (all for less
  than 10,000).
• I own equity in Lumen, Inc. (a company that is
  developing an embolic protection device) (greater
  than 10,000).
• No speakers bureaus

3
Issues

• Definitions of resistance or
  hyporesponsiveness
• How to make the diagnosis
• Implications for personalized medicine

4
Annual Number of Medline Articles with
Clopidogrel, Aspirin, or Antiplatelet and
Resistance or Responsiveness in the Title
1997-2007
100
80
60
40
20
0
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
Courtesy of Steve Steinhubl, MD
5
Class IIb In pts in whom subacute thrombosis
may be catastrophic or lethal (unprotected left
main, bifurcating left main, or last patent
vessel), platelet aggregation studies may be
considered and the dose of clopidogrel increased
to 150 mg per day if less than 50 inhibition of
platelet aggregation is demonstrated. (Level of
Evidence C)
Level of Evidence C Consensus opinion of
experts, case studies, or standard-of-care.
6
Methods to Assess Responsiveness of Antiplatelet
Agents

• Light transmission aggregometry (using different
  agonists, different concentrations of agonists
  using either the maximal, final, or slope of
  aggregation differing anticoagulants)
• Flow cytometry (VASP phosphorylation, P selectin,
  platelet microparticles, leukocyte aggregates,
  activated IIb/IIIa receptors
• VerifyNow
• Ichor device (PlateletWorks)

7
Methods to Assess Responsiveness of Antiplatelet
Agents

• PFA 100
• Thromboelastography (TEG) Platelet Mapping
• Urinary thromboxane metabolites
• Serum thromboxane metabolites (not commercially
  available)
• Thrombovision
• PlaCor device
• Whole blood impedance aggregometry

8
Definitions of Hyporesponsiveness

• Lower tertile, quartile, quintile of response
• Less than 10 or 20 reduction in responsiveness
• Bottom 10 or 20 or 50 of residual
  aggregability
• gt50 the aggregability of platelet poor plasma
• Many others, using many different methods

9
Responsiveness to Antiplatelet Drugs on Ex Vivo
Platelet Function Tests and Clinical Outcome
Which is pt is at higher risk?
40 Inhibition
Platelet Reactivity
lt10 Inhibition
Before
After
Before
After
Courtesy of Shamir Mehta
10
Methods to Assess Responsiveness of Antiplatelet
Agents

• It is not possible that all the devices are
  associated with thrombotic events (or bleeding)
  as they do not correlate with one another
• Several studies employed more than 1 device
  and only 1 correlated with outcome
• Studies have now been performed directly
  comparing device with one another
• There has been publication bias favoring the
  positive studies
• Therefore we can not know the true strength of
  the reported associations

11
Clopidogrel and Platelet REactivity in Patients
With and Without Stent Thrombosis CREST
5 µm ADP
20 µm ADP
P0.001
Aggregation ()
Aggregation ()
P0.05
No SAT SAT (n 20)
(n 100)
No SAT SAT (n 20) (n 100)
Gurbel PA, et al. JACC 2005461827-32
12

Platelet Aggregability and Activation in STEMI
Importance of Control Group
A
B

Lev EI et al. Am Heart J 2007, 15341.e1-41.e6
13
Prasugrel vs. Clopidogrel

• Prasugrel achieves much greater inhibition of
  aggregation than clopidogrel with both loading
  and maintenance doses
• If TRITON TIMI 38 had not indicated a
  significant reduction in thrombotic
  complications and a significant increase in
  bleeding with prasugrel, it would have been a
  major blow to a linkage between aggregability
  (on LTA) and outcome
• It did

14
TRITONEfficacy and Safety

15
138 events
Clopidogrel
HR 0.81(0.73-0.90)P0.0004
12.1
CV Death / MI / Stroke
9.9
10
NNT 46
Prasugrel
Endpoint ()
5
35 events
TIMI Major Non-CABG Bleeds
Prasugrel
2.4
HR 1.32(1.03-1.68)P0.03
1.8
Clopidogrel
0
NNH 167
0
30
60
90
180
270
360
450
Days
15
TRITON Bleeding Events(N13,457)
ICH in Pts w Prior Stroke/TIA (N518)
Clopidogrel
Prasugrel
Clop 0 (0) Pras 6 (2.3) (P0.02)
Events
ARD 0.6HR 1.32P0.03NNH167
ARD 0.5HR 1.52P0.01
ARD 0.2P0.23
ARD 0P0.74
ARD 0.3P0.002
16
Warfarins Narrow Therapeutic Window
Data from 42,451 pts, 3,533 deaths, 1.25 million
INRs
Oden, A. et al. BMJ 20023251073-1075
17
Prasugrel 60 mg LD vs Clopidogrel 300 mg LD Is
There an Optimal Degree of P2Y12 Inhibition?
100

80
Inhibition of Platelet Aggregation (20 µM) ()
60

40
20

0
-20
Prasugrel 60 mg LD
Clopidogrel 300 mg LD
IPA () to 20 µM ADP 24 hr after LD
From Brandt JT AHJ 153 66e9,2007
18
Prasugrel 60 mg LD vs Clopidogrel 300 mg LD Is
There an Optimal Degree of P2Y12 Inhibition?
100

80
Inhibition of Platelet Aggregation (20 µM) ()
60

40
20

0
-20
Prasugrel 60 mg LD
Clopidogrel 300 mg LD
IPA () to 20 µM ADP 24 hr after LD
From Brandt JT AHJ 153 66e9,2007
19
Prasugrel vs. Clopidogrel

• Suppose a pt had the same residual
  aggregability after prasugrel and clopidogrel
• Would their risk of thrombosis and bleeding be
  the same?
• If we are going to be able to use one or more
  measures of aggregability to personalize
  antiplatelet therapy, the answer has to be
  yes
• Requires standardizing definitions,
  methodology to quantify responsiveness

20
Prasugrel vs. Clopidogrel

• Four studies indicate greater inhibition of
  aggregation with 150 vs 75 mg of clopidogrel
• Studies of lower doses of prasugrel are
  planned in certain subgroups higher doses
  can also be taken
• Other P2Y12 inhibitors are being developed
• There is the ability to alter the level of
  inhibition achieved with most oral
  antiplatelet agents

21
Successful PCI with DES without major
complication or GPIIb/IIIa use
Post-PCI VerifyNow P2Y12 Assay (PRU) 12-24 hours
post-PCI
N 6600
PRU 230?
Yes
No
Responder
Non-Responder
Random Selection
A
B
C
N 583
N 1100
N 1100
Standard Therapy clopidogrel 75mg placebo/day
Standard Therapy clopidogrel 75mg placebo/day
Tailored Therapy clopidogrel 150-mg/day
Clinical Follow-up And VerifyNow Assessment at 30
days, 6 months
Primary Endpt 6 month CV Death, Non-Fatal MI,
ARC Def/Prob Stent Thrombosis
Study PI Matthew J. Price, MD
Coordinating Center Scripps Advanced Clinical
Trials
22
Relationship Between Aggregometry and Outcome
Summary

• Definitions of resistance (hyporesponsiveness)
  vary
• Not all methods to assess responsiveness are
  equal
• Has been publication bias supporting an
  association between responsiveness and outcome
• Has been misinterpretation of data believed to
  support a relationship between responsiveness and
  outcome
• There probably is an association, but much has to
  be learned before it should be routinely used to
  make clinical decisions

23
Question

• There are antiplatelet agents that cause greater
  inhibition of aggregation on platelet function
  testing than others but cause less bleeding
• A True
• B False
• Vote now!

24
Question

• There are antiplatelet agents that cause greater
  inhibition of aggregation on platelet function
  testing than others but cause more death and MI
• A True
• B False
• Vote now!

25
Question

• Within 10 years, one or more point-of-care
  platelet function assays will be developed and/or
  the studies performed confirming that a patients
  individual response to oral antiplatelet agents
  can be used to optimize therapy
• A True
• B False
• Vote now!

26
References

• Wiviott SD, Braunwald E, McCabe CH et al for the
  TRITON-TIMI 38 Investigators. Prasugrel versus
  Clopidogrel in Patients with Acute Coronary
  Syndromes
• Michelson AD. Platelet Function Testing in
  Cardiovascular Diseases Circulation.
  2004110e489-e493
• Lev EI, Alviar CL, Mehmet E et al. Platelet
  reactivity in patients with subacute stent
  thrombosis compared with non-stent-related acute
  myocardial infarction. Am Heart J
  200715341.e1241.e6