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`European Heart Journal (2006) 27, 1166–1173
`doi:10.1093/eurheartj/ehi877
`
`Clinical research
`Coronary heart disease
`
`Prasugrel achieves greater inhibition of platelet
`aggregation and a lower rate of non-responders
`compared with clopidogrel in aspirin-treated
`patients with stable coronary artery disease
`
`Tomas Jernberg1, Christopher D. Payne2, Kenneth J. Winters3, Christelle Darstein3,
`John T. Brandt3, Joseph A. Jakubowski3, Hideo Naganuma4, Agneta Siegbahn5,
`and Lars Wallentin1*
`
`1 Department of Medical Sciences, Cardiology and Uppsala Clinical Research Center, University Hospital, 751 85 Uppsala,
`Sweden; 2 Lilly Research Centre Ltd.,Windlesham, Surrey, UK; 3 Eli Lilly and Company, Indianapolis, IN, USA; 4 Clinical
`Pharmacology and Biostatistics Department, Sankyo Co. Ltd., Tokyo, Japan; and 5 Department of Medical Sciences, Clinical
`Chemistry, University Hospital, Uppsala, Sweden
`
`Received 3 September 2005; revised 6 March 2006; accepted 23 March 2006; online publish-ahead-of-print 18 April 2006
`
`KEYWORDS
`Prasugrel;
`CS-747;
`Thienopyridine;
`Clopidogrel;
`Platelets;
`Trials
`
`Aims This study was designed to compare the degree of inhibition of platelet aggregation (IPA) of
`prasugrel with that of clopidogrel in stable aspirin-treated patients with coronary artery disease (CAD).
`Methods and results Subjects (n ¼ 101) were randomly assigned to the following loading dose (LD) (day 1)/
`maintenance dose (MD) (days 2–28) combinations: prasugrel, 40 mg/5 mg; 40 mg/7.5 mg; 60 mg/10 mg;
`60 mg/15 mg; or clopidogrel, 300 mg/75 mg. Turbidometric platelet aggregation was measured at
`multiple timepoints during the study. At 4 h after dosing, with 20 mM ADP, both prasugrel LDs achieved
`significantly higher mean IPA levels (60.6% and 68.4 vs. 30.0%, respectively; all P , 0.0001) and lower
`percentage (3 vs. 52%, P , 0.0001) of pharmacodynamic non-responders (defined as IPA ,20%) than
`clopidogrel. Prasugrel 10 and 15 mg MDs achieved consistently higher mean IPA than clopidogrel
`75 mg at day 28 (all P , 0.0001). At pre-MD on day 28, there were no non-responders in the 10 and
`15 mg prasugrel group, compared with 45% in the clopidogrel group (P ¼ 0.0007).
`Conclusion In this population, prasugrel (40–60 mg LD and 10–15 mg MD) achieves greater IPA and
`a lower proportion of pharmacodynamic non-responders compared with the approved clopidogrel
`dosing.
`
`Introduction
`
`Thienopyridine derivatives inhibit platelet aggregation by
`blocking adenosine diphosphate (ADP)-dependent activation
`of platelets via the platelet P2Y12 receptor.1 Several studies
`have documented that a combination of aspirin and clopido-
`grel
`reduces both percutaneous coronary intervention
`related and spontaneous ischaemic events in patients with
`non-ST-elevation acute coronary syndrome (ACS) and patients
`undergoing PCI for stable coronary artery disease (CAD).2,3
`Therefore, the addition of clopidogrel has been recom-
`mended as standard care in these patients.4
`However, subacute stent thrombosis still occurs in 1–3% of
`the patients receiving dual antiplatelet therapy.5 Recent
`studies have demonstrated a marked interindividual variabil-
`ity of clopidogrel’s capacity to inhibit platelet aggregation
`
`*Corresponding author. Tel: þ46 18 611 00 00; fax: þ46 18 50 66 38.
`E-mail address: lars.wallentin@ucr.uu.se
`
`with a substantial proportion (11–34%) of the patients
`considered non-responders to clopidogrel treatment.6–9
`Thus, a more potent and consistent inhibitor of ADP-
`dependent platelet activation may offer the potential for
`improved clinical outcomes in ACS and PCI.
`Prasugrel (CS-747) is a new thienopyridine derivative that
`is 10 times more potent than clopidogrel in preclinical
`studies.10 Prasugrel has been evaluated both in healthy indi-
`viduals and in a recently reported study in patients under-
`going elective or urgent PCI
`in which it was shown to
`result in low and similar rates of bleeding when compared
`with clopidogrel.11
`The primary objective of the current study was to charac-
`terize, in aspirin-treated subjects with stable CAD, the
`degree of inhibition of platelet aggregation (IPA) associated
`with four dosing regimens of prasugrel compared with the
`currently approved clopidogrel loading dose (LD) and main-
`tenance dose (MD) regimen.
`
`& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
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`Methods
`
`Patients
`
`Two centres in two countries (Sweden and USA) enrolled patients
`between November 2002 and October 2003. This randomized
`(with stratification by centre), partially blind, parallel-group
`study was conducted in adult male and female patients with
`review board approval was
`CAD, aged 40–75 years. Ethical
`obtained for the study and written informed consent was obtained
`from each subject. Subjects were eligible for enrolment in the
`study if they had CAD, defined as subjects diagnosed with
`chronic stable angina, prior history of unstable angina or acute
`myocardial infarction, previous coronary revascularization or CAD
`in at least one coronary vessel at angiography; peripheral artery
`occlusive
`disease
`(intermittent
`claudication,
`ankle-brachial
`index ,0.9, or previous peripheral vascular intervention); or a
`documented previous history of cerebrovascular disease, including
`ischaemic stroke or history of a previous transient ischaemic
`attack.
`Subjects were excluded from the study if they met any of the fol-
`lowing criteria: ACS or PCI within 30 days, peripheral artery occlu-
`sive disease within 30 days of hospitalization or requiring previous
`amputation, history or presence of bleeding disorder, and history
`of recent surgery or severe trauma. Subjects were also excluded
`if there was evidence of active hepatic disease, uncontrolled hyper-
`tension, arrhythmia, or severe congestive heart failure.
`Subjects were also excluded if they had taken thienopyridines,
`antiplatelet agents (other than aspirin), inhibitors (ciprofloxacin,
`clarithromycin, erythromycin, fluconazole, fluvoxamine, itracona-
`zole, ketoconazole), or inducers (barbiturates, carbamazepine,
`phenytoin, rifampicin) of cytochrome P4503A4. In addition, proton
`pump inhibitors and H2 receptor antagonists were discontinued
`prior to the run-in period.
`
`Study design
`
`All subjects received enteric-coated aspirin (325 mg/day, Ecotrinw,
`GlaxoSmithKline) during a 7-day, open-label, run-in period and
`throughout the treatment period. After the run-in period, subjects
`were randomized to LD of study drug on day 1 and MD for 27 days.
`For logistical reasons, the patients were followed during dosing for a
`range of 26–32 days. A final study visit was scheduled between 7 and
`14 days after the last MD. Prasugrel, supplied as the 2.5, 5, and
`10 mg tablets of the base formulation, was manufactured by
`Sankyo Product Development Laboratories, Shinagawa-ku, Tokyo,
`Japan. Clopidogrel (Plavixw, Sanofi-Synthelabo) was supplied as
`75 mg tablets available commercially. Subjects were randomly
`assigned to one of five dosing regimens for the treatment period:
`(i) prasugrel 40 mg LD/5 mg MD; (ii) prasugrel 40 mg LD/7.5 mg
`MD; (iii) prasugrel 60 mg LD/10 mg MD; (iv) prasugrel 60 mg LD/
`15 mg MD); or (v) clopidogrel 300 mg LD/75 mg MD. The present
`study was double blind with respect to the prasugrel dose
`administered, while both aspirin and clopidogrel were dosed in an
`open-label manner.
`
`Pharmacodynamic measurements
`Venous blood samples of 15 mL were collected in one-tenth
`volume of 3.8% sodium citrate at the following timepoints: (i) visit
`1 (day 1)—pre-dose (duplicate samples), 2, 4, and 6 h post-dose;
`(ii) visit 2 (day 7–14)—two post-dose samples collected on the
`same day at least 1 h apart; (iii) visit 3 (day 26–32)—samples
`collected pre-dose, 2, 4, and 6 h post-dose.
`All
`laboratory personnel conducting the platelet aggregation
`studies were blinded as to patient treatment. Platelet-rich and
`platelet-poor plasma were prepared by differential centrifugation
`at room temperature. There was no adjustment of platelet count
`performed. Platelet aggregation studies were completed within
`3 h of sample collection. Turbidometric platelet aggregation was
`
`performed using platelet-rich plasma, with 0% light transmittance
`set with subject platelet-rich plasma and 100% transmittance set
`with subject platelet-poor plasma. The aggregometers used were
`as follows: in the US, a Bio-Data Model PAP-4; in Sweden a Chrono-
`log 490. Agonists used at each site were from the same source and
`prepared identically. Platelet aggregation was allowed to proceed
`for 8 min following addition of the agonist (5 or 20 mM ADP). The
`maximal platelet aggregation (MPAt) response during that time
`was recorded and used for data analysis. IPA was calculated using
`the following formula: %IPA ¼ [(MPA0 2 MPAt)/MPA0] 100, where
`MPA0 is the MPA at baseline on aspirin alone and MPAt ¼ MPA at
`time t on study drug plus aspirin.
`
`Adverse events
`
`Laboratory tests were performed at screening, prior to the first
`dose of study drug (day 21, day 1, or the run-in visit) and on
`visits 2 and 3. All unexpected signs and symptoms were recorded
`throughout the treatment period. Physical examinations were
`performed at screening and at the post-study visit.
`
`Statistical analysis of platelet aggregation data
`
`IPA data were analysed using a linear mixed-effect model with base-
`line MPA as a covariate, with fixed effects for dosing regimen, time
`since first dosing, study site, and for the interactions between
`dosing regimen and time since first dosing and respectively,
`between dosing regimen and site as fixed effects, and finally with
`subject as a random effect. The model allowed intersubject and
`intrasubject variabilities to be different across the treatment
`groups and time since first dosing. This analysis was implemented
`using the SAS MIXED procedure (SAS Institute Inc., Cary, NC, USA,
`version 8.2).
`The primary comparison of interest was between the four prasu-
`grel MD groups and the clopidogrel MD group on day 28 at pre-dose.
`A second comparison of interest was between the two prasugrel LD
`groups and the clopidogrel LD group on day 1 at 4 h post-dose.
`Dunnett’s adjustment for multiple comparisons to one control
`(clopidogrel) was used in both cases. For other comparisons, an
`overall test was run first, and this test being significant, individual
`tests were then run between each pair of treatments. All statistical
`tests performed were two-sided and carried out at the 0.05
`significance level.
`
`Statistical analysis of pharmacodynamic
`non-responders
`
`In order to further characterize the effect of prasugrel and clopido-
`grel on IPA, the percentage of pharmacodynamic non-responders in
`each treatment group was analysed. For this analysis, a thienopyr-
`idine non-responder on aspirin was defined by IPA criteria as an
`individual not achieving 20% IPA to 20 mM ADP by 4 h after an
`LD or not maintaining 20% IPA at subsequent pre-dose timepoints
`during MD administration. With 5 mM ADP as the agonist, the cri-
`terion defining a non-responder was not maintaining 25% IPA.
`This definition was derived from a model based on data acquired
`from previous investigations of clopidogrel in healthy human sub-
`jects, including intrasubject and intersubject variability, coeffi-
`cient of variation of the method to determine IPA, and an
`assumed incidence of 20–30% non-responders in the population
`(data on file, Eli Lilly and Company). Non-responders were also
`characterized using the definition derived by Gurbel et al.6,12
`This approach defines non-responders as those having an absolute
`difference between baseline MPA and post-treatment MPA (DMPA)
`of ,10% with either 5 or 20 mM ADP as the agonist. Non-responder
`rates among treatment groups were compared using Fisher’s
`exact test.
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`Results
`
`Patients
`
`A total of 101 subjects were enrolled in the study (Sweden,
`n ¼ 83; USA, n ¼ 18). Figure 1 illustrates the disposition of
`patients in the study. There were two discontinuations,
`one due to administration of an incorrect LD (50 mg prasu-
`grel instead of 60 mg) and one at the request of the investi-
`gator because of inadequate venous access. Thus, a total of
`99 subjects completed the study. All subjects were Caucasian
`
`T. Jernberg et al.
`
`and had CAD. Baseline characteristics and mean baseline
`MPA responses were consistent across treatment groups
`(Table 1).
`
`Inhibition of platelet aggregation
`Figure 2A and B illustrates the mean IPA for the LDs and MDs of
`prasugrel or clopidogrel at all study timepoints by treatment
`group. At 4 h after the LD on day 1, both the 40 and 60 mg
`LDs of prasugrel demonstrated at least a doubling of mean
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`Figure 1 Patient flow through the study.
`
`Table 1 Baseline characteristics of all enrolled subjects
`
`Prasugrel
`
`Clopidogrel
`
`All subjects
`(n ¼ 101)
`
`LD/MD
`
`Gender
`Male
`Female
`Age (years, mean + SD)
`Body weight (kg, mean + SD)
`Baseline MPA response with
`5 mM ADP (%, mean + SD)
`Baseline MPA response with
`20 mM ADP (%, mean + SD)
`Hypertension
`Diabetes
`Statin
`Previous MI
`Smokers
`
`40 mg/5 mg
`(n ¼ 19)
`
`40 mg/7.5 mg
`(n ¼ 19)
`
`60 mg/10 mg
`(n ¼ 19)
`
`60 mg/15 mg
`(n ¼ 21)
`
`300 mg/75 mg
`(n ¼ 23)
`
`16
`3
`65 + 8.7
`84.7 + 13.6
`60.6 + 16.6
`
`11
`8
`65 + 7.9
`84.2 + 10.0
`64.3 + 9.7
`
`18
`1
`65 + 6.4
`86.6 + 14.0
`65.6 + 8.7
`
`14
`7
`63 + 7.5
`84.7 + 16.7
`63.3 + 10.1
`
`21
`2
`61 + 8.0
`86.1 + 13.1
`61.4 + 13.5
`
`80
`21
`64 + 7.7
`85.3 + 13.4
`63.0 + 12.0
`
`72.5 + 14.1
`
`78.5 + 9.3
`
`78.2 + 8.8
`
`74.5 + 7.5
`
`75.2 + 7.3
`
`75.7 + 9.6
`
`10
`2
`12
`9
`3
`
`9
`0
`12
`10
`4
`
`11
`2
`13
`14
`2
`
`10
`4
`16
`11
`3
`
`8
`2
`16
`12
`5
`
`48
`10
`69
`56
`17
`
`LD, loading dose; MD maintenance dose; MPA, maximum platelet aggregation; ACE, angiotensin-converting enzyme; MI, myocardial infarction.
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`Figure 2 Mean inhibition of aggregation (IPA) induced by ADP over time in each dosing group. Panel A, the agonist is 5 mM ADP. Panel B, the agonist is 20 mM ADP.
`Values on the left side of the dashed line represent samples obtained pre-loading dose up to 6 h post-LD. Values on the right side of the dashed line represent
`samples obtained during the MD period. IPA values are adjusted for intersite variability. Statistically significant IPA of prasugrel dose vs. clopidogrel dose at each
`timepoint is indicated, *P , 0.05, **P , 0.01. aSamples designated as #1 and #2 (see Methods) at the 7 day timepoint. Pras, prasugrel; Clop, clopidogrel.
`
`Table 2 Summary of the inhibition of aggregation (5 and 20 mM ADP agonist) after prasugrel or clopidogrel
`LD and MD
`
`Hours
`post-dose
`
`Dose (mg)
`
`ADP 5 mM
`Mean % IPA (95% CI)
`
`ADP 20 mM
`Mean % IPA (95% CI)
`
`2 h*
`
`4 h*
`
`6 h*
`
`Day 7 (sample 2)
`
`Day 28 (0 h)
`
`LD
`Prasugrel/40, n ¼ 36
`Prasugrel/60, n ¼ 39
`Clopidogrel/300, n ¼ 23
`Prasugrel/40, n ¼ 37
`Prasugrel/60, n ¼ 38
`Clopidogrel/300, n ¼ 23
`Prasugrel/40, n ¼ 37
`Prasugrel/60, n ¼ 38
`Clopidogrel/300, n ¼ 23
`
`MD
`Prasugrel/5, n ¼ 18
`Prasugrel/7.5, n ¼ 19
`Prasugrel/10, n ¼ 19
`Prasugrel/15, n ¼ 19
`Clopidogrel/75, n ¼ 23
`Prasugrel/5, n ¼ 19
`Prasugrel/7.5, n ¼ 19
`Prasugrel/10, n ¼ 19
`Prasugrel/15, n ¼ 19
`Clopidogrel/75, n ¼ 22
`
`61.7 (55.1, 68.3)**
`70.0 (63.7, 76.3)**
`35.9 (28.8, 42.9)
`67.8 (62.0, 73.6)**
`73.8 (68.3, 79.2)**
`37.0 (24.7, 49.4)
`68.6 (63.0, 74.2)**
`74.8 (69.3, 80.3)**
`40.7 (30.7, 50.7)
`
`55.9 (42.8, 69.1)
`56.0 (44.6, 67.4)
`67.5 (57.4, 77.6)††
`78.9 (68.3, 89.6)††
`45.0 (32.8, 57.2)
`
`41.2 (30.1, 52.2)
`46.6 (36.0, 57.1)†
`59.3 (49.1, 69.5)††
`73.1 (62.8, 83.4)††
`30.5 (20.4, 40.6)
`
`55.1 (49.1, 61.1)**
`64.4 (58.0, 70.8)**
`30.2 (22.9, 37.5)
`60.6 (55.1, 66.0)**
`68.4 (62.8, 73.9)**
`30.0 (22.7, 37.4)
`60.0 (54.4, 65.7)**
`69.6 (64.2, 75.0)**
`31.1 (23.5, 38.7)
`
`42.9 (33.6, 52.3)
`50.8 (43.5, 58.1)
`62.2 (55.6, 68.7)††
`71.0 (63.8, 78.2)††
`40.4 (33.7, 47.1)
`
`34.5 (27.1, 41.9)
`43.4 (36.1, 50.7)†
`57.5 (50.2, 64.8)††
`65.8 (58.7, 72.8)††
`31.2 (23.9, 38.4)
`
`LD, loading dose; MD, maintenance dose; IPA, inhibition of platelet aggregation.
`*P , 0.01 for overall test, for both ADP 5 and 20 mM.
`**P , 0.01 vs. clopidogrel 300 mg LD.
`†P , 0.05.
`††P , 0.01 vs. clopidogrel 75 mg MD.
`
`IPA compared with the 300 mg LD of clopidogrel (60.6% and
`68.4 vs. 30.0%, respectively; 20 mM ADP, all P , 0.0001,
`Figure 2B and Table 2). With either 5 or 20 mM ADP, the
`mean IPA levels for both LDs of prasugrel at 2, 4, and 6 h
`post-LD were statistically greater than that achieved with
`the 300 mg LD of clopidogrel (Table 2). Although the overall
`
`levels of IPA were higher at one site, the relative treatment
`effects observed were the same at each site (Figure 3A and B).
`During the MD phase, the level of platelet inhibition main-
`tained was dose-related for the four prasugrel doses (Figures
`2A, B, and 3B). The prasugrel 10 and 15 mg daily MDs
`resulted in significantly higher mean levels of IPA than the
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`Figure 3 Distribution of IPA with 20 mM ADP as agonist. Panel A illustrates
`IPA values on day 1 at 4 h post-LD. Panel B illustrates IPA values on day 28
`at pre-MD. Stars
`represent
`IPA values obtained at
`site 1 and the
`open squares represent IPA values obtained at site 2. The horizontal line
`represents the mean of the entire treatment group. Pras, prasugrel; Clop,
`clopidogrel.
`
`clopidogrel 75 mg MD on both day 7–14 and on day 28 using
`either 5 or 20 mM ADP (P 0.01 at all timepoints, Table 2).
`At pre-dose on day 28, the primary MD timepoint of interest,
`both the 10 and 15 mg MDs of prasugrel maintained greater
`mean IPA compared with the 75 mg MD of clopidogrel (57.5%
`and 65.8 vs. 31.2%, respectively; 20 mM ADP, P 0.01,
`Figure 2B and Table 2).
`
`Pharmacodynamic non-responders
`
`The percentage of non-responders at 4 h post-LD on day 1
`and pre-MD on day 28, as defined by the model-based cri-
`teria of IPA ,25% in response to 5 mM ADP or IPA ,20% in
`response to 20 mM ADP is illustrated in Figure 4.
`
`Adverse events
`
`The majority of adverse events were rated as mild in sever-
`ity and no subject discontinued study drug dosing due to an
`adverse event. Only one patient (receiving prasugrel 5 mg
`MD þ aspirin) was classified as having a serious adverse
`event after being hospitalized on day 29 because of unstable
`angina.
`The number of bruising and minor bleeding events were
`similar in the three lower prasugrel dose groups and the clo-
`pidogrel group (Table 3). In the highest prasugrel MD group
`(15 mg), the increase in minor bruising (mainly bruises on
`
`Figure 4 Percentage of non-responders on day 1 at 4 h post-LD, and on day
`28 at pre-MD. For this study, a non-responder was defined as a subject with
`IPA ,25% in response to 5 mM ADP (panel A) or ,20% in response to 20 mM
`ADP (panel B). Bars to the left of the dashed line represent the percentage
`of non-responders 4 h post-LD. Bars to the right of the dashed line represent
`the percentage of non-responders on day 28 at pre-maintenance dose. Only
`statistically significant differences (P-value , 0.05) between groups are indi-
`cated. Pras, prasugrel; Clop, clopidogrel.
`
`the extremities at sites of venipuncture or bleeding times)
`and minor bleeding events (predominantly self-limiting epi-
`sodes of epistaxis) observed was not statistically significant.
`No bleeding events required medical intervention or were
`associated with a decrease in haematocrit. In an exploratory
`analysis, there was no apparent correlation between the
`level of IPA achieved and the occurrence of these minor
`bleeding events.
`
`Discussion
`
`The present trial is the first to examine the dose-dependent
`pharmacodynamic effects of prasugrel, a new P2Y12 ADP
`receptor antagonist, in an aspirin-treated population with
`stable atherosclerotic disease. Both prasugrel LDs (40 and
`60 mg) achieved significantly higher IPA compared with
`clopidogrel 300 mg LD. During daily dosing, prasugrel
`demonstrated dose-dependent IPA, with prasugrel 10 and
`15 mg MDs maintaining significantly higher IPA compared
`with clopidogrel 75 mg MD. In addition, the percentage of
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`Table 3 Adverse events in all enrolled subjects
`
`Number of adverse events (number of subjects) [percent of subjects]
`
`LD/MD
`
`Bruising [%]
`Bleeding [%]
`Bruising and bleeding [%]
`Epistaxis [%]
`
`Prasugrel
`
`(40/5 mg)
`(n ¼ 19)
`
`35 (12) [63]
`2 (2) [11]
`37 (13) [68]
`1 (1) [5]
`
`(40/7.5 mg)
`(n ¼ 19)
`
`49 (13) [68]a
`5 (4) [21]
`54 (15) [79]a
`2 (1) [5]
`
`(60/10 mg)
`(n ¼ 19)
`
`34 (12) [63]
`3 (2) [11]
`37 (13) [68]
`2 (1) [5]
`
`(60/15 mg)
`(n ¼ 21)
`
`47 (15) [71]
`12 (6) [29]
`59 (17) [81]
`8 (5) [24]
`
`Clopidogrel
`
`(300/75 mg)
`(n ¼ 23)
`
`25 (11) [48]
`7 (5) [22]
`31 (15) [65]
`4 (2) [9]
`
`Values in parentheses are the number of patients with the specified adverse event. Values in brackets are the percentage of patients within
`a treatment group with the specified adverse event. The following events are incorporated under the description of bleeding events: epi-
`staxis, gingival bleeding, haemoptysis, tongue haemorrhage, blister, wound, conjunctival haemorrhage, blood in stool, and haematuria
`(microscopic). No bleeding events were associated with a decrease in haematocrit. Bruising was most often associated with the study pro-
`cedures (venipucture, bleeding times). LD, loading dose; MD, maintenance dose.
`a The number of events in this treatment group was skewed because of a disproportionately high number of bruises reported by one subject
`(19 separate adverse events of contusion).
`
`non-responders was significantly lower in patients treated
`with a prasugrel 40 or 60 mg LD compared with clopidogrel
`300 mg (3 vs. 52%, respectively) and a prasugrel 10 or
`15 mg MD compared with clopidogrel 75 mg (0 vs. 45%,
`respectively).
`Both drugs were well tolerated with a similar incidence
`of bruising and bleeding events in the three lower dose pra-
`sugrel groups and the clopidogrel group. Minor bruising epi-
`sodes were common and were frequently associated with
`the study procedures such as venipuncture. There was a
`modest
`increase in the incidence of minor bleeding
`events in the highest dose prasugrel group. The majority
`of the bleeding events were considered mild to moderate
`in severity and did not result in discontinuation of study
`drug. In this study, there was no observed association
`between the level of IPA on study drug and incidence of
`bleeding.
`In previously published studies, with 20 mM ADP as
`the agonist, mean IPA observed with clopidogrel 300 mg
`LD ranges from 20 to 40%.13,14 In this study, with
`either 5 or 20 mM ADP as the agonist, prasugrel 40 and
`60 mg LD achieved at least a doubling of mean IPA
`compared with a mean IPA of about 30% observed with
`clopidogrel 300 mg LD.
`In recent studies of 600 mg clopidogrel, utilizing 20 mM
`ADP as the agonist, as we employed in the current study,
`IPA levels of 31–32% were reported.15,16 These IPA values
`are all substantially lower than the 64% IPA that we report
`here with the prasugrel 60 mg LD. However, given the lack
`of standardization in the measurement of IPA, determination
`of the relative levels of IPA achieved by the 60 mg prasugrel
`LD and the higher 600 mg clopidogrel LD requires a random-
`ized comparison in a clinical trial (such studies are currently
`ongoing).
`A potentially important observation made in the current
`study is the apparent lower non-responder rate associated
`with prasugrel. Although previous
`studies have used
`empiric definitions of non-responders,6,7,9,17 there is to
`date no consensus on how to define pharmacodynamic non-
`responders to thienopyridine treatment. In the present
`study, a non-responder was defined, using a model-based
`approach, as an individual not achieving 20% IPA to
`
`20 mM ADP by 4 h after an LD or at pre-dose timepoints
`under MD administration. The difference in non-responder
`definition used in this study is a major reason for the
`higher percentage of non-responders with clopidogrel
`300 mg LD (52%) seen in this study compared with previous
`studies (25–30%).6,7
`Using the DMPA criteria for non-responders reported by
`Gurbel et al.6,12
`the percentage of clopidogrel non-
`responders in this study is lower and comparable to the
`literature (20% non-responders with the clopidogrel
`300 mg LD and 30% with the clopidogrel 75 mg MD),
`reflecting the lower threshold of platelet inhibition required
`to be considered a pharmacodynamic
`responder
`to
`clopidogrel with this criteria. Similar to the results obtained
`using the model-based approach in the current study, the
`percentage of non-responders for prasugrel using Gurbel’s
`definition was still only 3% in the prasugrel 40 and 60 mg
`LD groups (and 0, 0, 10, and 20% at the prasugrel MDs of
`15, 10, 7.5, and 5.0 mg, respectively).
`In addition, in contrast to the results reported by Gurbel
`et al.6 suggesting a decrease in clopidogrel non-responders
`over time (from 31% at 5 days to 15% at 30 days), in the
`present study, there was a persistent high level of non-
`responders (45%, Figure 3) to clopidogrel MD even after 28
`days of daily treatment. Although assays for the active
`metabolites of prasugrel and clopidogrel were not available
`at the time of the current study, subsequent studies indicate
`differences in the pharmacokinetic profile of prasugrel are
`consistent with its greater and more consistent pharmaco-
`dynamic response.18,19
`Some studies have suggested that patients with clopido-
`grel resistance have an increased risk of subsequent stent
`thrombosis or other cardiovascular events.7,9,20 There are
`several potential mechanisms behind the high percentage
`of clopidogrel non-responders including variations in the
`absorption of the prodrug and generation and clearance of
`the active metabolite.21 Additional mechanisms for thieno-
`pyridine resistance may include differences in receptor
`expression, differences in post-receptor signalling path-
`ways, and P2Y12 receptor polymorphisms that have been
`demonstrated to contribute to varying degrees of platelet
`aggregation to ADP.22
`
`
`IPR2015-01492
`Panacea Biotec Ltd.
`
`
`
`
`Ex. 1037, p. 6 of 8
`
`
`
`Downloaded from
`
`http://eurheartj.oxfordjournals.org/
`
` at University of Wisconsin-Madison on July 18, 2014
`
`1172
`
`Study limitations
`
`There were several limitations to this study. At present,
`there is no agreed upon standard for defining non-
`responders to platelet inhibition with thienopyridines, thus
`our model-based methodology must be taken in context
`with varying approaches to defining non-responders in the
`literature. In addition, in this short-term study of a small
`population of stable CAD patients, there was only one clini-
`cal endpoint of note (serious adverse event of hospitaliz-
`ation for unstable angina), which makes it difficult to
`gauge the clinical significance of findings regarding higher
`levels of IPA and lower non-responder rates with prasugrel.
`There was variation in the aggregation responses between
`the two sites that participated in the study, possibly due to
`methodological differences or differences in ethnic origins
`of
`the patient population leading to potential CYP
`polymorphisms. However, separate analyses of data from
`each
`site
`still
`support
`the
`higher
`levels
`of
`IPA
`observed with prasugrel 60 mg LD and 10 mg MD over the
`clopidogrel 300 mg LD and 75 mg MD, results consistent
`with subsequent studies and with those reported by other
`investigators.6,7,12
`Furthermore, clopidogrel was dosed in an open-label
`manner; this approach should not have altered IPA responses
`to clopidogrel, but potentially could have impacted
`the reporting of adverse events. Finally, we cannot rule
`out
`the
`possibility
`of
`different
`IPA
`response
`or
`non-responder rates with either prasugrel or clopidogrel in
`an acute treatment situation in contrast to the elective
`setting in this study.
`
`Conclusion
`
`In conclusion, when added to aspirin in patients with
`stable atherosclerotic disease, prasugrel achieves signifi-
`cantly greater IPA with a significantly lower percentage
`of
`pharmacodynamic
`non-responders
`compared with
`clopidogrel. Prasugrel and clopidogrel were well-tolerated
`and the adverse event profiles were comparable. This
`study also helped to characterize the IPA associated
`with LDs and MDs of prasugrel evaluated in the recently
`completed JUMBO TIMI-26 phase 2 trial performed in the
`setting of urgent and elective PCI.11 These combined
`findings support the selection of the prasugrel 60 mg
`LD with a 10 mg MD, currently being evaluated against
`clopidogrel
`in the TRial
`to Assess
`Improvement
`in
`Therapeutic Outcome by Optimizing Platelet InhibitioN
`with Prasugrel (TRITON) TIMI-38 phase 3 clinical trial in
`ACS patients undergoing PCI.
`
`Acknowledgements
`
`The authors would like to acknowledge the writing and administra-
`tive assistance of Barbara Utterback of Eli Lilly and Company, as well
`as the editorial review by Elizabeth Agostinelli in the preparation of
`this manuscript. The work was performed at Quintiles AB Phase I
`Services, Uppsala, Sweden; Quintiles Phase I Services, Lenexa, KS;
`Lilly Research Centre Ltd., Windlesham, Surrey, UK; and Eli Lilly
`and Company, Indianapolis, IN, USA.
`
`Conflict of interest: none declared.
`
`T. Jernberg et al.
`
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