A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial.
ABSTRACT Patients with diabetes mellitus (DM) have increased platelet reactivity and reduced platelet response to clopidogrel compared with patients without DM. Prasugrel, a more potent antiplatelet agent, is associated with greater reductions in ischaemic events compared with clopidogrel, particularly in patients with DM. The aim of this study was to perform serial pharmacodynamic assessments of prasugrel with high-dose clopidogrel in patients with DM.
Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 was a prospective, randomized, double-blind, crossover study in patients with type 2 DM and coronary artery disease (CAD). Patients (n= 35) were randomly assigned to either prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD) or clopidogrel 600 mg LD/150 mg MD over two 1-week treatment periods separated by a 2-week washout period. Platelet function was assessed by VerifyNow® P2Y12 assay, light transmission aggregometry, and vasodilator-stimulated phosphoprotein phosphorylation at 0, 1, 4, and 24 h and 7 days. Greater platelet inhibition by VerifyNow® P2Y12 was achieved by prasugrel compared with clopidogrel at 4 h post-LD (least squares mean, 89.3 vs. 27.7%, P< 0.0001; primary endpoint). The difference in platelet inhibition between prasugrel and clopidogrel was significant from 1 h through 7 days (P < 0.0001). Similar results were obtained using all other platelet function measures. Prasugrel resulted in fewer poor responders at all time points irrespective of definition used.
In patients with type 2 DM and CAD, standard-dose prasugrel is associated with greater platelet inhibition and better response profiles during both the loading and maintenance periods when compared with double-dose clopidogrel.
- SourceAvailable from: PubMed CentralDiabetes care 05/2009; 32(4):531-40. · 8.09 Impact Factor
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ABSTRACT: To assess platelet function profiles in diabetic and nondiabetic patients on aspirin and clopidogrel therapy, two patient populations were included to investigate the 1) acute effects of a 300-mg clopidogrel loading dose (group 1, n = 52) and 2) long-term effects of clopidogrel (group 2, n = 120) on platelet function in diabetic compared with nondiabetic patients already on aspirin treatment. Patients were stratified according to the presence of type 2 diabetes. Platelet aggregation was assessed using light transmittance aggregometry (groups 1 and 2). Platelet activation (P-selectin expression and PAC-1 binding) was determined using whole-blood flow cytometry (group 2). Clopidogrel response was also assessed. In group 1, platelet aggregation was significantly increased in diabetic (n = 16) compared with nondiabetic (n = 36) patients at baseline and up to 24 h following a 300-mg loading dose (P = 0.005). In group 2, platelet aggregation and activation were increased in diabetic (n = 60) compared with nondiabetic (n = 60) subjects (P < 0.05 for all platelet function assays). Diabetic subjects had a higher number of clopidogrel nonresponders (P = 0.04). Diabetic patients have increased platelet reactivity compared with nondiabetic subjects on combined aspirin and clopidogrel treatment. Reduced sensitivity to antiplatelet drugs may contribute to the increased atherothombotic risk in diabetic patients.Diabetes 08/2005; 54(8):2430-5. · 7.90 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: This study sought to assess the influence of type 2 diabetes mellitus (T2DM) and the impact of hypoglycemic treatment (insulin vs. noninsulin) on platelet function profiles in patients treated with dual oral antiplatelet therapy. Insulin inhibits platelet aggregation by suppressing the P2Y12 pathway. However, T2DM patients have a loss of responsiveness to insulin that leads to upregulation of the P2Y12 pathway, increased platelet reactivity, and reduced responsiveness to antiplatelet agents. Patients with insulin-treated diabetes mellitus (ITDM) have a more advanced disease status and higher atherothrombotic risk compared with non-ITDM (NITDM). However, the impact of insulin therapy on platelet dysfunction in patients treated with P2Y12 antagonists is unknown. A total of 201 T2DM and 65 nondiabetic patients with coronary artery disease in a steady phase of aspirin and clopidogrel treatment were studied. Platelet aggregation was assessed using agonists specific (6 and 20 microM adenosine diphosphate [ADP]) and nonspecific (6 microg/ml collagen and 20 microM epinephrine) for the P2Y12 pathway. High shear-induced platelet reactivity was assessed by means of the PFA-100 system (Dade-Behring International, Miami, Florida). The T2DM patients had platelet aggregation and shear-induced platelet function significantly increased compared with nondiabetic patients using all assays. Platelet aggregation was increased in ITDM (n = 68) compared with NITDM (n = 133) patients after P2Y12-specific stimuli. Insulin treatment was the strongest predictor of ADP-induced aggregation. Platelet function profiles were similar between ITDM and NITDM using assays nonspecific to the P2Y12 pathway. Platelet dysfunction was independent of glycemic control and inflammatory status. The P2Y12-dependent and -independent pathways of platelet reactivity are altered in T2DM compared with nondiabetic patients, and ITDM have greater ADP-induced platelet aggregation compared with NITDM.Journal of the American College of Cardiology 08/2006; 48(2):298-304. · 14.09 Impact Factor
crossover study in patients with type 2 DM and coronary artery disease (CAD). Patients (n ¼ 35) were randomly
assigned to either prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD) or clopidogrel 600 mg LD/
150 mg MD over two 1-week treatment periods separated by a 2-week washout period. Platelet function was
assessed by VerifyNowwP2Y12 assay, light transmission aggregometry, and vasodilator-stimulated phosphoprotein
phosphorylation at 0, 1, 4, and 24 h and 7 days. Greater platelet inhibition by VerifyNowwP2Y12 was achieved by
prasugrel compared with clopidogrel at 4 h post-LD (least squares mean, 89.3 vs. 27.7%, P , 0.0001; primary end-
point). The difference in platelet inhibition between prasugrel and clopidogrel was significant from 1 h through 7
days (P , 0.0001). Similar results were obtained using all other platelet function measures. Prasugrel resulted in
fewer poor responders at all time points irrespective of definition used.
In patients with type 2 DM and CAD, standard-dose prasugrel is associated with greater platelet inhibition and better
response profiles during both the loading and maintenance periods when compared with double-dose clopidogrel.
Clinical trial identifier: www.clinicaltrials.gov—NCT00642174
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Diabetes mellitus † Coronary disease † Platelets
Coronary heart disease
A pharmacodynamic comparison of prasugrel vs.
high-dose clopidogrel in patients with type 2
diabetes mellitus and coronary artery disease:
results of the Optimizing anti-Platelet Therapy In
diabetes MellitUS (OPTIMUS)-3 Trial
Dominick J.Angiolillo1*, Juan JoseBadimon2, Jorge F.Saucedo3, Andrew L.Frelinger4,
Alan D. Michelson4, Joseph A. Jakubowski5, Baojin Zhu6, Clement K. Ojeh6,
Brian A. Baker7, and Mark B. Effron6
1University of Florida College of Medicine—Jacksonville, ACC 5th Floor, 655 W. Eighth Street, Jacksonville, FL 32209, USA;2The Mount Sinai Medical Center, New York, NY, USA;
3University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA;4Children’s Hospital Boston, Harvard Medical School, Boston, MA, USA;5Eli Lilly and Company,
Indianapolis, IN, USA;6Lilly USA, LLC, Indianapolis, IN, USA; and7Daiichi Sankyo, Inc., Parsippany, NJ, USA
Received 23 September 2010; revised 30 November 2010; accepted 7 December 2010; online publish-ahead-of-print 20 January 2011
Patients with diabetes mellitus (DM) have increased platelet reactivity and reduced platelet response to clopidogrel
compared with patients without DM. Prasugrel, a more potent antiplatelet agent, is associated with greater
reductions in ischaemic events compared with clopidogrel, particularly in patients with DM. The aim of this study
was to perform serial pharmacodynamic assessments of prasugrel with high-dose clopidogrel in patients with DM.
Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 was a prospective, randomized, double-blind,
* Corresponding author. Tel: +1 904 244 3933, Fax: +1 904 244 3102, Email: email@example.com; firstname.lastname@example.org
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: email@example.com.
The online version of this article has been published underanopen accessmodel. Users areentitled to use, reproduce,disseminate,ordisplaythe open accessversionof this article for
non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original
place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be
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European Heart Journal (2011) 32, 838–846
Patients with diabetes mellitus (DM) are characterized by
enhanced platelet reactivity and a reduced response to oral antipla-
telet medications used for the prevention of ischaemic events.1–3
Platelets from patients with DM demonstrate upregulation of
several signalling pathways, which may explain the increased preva-
lence of low platelet inhibition following clopidogrel treatment and
contribute to increased atherothrombotic risk in these patients
compared with those without DM.1,4Therefore, greater platelet
P2Y12receptor inhibition may provide more optimal platelet inhi-
bition in this high-risk patient population. In the Optimizing anti-
Platelet Therapy In diabetes MellitUS (OPTIMUS)-1 Study, a high
proportion of patients had a suboptimal response to a standard
dose of clopidogrel. Although a high maintenance dose (MD) of
clopidogrel (150 mg per day) enhanced platelet inhibition in
patients with DM presenting with elevated platelet reactivity
while on standard treatment regimens, a considerable proportion
of the population maintained persistently elevated platelet function
despite the more aggressive P2Y12 receptor blockade.5These
results demonstrate the need for alternative platelet inhibition
strategies for this high-risk patient population.
Prasugrel is a thienopyridine that produced a greater reduction
in ischaemic events than clopidogrel but with increased risk of
bleeding in moderate-to-high-risk patients with acute coronary
(PCIs) in the Trial to Assess Improvement in Therapeutic Out-
comes by OptimizingPlatelet
Thrombolysis in Myocardial Infarction (TRITON-TIMI 38).6In the
subgroup of patients with DM in TRITON, a 30% relative risk
reduction with prasugrel vs. clopidogrel in the primary composite
endpoint of cardiovascular death, non-fatal myocardial infarction,
or non-fatal stroke was demonstrated without an increased risk
of major bleeding.7However, randomization was not stratified
by diabetic status in this clinical study and there was no significant
interaction between patients with and without diabetes. Addition-
ally, two studies have examined, in non-randomized subgroup ana-
lyses, the pharmacodynamic profiles of prasugrel and clopidogrel in
stable coronary artery disease (CAD) patients with DM.8,9
However, neither of these analyses was from a prospectively
defined trial in a well-characterized DM population.
In patients with DM, a prospective comparison of the pharmaco-
(LD) and MD of clopidogrel is largely unexplored in a prospectively
the pharmacodynamic activity of standard-dose prasugrel with
double-dose clopidogrel in patients with type 2 DM who have
that prasugrel would achieve greater platelet inhibition compared
with double-dose clopidogrel in these patients.
Inhibition with Prasugrel-
Patient population and study design
OPTIMUS-3 was a prospective, randomized, double-blind, double-
dummy, active-controlled, two-period crossover study conducted
between April 2008 and January 2009 at four academic sites in the
USA. Patients with type 2 DM between 18 and 75 years of age
treated with oral and/or parenteral hypoglycaemic therapy for at
least 1 month were enrolled. All patients had known CAD and were
taking aspirin (81–325 mg/day). Patients were ineligible to participate
if any of the following criteria was met: a defined need for thienopyr-
idine therapy (e.g. within 12 months of an acute coronary syndrome
event or placement of a drug eluting stent; or within 1 month of place-
ment of a bare metal stent); within 30 days of coronary artery bypass
graft surgery or PCI without a stent placed; planned coronary revascu-
larization; glycosylated haemoglobin (HbA1c) ≥10 mg/dL within 3
months; treatment with fibrin-specific fibrinolytic therapy ,24 h or
non-fibrin-specific fibrinolytic therapy ,48 h prior to randomization;
presence of active internal bleeding or history of bleeding diathesis
or clinical findings associated with an increased risk of bleeding;
history of ischaemic or haemorrhagic stroke, transient ischaemic
attack, intracranial neoplasm, arteriovenous malformation, or aneur-
ysm; body weight ,60 kg; an international normalized ratio .1.5,
platelet count ,100 000/ mm3, or haemoglobin ,10 gm/dL within 1
week of study entry.
The trial was conducted in agreement with the Declaration of Hel-
sinki and the International Conference on Harmonisation Guidelines
for Good Clinical Practice. The protocol was approved by the local
Ethics Review Committee or institutional review board at each parti-
cipating site, and all patients gave written informed consent before
undergoing any study procedure or receiving any study treatment.
A clinical research organization (CRO) was contracted by the
sponsor to hold the data and perform the data analysis after data
lock and then deliver the database and the analysis results to the
sponsor. An independent expert was contracted to check the quality
of the blinded data prior to the data analysis by the CRO.
Patients who met all criteria for enrolment were randomized at the
first visit to double-blind treatment of either prasugrel 60 mg LD
orally followed by 10 mg/day MD for 7 days or clopidogrel 600 mg LD
orally [75 mg tablets Plavixw(clopidogrel bisulfate; Bristol–Myers
Squibb/sanofi-aventis, Bridgewater, NJ, USA)] followed by 150 mg/day
MD for 7 days (Figure 1A). The randomization ratio was 1:1 between
mined by a computer-generated random sequence using an interactive
salt in 10 mg tablets (Eli Lilly and Company, Indianapolis, IN, USA).
Patients were administered an equal number of identical tablets for
either the LDs (six prasugrel 10 mg tablets and eight placebo tablets
or eight clopidogrel 75 mg tablets and six placebo tablets) or MDs
(one prasugrel 10 mg tablet and two placebo tablets or two clopidogrel
75 mg tablets and one placebo tablet). Patients continued taking their
pre-study dosage of aspirin throughout the study. Platelet function
studies were performed at 0 (baseline), 1, 4, and 24 h, and 7 days (24 h
post last MD) after LD. After completion of the first 1-week treatment
period, patients discontinued the study drug, and platelet function
studies were repeated 1 and 2 weeks later, with the 2-week measure
serving as the baseline (0 h) for the second treatment period. After
the 2-week washout period, patients received the other study drug
regimen for 1 week, during which assessment of platelet function mir-
rored the first period. Final platelet function studies were performed 1
week after discontinuation of therapy.
Sample collection and platelet function
Blood for platelet function analyses was collected from an antecubital
vein at pre-defined time points into citrated tubes (Figure 1). Platelet
Prasugrel vs. clopidogrel in diabetes
function assays included VerifyNowwP2Y12 (Accumetrics, Inc., San
Diego, CA, USA), light transmission aggregometry (LTA), and
expressed as the platelet reactivity index (PRI). The VerifyNoww
P2Y12 assay is a rapid whole-blood point-of-care device and was uti-
lized according to the instructions of the manufacturer as described
Light transmission aggregometry was performed
according to standard protocols.2,3,5Maximum platelet aggregation
(MPA) was induced by 5 and 20 mM ADP and IPA% (IPA, inhibition
of platelet aggregation) was calculated as (baseline aggregation
response 2 post-dose aggregation
response × 100. Vasodilator-stimulated phosphoprotein phosphoryl-
ation was assessed as recommended by the manufacturer5using quan-
titative flow cytometry and commercially available labelled monoclonal
antibodies (Biocytex, Inc., Marseille, France) at a central laboratory at
the University of Massachusetts.
The primary endpoint of this study was IPA measured by the Verify-
NowwP2Y12 assay 4 h after the administration of the study drug
LD. This time point was selected because the peak (≥95%) effect of
prasugrel 60 mg occurs by 2 h post-LD and is sustained past 4 h,
whereas the peak effect of a clopidogrel 600 mg LD has been
measured at ≤4 h in several studies.12,13
Secondary measures included: IPA by VerifyNowwP2Y12 at all other
time points; VerifyNowwP2Y12 PRU, LTA (MPA and IPA), and VASP-P
PRI at all time points; and evaluation of the incidence of adverse events
such as thrombosis and haemorrhage. In addition, a responder-type
analysis was conducted in which a poor response to thienopyridine
treatment was defined as: VerifyNowwP2Y12 PRU .23514; 20 mM
ADP LTA MPA .50%5; 20 mM ADP LTA IPA ≤20%15; or VASP-P
PRI .50%.16Finally, the possibility of ‘rebound’ platelet activation
was evaluated in an analysis of the pharmacodynamic effect of prasu-
grel 6–8 days after treatment discontinuation for each study period.
Rebound was considered to have occurred if, after the cessation of
the study drug, a ≥20% increase in platelet reactivity above the 0 h
value was obtained at the start of each treatment period. A cut-off
value of 20% was chosen because it is outside the range of assay
A sample size of 30 patients was required to provide at least 90%
power to detect a 17.5% difference in VerifyNowwP2Y12 IPA
(primary endpoint) between treatment groups with a standard devi-
ation of 20% at a two-tailed significance level of 0.05. This difference
was based on the response to MD therapy with prasugrel compared
with clopidogrel in a previous study available at the time of the
OPTIMUS-3 design.17All statistical comparisons of platelet function
between prasugrel and clopidogrel for the primary endpoint and sec-
ondary endpoints with continuous variables were conducted using a
linear mixed-effect model with treatment group, sequence, and
treatment-group-by-sequence (i.e. period) as fixed effects and
patient as a random effect. Confidence intervals (CI) and all tests of
statistical significance for treatment comparisons were evaluated at a
two-tailed significance level of 0.05 using SAS version 9.1. Results
are reported as the least-squares mean with 95% CI. Sensitivity analysis
on the primary endpoint was conducted after adjusting baseline IPA
values assessed by VerifyNowwP2Y12 in the mixed-effect model. Cat-
egorical variables were analysed using Fisher’s exact tests.
All analyses of platelet function were conducted on the pharmaco-
dynamic population, which was defined as all randomized subjects who
received at least one dose of study drug and had blood draws for IPA
Figure 1 (A) Study design. (B) Patient disposition.
D.J. Angiolillo et al.
assessed by VerifyNowwP2Y12 4 h after the administration of the LD.
Safety analyses were conducted on the safety population, which
included all patients exposed to at least one dose of the study drug.
Safety was assessed by evaluating vital signs, all reports of bleeding,
and all reported adverse events including thrombotic cardiovascular
events, death, myocardial infarction, and stroke. Bleeding was classified
as major, minor, or insignificant according to the Thrombolysis In Myo-
cardial Infarction (TIMI) criteria.6
Forty-three patients were screened and 35 were randomly
assigned to either prasugrel (n ¼ 18) or clopidogrel (n ¼ 17) for
the first treatment period (Figure 1B). Of these 35 patients, 34
completed both treatment periods and served as their own
control. One patient who was initially assigned to the clopidogrel
group in the first treatment period was found to have an exclusion
criterion (HbA1c ≥10 mg/dL) and did not cross over to prasugrel.
Baseline characteristics are described in Table 1.
At 4 h post-LD (primary endpoint), patients treated with prasugrel
had significantly greater IPA compared with clopidogrel [89.3%
(95% CI ¼ 83.0–95.6) vs. 27.7% (95% CI ¼ 21.5–33.9), P ,
0.0001] (Figure 2A). Following ?1 week of MD therapy, the IPA
was still significantly greater with daily prasugrel 10 mg compared
with daily clopidogrel 150 mg [61.8% (95% CI ¼ 55.7–67.9) vs.
44.2% (38.1–50.3), P , 0.0001]. The difference between prasugrel-
and clopidogrel-treated patients was significant at all time points
from1 hpost-LDthrough7days(24 hafterthelastMD).Thediffer-
ence between prasugrel- and clopidogrel-treated patients was also
significant at all time points from 1 h post-LD through 7 days as
measured by VerifyNowwP2Y12 PRU (Figure 2B). When measured
at 1 week following discontinuation of study drug, platelet function
for prasugrel- and clopidogrel-treated patients returned to near
baseline (Figure 2A and B). The results were consistent irrespective
of the use of insulin for glycaemic control (data not shown).
Light transmission aggregation
Figure 3A shows MPA to 20 mM ADP using LTA. Maximum platelet
aggregation values at 0 h for patients in both treatment groups
were similar. At 4 h post-LD, patients treated with prasugrel had
significantly lower MPA compared with patients treated with
Age (years), mean+SD
Male, n (%)
Race, n (%)
Body mass index (kg/m2), mean+SD
Cardiovascular history, n (%)
Congestive heart failure
Prior myocardial infarction
Prior coronary artery bypass graft
Obesity (body mass index ≥30)
Duration of CAD (years), mean+SD
Duration of type 2 DM (years), mean+SD
Antihyperglycaemic medication, n (%)
Aspirin dose, n (%)
N 5 35
CAD, coronary artery disease; DM, diabetes mellitus; MI, myocardial infarction; N,
number of patients; n, number in group; PCI, percutaneous intervention; SD,
Figure 2 Platelet function by VerifyNowwP2Y12. (A) Inhibition
of platelet aggregation. (B) VerifyNowwP2Y12 PRU. Values are
expressed as the least-squares mean and 95% confidence inter-
vals. Prasugrel and clopidogrel values from each treatment
period have been combined. Time 0 is the baseline value (com-
bined for each treatment period). ***P , 0.0001.
Prasugrel vs. clopidogrel in diabetes
clopidogrel [22.4% (95% CI ¼ 17.0–27.8) vs. 57.5% (52.2–62.8), P
, 0.0001]. Following ?1 week of MD therapy, MPA was still
significantly lower with prasugrel compared with clopidogrel
[38.3% (95% CI ¼ 33.0–43.6) vs. 50.7% (95% CI ¼ 45.4–56.0),
P , 0.0001]. The differences between prasugrel- and clopidogrel-
treated patients were significant at all time points from 1 h
post-LD through 7 days. Similar findings were observed using
5 mM ADP (Figure 3B).
Figure 3C compares IPA by LTA in response to 20 mM ADP. At
4 h post-LD, IPA was significantly greater for prasugrel compared
with clopidogrel [71.2% (95% CI ¼ 64.7–77.7) vs. 25.9% (19.6–
32.3), P , 0.0001]. Following ?1 week of MD therapy, IPA was
still significantly greater with prasugrel 10 mg daily compared
with clopidogrel 150 mg daily [50.5% (95% CI ¼ 44.0–56.9) vs.
34.5% (28.1–40.9),P , 0.0001].
prasugrel- and clopidogrel-treated patients were significant at all
time points from 1 h post-LD through 7 days. Similar findings
were observed using 5 mM ADP (Figure 3D).
Baseline VASP PRI values for prasugrel- and clopidogrel-treated
patients were similar [83.5% (95% CI ¼ 78.8–88.3) vs. 80.6%
(95% CI ¼ 75.9–85.3), P ¼ 0.37] (Figure 4). At 4 h post-LD,
patients treated with prasugrel had significantly lower platelet reac-
tivity by VASP PRI than patients treated with clopidogrel [14.5%
(95% CI ¼ 7.7–21.4) vs. 67.5% (95% CI ¼ 60.8–74.2), P ,
0.0001]. Following ?1 week of MD therapy, VASP PRI was still sig-
nificantly lower with prasugrel 10 mg daily compared with clopido-
grel 150 mg daily [27.4% (95% CI ¼ 20.8–34.0) vs. 42.3 (95% CI ¼
35.7–48.9), P ¼ 0.0012]. The difference between prasugrel- and
clopidogrel-treated patients was significant at all time points
from 1 h post-LD through 7 days.
Figure 5 shows individual patient VerifyNowwP2Y12 PRU values at
baseline (0 h) and 4 h post-LD during the clopidogrel-to-prasugrel
crossover sequence (Figure 5A) and the prasugrel-to-clopidogrel
crossover sequence (Figure 5B). After the prasugrel 60 mg LD,
PRU was generally lower than that achieved after the clopidogrel
600 mg LD, regardless of whether prasugrel was administered in
the first or second treatment period. Figure 5 also illustrates less
variability in response to prasugrel compared with clopidogrel.
Three patients treated with clopidogrel achieved response rates
comparable with those treated with prasugrel.
Figure 6 presents the results of the poor responder analysis at 4
and 24 h post-LD and at 7 days. Regardless of the definition used,
Figure 3 Platelet aggregation by light transmission aggregometry. (A) Maximum platelet aggregation to 20 mM ADP; (B) maximum platelet
aggregation to 5 mM ADP; (C) inhibition of platelet aggregation in response to 20 mM ADP; (D) inhibition of platelet aggregation in response
to 5 mM ADP. Values are expressed as the least-squares mean and 95% confidence intervals. Prasugrel and clopidogrel values from each treat-
ment period have been combined. Time 0 is the baseline value (combined for each treatment period). *P ¼ 0.0002, **P ¼ 0.0001,
***P , 0.0001.
D.J. Angiolillo et al.
the poor responder rate was considerably higher with clopidogrel
compared with prasugrel (all P-values ,0.05). At 4 h post-LD, the
rate of poor responders ranged from 0 to 3.1% for prasugrel and
from 35.3 to 82.9% for clopidogrel. At 24 h post-LD, the rate of
prasugrel poor responders was 0% regardless of definition com-
pared with 51.5–78.8% for clopidogrel. At 7 days, the poor
responder rate ranged from 2.9 to 21.2% for prasugrel and from
23.5 to 52.9% for clopidogrel.
Rebound platelet activation
One patient on prasugrel and one patient on clopidogrel met
rebound criteria by MPA but not by the other assays. Similarly,
one prasugrel patient met rebound criteria by VerifyNoww
P2Y12 PRU; one patient on prasugrel and two patients on clopido-
grel met rebound criteria according to PRI using VASP-P; and none
of these patients met rebound criteria using the other assays. No
patient meeting rebound criteria on clopidogrel or prasugrel met
criteria with the alternative drug.
Major or minor bleeding by TIMI criteria did not occur with either
treatment regimen. Two TIMI minimal bleeding events that
occurred within 24 h of the last MD were observed in clopidogrel-
treated patients. One prasugrel-treated patient experienced a
vessel puncture site bleed. None of these episodes required inter-
vention to control bleeding. No deaths or other serious adverse
events occurred during the study. The incidence of adverse
events in the prasugrel group was 14.7% (5/34), and 25.7%
(9/35) in the clopidogrel group. The types of adverse events in
the prasugrel and clopidogrel groups were similar (Table 2). No
patients discontinued due to an adverse event.
The results of the OPTIMUS-3 study confirm the hypothesis that
treatment with prasugrel 60 mg LD/10 mg MD is associated with
greater platelet inhibition than double-dose clopidogrel 600 mg
LD/150 mg MD in a prospectively defined study in patients with
type 2 DM and CAD. This study enrolled a well-characterized
population of patients with DM, unlike previous studies. Platelet
Figure 4 Platelet function by vasodilator-stimulated phospho-
protein. Vasodilator-stimulated phosphoprotein platelet reactivity
index values are expressed as the least-squares mean and 95%
confidence intervals. Prasugrel and clopidogrel values from each
treatment period have been combined. Time 0 is the baseline
value (combined for each treatment period). **P , 0.01,
***P , 0.0001.
Figure 5 Individual response profiles. VerifyNowwP2Y12 PRU was measured at 0 h (baseline) and 4 h post-loading dose of prasugrel or clo-
pidogrel. (A) Patients dosed with clopidogrel first and then crossed over to prasugrel. (B) Patients dosed with prasugrel first and then crossed
over to clopidogrel. Baseline (0 h) values for the second treatment period were measured after the 2-week washout period. BL, baseline.
Prasugrel vs. clopidogrel in diabetes
inhibition was corroborated by multiple platelet function assess-
ments using different methodologies, including point-of-care
testing, LTA, and flow cytometry, which encompassed a range of
specificities for P2Y12-mediated platelet activation. This higher
level of platelet inhibition in prasugrel-treated patients was
evident at the first measurement (1 h post-LD) and continued
over 24 h. Although the level of platelet inhibition after 1 week
of prasugrel 10 mg MD was lower than the prasugrel LD, as the
need for very high levels of platelet inhibition is probably not
required in the absence of a procedure, the level of inhibition
associated with the prasugrel 10 mg MD was significantly higher
than with clopidogrel 150 mg MD. This study also provides
additional information on clopidogrel’s poor response in patients
with DM, examines potential rebound after 7 days of drug withdra-
wal, and provides adverse event data in the study population.
Numerous studies have demonstrated the clinical benefit associ-
ated with platelet P2Y12receptor inhibition with clopidogrel, par-
ticularly in high-risk patients.18,19However, patients with DM
continue to have a higher risk of recurrent ischaemic events, includ-
ing stent thrombosis, compared with patients without DM despite
the use of clopidogrel.1,18This may be attributed, at least in part,
to the greater prevalence of suboptimal P2Y12inhibition achieved
with a higher risk of atherothrombotic complications.1These
Figure 6 Poor responders. Poor responder analyses were con-
ducted at (A) 4 h post-loading dose; (B) 24 h post-loading dose;
and (C) 7 days by VerifyNoww(PRU .235), light transmission
aggregometry (MPA .50% and IPA ≤20%), or vasodilator-
stimulated phosphoprotein phosphorylation (PRI .50%) platelet
function assays. P-values for comparison between treatment
groups for each assay are indicated. MPA, maximum platelet
aggregation to 20 mM ADP by light transmission aggregometry;
IPA, inhibition of platelet aggregation with 20 mM ADP by light
Number of patients
with at least one
Number of events8
Pain in extremity1 (2.9)
Vessel puncture site
population of the OPTIMUS-3 Study
Summary of adverse events in the safety
Adverse eventPrasugrel 60 mg
LD/10 mg MD
(n 5 34), n (%)
Clopidogrel 600 mg
LD/150 mg MD
(n 5 35), n (%)
5 (14.7) 9 (25.7)
1 (2.9) 1 (2.9)
D.J. Angiolillo et al.
observations suggest the need for more effective P2Y12inhibition,
particularly in high-risk patients such as those with DM.
The OPTIMUS-1 study demonstrated that a high-clopidogrel
MD was associated with greater platelet inhibitory effects com-
pared with standard dosing in patients with DM and CAD who
presented with elevated platelet reactivity while on standard dual
antiplatelet therapy. However, inadequate platelet inhibition per-
sisted in 60% of patients.5In the PRINCIPLE-TIMI 44 Trial, the
rate of response to prasugrel 60 mg LD/10 mg MD was significantly
greater than double-dose clopidogrel in the overall patient popu-
lation,7as well as in patients with DM.9The rate of poor respon-
ders in patients with DM at 24 h post-LD was ?40%.9The
OPTIMUS-2 study showed that adjunctive treatment with cilosta-
zol (‘triple therapy’) enhances measures of platelet P2Y12inhibition
in patients with DM and CAD to a greater extent than standard
dual antiplatelet therapy with aspirin and clopidogrel.20However,
cilostazol is poorly tolerated and has an elevated prevalence of
side effects that limit treatment compliance.20Results from a sub-
group of 19 patients with DM were presented by Erlinge et al.8in a
study examining the pharmacodynamic poor responder rate with
high dose clopidogrel compared with prasugrel. There was a
higher rate of poor responders as measured by LTA and VASP
in the patients receiving clopidogrel 600 mg LD/75 mg MD com-
pared with prasugrel 60 mg LD/10 mg MD for 28 days. These pre-
vious investigations suggested the need to explore better tolerated
treatment strategies, which provide more effective P2Y12blockade,
as was assessed in the present study. The results from the
OPTIMUS-3 randomized trial in patients with DM confirmed
earlier pharmacodynamic observations from subgroup analyses
that the rate of response to prasugrel was greater than the
response to clopidogrel despite the use of double the approved
clopidogrel dose.19,21Additionally, both prasugrel and clopidogrel
were well tolerated in this population with DM.
Clinical outcome data demonstrating an increase in recurrent
ischaemic events following withdrawal of thienopyridine therapy
suggest the potential for rebound in platelet reactivity.22Although
limited by the short duration of the current study, no consistent
evidence of a rebound effect was measured at either 1 week fol-
lowing discontinuation of study drug or at 2 weeks when the
second baseline (post crossover) was compared with the first. If
rebound did exist, one would expect to find it in the early
period when new, fully functional platelets would be the majority
of platelets in circulation. This was an exploratory analysis and
not specifically designed to examine rebound; therefore, results
of our study should be interpreted with caution but are consistent
with those reported by Sibbing et al.,23who found no evidence of
rebound platelet activity on clopidogrel withdrawal in a prospec-
tively defined study. This suggests that the previously reported
increase in ischaemic events observed following thienopyridine
withdrawal may be the result of treatment cessation rather than
rebound platelet reactivity.
The aim of this study was to compare the antiplatelet effects of
prasugrel with double-dose clopidogrel in patients with DM; there-
fore, comparisons with patients without DM cannot be made.
Although adequately poweredfor thepharmacodynamic
endpoints, this study was conducted in a relatively small number
of patients, thus precluding an evaluation of clinical endpoints.
Additionally, the short duration of the trial did not allow for mean-
ingful assessment of bleeding events associated with antiplatelet
therapy and also limited conclusions regarding platelet function
and rebound following drug withdrawal to the time frame of the
study. Finally, patients included in the study were not indicated
for prasugrel or clopidogrel in order to allow a washout phase
without putting patients at risk. It should be underscored that in
the USA and Europe, prasugrel is indicated for ACS patients under-
going PCI, a population of patients not included in this study.
Compared with double-dose clopidogrel (600 mg LD/150 mg
MD), standard-dose prasugrel (60 mg LD/10 mg MD) resulted in
greater platelet inhibition in aspirin-treated patients with type 2
DM and CAD as assessed by multiple pharmacodynamic measures
in this prospective, randomized, double-blind, crossover study. Pra-
sugrel also resulted in a better response profile with lower rates of
poor responders after both the LD and MD periods, irrespective
of platelet function assay or definition used. These findings may
explain the clinical benefit observed with prasugrel in patients
Barbara Utterback (Eli Lilly and Company) provided writing and
project management support for the manuscript. Diana Swanson
and Caron Modeas, both of i3 Statprobe, provided technical
writing and editing, respectively, of the manuscript.
This work was supported by Daiichi Sankyo, Inc., and Eli Lilly and
Company. Funding to pay the Open Access publication charges for
this article was provided by Eli Lilly and Company.
Conflict of interest: The first author (D.J.A.) prepared the initial
draft of the manuscript. All authors participated in subsequent
review and revisions of the manuscript. The authors had full access
to the data and the ability to query the database, take full responsibility
for its integrity, and have agreed to the manuscript as written. D.J.A.
(corresponding author) reports: honoraria for lectures from Bristol–
Myers Squibb, sanofi-aventis, Eli Lilly and Company, and Daiichi
Sankyo, Inc.; consulting fees from Bristol–Myers Squibb, sanofi-aventis,
Eli Lilly and Company, Daiichi Sankyo, Inc., The Medicines Company,
Portola, Novartis, Medicure, Accumetrics, Arena Pharmaceuticals,
Merck, Evolva, and Astra Zeneca; and research grants from GlaxoS-
mithKline, Otsuka, Eli Lilly and Company, Daiichi Sankyo, Inc., The
Medicines Company, Portola, Accumetrics, Schering-Plough, Astra
Zeneca, Eisai, and Johnson and Johnson. J.B. reports: grant support
from Eli Lilly and Company, Daiichi Sankyo, Inc., and Bayer; and con-
sulting fees from Schering-Plough, Astellas Pharma US, Inc., Eli Lilly
and Company, and Daiichi Sankyo, Inc. J.F.S. reports: grant/research
support from The Medicines Company, Astra Zeneca, Abbott Vascu-
lar, Bristol–Myers Squibb, Medtronic, and Eli Lilly and Company; and
grant support/consulting/honoraria from Schering Plough. A.L.F.
sanofi-aventis, Eli Lilly and Company, Daiichi Sankyo, Inc., and
GLSynthesis; and consulting fees from Eli Lilly and Company. A.D.M.
Prasugrel vs. clopidogrel in diabetes
reports: research grants from Arena Pharmaceuticals, GLSynthesis, Eli
Lilly and Company, Daiichi Sankyo, Inc., sanofi-aventis, and Bristol–
Myers Squibb; member of the Data Safety Monitoring Board of Clopi-
dogrel to Lower Arterial Thrombotic Risk in Neonates and Infants
Trial (sanofi-aventis and Bristol–Myers Squibb); and consulting fees
from Arena Pharmaceuticals, Eli Lilly and Company, Daiichi Sankyo,
Inc., sanofi-aventis, and Bristol–Myers Squibb. J.A.J., B.Z., C.K.O, and
M.B.E. are employees of, and report equity ownership or stock
options in, Eli Lilly and Company. B.A.B. is an employee of Daiichi
Principal investigators and study sites
D.J.A., Cardiology Research, University of Florida—Jacksonville,
ACC Fifth Floor, 655 W. Eighth Street, Jacksonville, FL 32209,
USA; A.D.M., University of Massachusetts Memorial Medical
Center, 55 Lake Avenue North, Worcester, MA 01655, USA;
J.F.S., Cardiovascular Section, Department of Medicine, University
of Oklahoma Health Sciences Center, 920 Stanton L. Young Bou-
levard, WP 3010, Oklahoma City, OK 73104, USA; J.B., The Mount
Sinai Medical Center, Room AB6-20, Sixth Floor, Mount Sinai
School of Medicine Berg Building, 1428 Madison Avenue,
New York, NY 10029, USA.
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