Ndei Cardiovascular Disease In Diabetes Prothrombotic Milieu
Vulnerable Blood · Hypertension, Renal failure Procedural Variables: Stent Length, diameter, type....
Transcript of Vulnerable Blood · Hypertension, Renal failure Procedural Variables: Stent Length, diameter, type....
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Paul A. Gurbel, M.D.
Director, Sinai Center for Thrombosis Research
Professor of Medicine, Johns Hopkins University
Baltimore, Maryland, USA
Vulnerable Blood:
Clinical Utility of Genotyping and
Platelet Function Testing
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Disclosures
Research Grants/Support
Nanosphere
Haemonetics
Daiichi Sankyo/Lilly
CSL Pharmaceuticals
HCRI
NIH
Honoraria/Consulting
Pozen
Astra Zeneca
Daiichi Sankyo/Lilly
Accumetrics
Nanosphere
Boehringer
Merck
Medtronic
CSL
t2 Biosystems
Dr. Gurbel has patents in the field of platelet function testing
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What is (was) the Common Link Between These Men?
Highly Reactive Platelets- Inadequate Antiplatelet Therapy
CORONARY THROMBOSIS = Myocardial Infarction
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Second Biggest Fear: Bleeding
What Are the Main Fears We Have As Interventionalists?
Biggest Fear: Stent Thrombosis
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What Makes the Patient “High-Risk”?
Demographic VariablesWomen, Age, BMI, DM, Smoking,
Hypertension, Renal failure
Procedural Variables:Stent Length, diameter, type.
complex anatomy
High ThrombogenicityHigh platelet reactivity, Prothrombotic factors
Hypercoaguability, Inflammation
DM, women, age, smoking, race, renal failure
Clopidogrel- LoF Carriers, CCB’s, PPI’s, no-smoking
Poor LV Function
Last vessel to viable myocardium
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Thrombosis RIsk Progression (TRIP) StudyRelation Between Platelet Physiology, Inflammation and Disease Activity
Tantry US, Gurbel PA et al. Platelets. 2010;21:360-7
A distinct pathophysiological state of heightened platelet reactivity to ADP, platelet activation,
inflammation and hypercoagulability, marks the development of symptomatic cardiovascular disease
from chronic stable disease.
Reactive Platelets
Inflammation
? ? Prothrombotic State
(Hypercoagulability)Unstable Coronary
Artery Disease
Reactive Platelets
0
14
28
42
56
AS SA UA
GP
IIb
/III
a-
Un
sti
mu
late
d (
MF
I)
p=.051
P<.001
0
60
120
180
240
300
AS SA UA
GP
IIb
/III
a-
AD
P-S
tim
ula
ted
(M
FI)
P=.14
P=.002
Inflammation
CR
P
(ug
/mL
)
p=.006
p=0.2
0
5
10
15
20
25
AS SA UA
Inte
rle
uk
in-8
(p
g/m
L)
0
4
8
12
16
AS SA UA
P<.001
p=.11
Pla
tele
t-F
ibri
n
60
63
66
69
72
AS SA UA
Clo
t-S
tren
gth
(m
m)
P=.002
P=.053
AS SA UA
0
1.5
3
4.5
6
Fib
rin
og
en
(m
g/m
L)
P=.15P=.22
Prothrombotic State
AS = Asymptomatic CAD Patients, SA= Stable Angina, UA= Unstable Angina
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Post-PCI/MI Thrombotic Events- A “Plateletcentric” Problem!!!!
Gurbel PA et al. Circulation.
2012;125:1276-87
ThrombinADP TxA2
Sustained GPIIb/IIIa Activation
P2Y12
Blockers
x
Ischemic Events/Stent Thrombosis
PCI/ACS
Platelet Adhesion
/Activation
Platelet Aggregation
Hypercoagulability Inflammation
Aspirin
x
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Platelet Inhibition by Clopidogrel is UNPREDICTABLE
30 Days
% Inhibition
14
28
<= -30(-30,-20]
(-20,-10](-10,0]
(0,10](10,20]
(20,30](30,40]
(40,50](50,60]
>60
Resistance=15%
0
Gurbel PA et al. Circulation. 2003;107:2908-2913
% Inhibition
10
20
<= -30
(-30,-20]
(-20,-10]
(-10,0]
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
>60
Resistance = 31%
0
24 Hours
% Inhibition
% o
f P
ati
en
ts
11
22
<= -10(-10,0]
(0,10](10,20]
(20,30](30,40]
(40,50](50,60]
>60
Resistance=31%
0
5 Days
Gurbel PA et al. J Am Coll Cardiol. 2005;45:1392-6
0
3
6
9
12
15
18
21
24
27
30
33
<= 0(0,10]
(10,20](20,30]
(30,40](40,50]
(50,60]
(60,70](70,80]
(80,90)(90,100)
300 mg Clopidogrel
600 mg Clopidogrel
Pa
tie
nts
(%
)
On-Treatment Platelet
Aggregation at 24h
(5 M ADP)
On-treatment Platelet Reactivity is UNPREDICTABLE
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Until now, we did nothing to assess antiplatelet drug responsiveness:
WHY?
• Earlier platelet function studies were criticized for:
- laboratory artifacts
- assay variability
• Results regarded as “unconvincing”
- “the tests are crude substitutes for the …. interactions … in vivo”,
- “failed to satisfy … the minimal criteria to establish a causal relation
… between the results of the .. test and …. a thromboembolic event” .
Hirsh J. N Engl J Med. 1987;316:1543-4.
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POC and Near POC Tools to Measure Platelet Function
• Turbidometric based
• Activated platelets to bind
fibrinogen-coated beads
• No pipetting, whole blood
• P2Y12 and Aspirin Assays
• Most widely linked to outcome
VerifyNow
• Measures physical properties
of platelet-fibrin clot:
Platelet-fibrin clot strength
• Platelet Mapping Assay
- Aspirin and P2Y12 receptor
blocker response
• Labor intensive, cost
Thrombleastography Multiplatelet Analyzer
• Measures electrical resistance
between electrodes as activated
platelets adhere
• Antiplatelet effect of aspirin,
P2Y12 receptor blockers, and GPIIb/IIIa
antagonists
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Stent Thrombosis
~Immunity to
Stent
Thrombosis
42%
Gurbel PA et al. J Am Coll Cardiol. 2005; 46:1827-32
Post-PCI Ischemic Events
~Immunity to
Ischemic Event
Occurrence
46%
Periprocedural MI
~Immunity to
periprocedural MI
~50%
Relation of On-Treatment Platelet Reactivity to ADP to Clinical Outcomes
Emergence of a Therapeutic
Target
For P2Y12 Inhibitors
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Point-of-Care testing has markedly advanced the field:
- Easier to study platelet reactivity
- Facilitation of translational research
VerifyNow
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ADAPT-DES Registry: Stent Thrombosis by HPR
Stone G, et al. Presented at TCT 2011 and 2012
Multivariable Propensity Score Adjusted Risk of VerifyNow PRU >208
1-year Adverse Events
Event Adj HR [95%CI] P value
ST, def/prob 2.49 [1.43, 4.31] 0.001
- Definite 3.05 [1.62, 5.75] 0.0006
MI 1.42 [1.09, 1.86] 0.01
Major bleeding 0.73 [0.61, 0.89] 0.002
Death, all-cause 1.20 [0.85, 1.70] 0.30
N=8349
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Days0 5 10 15 20 25 30
0.81%
0.21%
P <0.001
HR [95% CI]=3.89 [1.90, 7.98]
30d
-D
efi
nit
e/P
rob
ab
le S
T (
%)
> 208 PRU
≤ 208 PRU 4x increased risk
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We now have data in tens of thousands of patients:
HPR is a major risk factor
for post-PCI thrombotic event occurrence.
J Am Coll Cardiol. 2010;56:919-33
Relation of HPR to Outcomes:
A Major Reason to Personalize of Antiplatelet Therapy
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There Have Been 2 Major Prospective Trials of
Personalized Antiplatelet Therapy
Using Platelet Function Testing
in the PCI Patient.
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Standard-Dose Clopidogrel†
clopidogrel 75-mg daily X 6 months
High-Dose Clopidogrel†
clopidogrel 600-mg, then
clopidogrel 150-mg daily X 6 months
Elective or Urgent PCI with DES
VerifyNow P2Y12 Test 12-24 hours post-PCI
PRU ≥ 230
R
GRAVITAS Study (n=2,214)
Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo
(5% Predicted Event Rate)
Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo
All patients received aspirin (81-162mg daily)
Price MJ et al. JAMA. 2011;3051097-105
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GRAVITAS Results
Price MJ et al. JAMA. 2011;3051097-105
500
400
300
200
100
0
PR
U
Post-PCI 30 d 6 mo
N=1012 N=944N=1109
p < 0.001
40% HPR at 30 days
150mg clopidogrel:
Effect on HPRPrimary Endpoint
- Low risk patients
- Suboptimal remedy for HPR (high dose clopidogrel)
- Low post-D/C event rates –
inadequately sized for post- D/C event occurrence
- Incomplete protocol following (ARCTIC)
- Inadequate to refute the utility of personalization
- The challenge for a future randomized trial:
Adequate n, Funding
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Efficacy of Personalized Antiplatelet Therapy in PCI patients:
Systematic review and meta-analysis
Aradi D et al. Int J Cardiol. 2012 Jun 15. [Epub ahead of print]
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Sibbing D et al. J Thromb Haemost. 2010;8:250-6
188 AU x minTIMI Major Bleeding
Multiplatele Analyzer
Campo G et al. J Am Coll Cardiol. 2011;57:2474–83
VerifyNow Assay
Role of POC Testing : Bleeding Risk in Clopidogrel-Treated Patients
Thrombelastography
Gurbel PA et al. Am Heart J. 2010;160:346-54
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Gurbel PA et al. J Am Coll Cardiol. 2007;50:1822-34 and Am Heart J. 2010;160:346-54, Campo G et al. J Am Coll Cardiol 2011;57:2474–83,
Jeong YH and Gurbel et al. Presented at ESC 2011. Gurbel PA et al. Thromb Haemost. 2011;106:263-4.
Sibbing D et al. Thromb Haemost 2010; 103: 151–159 and J Thromb Haemost. 2010;250-6
“Immunity”Thresholds
~170 PRU
~50% VASP-PRI
~35% 5 M ADP
~46% 20 M ADP
~416 AU* MULTIPLATE
~65 mm MAKH-TEG
BleedingThreshold<85 PRU<188 AU*<31mm MAKH
The Platelet Function Therapeutic Window
and the Concept of “Thrombosis Immunity”
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Genetic Testing
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http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020839s042lbl.pdf
Influence of Genetics on Clopidogrel Efficacy
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Shuldiner AR and Gurbel PA, et al. JAMA. 2009;302:849-57
Genome Wide Association Study ~ 500,000 SNP’s
- Healthy Amish subjects (n=429) with extensive family relationships treated with 75mg x7d clopidogrel
- Contribution of genetic component to clopidogrel response variability ~70%
- Contribution of CYP2C19 locus to clopidogrel response variability is only ~12%
- Majority of clopidogrel response variability remains unexplained
(rare/other genetic variants that escaped detection with GWAS)
13 SNP’s cluster
(1.5 mb on 10q24)
A genetic locus unequivocally associated with clopidogrel response variability
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HR = 2.42;95% CI, 1.18-4.99; P=0.02
Relation of CYP2C19*2 Allele to PD Response and Clinical Outcome
Shuldiner AR and Gurbel PA, et al. JAMA. 2009;302:849-57
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2C19 LoF Carriage Associated With Post-PCI Thrombotic Outcomes
Carriers Non-carriers
1.3
1.5
1.6
1.8
3.3
4.7
2.8
4.0
CYP2C19 LoF = ~ 30% Americans & ~ 2% are homozygotes
Platelet reactivity in the clopidogrel-treated homzygotes is very high
- a subject of FDA “boxed warning”
Is it rational take this 2% chance
when we have the capability of easily detecting 2C19 LoF?
JAMA 2010;304:1821-1830
Hulot: Meta-analysis TRITON TIMI-38
Pri
mary
Ou
tco
mes (
%)
J Am Coll Cardiol. 2010;56:134-43
0
2
4
6
8
10
12
14
Mega: Meta-analysis
1 LoF 2 LoF None 1 LoF 2 LoF None 1 LoF 2 LoF None Clopidogrel Prasugrel
n=11,959
n=5,694
Stent Thrombosis
n=9,685
Stent Thrombosis
n=5,787
n=1,477 n=1,466
N Engl J Med. 2009;360:354-62
Circulation. 2009;119:2553-60
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Near Point-of-Care Genotyping: Verigene SystemSingle-use disposable cartridgesBench top instrumentation
Blinded Methods
Comparison Study
Bi-Directional DNA Sequencing
*1/*1 *2/*1 *2/*2 *8/*1 *9/*1 *10/*1 *17/*1 *17/*1
7
Verigene®
Test
(*2-*10,
*13, *17
alleles)
*1/*1 38
*2/*1 26
*2/*2 2
*8/*1 1
*9/*1 1
*10/*1 1
*17/*1 29
*17/*17 2
Gurbel PA, et al. Presented at ACC 2011, New Orleans
100% concordance
with conventional
sequencing
Verigene® CYP2C19 Test Performance
Results
available
in 3 hours
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Spartan RX CYP2C19 System
• Sensitivity – 100%
• Specificity – 99.4%
Performance Characteristics of Rapid Testing vs. Direct DNA Sequencing
• Buccal Swab/Real Time PCR
• 60 minutes to identify:
• CYP2C19*2 carrier status
• Heterozygous vs. Homozygous
Roberts JD et al. Lancet. 2012;379:1705-11
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How Do Genotyping and Phenotyping Differ?
Genotyping
- Stable Risk Factor
- No Method Variability
- Assists in Choosing Initial Rx
- Provides “Yes” or “No” Readout
- Supported by Multicenter Trial Data
- No Proven Prospective Evidence
- Addressed in Guidelines
Platelet Function Testing
- Labile Risk Factor
- Method Variability
- No Assistance in Choosing Initial Rx
- Provides Continuous Readout
- Supported by Mostly Registry Data
- No Proven Prospective Evidence
- Addressed in Guidelines
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Guidelines for Platelet Function and Genetic Testing
IIb
Hamm CW et al. Eur Heart J. 2011;32:2999-3054
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TARGET-CABG Study
Clopidogrel naïve (n=95)
TEG MAADP
On clopidogrel (n=96)
Wait 5 d Wait 3-5 d < 1 d
35-50mm >50mm
TEG MAADP
Primary Endpoint: 24 hrs chest output
Secondary Endpoint: Hospital duration
<35mm
CATHETERIZATION
Role of POC Testing in Clopidogrel -Treated Patients Undergoing CABG
0
500
1000
1500
2000
2500
3000
3500
mL
Clopidogrel naïve
On Clopidogrel
4 hrs 12 hrs 24 hrs
p = NS p = NS p = NS
Post-Surgery
Primary Endpoint: 24 Hr Chest Output
Secondary Endpoint:
~ 50% shorter waiting time than recommended in
the current guidelines.
Mahla E et al. Circ Cardiovasc Interv. 2012 2012;5:261-9
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Ferraris FA. Ann Thorac Surg. 2012;94:1761-81.
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1) Clopidogrel resistance is a pharmacodynamic event associated
with a high risk of post-PCI thrombosis.
Conclusions
6) Irrational to give expensive drugs associated with more bleeding to all
patients - when clopidogrel works in ~ 2/3 of patients.
5) Irrational to give placebo to prevent a catastrophic thrombotic event.
4) Platelet reactivity easily and rapidly detected with POC.
2) HPR is an established risk factor- the most potent of all.
3) HPR is reliably overcome by ticagrelor and prasugrel.
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Who is the Optimal Patient for Testing?
What is “high risk”?
Variables mostly associated with increased risk of ST, MI, HPR:
- ACS (current or prior)
- H/O stent thrombosis, TVR
- Poor LV function
- Multivessel stenting
- Complex anatomy (e.g. bifurcation, long, small stents)
- BMI, DM, PPI
Selective testing in High risk PCI patients on clopidogrel-
phenotyping - can they safely stay on it?
genotyping - which drug to start?
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Current:Mostly a
Head-in-Sand Strategy
Future:
Thinking Man’s Strategy
Approach to Determining Blood Vulnerability