Higher body weight patients on clopidogrel maintenance therapyhave lower active metabolite concentrations, lower levelsof platelet inhibition, and higher rates of poor respondersthan low body weight patients

Henrik Wagner • Dominick J. Angiolillo • Jurrien M. ten Berg • Thomas O. Bergmeijer •

Joseph A. Jakubowski • David S. Small • Brian A. Moser • Chunmei Zhou •

Patricia Brown • Stefan James • Kenneth J. Winters • David Erlinge

Published online: 17 September 2013

� Springer Science+Business Media New York 2013

Abstract Body weight is a predictor of clopidogrel

response. However, no prospective studies have compared

pharmacodynamic (PD) and pharmacokinetic (PK) data

based on body weight. We compared PD and PK effects of

clopidogrel 75 mg in low body weight (LBW,\60 kg) and

higher body weight (HBW, C60 kg) patients with stable

coronary artery disease. LBW (n = 34, 56.4 ± 3.7 kg) and

HBW (n = 38, 84.7 ± 14.9 kg) aspirin-treated patients

received clopidogrel 75 mg for 10–14 days. The area under

the concentration–time curve of active metabolite (Clop-

AM) calculated through the last quantifiable concentration

up to 4 h postdose, AUC(0–tlast), was calculated by non-

compartmental methods. Light transmission aggregometry

(LTA) (maximum platelet aggregation and inhibition of

platelet aggregation to 20 lM adenosine diphosphate

(ADP), and residual platelet aggregation to 5 lM ADP),

VerifyNow� P2Y12 reaction units (PRU), and vasodilator-

associated stimulated phosphoprotein phosphorylation

platelet reactivity index (VASP–PRI) were performed.

Mean AUC(0–tlast) was lower in HBW than LBW patients:

12.8 versus 17.9 ng h/mL. HBW patients had higher

platelet reactivity as measured by LTA (all p B 0.01), PRU

(207 ± 68 vs. 152 ± 57, p \ 0.001), and VASP–PRI

(56 ± 18 vs. 39 ± 17, p \ 0.001). More HBW patients

exhibited high on-treatment platelet reactivity (HPR) using

PRU (35 vs. 9 %) and VASP–PRI (65 vs. 27 %). Body

weight correlated with PRU and VASP–PRI (both

p \ 0.001), and inversely with log transformed AUC(0–tlast)

(p \ 0.001). In conclusion, HBW patients had lower levels

of Clop-AM, and higher platelet reactivity and rates of

HPR than LBW subjects, contributing to their suboptimal

response to clopidogrel.

Keywords Body weight � Clopidogrel �Pharmacodynamics � Pharmacokinetics

Introduction

Clopidogrel is used in conjunction with aspirin for pre-

vention of stent thrombosis and recurrent myocardial

infarction (MI) in patients with acute coronary syndrome

(ACS) and/or those undergoing percutaneous coronary

intervention (PCI) with stenting. Unfortunately, some

patients have a suboptimal antiplatelet response to clopi-

dogrel, a phenomenon known as high on-treatment platelet

reactivity (HPR), and these patients have an increased risk

of recurrent cardiac events [1–4]. Known causes of HPR

with clopidogrel are genetic effects (polymorphisms of

CYP3A4, CYP2C19, GPIa, P2Y12, and GPIIIa) [5, 6],

H. Wagner (&) � D. Erlinge

Department of Cardiology, Skane University Hospital,

Lund University, Getingevagen 4, 221 85 Lund, Sweden

e-mail: Henrik.wagner@med.lu.se

D. J. Angiolillo

University of Florida College of Medicine-Jacksonville,

Jacksonville, FL, USA

J. M. ten Berg � T. O. Bergmeijer

Department of Cardiology, St Antonius Hospital, Nieuwegein,

The Netherlands

J. A. Jakubowski � D. S. Small � B. A. Moser � C. Zhou �P. Brown � K. J. Winters

Eli Lilly and Company, Indianapolis, IN, USA

S. James

Department of Medical Sciences and Uppsala Clinical Research

Center, Uppsala University, Uppsala, Sweden

123

J Thromb Thrombolysis (2014) 38:127–136

DOI 10.1007/s11239-013-0987-8

diabetes mellitus [7, 8], renal failure, age [ 65 years, ACS,

reduced left ventricular function [9], and high body mass

index (BMI) [10–12].

The relationship between body mass and the antiplatelet

effect of clopidogrel has important efficacy and safety

implications. In patients undergoing PCI, overweight

individuals (BMI C 25 kg/m2) have been shown to have

increased platelet aggregation by light transmission

aggregometry (LTA) and suboptimal platelet inhibition in

response to a 300 mg [10] or 600 mg [12] loading dose

(LD) of clopidogrel. In multivariate analyses, increased

BMI was the only independent baseline characteristic to

predict increased platelet aggregation in patients taking

clopidogrel [12], and patients with adequate platelet inhi-

bition had significantly lower BMI compared to patients

with suboptimal platelet inhibition [11]. A clinical link

between higher BMI and poor clinical outcome was seen in

a study by Sibbing and colleagues, in which patients with

higher BMI more often experienced stent thrombosis

within 30 days of stent placement [13].

Though there is evidence suggesting that BMI plays a

role in the pharmacodynamic (PD) and clinical outcomes

associated with clopidogrel, there have not been studies

linking BMI to pharmacokinetic (PK) parameters. In par-

ticular, it is not known whether the well-documented dif-

ferences in PD response to clopidogrel that are associated

with BMI are driven by differences in exposure to the

active metabolite of clopidogrel (Clop-AM). The

FEATHER trial provided an opportunity to examine this

question [14]. In FEATHER, the efficacy and safety of

prasugrel 5 mg maintenance dose (MD) in low body

weight (LBW,\60 kg) patients with stable coronary artery

disease (CAD) was compared to that of prasugrel 10 mg

MD in higher body weight (HBW, C60 kg) patients.

Clopidogrel at the approved MD of 75 mg was also

included as a comparator. In this post hoc analysis of data

from FEATHER, we assessed the possibility of lower

Clop-AM exposure as an explanation for HPR in HBW

patients treated with clopidogrel. We hypothesized that in

the HBW group, exposure to Clop-AM would be reduced,

the response to clopidogrel would be attenuated, and rates

of HPR would be higher compared to the LBW group.

Methods

Trial design

This was an analysis of a subset of data from the FEATHER

trial (ClinicalTrials.gov ID# NCT01107925), an interna-

tional, multi-center, randomized, active comparator, Phase

1b blinded trial conducted in 72 patients with stable CAD.

The trial consisted of a screening visit, at which time patients

were weighed and categorized as either LBW (\60 kg) or as

HBW (C60 kg). An aspirin (75–100 mg daily) treatment

run-in phase of 5–21 days was followed by three consecutive

12 ± 2-day treatment periods during which patients

received clopidogrel 75 mg/day, prasugrel 5 mg/day, and

prasugrel 10 mg/day in a cross-over design. In the single-

blind first study period, LBW patients received prasugrel

5 mg and HBW patients received prasugrel 10 mg. The

second and third study periods were double-blind, and

patients received the prasugrel dose they had not yet received

and clopidogrel 75 mg in random order. The study protocol

was approved by local investigational review boards and was

performed in compliance with the principles of good clinical

practice and in accordance with provisions of the Declaration

of Helsinki. All subjects provided written informed consent

prior to receiving any study drug or undergoing any study

procedure. The study was performed at five clinical sites in

four countries (Ireland, the Netherlands, Sweden, and the

United States) from March 2010 to August 2011. The

FEATHER trial showed that prasugrel 5 mg in LBW

patients reduced platelet reactivity to a similar extent as

prasugrel 10 mg in HBW patients and resulted in greater

platelet inhibition, lower HPR, and similar bleeding rates

compared with clopidogrel [14]. This report concerns the PK

and PD results from FEATHER associated with clopidogrel

treatment.

Participants

Included in the FEATHER trial were men (n = 31) and

women (n = 41) from age 18 to 75 years with a history of

stable CAD and no current indication for treatment with a

thienopyridine. Excluded were patients with a prior history

or presence of refractory ventricular arrhythmia, implan-

tation of a defibrillator device, or congestive heart failure

(New York Heart Association Class III or above); those

with a significant bleeding disorder, abnormal bleeding

tendency, or coagulation disorder; and patients with

uncontrolled hypertension, any coronary revascularization

or surgical procedure planned within 60 days postran-

domization, or contraindication for treatment with an

antiplatelet agent (including aspirin). Also excluded were

patients with a prior history or clinical suspicion of cerebral

vascular malformation, intracranial neoplasm, transient

ischemic attack, stroke, or presence of thrombocytopenia

or thrombocytosis. The study protocol specifically exclu-

ded patients with evidence of active hepatic disease, severe

hepatic impairment, or evidence of hepatitis B or C.

Pharmacodynamic analysis

Venous blood samples were collected at baseline and at the

pre-dose trough at the end of each of the treatment periods

128 H. Wagner et al.

123

(day 12 ± 2). For LTA, blood was collected in 3.2 %

citrate, and platelet-rich plasma and platelet-poor plasma

were prepared by differential centrifugation. Platelet counts

in platelet-rich plasma were not adjusted, and LTA was

performed as previously described [15] to determine

maximum platelet aggregation (MPA) in response to

20 lM adenosine diphosphate (ADP), residual platelet

aggregation (RPA) to 5 lM ADP, and inhibition of platelet

aggregation (IPA) in response to 20 lM ADP. For the

VerifyNow� P2Y12 (VN P2Y12) assay, blood was col-

lected into citrated Greiner tubes and the assay was per-

formed within a window of C10 min to B4 h post-

collection as described by the manufacturer (Accumetrics,

San Diego, CA). Reported measures included VN P2Y12

Reaction Units (VN PRU) and VN P2Y12 device-reported

percent inhibition. For the vasodilator-associated stimu-

lated phosphoprotein (VASP) phosphorylation assay,

3.2 % citrated blood samples were treated with prosta-

glandin E1 (PGE1) alone or PGE1 plus ADP, and the

platelet reactivity index (PRI) was calculated as per the

instructions of the manufacturer (BioCytex, Marseille,

France).

Pharmacokinetic analysis

Blood samples for PK analysis of the Clop-AM were col-

lected into EDTA tubes at 0.5, 1, 2, 3, and 4 h following the

first dose of each period and the last dose of period three and

processed as described by Farid and colleagues [16]. Clop-

AM was measured using validated liquid chromatography

methods with tandem mass spectrometric detection, as pre-

viously described [16, 17]. Noncompartmental analysis was

performed using WinNonlin version 5.3 (Pharsight, Cary,

NC). The primary PK parameter was the area under the

concentration–time curve calculated through the last quan-

tifiable concentration up to 4 h postdose, AUC(0–tlast). Also

measured were the maximum observed concentration

(Cmax), and observed time of Cmax (tmax).

High on-treatment platelet reactivity

The percent of LBW and HBW patients showing HPR to

MD clopidogrel was evaluated using the following previ-

ously established criteria: MPA to 20 lM ADP [ 50 %

[18], IPA to 20 lM ADP \ 20 % [19], RPA to 5 uM

ADP [ 14 % [20], VASP phosphorylation platelet reac-

tivity index (VASP–PRI) C 50 % [21], VN PRU [ 235

[22], and VN P2Y12 percent inhibition \ 15 % [23].

Statistical analysis

Values are presented as mean and standard deviation (SD)

for continuous variables and counts (percentages) for

categorical variables, unless noted otherwise. For all sta-

tistical comparisons, a p value \0.05 was considered sta-

tistically significant. The baseline characteristics of LBW

and HBW patients were compared using a two-sample

t-test for continuous variables and a Pearson Chi square test

for categorical variables. The primary outcome, MPA to

20 lM ADP following 12 ± 2 days of clopidogrel 75 mg/day

was compared between LBW and HBW cohorts using an

analysis of covariance (ANCOVA) model with adjustment

for site and baseline measurement. Between-cohort com-

parisons for other PD parameters were handled in a similar

manner. The log-transformed AUC(0–tlast) was compared

between weight cohorts using an analysis of variance

model with the weight cohort in the model. The rate of

HPR was compared between LBW and HBW patients

using Fisher’s exact test based on the pre-specified HPR

thresholds noted above. The correlations of PK and PD

parameters with body weight were assessed using Pearson

correlation coefficients. All statistical analyses were per-

formed using SAS version 9.1 (Cary, North Carolina USA).

Results

Patient disposition and baseline characteristics

Of the 72 patients who enrolled and received at least one

dose of study drug, 69 received clopidogrel (three patients

discontinued the study prior to reaching their clopidogrel

arm). One patient discontinued the study while taking

clopidogrel due to patient decision. The mean age for both

LBW and HBW groups was between 62 and 63 years

(Table 1). The groups differed in sex distribution (15 %

male for LBW and 68 % male for HBW), and mean body

weight (56.4 kg [3.7] vs. 84.7 kg [14.9]), height (161.5 cm

[6.2] for LBW vs. 170.4 cm [9.1] for HBW), and BMI

(21.7 kg/m2 [1.8] vs. 29.1 kg/m2 [4.5]), all comparisons

significant at the p \ 0.001 level. The study population

was typical of patients with stable CAD, in that 58.3 % had

had a prior MI, 63.9 % had hypertension, 79.2 % had

hyperlipidemia, and 15.3 % had diabetes. At baseline,

minimal elevations in serum creatinine were noted for three

patients within the HBW group. The LBW group had a

numerically greater proportion of current smokers than the

HBW group (44.1 vs. 23.7 %, p = 0.066). Compared with

LBW patients, HBW patients were less likely to have had

prior coronary artery bypass graft (CABG) surgery or prior

PCI and more likely to have been receiving treatment with

an angiotensin converting enzyme inhibitor or angiotensin

receptor blocker than LBW patients. The cohorts were

otherwise well-matched in terms of past medical history

and co-medications.

Clopidogrel pharmacokinetics/pharmacodynamics and body weight 129

123

Pharmacodynamic measures

The PD parameters for HBW and LBW groups with

clopidogrel 75 mg MD are shown in Table 2 and Fig. 1,

panels a–f. At the end of treatment, HBW patients had a

significantly higher mean MPA to 20 lM ADP, RPA to

5 lM ADP, VN PRU, and VASP–PRI compared with

LBW patients (all p B 0.01). The IPA to 20 lM ADP and

VN P2Y12 device-reported percent inhibition were sig-

nificantly lower in HBW patients than in LBW patients

(both p \ 0.01).

Pharmacokinetic parameters

Geometric mean exposure to Clop-AM was lower in HBW

patients than in LBW patients (ratio of geometric LS means

of AUC(0–tlast) = 1.4 [90 % CI 1.14, 1.71]) (Fig. 2).

Clopidogrel was rapidly absorbed, with active metabolite

median tmax occurring at 0.5 h for both body weight groups

(Table 3). Clop-AM concentrations approached the lower

Table 1 Baseline

Demographics, Medical

History, and Co-Medications for

LBW and HBW Patients

ACE angiotensin converting

enzyme, ARB angiotensin

receptor blocker, CABG

coronary artery bypass graft,

HBW higher body weight, LBW

low body weight, MI

myocardial infarction, PCI

percutaneous coronary

intervention

Demographic LBW (n = 34) HBW (n = 38) p value

Age, mean (SD) 62.2 (7.8) 62.8 (8.5) 0.763

Male, n (%) 5 (14.7) 26 (68.4) \0.001

Race, n (%) 0.090

White 33 (97.1) 34 (89.5)

Black 0 4 (10.5)

Asian 1 (2.9) 0

Mean (SD)

Height, (cm) 161.5 (6.2) 170.4 (9.1) \0.001

Weight, (kg) 56.4 (3.7) 84.7 (14.9) \0.001

Body mass index (kg/m2) 21.7 (1.8) 29.1 (4.5) \0.001

Systolic blood pressure (mmHg) 137.3 (24.3) 134.2 (17.8) 0.531

n (%)

Risk factors/medical history

Current smoker 15 (44.1) 9 (23.7) 0.066

Hypertension 18 (52.9) 28 (73.7) 0.067

Hyperlipidemia 26 (76.5) 31 (81.6) 0.594

Diabetes 5 (14.7) 6 (15.8) 0.898

Prior CABG 5 (14.7) 0 (0.0) 0.014

Prior MI 19 (55.9) 23 (60.5) 0.690

Prior PCI 32 (94.1) 29 (76.3) 0.036

Co-medications

ACE inhibitors/ARBs 21 (61.8) 32 (84.2) 0.031

Diuretics 4 (11.8) 9 (23.7) 0.189

Proton pump inhibitors 13 (38.2) 11 (28.9) 0.564

Calcium channel blockers 6 (17.6) 12 (31.6) 0.173

Beta blockers 25 (73.5) 29 (76.3) 0.785

Statins 32 (94.1) 37 (97.4) 0.491

Table 2 Pharmacodynamic measurements for LBW and HBW

patients treated with clopidogrel 75 mg/day maintenance dose for

12 ± 2 days

LBW HBW p value

MPA to 20 lM ADP,

% [SD]

51 [14] 65 [18] 0.010

RPA to 5 lM ADP,

% [SD]

17 [14] 34 [22] 0.004

IPA to 20 lM ADP,

% [SD]

33 [14] 16 [22] 0.008

VerifyNow PRU, PRU

[SD]

152 [57] 207 [68] \0.001

VN P2Y12 device-reported

percent inhibition, % [SD]

54 [17] 35 [20] \0.001

VASP–PRI, % [SD] 39 [17] 56 [18] \0.001

ADP adenosine diphosphate, HBW higher body weight, IPA inhibition

of platelet aggregation, LBW low body weight, MPA maximum

platelet aggregation, PRU P2Y12 reaction units, RPA residual platelet

aggregation, VASP–PRI vasodilator-associated stimulated phospho-

protein phosphorylation platelet reactivity index, VN VerifyNow

130 H. Wagner et al.

123

limit of quantification by 2 h postdose and fell below it by

3 h in most subjects. Per study protocol, concentration–

time profiles were also assessed in study period 3 and, as

expected, they were similar.

High on-treatment platelet reactivity analysis

The percentages of HBW and LBW patients who met

criteria for HPR by previously described criteria are shown

in Fig. 3. HBW patients had significantly higher rates of

HPR than LBW patients as measured by MPA to 20 lM

ADP, IPA to 20 lM ADP, RPA to 5 lM ADP, VASP–PRI,

and VN P2Y12.

Active metabolite exposure and platelet reactivity

as a function of weight

In Fig. 4, exposure to Clop-AM is shown as a function of

weight, where weight is a continuous variable. Increasing

weight is associated with lower log transformed AUC(0–tlast)

(r = -0.42, p \ 0.001). Figure 5 is a similar plot showing

VASP–PRI as a function of body weight. Here the corre-

lation coefficient is 0.52 (p = 0.001), and the relation-

ship is such that increasing weight is associated with higher

platelet reactivity as evidenced by increasing VASP–PRI.

A similar trend is seen with the relationship between VN

PRU and body weight (r = 0.45. p \ 0.001) (Fig. 6).

Fig. 1 Pharmacodynamic measurements for LBW and HBW patients

treated with clopidogrel 75 mg/day MD for 12 ± 2 days. Top and

bottom whiskers represent 90th and 10th percentiles, and the middle

line represents the median. The dotted line traversing the figure

indicates the high on treatment platelet reactivity threshold. Median

weight for the LBW cohort was 57.5 kg and for the HBW cohort was

82.6 kg. ADP adenosine diphosphate, HBW higher body weight, IPA

inhibition of platelet aggregation, LBW low body weight, MD

maintenance dose, MPA maximum platelet aggregation, RPA residual

platelet aggregation, VASP–PRI vasodilator-associated stimulated

phosphoprotein phosphorylation platelet reactivity index, VN Verify-

Now, VN PRU VerifyNowTM P2Y12 reaction units

Clopidogrel pharmacokinetics/pharmacodynamics and body weight 131

123

Discussion

In this analysis of HBW and LBW patients with stable

CAD who were treated with clopidogrel MD (75 mg

daily), heavier patients demonstrated higher platelet reac-

tivity than lighter patients after 12 days of treatment, a

result consistent across multiple PD measures. In addition,

heavier patients had significantly higher rates of HPR

compared to LBW patients. Unique to this study was the

finding that increased platelet reactivity and higher rates of

HPR in the HBW group corresponded to reduced exposure

to Clop-AM.

These findings are consistent with previous post hoc

analyses of body mass in the setting of clopidogrel treat-

ment, including that done by Feher and colleagues [11],

who showed that patients with effective clopidogrel

inhibition had significantly lower BMI, and by Sibbing and

colleagues [12], who concluded that a single 600 mg LD of

clopidogrel did not adequately inhibit platelet aggregation

in patients with a BMI of C25 kg/m2 to the same extent as

in patients with lesser BMI. In a multivariable regression

analysis, Hochholzer and colleagues [24] identified BMI as

an independent predictor for an insufficient antiplatelet

response to clopidogrel. Likewise, Angiolillo and col-

leagues [10] showed that heavier patients (BMI C 25 kg/m2)

who were scheduled for coronary stent placement had

higher platelet reactivity both at baseline and 24 h fol-

lowing a 300 mg LD of clopidogrel compared to those with

normal body weight (BMI \ 25 kg/m2). In another study,

Sibbing and colleagues [13] showed that platelet reactivity

was an independent predictor of stent thrombosis and that

patients with higher BMI more often exhibited low

response to clopidogrel than patients with lower BMI. Our

analysis supports and extends the above findings by

showing that in the current prospective study with prede-

fined HBW and LBW groups, differences in clopidogrel

PD response were attributed at least in part to differences in

PK that were, in turn, correlated with weight.

The link between clopidogrel-treated HBW patients and

reduced exposure to Clop-AM suggests a means by which

high BMI is predictive of suboptimal platelet inhibition. In

the literature, high BMI has more often been considered a

covariate for poor response, rather than defining a distinct

subpopulation of patients in whom response is poor. This

was perhaps because, no studies of clopidogrel had inclu-

ded a head-to-head, balanced comparison of higher and

lower body weight groups. In contrast, PK modeling of

aspirin-treated patients with CAD who were randomly

allocated to receive prasugrel or clopidogrel showed a

significant weight effect on apparent clearance (CL/F) of

prasugrel; however, weight was not a significant covariate

on CL/F in the clopidogrel population [25], though the

range of weight in that study was less than twofold

Fig. 2 Exposure to the active metabolite of clopidogrel in LBW and

HBW patients. AUC(0–tlast) area under the concentration versus time

curve (AUC) from time zero to time t, where t is the last time point

with a measurable concentration through 4 h postdose; CI confidence

interval; HBW higher body weight; LBW low body weight; LS least

squares

Table 3 Pharmacokinetic parameters for the active metabolite of clopidogrel in LBW and HBW patients treated with clopidogrel (75 mg/day)

LBW HBW

Visit(s) 3–4 5 3–4 5

N (n = 31) (n = 15) (n = 37) (n = 20)

Cmax (ng/mL)

Geometric mean (CV %) 17.8 (58) 21.6 (40) 11.3 (79) 12.2 (64)

tmax (h)

Median (minimum, maximum) 0.50 (0.50–2.00) 0.50 (0.50–0.50) 0.50 (0.50–3.00) 0.50 (0.50–2.00)

AUC(0–tlast) (ng h/mL)

Geometric mean (CV %) 17.9 (41)a 19.4 (32) 12.8 (62) 12.5 (59)

a n = 30, One patient was not included in calculation of the summary statistic due to an incomplete profile following treatment

AUC(0–tlast) = area under the concentration–time curve calculated through the last quantifiable concentration up to 4 h postdose, Cmax maximum

observed concentration, CV coefficient of variation, tmax observed time of Cmax, HBW higher body weight, LBW low body weight

132 H. Wagner et al.

123

(65–115 kg) and may have been too narrow to demonstrate

an effect. The weight range in the present study was

45–134 kg. Weight has been a known and reproducible

covariate on CL/F in subsequent studies of prasugrel [26].

In this trial, we observed an inverse correlation between

weight and exposure to Clop-AM. The mechanism by

which this phenomenon occurs—whether it is due to issues

with absorption, metabolism, or clearance—has yet to be

determined.

In this study, LBW patients were more likely to be

female, to have had a previous CABG or PCI, to be a

current smoker, and less likely to be using angiotensin

converting enzyme/angiotensin receptor blocker (ACE/

ARB)-treatment. These factors may have affected platelet

response to a minor extent. It is known, for example, that

female sex and smoking are associated with increased

platelet inhibition in response to clopidogrel [27]. Other

intrinsic and extrinsic factors that influence clopidogrel’s

PK and PD have been reviewed elsewhere [28]. In this

study, the comparison of HBW and LBW patients involved

an ANCOVA model that included adjustment for site and

baseline measurement. In a post hoc analysis, sex, smoking

status, and ACE inhibitor use were added into the model as

covariates and results showed that body weight category

(LBW and HBW) was an independent predictor of PD

response (data on file, Daiichi Sankyo, Inc. and Eli Lilly

and Company, Indianapolis, IN). Likewise, although some

CYP2C19 polymorphisms have been associated with a

significant reduction in PD response to clopidogrel [29], a

Fig. 3 The percent of LBW and HBW patients treated with

clopidogrel (75 mg/day) who met criteria for high on-treatment

platelet reactivity by previously described criteria. ADP adenosine

diphosphate, HBW higher body weight, HPR high on-treatment

platelet reactivity, IPA inhibition of platelet aggregation, LBW low

body weight, MPA maximum platelet aggregation, RPA residual

platelet aggregation, VASP–PRI vasodilator-associated stimulated

phosphoprotein phosphorylation platelet reactivity index, PRU P2Y12

reaction units

Fig. 4 Log transformed exposure to the active metabolite of

clopidogrel versus body weight. AUC(0–tlast) area under the curve of

concentration versus time through the last sampling time with a

quantifiable concentration through 4 h postdose

Fig. 5 VASP–PRI versus body weight. VASP–PRI vasodilator-asso-

ciated stimulated phosphoprotein phosphorylation platelet reactivity

index

Fig. 6 VerifyNow PRU versus body weight. PRU P2Y12 reaction

units, VN VerifyNow

Clopidogrel pharmacokinetics/pharmacodynamics and body weight 133

123

genetic analysis of a subset of patients in the FEATHER

study (n = 66) revealed similar distributions of polymor-

phisms (CYP2C19*2 and *17) within HBW and LBW

cohorts (data on file, Daiichi Sankyo, Inc. and Eli Lilly and

Company, Indianapolis, IN).

From a clinical standpoint, patients with higher BMI are

at risk for HPR when treated with clopidogrel, a condition

which places them at higher risk for adverse cardiac events,

including stent thrombosis, MI, and death [1–4]. In addi-

tion, patients with higher BMI have a slower onset of

response to clopidogrel [30]. Bedside platelet aggregation

testing might be warranted in patients with higher BMI.

However, attempting to enhance platelet inhibition by

increasing the dose of clopidogrel in patients with higher

BMI has not always proven successful [5, 31, 32]. To

reduce the risk of cardiac ischemic events after PCI in

HBW persons, newer medications with stronger inhibition

of the P2Y12 receptor may be indicated [33, 34].

Limitations

Conclusions from this study may be somewhat limited in

that HBW and LBW groups differed at baseline. The

higher proportion of women and higher frequency of car-

diac risk factors such as prior CABG and prior PCI in the

LBW group might have contributed to differences in

response to clopidogrel between treatment groups. In

addition, because our PK analysis did not include a rigor-

ous covariate assessment of parameters such as absorption

or clearance, a more detailed explanation for why HBW

patients had lower concentrations of Clop-AM cannot be

offered at this time. Finally, this study was short-term and

did not include an evaluation of clinical outcomes. Future

studies of clopidogrel in HBW and LBW patients might

include these outcomes.

Conclusion

Compared with LBW patients treated with clopidogrel,

those with HBW had lower active metabolite concentra-

tions, reduced platelet inhibition, and a greater incidence of

HPR. These results provide at least a partial explanation for

suboptimal clopidogrel response in HBW patients: low

exposure to Clop-AM leads to greater platelet reactivity

that crosses a threshold defined as HPR, which has asso-

ciated clinical implications. Patients with HBW might

benefit from platelet reactivity monitoring when treated

with clopidogrel or, likewise, benefit from use of treat-

ments with more efficient ADP-receptor inhibition.

Acknowledgments Appreciation for writing and editorial contri-

butions is expressed to Tamara Ball, MD, of inVentiv Health Clinical.

Eli Lilly contracted the technical writing of this manuscript with

inVentiv Health. Also acknowledged are: Keri Poi, PhD of Eli Lilly

for editorial assistance.

Conflict of interest Dr. Erlinge has received fees for being a

speaker from Daiichi Sankyo Company, Ltd. and Eli Lilly and

Company, AstraZeneca, Sanofi-Aventis and Accumetrics and for

being an advisory board member for AstraZeneca, Eli Lilly and

Company, and Merck. Dr Angiolillo reports receiving: honoraria for

lectures from Bristol Myers Squibb; Sanofi-Aventis; Eli Lilly Co;

Daiichi Sankyo, Inc; Astra Zeneca; consulting fees from Bristol

Myers Squibb; Sanofi-Aventis; Eli Lilly Co; Daiichi Sankyo, Inc.;

The Medicines Company; Portola; Novartis; Medicure; Accumetrics;

Arena Pharmaceuticals; Abbott Vascular; Astra Zeneca; research

grants from Bristol Myers Squibb; Sanofi-Aventis; GlaxoSmithKline;

Otsuka; Eli Lilly Co; Daiichi Sankyo, Inc., The Medicines Company;

Portola; Accumetrics; Schering-Plough; Astra-Zeneca; Eisai. Dr.

James has received institutional research grants and honoraria from

AstraZeneca, Eli Lilly and Company, Merck and Bristol-Myers

Squibb, fees for being an advisory board member for AstraZeneca, Eli

Lilly and Company, and Merck; and honoraria only from The Med-

icines Company.Dr. Wagner has received grants from JOLIFE Swe-

den AB/Physio-Control Inc. and Eli Lilly Sweden for consulting. Drs.

Jakubowski, Small, and Winters, as well as Mr. Moser, Ms. Zhou, and

Ms. Brown are employed by and minor shareholders in Eli Lilly and

Company. Dr. ten Berg denies any potential conflicts of interest.

Funding This study was funded by Daiichi Sankyo, Inc. and Eli

Lilly and Company, Indianapolis, Indiana, USA

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