Transcript PFA-100

Measurement of Antiplatelet
Therapeutic Efficacy
Bonnie H. Weiner MD MSEC MBA FSCAI FACC FAHA
Professor of Medicine
Director, Interventional Cardiology Research
St Vincent Hospital
Worcester MA
Disclosure
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No conflicts relative to this presentation
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General Disclosures
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Ownership Imaging Core Lab Services
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AtheroMed
Acclarent
Stryker/Surpass/Cersys
Consulting
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Boston Biomedical Associates
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Cormend
Honoraria
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Atricure
Atheromed
480 Biomedical
Angiolight
Creganna
Cardiac Assist
GI Dynamics
SCAI
FAAC
Accreditation for Cardiovascular Excellence
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Board Chair
Chief Medical Officer
Antiplatelet Drug “Resistance” / “Response Variability”
An Emerging Clinical Problem?
What Key Questions Would You Ask about
Platelet Function Testing?
What is the anti-platelet
effect of clopidogrel, asa,
and emerging agents?
Can increasing anti-platelet agent
doses affect high platelet reactivity?
High platelet reactivity:
quantifiable and modifiable
risk factor
Does laboratory
identification and
treatment of high
platelet reactivity
benefit the patient?
What does high
on-treatment platelet
reactivity mean to
the patient?
Tests of Aspirin Resistance
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Light transmission Aggregometry
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Arachadonic acid
ADP
Whole blood aggregometry
PFA-100® (platelet function analyzer)
VerifyNow Aspirin®
Urinary 11-dehydro-thromboxane B2
European Heart Journal (2007) 28, 1702–1708 doi:10.1093/eurheartj/ehm226
Comparison in Patients with
Stable CAD
Aspirin Resistance
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Lack of correlation between the different
tests
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Measure different aspects of platelet function
Aspirin Resistance
HOPE Trial
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Heart Outcomes Prevention Evaluation
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Urinary 11-dehydro thromboxane B2 levels
488 patients on aspirin who had CV events
compared to case controlled patients without
events
HOPE
30
P=0.01
P=0.003
NS
P<0.001
Baseline TXB2
25
20
Cases
Controls
15
10
5
0
Death/MI/Stroke
MI
Stroke
CV Death
HOPE
Odds ratio Death/MI/Stroke
2
1.8
1.8
1.6
1.2
1
1.4
1.3
1.4
1
0.8
0.6
0.4
0.2
0
TXB2
< 15.1
15.1-21.8
21.9-33.8
> 33.8
PCI and ASA Resistance
Ultegra Rapid
Platelet Function
Assay
(Accumetrics
Inc., San Diego,
California)
Risk of any cardiovascular event in aspirin resistant
patients
Krasopoulos, G. et al. BMJ 2008;336:195-198
Point-of-Care Platelet Function Testing
• At least 7 studies involving more than
3,000 patients have concluded that high
residual (on-clopidogrel) platelet reactivity
measured by the VerifyNow P2Y12 test is
associated with poor clinical outcomes after
PCI.
• A treatment strategy for patients with high
residual platelet reactivity has not been
tested in a large, randomized, clinical trial.
Baseline Platelet Reactivity* Determines
Outcomes Following Coronary Stenting
1.0
Low Reactivity Group
0.9
0.8
0.7
High Reactivity Group
0.6
P = 0.01
0.5
0
100
Kabbani SS et al. Am J Cardiol. 2003;91:876-878.
P = 0.006
200
Time (Days)
P = 0.043
300
* Fibrinogen binding in response to 0.2 M ADP
** Composite MI, UR, Revascularization
GRAVITAS Study Design
Elective or Urgent PCI with DES*
VerifyNow P2Y12 Test 12-24 hours post-PCI
PRU ≥ 230
R
High-Dose Clopidogrel†
clopidogrel 600-mg, then
clopidogrel 150-mg daily X 6 months
Standard-Dose Clopidogrel†
clopidogrel 75-mg daily X 6 months
Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo
Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo
Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months
*Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs
†placebo-controlled
All patients received aspirin (81-162mg daily)
GRAVITAS Patient Flow
5429 patients screened with VerifyNow P2Y12
12-24 hours post-PCI
2214 (41%) with high residual
platelet reactivity
(PRU ≥ 230)
Clopidogrel
High Dose
N=1109
Clopidogrel
Standard Dose
N=1105
3215 (59%) without high
residual platelet reactivity
(PRU < 230)
Primary Endpoint: CV Death, MI, Stent Thrombosis
Observed event rates are listed; P value by log rank test.
Secondary Comparison: High vs. Not High Reactivity
Treated with Clopidogrel 75-mg daily
Observed event rates are listed. P value by log-rank test.
GRAVITAS: Possible Explanations
• Underpowered: patients low-risk, low event rates?
• Given HR of 1.01 with more than 2,200 patients,
unlikely that a larger trial would show a clinically
meaningful benefit
• Pharmacodynamic effect of the intervention was
too weak?
• Stronger intervention and/or goal-directed
therapy with serial measurements merit study
(TRIGGER-PCI; ARCTIC; TARGET-PCI)
GRAVITAS: Summary
• Compared with standard-dose therapy, high-dose
clopidogrel achieved a modest
pharmacodynamic effect in patients with high
residual reactivity.
• In patients with high residual reactivity measured
after PCI, 6-months of high-dose clopidogrel did
not reduce the rate of cardiovascular death, nonfatal MI, or stent thrombosis and did not increase
GUSTO severe or moderate bleeding.
Primary Results of
Testing platelet Reactivity In patients underGoing
elective stent placement on clopidogrel
to Guide alternative thErapy with pRasugrel
TRIGGER-PCI Study
Study objective
… to assess whether the outcome of patients with high onclopidogrel platelet reactivity after elective PCI with drugeluting stents can be improved by switching from clopidogrel
to prasugrel.
Primary efficacy endpoint: Cardiovascular death or
myocardial infarction
Key safety endpoint:
Non-CABG TIMI major bleeding
TRIGGER-PCI
Successful PCI with DES without major complication and NO GPIIb/IIIa use
Post-PCI VerifyNow P2Y12 Assay (PRU) 2 - 4 hours after 1st MD of
clopidogrel 75 mg at day 1 post-PCI
N ~ 8800
Non-Responder
Yes
PRU ≥ 208?
No
Responder
PRU ≥ 140?
Random Selection
A
N = 1075
B
N = 1075
C
N = 550
D
E
N = 550
“Prasugrel arm”
“Clopidogrel arm”
“Prasugrel arm”
“Clopidogrel arm”
Prasugrel 60 mg LD
Prasugrel 10 mg MD
+ Clopidogrel placebo
Placebo LD
Clopidogrel 75 mg MD
+ Prasugrel placebo
Prasugrel 60 mg LD
Prasugrel 10 mg MD
+ Clopidogrel placebo
Placebo LD
Clopidogrel 75 mg MD
+ Prasugrel placebo
“Standard Therapy”
Clopidogrel 75 mg
Platelet function substudy:
VerifyNow Assessment at day 2 (2 – 4 h after 1st MD of study drug)
Clinical Follow-up and VerifyNow Assessment at 90 days, 180 days
Primary Endpoint: 6 month CV Death and MI
Sample size and power calculation
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6-month incidence of the composite
endpoint of cardiovascular death or MI
(including minor infarctions with elevated
troponin) expected as 4.7%.
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Randomization of 2,150 patients to
provide 93% power to detect a 50 %
relative risk reduction on prasugrel.
Early termination of TRIGGERPCI
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236 patients completed 6 months follow-up
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Only 1 clinical endpoint (peri-procedural MI)
observed
→ rate 0.4%
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Upper 95 %-confidence limit 1.25 %
Summary and conclusion:
 High on-clopidogrel platelet reactivity (>208 PRU by
VerifyNow P2Y12 test) was observed less frequently than
expected.
 Compared with standard-dose clopidogrel 75 mg QD,
prasugrel 10 mg QD substantially decreased platelet
reactivity in patients with high on-clopidogrel platelet
reactivity after elective PCI.
 Given the low event rate in elective PCI patients without
peri-procedural complications it was not possible to
assess the risk – benefit ratio with prasugrel treatment.
Therefore, the study was terminated prematurely for
futility.
ARCTIC
Trial design: Patients undergoing drug-eluting stent implantation were randomized to a
strategy of platelet function monitoring with antiplatelet dose adjustments as necessary (n =
1,213) vs. usual care without monitoring or drug adjustments (n = 1,227).
Results
(p = 0.10)
40
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MI, stroke, stent thrombosis, or urgent
revascularization: 35% of the monitoring
group vs. 31% of the usual care group (p
= 0.10)
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Death or myocardial infarction: 32% vs.
29% (p = 0.15), respectively
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Stent thrombosis: 1.0% vs. 0.7% (p =
0.51), respectively
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Major bleeding: 2.3% vs. 3.3% (p = 0.15),
respectively
35
31
%
20
0
Conclusions
MI, stroke, stent thrombosis, or urgent
revascularization
Platelet function
monitoring
Usual
care
• Among a relatively high-risk cohort of patients
undergoing drug-eluting stent implantation, a
strategy to monitor platelet reactivity to guide
antiplatelet dosing failed to improve clinical
outcomes
Collet JP, et al. N Engl J Med
ARCTIC
ARCTIC
Conclusions
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Variability in platelet function testing
Focus has been on P2Y12 resistance
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Newer more potent agents appear to be
beneficial
No clear correlation with clinical events or that
correcting the laboratory finding affects clinical
endpoints
May be a relationship between ASA
resistance and events