Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial.

Abstract

High platelet reactivity while receiving clopidogrel has been linked to cardiovascular events after percutaneous coronary intervention (PCI), but a treatment strategy for this issue is not well defined.
To evaluate the effect of high-dose compared with standard-dose clopidogrel in patients with high on-treatment platelet reactivity after PCI.
Randomized, double-blind, active-control trial (Gauging Responsiveness with A VerifyNow assay-Impact on Thrombosis And Safety [GRAVITAS]) of 2214 patients with high on-treatment reactivity 12 to 24 hours after PCI with drug-eluting stents at 83 centers in North America between July 2008 and April 2010.
High-dose clopidogrel (600-mg initial dose, 150 mg daily thereafter) or standard-dose clopidogrel (no additional loading dose, 75 mg daily) for 6 months.
The primary end point was the 6-month incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. The key safety end point was severe or moderate bleeding according to the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) definition. A key pharmacodynamic end point was the rate of persistently high on-treatment reactivity at 30 days.
At 6 months, the primary end point had occurred in 25 of 1109 patients (2.3%) receiving high-dose clopidogrel compared with 25 of 1105 patients (2.3%) receiving standard-dose clopidogrel (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.58-1.76; P = .97). Severe or moderate bleeding was not increased with the high-dose regimen (15 [1.4%] vs 25 [2.3%], HR, 0.59; 95% CI, 0.31-1.11; P = .10). Compared with standard-dose clopidogrel, high-dose clopidogrel provided a 22% (95% CI, 18%-26%) absolute reduction in the rate of high on-treatment reactivity at 30 days (62%; 95% CI, 59%-65% vs 40%; 95% CI, 37%-43%; P < .001).
Among patients with high on-treatment reactivity after PCI with drug-eluting stents, the use of high-dose clopidogrel compared with standard-dose clopidogrel did not reduce the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis.
clinicaltrials.gov Identifier: NCT00645918.

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ORIGINAL CONTRIBUTION
Standard- vs High-Dose Clopidogrel
Based on Platelet Function Testing
After Percutaneous Coronary Intervention
The GRAVITAS Randomized Trial
Matthew J. Price, MD
Peter B. Berger, MD
Paul S. Teirstein, MD
Jean-Franc ¸ois Tanguay, MD
Dominick J. Angiolillo, MD
Douglas Spriggs, MD
Sanjeev Puri, MD
Mark Robbins, MD
Kirk N. Garratt, MD
Olivier F. Bertrand, MD
Michael E. Stillablower, MD
Joseph R. Aragon, MD
David E. Kandzari, MD
Curtiss T. Stinis, MD
Michael S. Lee, MD
Steven V. Manoukian, MD
Christopher P. Cannon, MD
Nicholas J. Schork, PhD
Eric J. Topol, MD
for the GRAVITAS Investigators
C
drug-elutingstentimplantationwitha
combination of aspirin and P2Y12an-
tagonist for at least 1 year.1Clopido-
grelisaprodrugthatrequiresbiotrans-
formation into an active metabolite in
order to exert its inhibitory effect on
platelet activation and aggregation.2
URRENT GUIDELINES RECOM-
mend treating patients un-
dergoingpercutaneouscoro-
nary intervention (PCI) and
Author Affiliation: Scripps Clinic (Drs Price, Teirstein,
Stinis, and Topol), Scripps Translational Science Insti-
tute (Drs Price, Teirstein, Schork, and Topol), and
Scripps Research Institute (Dr Schork), La Jolla,
California; Geisinger Clinic, Danville, Pennsylvania
(DrBerger);MontrealHeartInstitute,Montreal,Canada
(Dr Tanguay); University of Florida at Shands-
Jacksonville, Jacksonville (Dr Angiolillo); Clearwater
Cardiovascular Consultants, Clearwater, Florida
(Dr Spriggs); Trinity Medical Center, Moline, Illinois
(Dr Puri); Vanderbilt University, Nashville, Tennessee
(DrRobbins);LenoxHillHospital,NewYork,NewYork
(Dr Garratt); Laval Hospital, Quebec City, Quebec,
Canada(DrBertrand);ChristianaHospital,Newark,Dela-
ware (Dr Stillablower); Sansum Clinic, Santa Barbara,
California(DrAragon);PiedmontHeartInstitute,Atlanta,
Georgia (Dr Kandzari); University of California at Los
Angeles(DrLee);SarahCannonResearchInstituteand
Hospital Corporation of America, Nashville, Tennes-
see(DrManoukian);andBrighamandWomen’sHos-
pital, Boston, Massachusetts (Dr Cannon).
A List of the GRAVITAS Investigators appears at the
end of this article.
CorrespondingAuthor:MatthewJ.Price,MD,10666
NTorreyPinesRd,MaildropS1056,LaJolla,CA92037
(price.matthew@scrippshealth.org).
Context High platelet reactivity while receiving clopidogrel has been linked to car-
diovascular events after percutaneous coronary intervention (PCI), but a treatment
strategy for this issue is not well defined.
Objective To evaluate the effect of high-dose compared with standard-dose clopi-
dogrel in patients with high on-treatment platelet reactivity after PCI.
Design,Setting,andPatients Randomized,double-blind,active-controltrial(Gaug-
ing Responsiveness with A VerifyNow assay—Impact on Thrombosis And Safety
[GRAVITAS])of2214patientswithhighon-treatmentreactivity12to24hoursafterPCI
withdrug-elutingstentsat83centersinNorthAmericabetweenJuly2008andApril2010.
Interventions High-dose clopidogrel (600-mg initial dose, 150 mg daily thereaf-
ter)orstandard-doseclopidogrel(noadditionalloadingdose,75mgdaily)for6months.
MainOutcomeMeasures Theprimaryendpointwasthe6-monthincidenceofdeath
from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. The key
safety end point was severe or moderate bleeding according to the Global Utilization of
Streptokinaseandt-PAforOccludedCoronaryArteries(GUSTO)definition.Akeyphar-
macodynamicendpointwastherateofpersistentlyhighon-treatmentreactivityat30days.
Results At 6 months, the primary end point had occurred in 25 of 1109 patients
(2.3%) receiving high-dose clopidogrel compared with 25 of 1105 patients (2.3%)
receiving standard-dose clopidogrel (hazard ratio [HR], 1.01; 95% confidence inter-
val [CI], 0.58-1.76; P=.97). Severe or moderate bleeding was not increased with the
high-dose regimen (15 [1.4%] vs 25 [2.3%], HR, 0.59; 95% CI, 0.31-1.11; P=.10).
Comparedwithstandard-doseclopidogrel,high-doseclopidogrelprovideda22%(95%
CI, 18%-26%) absolute reduction in the rate of high on-treatment reactivity at 30
days (62%; 95% CI, 59%-65% vs 40%; 95% CI, 37%-43%; P?.001).
Conclusions Among patients with high on-treatment reactivity after PCI with drug-
eluting stents, the use of high-dose clopidogrel compared with standard-dose clopi-
dogreldidnotreducetheincidenceofdeathfromcardiovascularcauses,nonfatalmyo-
cardial infarction, or stent thrombosis.
Trial Registration clinicaltrials.gov Identifier: NCT00645918
JAMA. 2011;305(11):1097-1105
www.jama.com
For editorial comment see p 1136.
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Pharmacokinetic and pharmacody-
namicstudieshavedemonstratedwide
interindividual variability in the con-
centration of active metabolite and in
the magnitude of platelet inhibition
achievedbyrecommendedloadingand
maintenancedosesofclopidogrel.3-5Al-
though some of this variability is due
togeneticpolymorphismsthataffectthe
functionalactivityoftheCYP2C19en-
zyme, most cannot be explained by
genotype or other clinical characteris-
tics.6,7
Several studies have suggested that
patientswithhighon-treatmentplatelet
reactivity while receiving clopidogrel
are at an increased risk of cardiovas-
cular events after PCI, including stent
thrombosis.8WeconductedtheGaug-
ing Responsiveness with A VerifyNow
assay—Impact on Thrombosis And
Safety (GRAVITAS) trial to determine
whether high-dose clopidogrel is su-
perior to standard-dose therapy for
thepreventionofcardiovascularevents
after PCI in patients with high on-
treatment reactivity according to a
point-of-care platelet function assay.
METHODS
Trial Design
GRAVITASwasamulticenter,random-
ized,double-blind,active-controltrial.
The details of the study design have
beenpublishedpreviously.9Patientflow
is shown in FIGURE 1. An indepen-
dent data and safety monitoring board
monitored the trial and had access to
the unblinded data. The trial was ap-
provedbytheinstitutionalethicscom-
mittee of each participating institu-
tion as well as by the appropriate
national ethics committees. All pa-
tients provided written informed con-
sent.
Study Population
Patients were eligible to be enrolled if
theyhadundergonePCIwith1ormore
drug-elutingstentsforthetreatmentof
stable coronary artery disease or non–
ST-elevation acute coronary syn-
dromes. Race and ethnicity were self-
identified. A protocol amendment
during the conduct of the study al-
lowed for the enrollment of patients
with ST-elevation myocardial infarc-
tion. Major exclusion criteria in-
cluded the use of periprocedural gly-
coprotein IIb/IIIa inhibitors, the
planned future use of oral anticoagu-
lanttherapy,andbleedingpriortoplate-
letfunctionmeasurement.Patientswere
also excluded if they did not receive a
clopidogrelregimenaroundthetimeof
PCI that ensured that they were near
to or at their steady state level of inhi-
bition at the time of platelet function
measurement. Specifically, if the pa-
tient had no prior exposure to clopi-
dogrel, a dose of 600 mg had to have
beenadministerednolaterthan2hours
afterPCI;patientsalreadytreatedwith
clopidogrel must have received 75 mg
daily for at least 7 days, or, if less than
7days,theymusthavereceivedaload-
ingdoseof300mgormoreatthetime
that clopidogrel was initiated. Pa-
tients could not receive an additional
loading dose prior to assessment of
platelet function.
Study Procedures
Plateletfunctionwasmeasuredwiththe
VerifyNow P2Y12 test (Accumetrics,
Figure 1. Trial Profile
5429 Patients assessed by VerifyNow P2Y12 test
2214 Had high on-treatment
reactivity (PRU ≥230)
3215 Did not have high on-treatment
reactivity (PRU <230)
586 Randomly selected for observational cohort
1109 Randomized to receive high-dose clopidogrel
1095 Received intervention as randomized
14 Did not receive intervention
1 Did not meet inclusion criteria
11 Patient decision
1 Had protocol deviation
1 Unknown reason
1105 Randomized to receive standard-dose
clopidogrel
1092 Received intervention as randomized
13 Did not receive intervention
5 Did not meet inclusion criteria
8 Patient decision
586 Received standard-dose clopidogrel as
assigned
584 Received intervention as randomized
2 Did not meet inclusion criteria
1109 Included in primary analysis1105 Included in primary analysis586 Included in primary analysis
2629 Excluded per study protocol
2214 Randomized
2 Lost to follow-up
175 Discontinued intervention
6 Had a cardiovascular event
19 Had bleeding
42 Had an adverse event
108 Had other reasons
0 Lost to follow-up
157 Discontinued intervention
12 Had a cardiovascular event
16 Had bleeding
31 Had an adverse event
98 Had other reasons
2 Lost to follow-up
78 Discontinued intervention
2 Had a cardiovascular event
14 Had bleeding
22 Had an adverse event
40 Had other reasons
PRU indicates P2Y12reaction units.
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San Diego, California) 12 to 24 hours
after PCI. This test has been previ-
ously described in detail.10In brief,
this test measures adenosine
diphospate−induced platelet aggluti-
nation as an increase in light transmit-
tance and uses a proprietary algo-
rithm to report values in P2Y12
reaction units (PRU). A higher PRU
result reflects greater P2Y12-mediated
reactivity. Specialized software devel-
oped for the trial encrypted the plate-
let function results to maintain double
blinding. Study drug assignment was
performed centrally by an interactive
voice-response system. The clopido-
grel and placebo were in tablet form
and identical in appearance. Patients
with high on-treatment platelet reac-
tivity according to the platelet func-
tion test were randomly assigned in a
1:1 fashion to a regimen of high-dose
or standard-dose clopidogrel. High-
dose clopidogrel was given as a total
first-day dose of 600 mg followed
thereafter by a dose of 150 mg daily
for 6 months. Standard-dose clopido-
grel was prescribed as a loading dose
of placebo followed by a dose of 75
mg and placebo tablet daily. A ran-
dom sample of patients without high
on-treatment reactivity was enrolled
and assigned to standard-dose clopi-
dogrel in a blinded fashion (placebo
loading dose followed by a dose of 75
mg and placebo tablet daily). A per-
muted block design was used to
select these patients over the course
of the trial. Patients without high
on-treatment reactivity who were not
selected by the interactive voice-
response system were not followed
up. Aspirin treatment was required at
a dose of 75 to 162 mg daily. Study
visits and platelet function testing
with the VerifyNow P2Y12 test were
conducted at 30 days and 6 months.
End Points
High on-treatment reactivity was
defined as 230 PRU or higher. This
cutoff was chosen because it was
similar to the cutoff suggested by a
prior observational study that used
receiver-operating characteristic
(ROC) curve analysis to identify the
level of on-treatment reactivity that
provided the maximal sensitivity and
specificity for the prediction of major
adverse cardiovascular events after
PCI.11The cutoff is also consistent
with the suggested cutoffs derived by
ROC curve analyses in several subse-
quent observational studies.12-14The
primary efficacy variable was a com-
posite of death from cardiovascular
causes, nonfatal myocardial infarc-
tion, or stent thrombosis. All deaths
were considered cardiovascular unless
an unequivocal noncardiovascular
cause could be established; hemor-
rhagic deaths were also considered to
be cardiovascular. Myocardial infarc-
tion followed the American College of
Cardiology definition.15Stent throm-
bosis was defined as definite or prob-
able according to the Academic
Research Consortium definitions.16
The key safety end point was severe
or moderate bleeding according to the
Global Utilization of Streptokinase
and t-PA for Occluded Coronary
Arteries (GUSTO) definition.17All
potential events were identified by site
investigators. A clinical events com-
mittee blinded to treatment assign-
ment and independent of the trial
sponsor adjudicated all suspected pri-
mary efficacy end points.
Statistical Analysis
Efficacy comparisons were performed
onthebasisofthetimetothefirstevent
accordingtotheintention-to-treatprin-
ciple. No imputation of missing data
was performed; patients lost to fol-
low-upwerecensoredatthedateoflast
contact.Safetyanalyseswerecarriedout
on data from patients who had re-
ceivedatleast1doseofthestudydrug.
Survival curves were generated by the
Kaplan-Meiermethod,andsurvivaldif-
ferences between groups were com-
pared by the log-rank test stratified by
acute coronary syndromes. We esti-
mated that, assuming an event rate of
5% in patients with high on-treatment
reactivity treated with standard-dose
clopidogrel and a withdrawal rate of
10%, 2200 patients with high on-
treatment reactivity (1100 in each
group)wouldprovide80%powertode-
tecta50%relativeriskreductioninthe
rate of the primary efficacy variable at
the 2-sided .05 significance level. This
wouldtranslateintotheexpectationof
68eventstohave82%power.9Thean-
ticipated event rate in the active con-
trol group was based on prospective,
observational studies of the relation-
ship between high on-treatment reac-
tivityandischemicevents.11,18Theevent
rate was further supported by the re-
sults of a large observational study re-
ported after the trial began enroll-
ment.14The estimated relative risk
reduction underlying the trial’s power
calculation is greater than that of tra-
ditional megatrials, but we purpose-
fully selected the patients who would
be biologically most likely to have the
most powerful clinical response to the
interventionthatwastested.19Thises-
timateisalsoconsistentwiththetreat-
ment effect observed in the placebo-
controlled trials of thienopyridine
therapy in patients undergoing coro-
nary intervention with bare metal
stents.20,21
Theprincipalsecondaryanalysiswas
anobservationalcomparisonoftherate
oftheprimaryefficacyvariableamong
thepatientswithandwithouthighon-
treatment reactivity treated with stan-
dard-dose clopidogrel. We estimated
that 583 patients would provide 80%
power at the 2-sided .05 significance
level based on the assumptions above
andaneventrateof2%inpatientswith-
out high on-treatment reactivity.
Prespecifiedanalysesincludedland-
mark analyses of the primary efficacy
end point in patients event-free at 30
days. The statistical analysis plan also
prespecifiedpharmacodynamicanaly-
ses of the randomized groups that in-
cluded an assessment of the absolute
level of on-treatment reactivity, the
changeinon-treatmentreactivity,and
the rate of high on-treatment reactiv-
ity at 30 days and 6 months using the
Wilcoxonranksumand?2tests.Analy-
ses were performed with SAS version
9.1.3 (SAS Institute Inc, Cary, North
Carolina).
STANDARD- VS HIGH-DOSE CLOPIDOGREL AFTER PCI
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Table 1. Baseline Clinical and Procedural Characteristics of the Study Patients, According to Treatment Group
Characteristic
High On-Treatment Reactivity,
Randomized Comparison
Not High On-Treatment Reactivity,
Observational
High-Dose Clopidogrel
(n = 1109)
282 (255-320)
Standard-Dose Clopidogrel
(n = 1105)
283 (255-321)
P
Value
.98
Standard-Dose Clopidogrel
(n = 586)
151 (105-191)
P
Valuea
?.001
Residual platelet reactivity at enrollment,
median (25th percentile-75th percentile),
PRU
Age, mean (SD), y
Sex, No./total No. (%)
Men
Body weight, median (range), kg
BMI, median (range)
White race, No./total No. (%)b
Medical history, No./total No. (%)
Diabetes mellitus
Hypertension
Hyperlipidemia
Current smokerc
Myocardial infarction
PCI
CABG surgery
Renal insufficiencyd
Indication for procedure, No./total No. (%)
Stable angina or ischemia
UA without ST-segment depression
or elevated biomarker levels
Non−ST-elevation ACS
Elevation of cardiac biomarker levels
UA with ST depression
ST-elevation MI
Pharmacotherapy at admission,
No./total No. (%)
?-Blocker
Calcium channel blocker
ACE inhibitor
Angiotensin receptor blocker
Statin
Aspirin
Proton pump inhibitor
Clopidogrel exposure at time of enrollment,
No./total No. (%)
600-mg loading dose
75 mg/d ?7 d
Loading dose ?300 mg, followed
by 75 mg/d ?7 d
Procedural variables
Treated lesions per patient, mean (SD)
Stents per patient, mean (SD)
Total stented length, mean (SD), mm
Multivessel PCI, No./total No. (%)
Antithrombin use to support PCI,
No./total No. (%)
Unfractionated heparin
Low-molecular-weight heparin
Bivalirudin
Abbreviations: ACE, angiotensin-converting enzyme; ACS, acute coronary syndromes; BMI, body mass index, which is calculated as weight in kilograms divided by height in meters
squared; CABG, coronary artery bypass graft; MI, myocardial infarction, PCI, percutaneous coronary intervention; PRU, P2Y12reaction units; UA, unstable angina.
aP value for the comparison of patients with or without high platelet reactivity assigned standard-dose clopidogrel.
bRace was self-reported.
cDefined as smoker within previous 7 days.
dRenal insufficiency was defined as a calculated creatinine clearance of less than 60 mL per minute as determined by the Cockcroft-Gault equation.
64.0 (10.5)64.3 (10.5).4661.9 (10.1)
?.001
718/1109 (64.7)
90.7 (42-220)
31 (15-66)
993/1108 (89.6)
723/1105 (65.4)
90.5 (45-193)
31 (15-60)
1009/1105 (91.3)
.73
.82
.75
.23
470/586 (80.2)
88.0 (38-167)
29 (12-69)
543/586 (92.7)
?.001
.01
?.001
.64
486/1109 (43.8)
943/1109 (85.0)
976/1109 (88.0)
163/1109 (14.7)
334/1109 (30.1)
554/1109 (50.0)
233/1109 (21.0)
441/1099 (40.1)
518/1105 (46.9)
943/1105 (85.3)
958/1105 (86.7)
150/1105 (13.6)
315/1105 (28.5)
501/1105 (45.3)
241/1105 (21.8)
456/1098 (41.5)
.15
.84
.35
.45
.41
.03
.65
.50
170/586 (29.0)
450/586 (76.8)
495/586 (84.5)
120/586 (20.5)
189/586 (32.3)
268/586 (45.7)
109/586 (18.6)
159/584 (27.3)
?.001
?.001
.21
?.001
.11
.88
.12
?.001
667/1109 (60.2)
269/1109 (24.3)
664/1103 (60.2)
266/1103 (24.1)
325/586 (55.5)
166/586 (28.3)
.57.41
111/1109 (10.0)
56/1109 (5.0)
6/1109 (0.5)
113/1103 (10.2)
58/1103 (5.3)
2/1103 (0.2)
65/586 (11.1)
28/586 (4.8)
2/586 (0.3)
736/1095 (67.2)
269/1095 (24.6)
506/1095 (46.2)
215/1095 (19.6)
854/1095 (78.0)
967/1109 (87.2)
327/1095 (29.9)
705/1092 (64.6)
267/1092 (24.5)
496/1092 (45.4)
222/1092 (20.3)
844/1092 (77.3)
984/1105 (89.0)
328/1092 (30.0)
.19
.95
.71
.68
.69
.18
.92
373/584 (63.9)
101/584 (17.3)
258/584 (44.2)
90/584 (15.4)
424/584 (72.6)
510/586 (87.0)
115/584 (19.7)
.78
?.001
.63
.01
.03
.22
?.001
591/1108 (53.3)
429/1108 (38.7)
88/1108 (7.9)
582/1104 (52.7)
410/1104 (37.1)
112/1104 (10.1)
306/586 (52.9)
221/586 (37.7)
59/586 (10.1)
.19.97
1.4 (0.6)
1.7 (1.0)
29.6 (23.2)
192/1109 (17.3)
1.4 (0.7)
1.6 (1.0)
29.3 (20.8)
176/1104 (15.9)
.19
.23
.90
.39
1.4 (0.7)
1.6 (1.0)
29.6 (19.2)
86/586 (14.7)
.28
.25
.29
.49
427/1109 (38.6)
22/1109 (2.0)
699/1109 (63.1)
430/1104 (38.9)
29/1104 (2.6)
703/1104 (63.7)
.86
.32
.79
218/1104 (37.2)
7/1104 (1.2)
382/586 (65.2)
.48
.05
.54
STANDARD- VS HIGH-DOSE CLOPIDOGREL AFTER PCI
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RESULTS
BetweenJuly2008andApril2010,5429
patients from 83 sites in the United
States and Canada were screened with
plateletfunctiontesting12to24hours
after PCI. Of these, 2214 (40.8%) had
high on-treatment reactivity and were
randomlyassignedtoeitherhigh-dose
orstandard-doseclopidogrel(Figure1).
The treatment groups were generally
well balanced with regard to baseline
demographic, clinical, and procedural
characteristics (TABLE 1). An addi-
tional 586 patients without high on-
treatmentreactivitywereselectedatran-
dom and assigned to treatment with
standard-dose clopidogrel. Demo-
graphicandclinicalcharacteristicswere
similar between patients who were or
werenotselected,exceptmorepatients
with prior myocardial infarction were
intheselectedcohort(189[32%]vs711
[27%], P=.01). As shown in Table 1,
there were several differences in the
baseline demographics, medical his-
tory, and concomitant medications of
the selected patients without high
on-treatmentreactivitycomparedwith
the patients in the randomized groups
withhighon-treatmentreactivity.Clo-
pidogrel exposure prior to enrollment
was similar across all 3 treatment
groups.Fourpatients(0.1%)werelost
to follow-up.
Efficacy End Points
The rate of death from cardiovascular
causes,nonfatalMI,orstentthrombo-
sis was not different with high-dose
comparedwithstandard-doseclopido-
grel in the patients with high on-
treatment reactivity (25 [2.3%] vs 25
[2.3%]; hazard ratio [HR], 1.01; 95%
confidence interval [CI], 0.58-1.76;
P=.97; TABLE 2 and FIGURE 2). The
eventratesinthe2groupsafter30days
were not different by landmark analy-
sis (20 [1.9%] vs 17 [1.6%]; HR 1.19;
95% CI, 0.62-2.27; P=.60).
Inthesecondary,observationalcom-
parison of patients with and without
high on-treatment reactivity treated
Table 2. Major Efficacy and Safety End Points at 6 Months in Randomized Patients With High On-Treatment Platelet Reactivitya
No. (%) of Patients Taking Clopidogrel
End Point
HR for High-Dose Clopidogrel
(95% CI)
1.01 (0.58-1.76)
P
Valueb
.97
High Dose
(n = 1109)
25 (2.3)
Standard Dose
(n = 1105)
25 (2.3)
Death from cardiovascular causes,
nonfatal myocardial infarction, or stent
thrombosis (primary end point)
Death from cardiovascular causes
Nonfatal myocardial infarction
Stent thrombosisc
Death from cardiovascular causes
or nonfatal myocardial infarction
Death from any cause
Abbreviations: CI, confidence interval; HR, hazard ratio.
aPercentages are event rates from observed data.
bHazard ratios and P values were calculated with the log-rank test stratified by acute coronary syndromes status.
cStent thrombosis was defined as definite or probable thrombosis, according to the Academic Research Consortium.
3 (0.3)
20 (1.8)
5 (0.5)
23 (2.1)
8 (0.7)
18 (1.6)
8 (0.7)
25 (2.3)
0.38 (0.10-1.43)
1.12 (0.59-2.12)
0.63 (0.21-1.93)
0.93 (0.53-1.64)
.14
.72
.42
.80
7 (0.6) 10 (0.9)0.70 (0.27-1.85) .48
Figure 2. Cumulative Kaplan-Meier Estimates of the Time to the First Adjudicated Occurrence of the Primary Efficacy End Point
4
3
2
1
0
No. at risk
High-dose clopidogrel
Standard-dose clopidogrel 1105
1109
30
1057
1056
60
1028
1029
90
1020
1017
120
1015
1007
150
1005
998
180
773
747
210
53
54
Days
Patients with high on-treatment platelet reactivity
receiving high- or standard-dose clopidogrel
Hazard ratio, 1.68; 95% CI, 0.76-3.72; P = .20
Cumulative Incidence of
Primary End Point, %
Clopidogrel dose
High
Standard
4
3
2
1
0
No. at risk
High on-treatment reactivity
Not high on-treatment reactivity 586
1105
30
565
1057
60
552
1028
90
551
1020
120
549
1015
150
546
1005
180
415
773
210
19
53
Days
Patients with and without high on-treatment platelet
reactivity receiving standard-dose clopidogrel
Hazard ratio, 1.01; 95% CI, 0.58-1.76; P = .97
Cumulative Incidence of
Primary End Point, %
On-treatment platelet reactivity
High
Not high
The primary end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. Data were analyzed according to the
intention-to-treat principle.
STANDARD- VS HIGH-DOSE CLOPIDOGREL AFTER PCI
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withstandard-doseclopidogrel,therate
of death from cardiovascular causes,
nonfatal MI, or stent thrombosis was
numericallygreaterinthepatientswith
high on-treatment reactivity than in
thosewithouthighon-treatmentreac-
tivity,butthisdifferencedidnotreach
statistical significance (25 [2.3%] vs 8
[1.4%]; HR, 1.68; 95% CI, 0.76-3.72;
P=.20; TABLE 3 and Figure 2). Land-
mark analysis at 30 days also demon-
stratedagreater,butnotsignificant,risk
of events in patients with high on-
treatment reactivity (17 [1.6%] vs 4
[0.7%]; HR, 2.27; 95% CI, 0.76-6.74;
P=.13).
Safety End Points
The frequencies of bleeding events are
shown in TABLE 4. Intracranial hem-
orrhage occurred in none of the pa-
tients with high on-treatment reactiv-
ity randomly assigned to high-dose
clopidogrel, in 2 patients (0.2%) with
high on-treatment reactivity ran-
domly assigned to standard-dose clo-
pidogrel,andin1patient(0.2%)with-
outhighon-treatmentreactivitytreated
with standard-dose clopidogrel. The
rate of discontinuation of study drug
due to GUSTO severe or moderate
bleedingwassimilaracrossall3groups:
8 patients (0.7%), 11 patients (1.0%)
and 6 patients (1.0%), respectively.
Pharmacodynamic Outcomes
The pharmacodynamic effect of the
study drug in patients randomly
assigned to high-dose or standard-
dose clopidogrel according to the
intent-to-treat principle is illus-
trated in FIGURE 3. The level of
on-treatment reactivity decreased sig-
nificantly over the first 30 days in
both groups, from 283 PRU (inter-
quartile range [IQR], 255-321 PRU)
to 250 PRU (IQR, 206-298 PRU)
with standard-dose clopidogrel
(P?.001) and from 282 PRU (IQR,
255-320 PRU) to 211 PRU (IQR,
155-262 PRU) with high-dose clopi-
dogrel (P?.001). The reduction in
on-treatment reactivity at 30 days
and at 6 months after randomization
was significantly greater with high-
dose than with standard-dose clopi-
dogrel (80 PRU; IQR, 37-128 PRU vs
37 PRU; IQR, 1-79 PRU; P?.0001
and 85 PRU; IQR, 37-138 PRU vs 44
PRU; IQR, 3.5-91 PRU; P?.001,
respectively). High-dose clopidogrel
led to an absolute 22% (95% CI,
18%-26% and 24%, 95% CI, 20%-
28%) lower rate of high on-treatment
reactivity (ie, PRU?230) compared
with standard-dose clopidogrel at 30
days and 6 months (40%; 95% CI,
37%-43% vs 62%; 95% CI, 59%-65%;
P?.001 and 36%; 95% CI, 33%-39%
Table 3. Major Efficacy and Safety End Points at 6 Months for the Nonrandomized Comparison of Patients With or Without High
On-Treatment Platelet Reactivity Treated With Standard-Dose Clopidogrela
No. (%) of Patients
End Point
HR for High On-Treatment
Reactivity
(95% CI)
1.68 (0.76-3.72)
P
Valueb
.20
High On-Treatment
Reactivity
(n = 1109)
25 (2.3)
Not High On-Treatment
Reactivity
(n = 586)
8 (1.4)
Death from cardiovascular causes,
nonfatal myocardial infarction,
or stent thrombosis
Death from cardiovascular
causes
Nonfatal myocardial infarction
Stent thrombosisc
Death from any cause
Abbreviations: CI, confidence interval; HR, hazard ratio.
aPercentages are event rates from observed data.
bHazard ratios and P values were calculated with the log-rank test stratified by acute coronary syndromes status.
cStent thrombosis was defined as definite or probable thrombosis, according to the Academic Research Consortium.
8 (0.7)3 (0.5)1.42 (0.38-5.36) .60
18 (1.6)
8 (0.7)
10 (0.9)
5 (0.9)
2 (0.3)
4 (0.7)
1.93 (0.72-5.21)
2.16 (0.46-10.19)
1.34 (0.42-4.28)
.19
.31
.62
Table 4. Bleeding Events at 6 Months by GUSTO Criteria
End Point
Clopidogrel Use
Standard-Dose Clopidogrel
No./Total No. (%) of Events
for Patients With
High On-Treatment
Reactivity
HR (95% CI)a
0.59 (0.31-1.11)
P
Valuea
.10
No./Total No. (%) of Events
for Patients Without
High On-Treatment
Reactivity
7/586 (1.2)
HR (95% CI)a
0.51 (0.22-1.19)
P
Valuea
.12
High Dosage
15/1095 (1.4)
Standard
Dosage
25/1092 (2.3)
Severe or moderate
bleeding (key safety
end point)
Any bleeding
Abbreviations: CI, confidence interval; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; HR, hazard ratio.
aCompared with standard-dose clopidogrel in patients with high on-treatment reactivity.
133/1109 (12)113/1105 (10.2)1.19 (0.93-1.53) .1862/586 (10.6)1.02 (0.75-1.39) .87
STANDARD- VS HIGH-DOSE CLOPIDOGREL AFTER PCI
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vs 60%; 95% CI, 57%-63%; P?.001,
respectively).
COMMENT
Pharmacodynamic studies have dem-
onstratedwideinterindividualvariabil-
ity in the platelet inhibitory response
toclopidogrel,andobservationalstud-
ies have linked a poor pharmacody-
namicresponsetocardiovascularevents
after PCI.8,22We found that compared
withthestandardmaintenancedoseof
75 mg daily, prolonged high-dose clo-
pidogreltherapyinapopulationofpa-
tients with high on-treatment reactiv-
ity after PCI provided a modest
pharmacodynamiceffectbutdidnotre-
duce the rate of death from cardiovas-
cular causes, nonfatal myocardial in-
farction, or stent thrombosis.
Several potential mechanisms may
explain the lack of a beneficial treat-
ment effect with high-dose clopido-
grel. The possibility that on-treatment
plateletreactivityisnotamodifiablerisk
factor for thrombotic events after PCI
cannot be excluded. However, under-
treatmentmayexplainourfindingsbe-
causehigh-doseclopidogrelresultedin
onlyamodestreductioninthelevelof
on-treatment reactivity and in the rate
of high on-treatment reactivity com-
pared with standard-dose clopidogrel.
Thisobservationisconsistentwithpre-
vious smaller studies demonstrating
that clopidogrel 150 mg daily pro-
videsonlyamoderateincreaseinplate-
letinhibitionabovethatprovidedby75
mg daily in patients with high on-
treatment reactivity, and that height-
enedplateletreactivitypersistsinalarge
proportion of patients.23-27Carriers of
areducedfunctionCYP2C19alleleare
at greater risk for high on-treatment
platelet reactivity while taking clopi-
dogrel,6and higher-dose clopidogrel
may have only a marginal pharmaco-
dynamic effect in these patients, espe-
cially in homozygotes.25,28,29It is pos-
siblethatothermorepotentinhibitors
of platelet aggregation may have been
beneficial. Prasugrel has a strong and
consistent pharmacodynamic effect in
clopidogrelnonresponders30andisnot
affected by genetic variation of the
CYP2C19 enzyme.31The clinical im-
pact of prasugrel in patients with high
reactivitywhilereceivingclopidogrelis
currently being examined in an ongo-
ing clinical trial (clinicaltrials.gov,
NCT00910299).
Therelativebenefitofhigh-doseclo-
pidogrelmayalsohavebeendilutedby
the decrease in the frequency of high
on-treatment reactivity in both ran-
domizedgroupsovertheinitial30days
after PCI. High on-treatment reactiv-
ity measured 12 to 24 hours after PCI
resolvedatthe30-dayfollow-upin38%
of the patients randomly assigned to
standard-dose clopidogrel. A possible
explanation for this decrement in re-
activity in the post-PCI period may be
that early high on-treatment reactivity
isamanifestationofpoststentingplate-
let activation in a subset of patients.32
The clinical, procedural, and genetic
predictorsoftheearlyresolutionofhigh
on-treatment reactivity after PCI de-
serve further evaluation. The dynamic
natureofplateletreactivitythatwasob-
served underscores the importance of
understanding the effect of the timing
of measurement on the level of reac-
tivity and its association with adverse
outcomes.
Inasecondary,nonrandomized,ob-
servationalcomparisonwithinthecur-
rent trial, there was a numerically
greaterrateofthecompositeendpoint
in patients with high on-treatment re-
activity12to24hoursafterPCI.How-
ever, the low event rates and modest
sample size reduced the power of the
study to identify statistically signifi-
cant differences. Many prior studies
havedocumentedaconsistentandsig-
nificant association between on-
treatment reactivity and early and late
cardiovascularevents,andseveralstud-
ies have demonstrated the prognostic
utilityoftheplateletfunctiontestused
in the current study.8,12-14,18,22,33-37The
prognostic strength of a single mea-
surementofplateletreactivityafterPCI
maybeweakenedbythediminutionof
platelet reactivity that we observed at
30 days after PCI. This observation,
combinedwiththevariablepharmaco-
dynamic response to high-dose clopi-
dogrel, suggests that rather than pre-
scribing a fixed, higher dose of
clopidogrelbasedonasinglepost-PCI
platelet function test, a strategy of re-
peated platelet function testing may
havemerit,andthishypothesisshould
be explored further.
Thedurationoftreatmentwithhigh-
dose maintenance clopidogrel in the
presenttrialissubstantiallylongerthan
previously examined. We found that
treatment with a 6-month post-PCI
regimen of high-dose clopidogrel did
notappeartobeaccompaniedbyanex-
cess of severe or moderate bleeding
eventsorintracranialhemorrhagecom-
pared with a standard-dose regimen.
This clinical finding is consistent with
ourpharmacodynamicobservationthat
high-dose clopidogrel provided only a
modest amount of incremental plate-
letinhibitioninpatientswithhighon-
treatment reactivity. The Clopidogrel
andAspirinOptimalDoseUsagetoRe-
duceRecurrentEvents–SeventhOrga-
nization to Assess Strategies in Ische-
Figure 3. Pharmacodynamic Effect of High-
and Standard-Dose Clopidogrel in
Randomized Patients With High
On-Treatment Platelet Reactivity
Randomization
Follow-up
30 d
6 mo
500
400
300
200
100
0
No. of patients
P2Y12 Reaction Unit
Treatment Group
Standard Dose
1105 1013 940
High Dose
1109 1012 944
High-dose clopidogrel resulted in significantly lower
levels of on-treatment platelet reactivity at 30 days
and6monthsthanstandard-doseclopidogrel(P?.001,
respectively, not corrected for multiple compari-
sons). The horizontal line in the middle of each box
indicates the median; the top and bottom borders of
each box indicate the interquartile range (IQR). The
whiskers above and below the box indicate plus/
minus 1.5 IQRs, respectively.
STANDARD- VS HIGH-DOSE CLOPIDOGREL AFTER PCI
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mic Syndromes (CURRENT-OASIS 7)
trial evaluated a 600-mg clopidogrel
loadingdosefollowedby7daysof150
mgofclopidogrelinpatientswithacute
coronary syndromes not selected by
platelet function testing and found an
increased risk of bleeding that re-
quiredbloodtransfusion.38Thediscor-
dant findings between that study and
GRAVITASmayinpartbeexplainedby
differencesinthestudypopulations:in
the current trial, we enrolled patients
with high on-treatment reactivity and
excluded those with major bleeding
aroundthetimeoftheindexPCI,while
CURRENT-OASIS 7 enrolled patients
priortoPCIwithoutregardtothelevel
of on-treatment reactivity.
Although GRAVITAS is the largest
randomized trial to date of individual-
ized antiplatelet therapy based on ex
vivo platelet function testing, the de-
siredpowerofourprimaryanalysiswas
reduced because we observed only 50
events,yetanticipated68eventstohave
greaterthan80%powertodetecta50%
relative risk reduction with our inter-
vention. A treatment effect of high-
doseclopidogrelthereforecannotbeex-
cluded.
Our trial has several limitations. Al-
though eligible to be enrolled, few pa-
tients in the trial had high-risk acute
coronary syndromes (biomarker-
positive non–ST-elevation and ST-
elevation myocardial infarction); ac-
cordingly,theresultsmaynotapplyto
suchpatients.Wemeasuredplateletre-
activity and assigned study drug after
PCI,andthereforecouldnotassessthe
effectiveness of high-dose clopidogrel
in reducing the incidence of peripro-
cedural myocardial infarction. Our
therapeutic intervention was a higher,
fixed dose of clopidogrel, rather than
a strategy of iterative-dose adjustment
to “normalize” platelet reactivity to a
specifictarget.Thebaselinecharacter-
isticsofpatientswithandwithouthigh
on-treatmentreactivitydifferedgreatly,
as noted in previous, smaller stud-
ies.7,39-41We did not adjust our analy-
sesforthesedifferencesbecauseofthe
large number of independent vari-
ablescomparedwiththerelativelysmall
numberofevents.42Therefore,thecur-
rentstudycannotaddresswhetheron-
treatment reactivity is an independent
predictor of thrombotic risk.14
In conclusion, high-dose clopido-
grel for 6 months in patients with
high on-treatment platelet reactivity
12 to 24 hours after PCI with drug-
eluting stents did not reduce the rate
of death from cardiovascular causes,
nonfatal myocardial infarction, or
stent thrombosis compared with
standard-dose clopidogrel. The
results of GRAVITAS do not support
a uniform treatment strategy of high-
dose clopidogrel in patients with
high on-treatment reactivity identi-
fied by a single platelet function test
after PCI. Alternative treatment strat-
egies incorporating platelet function
testing merit further investigation.
Author Contributions: Dr Price had full access to all
of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data
analysis.
Study concept and design: Price, Berger, Cannon,
Angiolillo, Topol
AcquisitionofData:Price,Berger,Teirstein,Tanguay,
Angiolillo, Spriggs, Puri, Robbins, Garratt, Bertrand,
Stillablower, Aragon, Manoukian
Analysis and Interpretation of the data: Price, Berger,
Cannon, Teirstein, Angiolillo, Schork, Topol
Drafting of the manuscript: Price
Critical revision of the manuscript for important in-
tellectual content: Price, Berger, Cannon, Teirstein,
Tanguay, Angiolillo, Topol, Schork, Spriggs, Puri,
Robbins,Garratt,Bertrand,Stillablower,Aragon,Stinis,
Kandzari, Lee, Manoukian
Statistical analysis: Price, Schork
Obtained funding: Price, Topol
Study supervision: Price, Berger, Cannon, Tanguay,
Teirstein, Topol
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for Dis-
closure of Potential Conflicts of Interest. Dr Price
reported receiving consulting fees from Bristol-
Myers Squibb/sanofi-aventis, Daiichi Sankyo/Eli
Lilly & Co, Accumetrics, AstraZeneca, and Medi-
cure; speakers fees from Daiichi Sankyo/Eli Lilly &
Co; and grant support from Bristol-Myers Squibb/
sanofi-aventis. Dr Tanguay reported receiving
consulting and speakers fees from Bristol-Myers
Squibb/sanofi-aventis, Daiichi Sankyo/Eli Lilly & Co,
GlaxoSmithKline, Abbott Vascular, and AstraZeneca
and speakers fees from Boehringer Ingelheim. Dr
Angiolillo reported receiving consulting fees from
Bristol-Myers Squibb/sanofi-aventis, Daiichi
Sankyo/Eli Lilly & Co, AstraZeneca, The Medicines
Company, Portola, Novartis, Medicure, Accumet-
rics, Arena Pharmaceuticals, and Merck; and speak-
ers fees from Bristol-Myers Squibb/sanofi-aventis
and Daiichi Sankyo/Eli Lilly & Co; Dr Garratt
reported receiving consulting fees from The Medi-
cines Company; speakers fees from Boston Scien-
tific, The Medicines Company, sanofi-aventis, Daii-
chi Sankyo/Eli Lilly & Co, Medtronic, and Abbott
Vascular; and serving on the advisory board of Bos-
ton Scientific. Dr Aragon reported receiving con-
sulting and speakers fees from The Medicines Com-
pany, and speakers fees from Bristol-Myers Squibb/
sanofi- aventis. Dr Kandzari reported receiving
consulting and speakers fees from Daiichi Sankyo/
Eli Lilly & Co. Dr Lee reported receiving speakers
fees from Bristol-Myers Squibb/sanofi-aventis. Dr
Cannon reports receiving consulting fees from
Bristol-Myers Squibb/sanofi-aventis, Alynlam,
and Novartis and grant support from Intekrin
Therapeutics; and serving on the advisory board for
GlaxoSmithKline and Merck. The other authors
reported no disclosures.
Funding/Support:TheGRAVITAStrialwasfundedby
Accumetrics. The study drug was provided by an
investigator-initiatedgrantfromBristol-MyersSquibb/
sanofi-aventis.
Role of the Sponsor: The executive committee,
consisting of both academic members and nonvot-
ing representatives of the sponsor, designed and
oversaw the conduct of the trial. The sponsor coor-
dinated the data management with a contract
research organization (Synteract, Carlsbad, Califor-
nia). Bristol-Myers Squibb/sanofi-aventis had no
role in the design and management of the trial or in
the analysis of the data.
GRAVITASInvestigators:D.Spriggs,S.Puri,M.Robbins,
P. Teirstein, K. Garratt, O. Bertrand, M. Stillablower, J.
Aragon,E.D.Nukta,J.F.Tanguay,A.Abbas,T.Mann,
W. Batchelor, P. Gordon, M. Schwieger, M. Amine, P.
Berger, N. Chronos, D. So, R. Stoler, S. Marshalko, R.
Waksman, C. O’Shaughnessy, E. Fry, D. Angiolillo, B.
McLaurin, S. Rao, R. Gammon, M. Z. Jafar, G. Wong,
D.Cohen,J.Robb,M.Lucca,S.Ward,D.Rizik,J.Wang,
R. Minutello, E. Mahmud, P. K. Cheung, M. Fugit, G.
Mishkel, A. Jacobs, C. Meritt, M. Lurie, S. Manoukian,
M.Turco,J.P.Reilly,M.Buchbinder,H.Herrmann,M.
Vidovich,D.Purdy,M.Warshofsky,J.Saucedo,L.Can-
non, S. Waxman, G. Goulet, H. B. Cheek, R. Apple-
gate,D.Simon,S.Plante,H.Aronow,V.Misra,S.Mehta,
A. Malik, S. Bailey, A. Cheema, J. Nappi, D. Abbott,
J. Kao, O. Gigliotti, S. DeMaio, T. McGarry, A. Wu,
D. Henderson, E. Schampaert, J. Joye, T. Huynh, J. P.
Pelletier, D. Kereiakes, N. Kleiman, L. Bellumkonda, L.
Gruberg.
Previous Presentation: This study was presented as a
late-breaking clinical trial at the American Heart As-
sociationScientificSessions,Chicago,Illinois,Novem-
ber 16, 2010.
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STANDARD- VS HIGH-DOSE CLOPIDOGREL AFTER PCI
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