prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned...

ISSN: 1524-4539 Copyright © 2007 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online

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DOI: 10.1161/CIRCULATIONAHA.107.740324 2007;116;2923-2932; originally published online Dec 3, 2007; Circulation

PRINCIPLE-TIMI 44 Investigators A. Murphy, Carolyn H. McCabe, Elliott M. Antman, Eugene Braunwald and for the Gilles Montalescot, Debra L. Miller, Joseph A. Jakubowski, Richard Cairns, Sabina

Franz-Josef Neumann, Alan D. Michelson, Dominick J. Angiolillo, Hanoch Hod, Stephen D. Wiviott, Dietmar Trenk, Andrew L. Frelinger, Michelle O’Donoghue,

Aggregation�Thrombolysis in Myocardial Infarction 44 TrialComparison to Clopidogrel for Inhibition of Platelet Activation and

Patients With Planned Percutaneous Coronary Intervention: The Prasugrel in Prasugrel Compared With High Loading- and Maintenance-Dose Clopidogrel in

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Prasugrel Compared With High Loading- andMaintenance-Dose Clopidogrel in Patients WithPlanned Percutaneous Coronary Intervention

The Prasugrel in Comparison to Clopidogrel for Inhibition of PlateletActivation and Aggregation–Thrombolysis in Myocardial Infarction 44 Trial

Stephen D. Wiviott, MD; Dietmar Trenk, PhD; Andrew L. Frelinger, PhD; Michelle O’Donoghue, MD;Franz-Josef Neumann, MD; Alan D. Michelson, MD; Dominick J. Angiolillo, MD, PhD;

Hanoch Hod, MD; Gilles Montalescot, MD, PhD; Debra L. Miller, RN, RCIS;Joseph A. Jakubowski, PhD; Richard Cairns, MSc; Sabina A. Murphy, MPH;Carolyn H. McCabe, BS; Elliott M. Antman, MD; Eugene Braunwald, MD;

for the PRINCIPLE-TIMI 44 Investigators

Background—The increasing use of higher-than-approved doses of clopidogrel in clinical practice is based in part on the desirefor greater levels of inhibition of platelet aggregation (IPA). Prasugrel is a new thienopyridine that is more potent thanstandard-dose clopidogrel in healthy subjects and patients with stable coronary artery disease. The relative antiplatelet effectsof prasugrel versus high-dose clopidogrel in percutaneous coronary intervention patients are unknown.

Methods and Results—Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation–Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) was a randomized, double-blind, 2-phase crossoverstudy of prasugrel compared with high-dose clopidogrel in patients undergoing cardiac catheterization for plannedpercutaneous coronary intervention. The primary end point of the loading-dose phase (prasugrel 60 mg versusclopidogrel 600 mg) was IPA with 20 �mol/L ADP at 6 hours. Patients with percutaneous coronary intervention enteredthe maintenance-dose phase, a 28-day crossover comparison of prasugrel 10 mg/d versus clopidogrel 150 mg/d with aprimary end point of IPA after 14 days of either drug. In this study, 201 subjects were randomized. IPA at 6 hours wassignificantly higher in subjects receiving prasugrel (mean�SD, 74.8�13.0%) compared with clopidogrel (31.8�21.1%;P�0.0001). During the maintenance-dose phase, IPA with 20 �mol/L ADP was higher in subjects receiving prasugrel(61.3�17.8%) compared with clopidogrel (46.1�21.3%; P�0.0001). Results were consistent across all key secondaryend points; significant differences emerged by 30 minutes and persisted across all time points.

Conclusions—Among patients undergoing cardiac catheterization with planned percutaneous coronary intervention, loadingwith 60 mg prasugrel resulted in greater platelet inhibition than a 600-mg clopidogrel loading dose. Maintenance therapy withprasugrel 10 mg/d resulted in a greater antiplatelet effect than 150 mg/d clopidogrel. (Circulation. 2007;116:2923-2932.)

Key Words: anticoagulants � antiplatelet agents � coronary disease � platelets � thrombosis

Pharmacological inhibition of platelets with a combinationof aspirin and a thienopyridine is a key strategy for the

prevention of recurrent ischemic events in patients with acutecoronary syndromes and those undergoing percutaneous cor-

onary intervention (PCI).1–4 Despite important clinical bene-fits of clopidogrel, significant limitations exist.5 Clopidogrelat approved doses has a delayed antiplatelet effect, requiringa substantial period of pretreatment to achieve the desired

Received September 14, 2007; accepted October 17, 2007.From the TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Mass (S.D.W., S.A.M., C.H.M., E.M.A., E.B.);

Cardiovascular Division, Massachusetts General Hospital, Boston (M.O.); Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany (D.T., F.-J.N.);Center for Platelet Function Studies, Departments of Pediatrics, Medicine and Pathology, University of Massachusetts Medical School, Worcester (A.L.F.,A.D.M.); University of Florida, College of Medicine, Jacksonville (D.J.A.); The Heart Institute, Sheba Medical Center, Tel Hashomer, Sackler Facultyof Medicine, Tel Aviv, Israel (H.H.); Institut de Cardiologie and INSERM Unit 856, Petie-Salpetriere University Hospital, Paris, France (G.M.); LillyResearch Laboratories, Eli Lilly and Co, Indianapolis, Ind (D.L.M., J.A.J.); and Nottingham Clinical Research Ltd, Nottingham, UK (R.C.).

The online Data Supplement, which contains an Appendix listing the participants in Prasugrel in Comparison to Clopidogrel for Inhibitionof Platelet Activation and Aggregation–Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) can be found with this article athttp://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.740324/DC1.

Guest Editor for this article was James E. Udelson, MD.Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00357968.Correspondence to Stephen D. Wiviott, MD, Brigham and Women’s Hospital, Cardiovascular Division, 75 Francis St, Boston, MA 02115. E-mail

[email protected]© 2007 American Heart Association, Inc.

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.107.740324

2923

Coronary Heart Disease



clinical effect.6 In addition, clopidogrel at approved dosesachieves a modest antiplatelet effect by laboratory testing,and although no standard definition exists, studies estimatethat up to one third of patients have poor antiplateletresponses (or “resistance”) to clopidogrel.7–9

Clinical Perspective p 2932Studies of higher loading doses (LDs) and maintenance

doses (MDs) of clopidogrel have reported small but statisti-cally significant improvements in the speed of onset, inten-sity, and consistency of inhibition.10–16 Although there arelimited prospective data to support clinical superiority,17,18

many clinicians use higher doses of clopidogrel in clinicalpractice, and recent guidelines support this practice in se-lected patients.4,19

Prasugrel is a third-generation thienopyridine. Both pra-sugrel and clopidogrel require cytochrome-dependent metab-olism for activity; however, prasugrel is more efficient with asingle-step rather than a multiple-step process for activa-tion.20,21 Studies in healthy volunteers and patients withchronic coronary artery disease have shown that prasugrel ismore potent, more rapid in onset, and more consistent ininhibiting platelet aggregation than standard doses of clopi-dogrel.22–24 Because of the frequent use of higher-than-approved LD clopidogrel in clinical practice and the potentialfuture use of higher-MD clopidogrel, we designed the presentstudy to compare prasugrel with higher than the currentlyapproved 300-mg LD and 75-mg/d MD of clopidogrel.

MethodsPatient PopulationSubjects were eligible for enrollment if they were at least 18 years ofage and were scheduled to undergo cardiac catheterization withplanned PCI for angina and at least one of the following: coronaryangiography within 14 days with at least 1 lesion amenable to PCI,a functional study within 8 weeks with objective findings ofischemia, or prior PCI or coronary artery bypass graft surgery. Keyexclusions included planned PCI for immediate treatment of myo-cardial infarction, any thienopyridine within 5 days, glycoprotein(GP) IIb/IIIa inhibitor within 7 days or planned use (bailout waspermitted), high risk of bleeding, thrombocytopenia, or anemia.

All subjects provided written informed consent before participa-tion. A sample size of 96 evaluable subjects with PCI was expectedto yield 90% power to demonstrate a 15% absolute difference ininhibition of platelet aggregation (IPA) with 20 �mol/L ADP at 6hours, assuming ��0.05 and intersubject variability of 25% forclopidogrel and 15% for prasugrel. We estimated that it would benecessary to enroll 180 subjects to obtain 110 subjects with PCI with96 evaluable at 6 hours.

Study ProtocolPrasugrel in Comparison to Clopidogrel for Inhibition of PlateletActivation and Aggregation–Thrombolysis in Myocardial Infarc-tion 44 (PRINCIPLE-TIMI 44) was a multicenter, randomized,double-blind, double-dummy, active comparator– controlled,2-phase trial that included a crossover design (Figure 1). Theprotocol was approved by the institutional review boards at allparticipating centers. Subjects were randomized to treatment withclopidogrel 600-mg or prasugrel 60-mg LD. After randomizationand before receiving study drug, all subjects were to have bloodobtained for baseline platelet measures, including light-transmission aggregometry (LTA) and vasodilator-stimulatedphosphoprotein (VASP). VASP is an intracellular protein with aphosphorylation state dependent on ADP P2Y12 signaling. The LD

of the blinded study drug was given as a pretreatment �1 hour (noless than 30 minutes) before the time that cardiac catheterizationwas expected to begin. Subjects were then to undergo PCI ifcoronary anatomy was suitable. After PCI, subjects were toreceive a once-daily MD for 14�2 days of either prasugrel 10 mgor clopidogrel 150 mg corresponding to the LD assignment. A15�2-day visit was performed for collection of end points, safetyinformation, platelet measures, and crossover directly to thealternate maintenance therapy for an additional 14�2 dayswithout an intervening washout period. A 29�4-day follow-upvisit was performed with assessment of clinical end points, safetyinformation, and platelet measures. For treated subjects withoutPCI, a telephone call at day 15 was performed to assess clinicalevents.

Platelet measures included LTA and the VerifyNow P2Y12 assay(Accumetrics, San Diego, Calif) and VASP. For all subjects,measures were performed at 30�5 minutes (except VASP), at 2hours (�10 minutes), or after completion of the diagnostic angio-gram, whichever occurred sooner (except VerifyNow), and 6hours(�30 minutes) after the LD. For PCI subjects only, plateletmeasures were performed at 18 to 24 hours, the 15-day visit, and the29-day visit (except VerifyNow). An independent physician moni-tored bleeding and adverse event data.

Laboratory ProceduresBefore study participation, study participants were trained by corelaboratory personnel to ensure consistent LTA protocols amongsites, and local tracings were reviewed for quality before the firstsubject was randomized at each site. Blood was drawn fromvenipuncture or indwelling catheters. The first 5 mL was to bediscarded. For LTA, blood was drawn into a 4.5-mL, 3.2% citrateVacutainer tube and centrifuged to prepare platelet-rich plasma andplatelet-poor plasma. ADP aliquots were prepared centrally andshipped to investigative sites. LTA was determined with 20 �mol/LADP and 5 �mol/L ADP separately.25 Maximal platelet aggregation(MPA) and final platelet aggregation (FPA) were determined byblinded laboratory personnel. IPA at time t is defined as follows:{1�[(MPA at time t after LD)/(MPA at baseline)]}�100. IPA (final)at time t is defined as follows: {1�[(FPA at time t after LD)/(FPAat baseline)]}�100. Evidence of hemolysis, platelet count of theplatelet-rich plasma, and procedural irregularities were reported. Alltracings were read locally and overread by a single reader blinded totreatment assignment at a central core laboratory (Center for PlateletFunction Studies, University of Massachusetts, Worcester). Centralreadings were used for all analyses.

For the VerifyNow P2Y12 assay, blood was drawn into a GreinerBio-One 3.2% citrate vacuette tube. Samples were run locallyaccording to the device package insert between 30 minutes and 4hours after sampling. Percent inhibition was reported and corre-sponded to 100�(P2Y12 reaction units)/[thrombin receptor activat-ing peptide–stimulated aggregation (base)]. For VASP assays, sam-

N = approx 110

Loading Dose Phase

Maintenance Dose Phase

No PCI

6h* Labs, 15d Events

Coronary AngiographyPost-Angiography Labs

Planned Elective PCIBaseline Laboratory Measures

Prasugrel60 mg

Clopidogrel600 mg

0.5 h Post Loading Dose Labs

PCI

6h*, 18-24h Labs

Clopidogrel150 mg x 14d

Prasugrel10 mg x 14d

Prasugrel10 mg x 14d

Clopidogrel150 mg x 14d 15d Clinical Events,

Labs#, CROSSOVER

29d Clinical Events, Labs#

Clopidogrel NaÔve

No planned GP IIb/IIIa use

EPs: *Loading = 6h IPA (20 µM ADP), # Maintenance = 14d & 29d IPA (20 µM ADP)

Figure 1. Schematic of trial design of PRINCIPLE-TIMI 44.

2924 Circulation December 18/25, 2007



ples were drawn into a citrated tube, capped, stored, and shipped atambient temperature to 1 of 2 core labs (University of Massachu-setts, Worcester, for US sites and Herz-Zentrum, Bad Krozingen,Germany, for European and Israeli sites). VASP phosphorylation inresponse to prostaglandin E1 with and without ADP was determinedby whole-blood flow cytometry as described in the manufacturer’sbrochure (BioCytex, Marseilles, France) using a single lot offluorescently labeled monoclonal antibody. Flow cytometers werecalibrated daily with a single standardization protocol (and a singlelot of calibration particles) at both core laboratories. VASP phos-phorylation data were expressed as platelet reactivity index (inpercent) defined as [(MFI(PGE1)�MFI(PGE1�ADP))/MFI(PGE1)]�100],where MFI is mean fluorescence index and PGE1 is prostaglandinE1. A lower platelet reactivity index indicates greater antiplateleteffect.

Each determination was assessed for validity by the blinded corelaboratory personnel using standardized criteria for each assay type.Conditions that invalidated LTA samples included but were notlimited to hemolysis, very low platelet-rich plasma platelet counts(�150 000/�L), and instability of baseline in LTA tracings indicat-ing instability of sample temperature or preagonist sample activation.Samples considered to be invalid were not included in the analyses,and subjects were considered to be nonevaluable for the givenmeasure and time point. For IPA analyses, for a subject to beevaluable at time t, both a valid baseline measurement and time tMPA measurement were required. For MPA, VerifyNow, and VASPanalyses, a subject would be evaluable at time t with a validmeasurement at time t regardless of baseline measures.

End Points

PharmacodynamicAll end points were prespecified in the study protocol and statisticalanalysis plan. The primary efficacy end point of the loading phasewas IPA with 20 �mol/L ADP at 6 hours in subjects who receivedan LD and did not receive a GP IIb/IIIa inhibitor, regardless of PCIstatus. The primary efficacy measure of the MD phase was IPA with20 �mol/L ADP determined after 14�2 days of prasugrel comparedwith 14�2 days of high-dose clopidogrel, including both precross-over and postcrossover periods during the MD phase. Thienopyri-dine hyporesponsiveness was defined as IPA with 20 �mol/L ADP�20% based on previous work.22 Key secondary end points for theLD and MD phases were mean MPA with 20 �mol/L ADP and meanVerifyNow percent inhibition. An MPA �50% on therapy wasconsidered another key prespecified measure of poor response toantiplatelet therapy.3,15 Additional efficacy measures include pri-mary and key secondary measures at 30 minutes, 2 hours, and 18 to24 hours; IPA with 5 �mol/L ADP; and IPA (final).

ClinicalThe primary safety measure was non–coronary artery bypass graftsurgery–related TIMI major or minor bleeding in the treated subjectsthrough the 15-day visit. Bleeding events were adjudicated by anindependent clinical events committee if there was a hemoglobindecrease of �3 g/dL or if bleeding required medical or surgicaltherapy or specific laboratory evaluation according to previouslypublished definitions.26 Bleeding events reported by investigatorsregardless of clinical events committee adjudication were consideredadverse hemorrhagic events. The key clinical efficacy end point wasclinical events committee–adjudicated major adverse cardiac events,including cardiovascular death, myocardial infarction, and strokeoccurring during the combined LD and precrossover MD phase.

Statistical Analysis

Treatment PopulationsThe LD-phase analysis population consisted of subjects who re-ceived the LD of the study drug and did not receive a GP IIb/IIIainhibitor. This population was used for all analyses of plateletfunction measures within 24 hours after the LD, although onlysubjects with PCI had 18- to 24-hour measures. The MD-phaseanalysis population consisted of subjects who received a PCI

regardless of whether they received a GP IIb/IIIa inhibitor. Thispopulation was used for all analyses of platelet function measures�24 hours after the LD. In every instance, the analyses consideredonly subjects with evaluable measurements available for a given timepoint.

General ConsiderationsAll tests were 2 sided and conducted at an ��0.05 level ofsignificance. All CIs presented were 2-sided 95% CIs. Standard2-sample comparisons between treatment groups were carried outusing the following methods unless otherwise specified. Categoricaldata were compared by use of Pearson’s �2 test, except when theabsolute number of events in each group was �10, in which caseFisher’s exact test was used. Continuous data were compared with a2-sample t test. The analyses were performed by the Department ofStatistics at Nottingham Clinical Research Ltd (Nottingham, UK)using SAS version 9.1 or S-PLUS 6.2 (SAS Institute Inc, Cary, NC).The TIMI Study Group had full access to raw trial databases, and allkey analyses were independently verified.

Study MeasuresMeans and SDs are used to describe the platelet function measures(IPA, MPA, VASP, and VerifyNow P2Y12 measurements). Theprimary analysis for LD-phase platelet function measures wasassessed by the difference between the treatment groups and ana-lyzed with an ANCOVA model with factors for treatment and studysite and a single covariate for MPA at baseline. This is expressed asadjusted least square (LS) mean difference between treatment armswith 95% CIs or probability value.

The MD-phase primary efficacy measure was analyzed via ahierarchical ANCOVA (or mixed-effects) model with factors fortreatment, study site, study phase, treatment order (“carryover”), andsubject within treatment order as a random effect and a covariate forMPA value at baseline. For IPA measures, data were included forsubjects with evaluable maximal MPA measurements taken beforetreatment and after 14�2 days of treatment with either of the studymedications (ie, precrossover and/or postcrossover visit measure-ments). The rates of hyporesponsiveness during the MD phase wereanalyzed with an exact Prescott test for subjects with both day 15 and29 data available. Key secondary and additional platelet functionanalyses were performed in the same manner as the primaryanalyses.

Clinical MeasuresMajor adverse cardiac events were evaluated in the on-treatmentpopulation during the loading and precrossover maintenance period(from LD to 15-day visit). The frequency of major adverse cardiacevents was summarized by treatment group and study period amongall subjects who were treated with the study medication and receivedPCI. The primary safety measure, non–coronary artery bypass graftsurgery–related TIMI significant bleeding, was compared in theon-treatment precrossover group (through the 15-day visit) using anexact logistic regression model, and the incidence of all bleedingevents (TIMI major or minor bleeds and other hemorrhagic nonse-rious adverse events) was summarized similarly. Events occurringafter crossover are reported in a descriptive manner only.

The authors had full access to and take responsibility for theintegrity of the data. All authors have read and agree with themanuscript as written.

ResultsThere were 201 subjects randomized at 14 investigative sitesin 4 countries (see the Appendix in the Data Supplement).Baseline features of the randomized subjects were wellmatched (Table 1). Pretreatment platelet aggregation wassimilar with mean MPA with 20 �mol/L ADP in theprasugrel group (mean�SD, 75.7�11.8%) compared withthe clopidogrel group (77.0�9.7%; P�0.43). Four subjectsreceived a GP IIb/IIIa inhibitor at the time of PCI and were

Wiviott et al Prasugrel Versus High-Dose Clopidogrel 2925



excluded from LD-phase analyses, which therefore included197 subjects (99 prasugrel, 98 clopidogrel). Across all timepoints, 149 of 1134 potential samples were considered invalidfor MPA with 20 �mol/L ADP measurement (13.1%), withthe major reasons being hemolysis (n�74), platelet-richplasma platelet count �150 000/�L (n�22), insufficientsample (n�12), or unstable baseline (n�12). There were nostatistically significant differences in the number of evaluablesubjects by treatment or differences in baseline characteristicsof evaluable compared with nonevaluable subjects or be-tween nonevaluable subjects compared by treatment group.The flow of subjects through the trial and the numberevaluable for the key efficacy measures are summarized inFigure 2.

LD-Phase End PointsThe primary efficacy end point of IPA with 20 �mol/L ADPat 6 hours after LD was significantly greater after prasugrel60 mg (mean, 74.8�13.0%) compared with clopidogrel 600mg (31.8�21.1%), with an LS mean difference of 43.2%(95% CI, 38.0 to 48.4; P�0.0001). In addition to a greaterantiplatelet effect (higher mean IPA), subjects treated withprasugrel had more consistent levels of inhibition, with lowerintersubject variability (F-test probability value comparingstandard deviations �0.0001). The greater antiplatelet effectof the prasugrel LD measured by IPA with 20 �mol/L ADPwas apparent after 30 minutes (30.8�29.0% versus4.9�13.2%; P�0.0001) and maintained through 18 to 24hours (Figure 3A). Fewer prasugrel-treated subjects metpredefined criteria for hyporesponsiveness (Table 2).

Prasugrel also showed greater antiplatelet effect as as-sessed by the key secondary end points with lower levels ofMPA with 20 �mol/L ADP (18.9�9.5% versus52.1�16.1%), LS mean difference of 33.1% (95% CI, 29.2 to37.1; P�0.0001), and greater platelet inhibition with theVerifyNow P2Y12 assay (89.5�10.5% versus 38.4�26.1%),LS mean difference of 51.4% (95% CI 45.5 to 57.4),P�0.0001), at 6 hours. Overall, consistent differences be-tween the treatment groups were seen across multiple plateletinhibition measures and time points, including IPA with 5 or20 �mol/L ADP, MPA with 5 or 20 �mol/L ADP, and IPA(final) with 5 or 20 �mol/L ADP (Table 3). Greater inhibitionof ADP signaling as measured by VASP also was demon-strated at each time point (Figure 3B).

MD-Phase End PointsThe primary efficacy end point of IPA with 20 �mol/L ADPafter 14�2 days of MD therapy (ie, day 15 and 29 datacombined) was significantly greater in subjects receivingprasugrel 10 mg/d (mean 61.3�17.8%) compared with clo-pidogrel 150 mg/d (46.1�21.3%), with an LS mean differ-ence of 14.9% (95% CI, 10.6 to 19.3; P�0.0001). Similarresults with highly significant differences between groupswere seen for IPA with 20 �mol/L ADP at day 14 and 29visits (Figure 4A). Prasugrel demonstrated a greater antiplate-

Table 1. Baseline Characteristics

Prasugrel (n�102) Clopidogrel (n�99)

Female, % 28.4 22.2

Age, mean (25%–75%), y 64 (56–71) 63.8 (57–70)

Age �65 y, % 54.9 52.5

BMI, mean, kg/m2 28.7 29.4

Prior MI, % 30.4 28.3

HTN, % 85.3 77.8

Prior CABG, % 16.7 22.2

Dyslipidemia, % 90.2 86.9

DM, % 32.4 29.3

Smoker (current), % 17.6 16.2

Angina, CCS III or IV, % 37.3 38.4

Prior aspirin, % 88.2 86.9

�-Blocker, % 80.4 79.8

Statin, % 89.2 89.9

PCI for index event, % 53.9 57.6

BMI indicates body mass index; MI, myocardial infarction; HTN, hypertension;CABG, coronary artery bypass grafting surgery; DM, diabetes mellitus; CCS,Canadian Cardiovascular Society; statin, hydroxymethyl glutaryl coenzyme Areductase inhibitor; and PCI, percutaneous coronary intervention. P�NS for allcomparisons.

Randomized (201)

Prasugrel LD (102)Evaluable MPA = 84

Clopidogrel LD (99) Evaluable MPA = 84

PCI(55)GP IIb/IIIa =3

Evaluable 6 H MPA = 37Evaluable 6 H IPA = 37

No PCI (47)Evaluable 6 H MPA = 35Evaluable 6 H IPA = 35

PCI (57)GP IIb/IIIa =1

Evaluable 6 H MPA = 47Evaluable 6H IPA = 47

No PCI (42)Evaluable 6 H MPA = 30Evaluable 6H IPA = 30

Prasugrel MD (55)Evaluable 15 D MPA = 40Evaluable 15 D IPA = 40

Clopidogrel MD (55)Evaluable 15 D MPA = 47Evaluable 15 D IPA = 46

W/D Consent (2)

Clopidogrel MD (53)Evaluable 29 D MPA = 40Evaluable 29 D !PA = 40

Prasugrel MD (55)Evaluable 29 D MPA = 46Evaluable 29 D IPA = 45

W/D Consent (1)D/C Study Drug(1)

Figure 2. Subject disposition. Listedin each box is the number of subjects evalu-able for a given measure at a given timepoint. W/D indicates withdrawal; D/C,discontinuation.




let effect with lower MPA (29.2�13.2% versus40.9�15.9%), LS mean difference of 11.3% (95% CI, 8.1 to14.5; P�0.0001). Greater platelet inhibition with theVerifyNow P2Y12 assay (83.3�16.0% versus65.1�23.1%), LS mean difference of 18.9% (95% CI, 11.7to 26.1; P�0.0001), also was seen at 15 days. Consistentdifferences between treatment groups were seen across

multiple measures of platelet aggregation and time points,including IPA with 5 or 20 �mol/L ADP, MPA with 5 or20 �mol/L ADP, and IPA (final) with 20 �mol/L ADP(Table 4). In addition, more inhibition of ADP signalingwas demonstrated with a lower VASP platelet reactivityindex (Figure 4B). Despite the lack of washout period, nocarryover effect was seen.

Table 2. Prevalence of Thienopyridine Hyporesponsiveness

Time Point

IPA With 20 �mol/L ADP �20% MPA to 20 �mol/L ADP �50%

n Prasugrel, % Clopidogrel, % P n Prasugrel, % Clopidogrel, % P

At 0.5 h 143 42.9 87.7 �0.0001 144 50 98.6 �0.0001

At 2 h or aftercatheterization

152 2.7 55.1 �0.0001 153 8.1 79.7 �0.0001

At 6 h 149 0 27.3 �0.0001 149 0 49.4 �0.0001

At 18–24 h 85 0 30.4 0.0002 86 0 51.1 �0.0001

Precrossover MD 86 2.5 15.2 0.06 87 7.5 21.3 0.07

Postcrossover MD 85 2.2 10 0.18 86 8.7 25.0 0.04

MD phase 171 2.4 12.8 0.02 173 8.1 23.0 0.007

Precrossover indicates 15-day visit only; postcrossover, 29-day visit only; and MD phase, measures from 15- or 29-day visits.

0.5 H 2 H 6H 18 - 24H

Prasugrel N = 70 N = 74 N = 72 N = 39

Clopidogrel N = 73 N = 78 N = 77 N = 46

LSM Difference (95% CI)

26.0 (18.9 –33.2)

44.8 (38.4 –51.2)

43.2 (38.0 – 48.4)

36.4 (29.0 – 43.8)

Prasugrel 60 mg

***P<0.0001

***

***

Hours

IPA

(20

µM

AD

P, %

)

Prasugrel 60 mg

***P<0.0001***

***

Baseline 2 H 6H 18 - 24H

Prasugrel N = 89 N = 93 N = 68 N = 48

Clopidogrel N = 89 N = 88 N = 68 N = 54


54.3(47.4 –61.2)

60.5(54.0 – 67.1)

56.2 (49.2 – 63.2)

VA

SP

PR

I (%

)

Hours

A

B

Figure 3. LD-phase platelet function measures. A,IPA with 20 �mol/L ADP. B, VASP platelet reactiv-ity index (PRI). Data are mean�SD. The primaryend point of the LD phase is the 6-hour compari-son. Blue circles and lines indicate prasugrel mea-surements and treatment periods; green trianglesand lines, clopidogrel measurements and treat-ment periods. LSM indicates LS mean.




Clinical End PointsBoth treatments were well tolerated. No TIMI major bleedswere observed in either treatment arm during the studyperiod. No subject discontinued study drug prematurely forbleeding. Two subjects (2.0%) in the prasugrel group and noclopidogrel-treated subject experienced a TIMI minor bleed-ing episode before the crossover. There were no TIMI majoror minor bleeding events reported after the LD phase (day 2to 29) in either treatment group. When all investigator-reported hemorrhagic adverse events (regardless of whetherevents met TIMI major or minor hemorrhage criteria) wereincluded, a total of 19 subjects (18.6%) in the prasugrel groupexperienced a bleeding event compared with 14 subjects(14.1%) in the clopidogrel group during the LD and precross-over MD period (P�NS). After crossover, 4 subjects in theclopidogrel followed by prasugrel group and no subject in theprasugrel followed by clopidogrel group experienced a hem-orrhagic adverse event.

Major adverse cardiac events end points also were infre-quent. One subject in the clopidogrel group had acute stentthrombosis resulting in a myocardial infarction and requiredurgent target vessel revascularization, and 2 subjects in theprasugrel group had periprocedural myocardial infarctions.One subject in the prasugrel followed by clopidogrel groupexperienced a myocardial infarction after the crossover. Nodeaths or strokes occurred in either treatment group.

DiscussionIn this trial, we compared the effects of a prasugrel 60-mg LDand 10-mg/d MD with high-dose clopidogrel (600-mg LDand 150-mg/d MD) on laboratory measures of platelet func-tion. We observed substantially and statistically significantlygreater platelet inhibition with prasugrel at all time points

studied during the LD and MD phases. In the LD phase,pretreatment with prasugrel 60 mg before cardiac catheter-ization in subjects with presumed coronary artery diseaseshowed substantially greater levels of IPA than 600 mg ofclopidogrel when measured by LTA (using 2 agonist concen-trations and multiple metrics: IPA, IPA [final], and MPA),VerifyNow P2Y12, and VASP platelet reactivity index.Highly significant differences emerged at 30 minutes, thetime of the first assessment, and were present at every timepoint measured throughout the LD phase. Prasugrel alsoexhibited more rapid onset of antiplatelet effects, and fewersubjects treated with prasugrel had poor response measuredwith IPA and MPA at each time point.

Published data comparing prasugrel with the standardapproved LD of clopidogrel (300 mg) in healthy subjects andpatients with chronic coronary artery disease not undergoingcardiac catheterization or PCI22,23 showed higher levels ofIPA and less variability. The data from PRINCIPLE-TIMI 44extend the results of preliminary reports of the comparison of60 mg prasugrel with 600 mg clopidogrel observed in healthysubjects27 and patients with chronic coronary artery disease.28

Our findings indicate that prasugrel is more potent andconsistent in the setting of procedures such as vascular accessand PCI and that prasugrel can be expected to achieve rapid,high, and consistent levels of inhibition of ADP-inducedplatelet aggregation in this clinical setting.

Several studies have shown increased inhibition, fasteronset, and fewer poor responders with 600-mg clopidogrelcompared with 300-mg LDs.10,11,29 As a result, testing of evenhigher LDs of clopidogrel has been undertaken to try toimprove further on these parameters. In both the Assessmentof the Best Loading Dose of Clopidogrel to Blunt PlateletActivation, Inflammation and Ongoing Necrosis (ALBION)

Table 3. LD-Phase Platelet Function Measures

Time n Prasugrel Clopidogrel P LS Mean Difference (95% CI)

MPA to 20 �mol/L ADP, %

At 0.5 h 144 52.4�21.7 72.5�10.0 �0.0001 20.3 (14.8–25.7)

At 2 h or after catheterization 153 26.8�15.4 60.7�14.5 �0.0001 34.0 (29.2–38.7)

At 6 h 149 18.9�9.5 52.1�16.1 �0.0001 33.1 (29.2–37.1)

At 18–24 h 86 23.2�10.2 51.1�14.4 �0.0001 27.4 (21.9–32.9 )

VerifyNow P2Y12, %

At 0.5 h 165 45.6�34.7 11.0�8.5 �0.0001 34.6 (26.7–42.5)

At 6 h 173 89.5�10.5 38.4�26.1 �0.0001 51.4 (45.5–57.4)

LTA IPA with 5 �mol/L ADP, %

At 0.5 h 140 34.7�28.2 4.3�18.1 �0.0001 29.7 (22.1–37.3)


At 6 h 147 76.2�13.1 36.8�23.2 �0.0001 39.4 (33.5–45.3)

At 18–24 h 87 71.0�12.6 34.5�21.9 �0.0001 36.4 (28.7–44.1)

LTA IPA (final) with 20 �mol/L ADP (%)

At 0.5 h 143 47.7�41.8 5.0�21.3 �0.0001 42.1 (31.4–52.7)


At 6 h 149 97.0�5.4 52.1�30.3 �0.0001 45.1 (38.3–51.8)

At 18–24 h 85 94.4�9.5 53.5�28.7 �0.0001 40.7 (31.6–49.9)

n indicates number of subjects with evaluable measure. Values for prasugrel and clopidogrel are mean�SD. The prespecified primary point of IPAwith 20 �mol/L ADP is shown in Figure 3.




study and the Intracoronary Stenting and AntithromboticRegimen: Choose Between 3 High Oral Doses for ImmediateClopidogrel Effect (ISAR-CHOICE) study, clopidogrel 600and 900 mg showed greater inhibition than 300 mg.13,14 Anincremental benefit from 600 to 900 mg was observed inALBION. In ISAR-CHOICE, platelet aggregation and bloodlevels of clopidogrel and its active metabolite were similarafter 600-and 900-mg doses, suggesting that there may besaturable absorption and/or metabolism. Human and animalstudies have demonstrated that the active metabolites ofprasugrel and clopidogrel have similar potency at the plateletlevel.30 The greater potency of prasugrel compared withstandard clopidogrel has been confirmed to be related to moreefficient generation of the active metabolite.22,30

In the MD phase of our study, a 10-mg/d dose of prasugrelwas compared with 150 mg/d clopidogrel with a crossoverdesign among the subjects who underwent PCI. Highlystatistically significant differences were seen, with prasugreltreatment resulting in greater levels of platelet inhibition, afinding consistent across multiple LTA measurements, withthe VerifyNow P2Y12, and with VASP. These findingsextend previous comparisons of 10 mg prasugrel with 75 mgclopidogrel.23,31

At least 2 published studies have compared high-MDclopidogrel (150 mg/d) with standard-dose (75 mg/d) clopi-dogrel. In the Optimizing Antiplatelet Therapy in DiabetesMellitus (OPTIMUS) study, diabetic subjects with residualMPA �50% were randomized to continue therapy with 75mg clopidogrel or to transition to 150 mg clopidogrel daily.15

The ISAR-CHOICE 2 study randomized 60 patients aftersuccessful PCI to 150 or 75 mg/d clopidogrel.16 Both showedgreater platelet inhibition with 150 compared with 75 mg/dbut also the persistence of variability of response and thepresence of poor responders. No clinical outcomes data withhigh- compared with standard-MD clopidogrel are available.Findings of an improved pharmacological profile have led

some to speculate that higher-MD clopidogrel may result inimproved clinical outcomes, although few have adopted thisinto clinical practice at this time.3

PRINCIPLE-TIMI 44 is the first study to compare prasug-rel with high-MD clopidogrel in any patient population. Theresults of our study extend the observation regarding thepharmacological superiority of a MD of prasugrel 10 mg/d toa higher-than-standard dose of clopidogrel (150 mg/d) withgreater levels of inhibition and fewer patients with poorresponse. Furthermore, this study suggests that even if a150-mg/d MD of clopidogrel is adopted in the future, greaterinhibition of platelet function would be achieved with pra-sugrel 10 mg/d.

As would be expected from greater platelet inhibition data,rates of hemorrhagic events tended to be higher, although notstatistically different, in the prasugrel-treated subjects. Ifthese trends toward more bleeding events are confirmed inlarger trials, it will be important to assess the balance amongefficacy, safety, and tolerability with prasugrel. The presentstudy was not powered to detect clinical efficacy differencesbetween the 2 treatment groups, and there were too few majoradverse cardiovascular events in the present study to drawany meaningful conclusions in this regard.

A growing body of literature links poor antiplatelet re-sponse to clopidogrel to adverse clinical outcomes, includingrecurrent ischemic events, periprocedural myocardial infarc-tion, and stent thrombosis.32–37 Although these data establishan association between aggregation and ischemic events, itremains uncertain whether this is merely a marker of risk ora modifiable risk factor.36 The Antiplatelet Therapy forReduction of Myocardial Damage During Angioplasty(ARMYDA)-2 study comparing 600 versus 300 mg clopi-dogrel before PCI showed lower rates of periprocedural MIwith the higher dose.17 The Trial to Assess Improvement inTherapeutic Outcomes by Optimizing Platelet InhibitionWith Prasugrel Thrombolysis in Myocardial Infarction 38

Table 4. MD-Phase Platelet Function Measures

Time n Prasugrel Clopidogrel P LS Mean Difference (95% CI)

MPA with 20 �mol/L ADP, %

Precrossover MD 87 28.5�12.9 41.5�14.1 0.0004 12.1 (7.4–16.8)

Postcrossover MD 86 29.7�13.6 40.2�17.9 �0.0001 11.0 (5.1–16.9)

MD Phase 173 29.2�13.2 40.9�15.9 �0.0001 11.3 (8.1–14.5)

VerifyNow P2Y12, %

Precrossover MD 103 83.3�16.0 65.1�23.1 �0.0001 18.9 (11.7–26.1)

IPA to 5 �mol/L ADP, %

Precrossover MD 87 63.3�17.6 48.5�19.1 0.0006 12.9 (5.7–20.0)

Postcrossover MD 86 62.9�16.4 52.2�20.3 0.002 12.1 (4.6–19.6)

MD phase 173 63.1�16.9 50.2�19.6 �0.0001 12.8 (8.9–16.7)

IPA (final) with 20 �mol/L ADP, %

Precrossover MD 86 88.3�16.3 73.1�26.4 0.001 14.0 (5.9–22.1)

Postcrossover MD 85 88.2�20.7 72.6�26.7 0.0008 16.8 (7.2–26.4)

MD phase 171 88.2�18.6 72.9�26.3 �0.0001 14.5 (9.1–20.0)

n indicates number of subjects with evaluable measure; precrossover MD, 15-day visit only; postcrossover MD, 29-day visit; and MD phase, allmeasures from 15- or 29-day visits. Values for prasugrel and clopidogrel are mean�SD. The prespecified primary point of IPA with 20 �mol/L ADPis shown in Figure 4.




(TRITON-TIMI 38) compared the clinical outcomes amongsubjects treated with a 60-mg LD and 10-mg/d MD ofprasugrel versus the standard approved 300-mg LD and75-mg/d MD of clopidogrel regimen in patients with acutecoronary syndromes undergoing PCI and demonstrated asignificant reduction in ischemic events.26,38 TRITON-TIMI38 and other studies of agents in development may help toanswer the question of whether greater levels inhibition willprovide anti-ischemic efficacy with acceptable safety.26 Cur-rently available data do not allow identification of an optimalmethod for determining antiplatelet effect or a specific targetlevel. However, if clinical trials support greater plateletinhibition in acute and chronic therapy, the current datasupport that this goal can be achieved more consistently witha 60-mg LD of prasugrel and a 10-mg/d MD than withclopidogrel 600 mg and 150 mg/d.

Study LimitationsLTA requires very precise sample conditions and processing.Even among expert sites with experience in platelet functiontesting, a significant proportion of samples did not meet

prespecified conditions and were excluded from analyses.This had the potential to reduce the power of the study todetect a difference between treatments, although highlysignificant differences were still seen. There were no signif-icant differences in baseline characteristics among subjectswho were evaluable or not evaluable for the primary endpoint or among nonevaluable subjects between therapies,making any influence on the study outcomes unlikely. Thenumber of nonevaluable subjects in a controlled study withexperienced sites raises concern about the utility of LTAfor routine clinical monitoring. The absence of a washoutperiod between MD treatments also could be consideredlimiting; however, this could not be performed acutelybecause of the use of coronary stents in PCI subjects. Theduration of treatment should have been adequate to removeany influence of the prior therapy, and no carryover effectwas observed.

ConclusionsAmong subjects undergoing cardiac catheterization andplanned PCI, a 60-mg prasugrel LD resulted in more rapid

IPA

(20

µM

AD

P, %

) Prasugrel 10 mg Prasugrel 10 mg

A

B

15 D 29D

Prasugrel N = 40 N = 40

Clopidogrel N = 46 N = 45


15.7 (9.2 – 22.2)

14.8 (7.1 – 22.5)

P –Value <0.0001 0.0003

Days

LSM Difference 15 & 29 d: 14.9 [95% CI 10.6 , 19.3], P<0.0001

Prasugrel 10 mg Prasugrel 10 mg

LSM Difference 15 & 29 d: 20.1 [95% CI 14.5 – 25.7], P<0.0001

VA

SP

PR

I (%

)

15 D 29D

Prasugrel N = 50 N = 51

Clopidogrel N = 52 N = 50

LSM Difference(95% CI)

17.9(9.1 ñ 26.6)

21.7(12.4 ñ 31.0)

P ñValue 0.0001 <0.0001

Days

Figure 4. MD phase platelet function measures. A,IPA with 20 �mol/L ADP. B, VASP platelet reactiv-ity index (PRI). Data are mean�SD. The primaryend point of the MD phase is the combined 15-and 29-day comparison. Blue circles and linesindicate prasugrel measurements and treatmentperiods; green triangles and lines, clopidogrelmeasurements and treatment periods. LSM indi-cates LS mean.




onset and higher and more consistent levels of antiplateleteffect than a 600-mg clopidogrel LD given at least 30 minutesbefore catheterization. Similarly, prasugrel 10 mg/d resultedin higher and more consistent levels of antiplatelet effect than150 mg/d clopidogrel. If a clinical goal is to achieve higherlevels of IPA, this can be done more effectively withprasugrel than high-dose clopidogrel.

Sources of FundingThe PRINCIPLE-TIMI 44 study was supported by Daiichi SankyoCompany, Limited, and Eli Lilly and Company.

DisclosuresThe PRINCIPLE-TIMI 44 study was supported by Daiichi SankyoCompany, Limited, and Eli Lilly and Company. The TIMI StudyGroup (Drs Wiviott, O’Donoghue, Antman, and Braunwald; S.A.Murphy; C.H. McCabe) has received research grant support for thisand other studies from Eli Lilly and Daiichi Sankyo and for otherstudies from Sanofi-Aventis. Dr Wiviott reports receiving consultingfees from or serving on paid advisory boards for Sanofi-Aventis andArena Pharmaceuticals; he also reports receiving lecture fees fromEli Lilly, Daiichi Sankyo, Accumetrics, and Merck and Co. Dr Trenkreports receiving research funding from Eli Lilly and DaiichiSankyo. Dr Frelinger reports research funding from Accumetrics,Arena Pharmaceuticals, Biocytex, Dade Behring, Daiichi Sankyo,Eli Lilly, and GL Systems. Dr Neumann reports research fundingfrom Eli Lilly and Daiichi Sankyo. Dr Michelson reports receivingconsulting fees from or serving on paid advisory boards for Sanofi-Aventis, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, andMcNeil; he also reports receiving research funding from Accumet-rics, Arena Pharmaceuticals, Biocytex, Dade Behring, DaiichiSankyo, Eli Lilly, Bristol Myers Squibb, and Sanofi-Aventis. DrAngiolillo reports receiving speakers’ bureau fees from BristolMyers Squibb/Sanofi-Aventis, Daiichi Sankyo, and Eli Lilly, as wellas receiving consulting fees from or serving on paid advisory boardsfor Bristol Myers Squibb/Sanofi-Aventis, Daiichi Sankyo, and EliLilly. Dr Montalescot reports receiving consulting fees from orserving on paid advisory boards for and receiving lecture fees andresearch funding from Bristol-Myers Squibb, Eli Lilly, and Sanofi-Aventis. D.L. Miller and Dr Jakubowski are employees of Eli Lillyand Co and report equity ownership or stock options in Eli Lilly. DrAntman reports receiving consulting fees from or serving on paidadvisory boards for Sanofi-Aventis and receiving lecture fees fromEli Lilly and Sanofi-Aventis. Dr Braunwald reports receiving con-sulting fees from or serving on paid advisory boards for DaiichiSankyo and Sanofi-Aventis; receiving lecture fees from Eli Lilly andSanofi-Aventis; and receiving research funding to the TIMI StudyGroup from Astra Zeneca, Beckman Coulter, Bristol Myers Squibb,Cardiovascular Therapeutics, Genentech, Johnson and Johnson,Merck and Co, Novartis, Pfizer, Roche Diagnostics, and ScheringPlough Research Institute. The other authors report no conflicts.

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38. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, GottliebS, Neumann FJ, Ardissino D, DeServi S, Murphy SA, Riesmeyer J, Weer-akkady G, Gibson CM, Antman EM, TRITON-TIMI 38 Investigators. Pra-sugrel versus clopidogrel in patients with acute coronary syndromes. N EngJ Med. 2007;357:2001–2015.

CLINICAL PERSPECTIVEA growing literature relates the extent and variability of antiplatelet response to clopidogrel to clinical ischemic events. Inpart, the increasing use of higher-than-approved doses of clopidogrel in clinical practice is based on the desire for greaterlevels of inhibition of platelet aggregation and more rapid onset of antiplatelet effect. Prasugrel is a new thienopyridine thatis more potent than standard-dose clopidogrel in healthy subjects and patients with stable coronary artery disease. Therelative antiplatelet effects of prasugrel versus high-dose clopidogrel in percutaneous coronary intervention patients areunknown. Therefore, we addressed this question in the Prasugrel in Comparison to Clopidogrel for Inhibition of PlateletActivation and Aggregation–Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) trial, comparing prasugrel60-mg loading dose followed by 10 mg/d versus clopidogrel 600-mg loading dose followed by 150 mg/d in 201 patientsundergoing cardiac catheterization for planned percutaneous coronary intervention. Greater inhibition of plateletaggregation at all time points measured from 30 minutes to 24 hours was observed with patients receiving prasugrelcompared with high-loading-dose clopidogrel. During the maintenance-dose phase, greater inhibition of plateletaggregation also was seen in subjects receiving prasugrel compared with high-maintenance-dose clopidogrel. The trial wasnot powered for clinical end points. Bleeding tended to be more frequent with prasugrel, although no significant differenceswere observed. Prasugrel has been compared with standard-dose clopidogrel in a large-scale clinical events trial (Trial toAssess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis inMyocardial Infarction 38 [TRITON-TIMI 38]), and the data from the present study demonstrate that greater inhibition ofplatelet aggregation is seen with prasugrel compared with high-loading-dose and high-maintenance-dose clopidogrel.




prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned...

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