`~ "e NEW ENGLAND
`JOURNAL of MEDICINE
`
`VOL 357 NO. 20
`
`ESTABL I SH ED IN 1812
`
`NOVEMBER 15, 2007
`
`WWW . NEJM.ORG
`
`2000 THIS WEEK IN THE JOURNAL
`
`PERSPECTIVE
`1993 The Ongoing Regulation of Generic Drugs
`R.G Frank
`1996 Closing the Affordability Gap for Drugs
`in Low-Income Countries R. Steinbrook
`
`ORIGINAL ARTICLES
`2001 Prasugrel versus Clopidogrel in Patients
`with Acute Coronary Syndromes
`S.D. Wiv1ott and Others
`
`2016 A Chitinase-like Protein in the Lung
`and Circulation of Patients with Severe Asthma
`G.L. Chupp and Others
`
`2028 Teriparatide or Alendronate in Glucocorticoid(cid:173)
`Induced Osteoporosis
`K.G. Saag and Others
`
`2040 Cetuximab for the Treatment ofColorectal Cancer
`D.J. Jonker and Others
`
`SPECIAL ARTICLE
`2049 The Anatomy of Medical School Patenting
`P. Azoulay, R. M1chigan, and B.N. Sampat
`
`CLINICAL PRACTICE
`2057 Diverticulitis
`D.O. jacobs
`
`EBLING LIBRARY
`UNIVERSITY OF WISCONSIN
`
`NOV 1 3 2007
`
`750 HiQhland Avenue
`Madison. Wl53705
`
`1.
`
`17
`37
`s
`9
`
`IMAGES IN CLINICAL MEDICINE
`2067 Quinolone-Associated Rupture of the Achilles'
`Tendon
`H. Vyas and G. Krishnaswamy
`
`e22 Harlequin's Darker Side
`M.E. Duddy and M.R Baker
`
`CASE RECORDS OF THE MASSACHU S ETTS
`GENERAL HOSPITAL
`2068 A Man with Inflammatory Bowel Disease
`and Recent Onset of Fever and Bloody Diarrhea
`M.W. Babyatsky and Others
`
`2078
`
`EDITORIALS
`Intensifying Platelet Inhibition- Navigating
`between Scylla and Charybdis
`D.L. Bhatt
`
`2082 exoskeletons and Exhalation
`B.F. Dickey
`
`2084 Anabolic Therapy in Glucocorticoid-Induced
`Osteoporosis
`P.N. Sambrook
`2087 CORRESPONDENCE
`Prophylaxis vs. Episodic Treatment to Prevent
`)oint Disease in Severe Hemophilia
`Rheumatic Heart Disease Detected
`by Echocardiographic Screening
`RJ1eumatic Heart Disease in Developing Countries
`Methicillin-Resistant Staphylococcus au reus Infections
`Bag and Mask Ventilation
`Multiple Alloantibodies after Transfusion
`in an Infant Treated with Infliximab
`
`2094 BOOK REVIEWS
`
`2097 CONTINUIN G MEDICAL EDUCATION
`
`IPR2015-01492
`Panacea Biotec Ltd.
`
`Ex. 1027, 1 of 16
`
`
`
`
`
`The NEW ENGLAND
`JOURNAL of MEDICINE
`
`ESTABLISH EO IN 1812
`
`NOVEMBER 1 5, 2007
`
`VOL. 357 NO. 20
`
`Prasugrel versus Clopidogrel in Patients
`with Acute Coronary Syndromes
`
`Stephen D. Wiviott, M.D., Eugene Braunwald, M.D., Carolyn H. McCabe, B.S., Gilles Montalescot, M.D., Ph.D.,
`Witold Ruzyllo, M.D., Shmuel Gottlieb, M.D., Franz-Joseph Neumann, M.D., Diego Ardissino, M.D.,
`Stefano De Servi, M.D., Sabina A. Murphy, M.P.H.,Jeffrey Riesmeyer, M.D., Govinda Weerakkody, Ph.D.,
`C. Michael Gibson, M.D., and Elliott M. Antman, M.D., for the TRITON-TIM I 38 Investigators*
`
`ABSTRACT
`
`BACKGROUND
`Dual-antiplatelet therapy with aspirin and a thienopyridine is a cornerstone of treat(cid:173)
`ment to prevent thrombotic complications of acute coronary syndromes and percu(cid:173)
`taneous coronary intervention.
`
`METHODS
`To compare prasugrel, a new thienopyridine, with clopidogrel, we randomly assigned
`13,608 patients with moderate-to-high-risk acute coronary syndromes with sched(cid:173)
`uled percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose
`and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a
`75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point
`was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal
`stroke. The key safety end point was major bleeding.
`
`RESULTS
`The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel
`and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel,
`0.81; 95% confidence interval [CI), 0.73 to 0.90; P<0.001). We also found significant
`reductions in the prasugrel group in the rates of myocardial infarction (9.7% for
`clopidogrel vs. 7.4% for prasugrel; P<O.OOl), urgent target-vessel revascularization
`(3.7% vs. 2.5%; P<O.OOl), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleed(cid:173)
`ing was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients
`receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P=0.03). Also great(cid:173)
`er in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%;
`P=0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P=0.23)
`and fatal bleeding (0.4% vs. 0.1%; P=0.002).
`
`CONCLUSIONS
`In patients with acute coronary syndromes with scheduled percutaneous coronary
`intervention, prasugrel therapy was associated with significantly reduced rates of
`ischemic events, including stent thrombosis, but with an increased risk of major
`bleeding, including fatal bleeding. Overall mortality did not differ significantly
`between treatment groups. (ClinicalTrials.gov number, NCT00097591.)
`
`From Brigham and Women's Hospital and
`Harvard Medical School, Boston (S.D.W.,
`E.B .. C.H.M .. S.A.M .. C.M.G .. E.M.A.);
`lnstitut de Cardiologie and INSERM Unit
`856, Piti~-Salp@trithe University Hospital,
`Paris (G.M.); lnstytut Kardiologii, Warsaw,
`Poland (W.R.); Bikur Cholim Hospital,
`Jerusalem, Israel (S.G.); Herz-Zentrum
`Bad Krozingen, Bad Krozingen, Germany
`(F.·J.N.); Azienda Ospedaliero-Universi·
`tan a di Parma, Parma, Italy (D.A.); Azien·
`da Ospedaliera Civile di Legano, Legano,
`Italy (S.O.S.); and Eli Lilly Research Labo·
`ratories,lndianapolis U.R., G.W.).Address
`reprint requests to Dr. Antman at the Car(cid:173)
`diovascular Division, Brigham and Wom·
`en's Hospital, TIM! Study Group, 350
`Longwood Ave.,lst Fl., Boston, MA 02115,
`or at eantman@rics.bwh.harvard.edu.
`
`"'The members of the Steering and Oper(cid:173)
`ations Committees of the Trial to Assess
`Improvement in Therapeu tic Outcomes
`by Optimizing Platelet Inhibition with
`Prasugrei-Thrombolysis in Myocardial
`Infarction (TRITON-TIM!) 38 are listed
`in the Appendix. The TRITON-TIM! 38
`Investigators are listed in the Supple·
`mentary Appendix, available with the full
`text of this article at www.nejm.org.
`
`Th1s article (10.1056JNEJMoa0706482) was
`published at www.nejm.org on Novem·
`ber4, 2007.
`
`N Engl J Med 2007;357:2001·15.
`Cop)lright Q 2007 Mo$34chUSlllS Medico/ So<iety.
`
`N ENGlJ MED 357;20 WWW.NEJM.ORG NOVEMBER 15,2007
`
`2001
`
`IPR2015-01492
`Panacea Biotec Ltd.
`
`Ex. 1027, 2 of 16
`
`
`
`
`
`Tht NEW ENGLAND JOURNAL of MEOlCINE
`
`U E SHORT-TERM AND LONG-TERM BEN(cid:173)
`
`fits of dual-antiplatelet therapy with aspi(cid:173)
`n and clopidogrel have been established
`for patients with acute coronary syndromesl-3 and
`those undergoing percutaneous coronary interven(cid:173)
`tion (PCI).4•5 Despite these benefits, many patients
`continue to have recurrent atherothrombotic events
`while receiving standard dual anti platelet therapy.1
`In addition, important limitations of clopidogrel
`remain, such as only a modest antiplatelet effect,
`with substantial interpatient variability6 •7 and a de(cid:173)
`layed onset of action. 5 Small clinical studies have
`suggested that patients with a reduced pharma(cid:173)
`cologic response to dopidogrel may be at increased
`risk for adverse clinical events, including myocar(cid:173)
`dial infarction and coronary-stent thrombosis. 8"11
`Prasugrel -
`a novel thienopyridine -
`is a pro(cid:173)
`drug that, like clopidogrel, requires conversion to
`an active metabolite before binding to the plate(cid:173)
`let P2Y12 receptor to confer antiplatelet activity.12
`At the currently studied doses, prasugrel inhibits
`adenosine diphosphate-induced platelet aggrega(cid:173)
`tion more rapidly, more consistently, and to a
`greater extent than do standard and higher doses
`of clopidogrel in healthy volunteers13 and in pa(cid:173)
`tients with coronary artery disease,14•1s including
`those undergoing PCI.16 Phase 2 testing of prasu(cid:173)
`grel, as compared with clopidogrel, in patients
`undergoing elective or urgent PCI showed a trend
`toward fewer ischemic events, with an acceptable
`safety profileP Thus, we designed the Trial to As(cid:173)
`sess Improvement in Therapeutic Outcomes by
`Optimizing Platelet Inhibition with Prasugrel(cid:173)
`Thrombolysis in Myocardial Infarction (TIUTON(cid:173)
`TlMI) 38, a phase 3 trial involving patients with
`acute coronary syndromes with scheduled PCI,
`comparing a regimen of prasugrel with the stan(cid:173)
`dard-dose regimen of clopidogrel approved by the
`Food and Drug Administration.1.s Although our
`trial was designed to compare regimens of prasu(cid:173)
`grel and clopidogrel, it also tests the hypothesis
`that the use of an agent producing a higher level
`of inhibition of adenosine diphosphate-induced
`platelet aggregation and a less-variable response
`than standard-dose clopidogrel reduces ischemic
`events.
`
`METHODS
`
`TRITON-TIM! 38 was designed as a collaboration
`between the TIMI Study Group, the sponsors -
`Daiichi Sankyo and Eli Lilly -
`and a steering
`committee of investigators (see the Appendix).
`
`Quintiles Corporation provided data- and site-man(cid:173)
`agement services. All key prespecified and explor(cid:173)
`atory analyses were performed by the TIMI Study
`Group, using an independent copy of the complete
`database. The academic authors wrote all drafts of
`the manuscript and vouch for the veracity and com(cid:173)
`pleteness of its content. The database was locked
`on September 22, 2007; the analyses reported here(cid:173)
`in were completed on October 26, 2007.
`
`STUDY POPULATION
`We enrolled 13,608 patients with acute coronary
`syndromes (representative of the entire spectrum
`of those syndromes) with scheduled PCJ. Patients
`were randomly assigned to the clopidogrel group
`or the prasugrel group in two strata: 10,074 pa(cid:173)
`tients with moderate-to-high-risk unstable angi(cid:173)
`na or non-ST-elevation myocardial infarction and
`3534 patients with ST-elevation myocardial infarc(cid:173)
`tion. The inclusion criteria for patients with un·
`stable angina or non-ST-elevation myocardial
`infarction were ischemic symptoms lasting 10
`minutes or more and occurring within 72 hours
`before randomization, a TIMI risk score19 of3 or
`more, and either ST-segment deviation of 1 mm
`or more or elevated levels of a cardiac biomarker
`of necrosis. Patients with ST-elevation myocardial
`infarction could be enrolled within 12 hours after
`the onset of symptoms if primary PCI was planned
`or within 14 days after receiving medical treat(cid:173)
`ment for ST-elevation myocardial infarction.18
`Full exclusion criteria have been published pre(cid:173)
`viously.18 Key exclusion criteria included an in(cid:173)
`creased risk of bleeding, anemia, thrombocyto(cid:173)
`penia, a history of pathologic intracranial findings,
`or the use of any thienopyridine within 5 days
`before enrollment.18 The protocol was approved
`by the institutional review boards associated with
`all participating centers, and written informed
`consent was provided by all patients.
`
`STUDY PROTOCOL
`A loading dose of study medication (60 mg of pra·
`sugrel or 300 mg of clopidogrel) was administered,
`in a double-blind manner, anytime between ran(cid:173)
`domization and 1 hour after leaving the cardiac
`catheterization laboratory. Since the protocol was
`designed as a trial of patients with acute coronary
`syndromes who were undergoing PCI, the coro(cid:173)
`nary anatomy had to be known to be suitable for
`PCI before randomization in all patients with un(cid:173)
`stable angina or non-ST-elevation myocardial in(cid:173)
`farction, or in those enrolled after medical treat-
`
`2002
`
`N ENClJ M EO 357;20 WWW.NEJM.ORC NOVEMBER 15, 2007
`
`IPR2015-01492
`Panacea Biotec Ltd.
`
`Ex. 1027, 3 of 16
`
`
`
`
`
`PRASUGREL VS. CLOP!OOGREL IN PATIENTS WITH ACUTE CORONARY SYNDROMES
`
`ment forST-elevation myocardial infarction. If the
`coronary anatomy was previously known or pri(cid:173)
`mary PCI for ST-elevation myocardial infarction
`was planned, pretreatment with the study drug was
`permitted for up to 24 hours before PCI. Random(cid:173)
`ization was to occur before PCI was performed,
`and the study drug was to be administered as soon
`as possible after randomization.
`The choice of vessels treated, devices used, and
`adjunctive medication administered to support PCI
`was left to the discretion of the treating physician.
`After PCI, patients received maintenance doses
`of either prasugrel (10 mg) or clopidogrel (75 mg)
`daily. Use of aspirin was required, and a daily dose
`of 75 to 162 mg was recommended. Study visits
`were conducted at hospital discharge, at 30 days,
`at 90 days, and at 3-month intervals thereafter,
`for a total of 6 to 15 months.18
`
`END POINTS
`The primary efficacy end point was a composite
`of the rate of death from cardiovascular causes,
`nonfatal myocardial infarction, or nonfatal stroke
`during the follow-up period. Key secondary end
`points at 30 and 90 days were the primary com(cid:173)
`posite end point and a composite of death from
`cardiovascular causes, nonfatal myocardial infarc(cid:173)
`tion, or urgent target-vessel revascularization. Key
`secondary end points for the entire follow-up pe(cid:173)
`riod were stent thrombosis and a composite of
`death from cardiovascular causes, nonfatal myo(cid:173)
`cardial infarction, nonfatal stroke, or rehospital(cid:173)
`ization due to a cardiac ischemic event. Addition(cid:173)
`al prespecified analyses included an analysis of the
`rates of the primary end point from randomization
`to day 3 and a landmark analysis of those data
`from day 3 to the end of the study. Key safety end
`points were TIMl major bleeding not related to
`coronary-artery bypass grafting (CABG), non(cid:173)
`CABG-related TIMT life-threatening bleeding, and
`TIMI major or minor bleeding, as previously de(cid:173)
`fined.18 Stent thrombosis was defined as definite
`or probable stent thrombosis according to the
`Academic Research Consortium.20 All components
`of the primary, secondary, and key safety end points
`were adjudicated by members of an independent
`clinical events committee that was unaware of the
`group assignments.
`
`STATISTICAL ANALYSIS
`Efficacy comparisons were performed on the ba(cid:173)
`sis of the time to the first event, according to the
`intention-to-treat principle. Safety analyses were
`
`carried out on data from patients who received at
`least one dose of the study drug. The Gehan-Wil(cid:173)
`coxon test was used to compare the treatment
`groups with regard to the primary efficacy end
`point18; the log-rank test was used in a prespeci(cid:173)
`fied sensitivity analysis for the primary end point
`and in all analyses of key secondary and safety end
`points. Because of the substantial overlap between
`the cohort of patients with unstable angina or non(cid:173)
`ST-elevation myocardial infarction and the over(cid:173)
`all population of patients with acute coronary syn(cid:173)
`dromes, and to preserve the statistical power to
`detect a difference between the two treatment
`groups, we used a closed testing procedure. The
`primary efficacy end point was analyzed in the
`cohort with unstable angina or non-ST-elevation
`myocardial infarction first, and only if there was
`a statistically significant difference between the
`treatment groups was this end point analyzed in
`the overall cohort.18 Rates of the end points are
`expressed as Kaplan-Meier estimates at 15 months
`and were compared with the use of hazard ratios
`and two-sided 95% confidence intervals. An inde(cid:173)
`pendent data monitoring committee monitored
`the safety and efficacy of the study drugs. P val(cid:173)
`ues ofless than 0.05 were considered to indicate
`statistical significance.
`We calculated that a total of 875 primary end
`points would be required for the study to have a
`90% power to detect a 20% reduction in the rela(cid:173)
`tive risk of the primary end point among patients
`with unstable angina or non- ST-elevation myocar(cid:173)
`dial infarction receiving prasugrel, as compared
`with clopidogrel. It was estimated that 9500 pa(cid:173)
`tients with unstable angina or non-ST-elevation
`myocardial infarction would need to be enrolled
`to achieve this number of end points.18 A pre(cid:173)
`specified assessment conducted when 650 patients
`bad had a primary end point found a slightly
`lower-than-expected aggregate rate of the end
`point, which led us to increase the number of pa(cid:173)
`tients in the cohort with unstable angina or non(cid:173)
`ST-elevation myocardial infarction to approximate(cid:173)
`ly 10,100.18
`
`RESULTS
`
`We randomly assigned 13,608 patients (10,074 with
`unstable angina or non-ST-elevation myocardial
`infarction and 3534 with ST-elevation myocardial
`infarction), from 707 sites in 30 countries, to a
`treatment group between November 2004 and Jan(cid:173)
`uary 2007. The baseline characteristics were sim-
`
`N ENGLJ M£0 357;20 WWW.NEJM.ORG NOVEMSER 15,2007
`
`2003
`
`IPR2015-01492
`Panacea Biotec Ltd.
`
`Ex. 1027, 4 of 16
`
`
`
`
`
`Tht NEW ENGLAND JOURNAL of MEDICINE
`
`ilar to those in contemporary studies of patients
`with acute coronary syndromes who were under(cid:173)
`going PCI and were well matched between the
`treatment groups (Table 1). The median duration
`of therapy was 14.5 months. A total of14 patients
`(0.1%) were lost to follow-up.
`Nearly all patients (99%) had PCI at the time
`of randomization, 94% received at least one in(cid:173)
`tracoronary stent, and 47% received at least one
`drug-eluting stent. The study drug was adminis(cid:173)
`tered before the first coronary guidewire was
`placed in 25% of patients, after the first coro(cid:173)
`nary guidewire was placed and during the PCI or
`within 1 hour after PCI in 74%, and more than
`1 hour after PCI in 1%.
`
`EFFICACY END PO I NT S
`The rate of the primary efficacy end point was
`significantly reduced in favor ofprasugrel among
`the patients with unstable angina or non-ST-eJeva(cid:173)
`tion myocardial infarction (hazard ratio, 0.82; 95%
`confidence interval (CI], 0.73 to 0.93; P=0.002);
`therefore, as prespecified, the analysis was also
`performed in the overall cohort of patients with
`acute coronary syndromes. A significant benefit
`of prasugrel was also observed in the ST-elevation
`myocardial infarction cohort alone (hazard ratio,
`0.79; 95% CI, 0.65 to 0.97; P=0.02), and there
`was no significant interaction between treatment
`group and enrollment stratum (unstable angina
`or non-ST-elevation myocardial infarction vs. ST(cid:173)
`elevation myocardial infarction).
`In the overall cohort, a total of 781 patients
`(12.1%) in the clopidogrel group had the primary
`end point, as compared with 643 patients (9.9%)
`in the prasugrel group (hazard ratio, 0.81; 95% CI,
`0.73 to 0.90; P<0.001) (Table 2 and Fig. 1A), sup(cid:173)
`porting the primary hypothesis of superior effi(cid:173)
`cacy. A significant reduction in the primary end
`point was seen in the prasugrel group by the first
`prespecified time point, 3 days (5.6% in the clopi(cid:173)
`dogrel group vs. 4.7% in the prasugrel group;
`hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01)
`(Fig. lB), and persisted throughout the follow-up
`period. From 3 days to the end of the study, the
`primary end point had occurred in 6.9% of pa(cid:173)
`tients receiving clopidogrel and in 5.6% of pa(cid:173)
`tients receiving prasugrel (hazard ratio, 0.80; 95%
`CI, 0.70 to 0.93; P=0.003) (Fig. 1C). The difference
`between the treatment groups with regard to the
`rate of the primary end point was largely related
`to a significant reduction in myocardial infarc-
`
`tion in the prasugrel group (9.7% in the clopido(cid:173)
`grel group vs. 7.4% in the prasugrel group; haz(cid:173)
`ard ratio, 0.76; 95% CI, 0.67 to 0.85; P<0.001). The
`rate of myocardial infarction with subsequent
`death from cardiovascular causes (including ar(cid:173)
`rhythmia, congestive heart failure, shock, and
`sudden or unwitnessed death) was also reduced
`in the prasugrel group (0.7% in the clopidogrel
`group vs. 0.4% in the prasugrel group; hazard
`ratio, 0.58; 95% CI, 0.36 to 0.93; P=0.02). There
`was no significant difference between the two
`treatment groups in the rate of stroke or of death
`from cardiovascular causes not preceded by re(cid:173)
`current myocardial infarction.
`Prasugrel showed superior efficacy in major
`prespecified subgroups (Fig. 2), without signifi(cid:173)
`cant interactions between the characteristics of the
`patients and the treatment group. A benefit with
`prasugrel with regard to the primary end point
`was found both with the use of glycoprotein
`Ilb/illa-receptor antagonists during the index hos(cid:173)
`pitalization (hazard ratio for prasugrel vs. clopi(cid:173)
`dogrel, 0.79; 95% CI, 0.69 to 0.91; P<0.001) or
`without such use (hazard ratio, 0.84; 95% CI, 0.72
`to 0.99; P=0.03). The benefit tended to be greater
`among the 3146 patients with diabetes (17.0% of
`whom had the primary end point in the clopido(cid:173)
`grel group, vs. 12.2% in the prasugrel group; haz(cid:173)
`ard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001) than
`among the 10,462 patients without diabetes (10.6%
`of whom had the primary end point in the clopi(cid:173)
`dogrel group, vs. 9.2% in the prasugrel group;
`hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02).
`There was no significant interaction between treat(cid:173)
`ment effect and diabetes status (P=0.09) or the
`timing of the study-drug administration (P=0.40).
`Similar significant reductions were seen for
`prasugrel in the overall cohort with regard to the
`prespecified secondary end point of death from
`cardiovascular causes, nonfatal myocardial infarc(cid:173)
`tion, or urgent target-vessel revascularization at
`30 days (hazard ratio, 0.78; 95% cr, 0.69 to 0.89;
`P<0.001) and at 90 days (hazard ratio, 0.79; 95%
`CI, 0.70 to 0.90; P<0.001). A significant reduction
`in the rate of urgent target-vessel revasculariza(cid:173)
`tion alone was also found in the prasugrel group
`by the end of the follow-up period (hazard ratio,
`0.66; 95% CI, 0.54 to 0.81; P<0.001) (Table 2).
`A reduction in favor of prasugrel was also seen by
`the end of the follow-up period for the end point
`of death from cardiovascular causes, nonfatal
`myocardial infarction, nonfatal stroke, or rehos-
`
`2004
`
`N ENCLJ MED 357;20 WWW. NEJM.ORC NOVEMBER 15,2007
`
`IPR2015-01492
`Panacea Biotec Ltd.
`
`Ex. 1027, 5 of 16
`
`
`
`
`
`l'RASUGRilL VS. CLOPJOOGREL IN PATIENTS WITH ACUTE CORONARY SYNDROMES
`
`pitalization for ischemia (hazard ratio, 0.84; 95%
`CI, 0.76 to 0.92; P<0.001) (Table 2). The rate of
`definite or probable stent thrombosis, as defined
`by the Academic Research Consortium, was sig(cid:173)
`nificantly reduced in the prasugrel group as com(cid:173)
`pared with the clopidogrel group, with 68 patients
`(1.1%) and 142 patients (2.4%), respectively, hav(cid:173)
`ing at least one occurrence (hazard ratio, 0.48;
`95% CI, 0.36 to 0.64; P<0.001). The significant re(cid:173)
`duction in the rate of stent thrombosis was also
`found among patients receiving prasugrel in com(cid:173)
`bination with bare-metal stents alone (hazard ra(cid:173)
`tio, 0.52; 95% CI, 0.35 to 0.77; P<0.001) and among
`those receiving prasugrel in combination with at
`least one drug-eluting stent (hazard ratio, 0.43;
`95% Cl, 0.28 to 0.66; P<0.001).
`
`SAFETY END POINTS
`Among patients treated with prasugrel, 146 (2.4%)
`had at least one TIMI major hemorrhage that was
`not related to CABG, as compared with 111 pa(cid:173)
`tients (1.8%) treated with clopidogrel (hazard ra(cid:173)
`tio, 1.32; 95% CI, 1.03 to 1.68; P=0.03) (Table 3).
`This excess of TIMI major blt:t:ding im.:luded a
`higher rate oflife-threatening bleeding in the pra(cid:173)
`sugrel group (1.4%, vs. 0.9% in the clopidogrel
`group; hazard ratio, 1.52; 95% CI, 1.08 to 2.13;
`P = 0.01) at the end of the study, as well as from
`the time of randomization to day 3 (0.4% vs. 0.3%;
`hazard ratio, 1.38; 95% CI, 0.79 to 2.41; P=0.26)
`and from day 3 to the end of the study (1.0% vs.
`0.6%; hazard ratio, 1.60; 95% CI, 1.05 to 2.44;
`P=0.03). Fatal TIMI major bleeding occurred in
`significantly more patients treated with prasugrel
`(0.4%) than those treated with clopidogrel (0.1%)
`(P=0.002) (Table 3), and more patients in the pra(cid:173)
`sugrel group had nonfatal life-threatening bleed(cid:173)
`ing (1.1%, vs. 0.9% in the clopidogrel group;
`hazard ratio, 1.25; 95% Cl, 0.87 to 1.81; P=0.23).
`A higher rate of TIMI major bleeding related to
`instrumentation and a significantly higher rate
`of spontaneous TIM I major bleeding were seen
`in the prasugrel group than in the clopidogrel
`group (Table 3). Intracranial hemorrhage was
`reported in 19 patients (0.3%) receiving prasu(cid:173)
`grel and 17 patients (0.3%) receiving clopidogrel
`(P=0.74). The combination of non-CABG-related
`TIMI major or minor hemorrhage was more fre(cid:173)
`quent among patients receiving prasugrel than
`among those receiving clopidogrel (hazard ratio,
`1.31; 95% CI, 1.11 to 1.56; P::::0.002) (Table 3).
`Few patients underwent CABG; among them,
`
`the rate ofTIMI major bleeding was also greater
`with prasugrel than with clopidogrel (Table 3).
`More patients treated with prasugrel (2.5%, vs.
`1.4% of patients treated with clopidogrel; P<0.001)
`discontinued the study drug owing to adverse
`events related to hemorrhage.
`When the rates of certain efficacy and bleed(cid:173)
`ing end points -death from any cause, nonfa(cid:173)
`tal myocardial infarction, nonfatal stroke, and
`TIMI major hemorrhage -were included in a
`prespecified analysis of net clinical benefit, the
`findings favored prasugrel (13.9% of patients in
`the clopidogrel group vs. 12.2% in the prasugrel
`group; hazard ratio, 0.87; 95% CI, 0.79 to 0.95;
`P::::0.004). Death from cardiovascular causes (in(cid:173)
`cluding death related to intracranial hemorrhage
`or to bleeding related to a cardiovascular proce(cid:173)
`dure) or fatal hemorrhage occurred in 151 patients
`(2.4%) receiving clopidogrel and in 142 patients
`(2.2%) receiving prasugrel (hazard ratio, 0.94; 95%
`CI, 0.75 to 1.18; P::::O.S9).
`As a result of the discordance between the ef(cid:173)
`ficacy results (lower rates of ischemic end points in
`the prasugrel group than in the clopidogrel group)
`and the safety results (higher rates of bleeding
`end points with prasugrel than with clopidogrel)
`during the entire follow-up period, we performed
`a series of post hoc exploratory analyses to iden(cid:173)
`tify the subgroups of patients who did not have
`a favorable net clinical benefit (defined as the rate
`of death from any cause, nonfatal myocardial in(cid:173)
`farction, nonfatal stroke, or non-CABG-related
`nonfatal TIMI major bleeding) from the use of
`prasugrel or who had net harm. There were
`three specific groups of interest; patients who
`had a previous stroke or transient ischemic at(cid:173)
`tack had net harm from prasugrel (hazard ratio,
`1.54; 95% CI, 1.02 to 2.32; P::::0.04), patients 75
`years of age or older had no net benefit from
`prasugrel (hazard ratio, 0.99; 95% CI, 0.81 to
`1.21; P::::0.92), and patients weighing less than
`60 kg had no net benefit from prasugrel (haz(cid:173)
`ard ratio, 1.03; 95% Cl, 0.69 to 1.53; P=0.89).
`In both treatment groups, patients with at least
`one of these three risk factors had higher rates
`of bleeding than those without them (Table 4).
`Patients with a history of cerebrovascular events
`bad no evidence of a clinical benefit from prasu(cid:173)
`grel (as compared with clopidogrel), as evaluated
`by the primary efficacy end point, and had a
`strong trend toward a greater rate ofTlMI major
`bleeding (P=0.06), including intracranial hemor-
`
`N ENCLJ MEO 357;20 WWW.NEJM.ORC NOVEMBER 15, 1007
`
`2005
`
`IPR2015-01492
`Panacea Biotec Ltd.
`
`Ex. 1027, 6 of 16
`
`
`
`
`
`Tht NEW ENGLAND JOURNAL of MEOlClNE
`
`Table 1. Baseline Characteristics of the Patients.*
`
`Characteristic
`Unstable angina or NSTEMI (%)
`STEMI (%)
`
`Age
`Median (yr)
`25th percentile, 75th percentile (yr)
`2:75 yr (%)
`Female sex (%)
`
`BMit
`Median
`25th percentile, 75th percentile
`White race(%):~
`Region of enrollment (%)
`North America
`Western Europe
`Eastern Europe
`Middle East, Africa, or Asia-Pacific region
`
`South America
`Medical history (%)
`Hypertens1on
`Hypercholesterolemia
`Diabetes mellitus
`Tobacco use
`Previous Ml
`Previous CABG
`Creatinine clearance <60 mlfmin (%)J
`Index procedure(%)
`PCI
`CABG
`Stent
`Bare-metal stent only
`2:1 Drug-eluting stent
`Multivessel PCI
`Antithrombin use to support PCI (%)
`Heparin
`LMWH
`Bivalirudin
`Other or multiple therapies
`Glycoprotein lib/lila-receptor antagonist use during index hospitalization (%)
`Timing of study-drug administration (%)1!
`Before PCI
`During PCI
`After PCI
`
`Pra.sugrel
`(N=6813)
`74
`26
`
`Clopidogrel
`(N=6795)
`74
`
`26
`
`61
`53,69
`
`13
`25
`
`28
`25,31
`
`92
`
`32
`26
`24
`14
`
`4
`
`64
`56
`23
`38
`18
`8
`11
`
`99
`
`94
`48
`47
`14
`
`66
`9
`3
`22
`54
`
`26
`73
`
`1
`
`61
`53, 70
`
`13
`27
`
`28
`25,31
`
`93
`
`32
`
`26
`25
`14
`4
`
`64
`
`56
`23
`38
`18
`7
`12
`
`99
`
`95
`47
`47
`14
`
`65
`8
`
`3
`23
`55
`
`25
`74
`1
`
`2006
`
`N ENGLJ MEO 357;20 WWW.NEJM.ORG NOVEMBER 15, 2007
`
`IPR2015-01492
`Panacea Biotec Ltd.
`
`Ex. 1027, 7 of 16
`
`
`
`
`
`t>RASUOREJ.. VS. CLOP I DOOREL IN PATIENTS WITH ACUTE COROl)IARY SYNDROMES
`
`Table 1. (Continued.)
`
`Characteristic
`Pharmacotherapy during index hospitalization (%)
`ACE inhibitor or ARB
`Beta-blocker
`Stat in
`Calcium·channel blocker
`Aspirin
`
`Prasugrel
`(N=6813)
`
`Clopidogrel
`(N=6795)
`
`76
`
`88
`
`92
`
`18
`
`99
`
`75
`
`88
`
`92
`
`17
`
`99
`
`*Patients could have had more than one type of medical history, undergone more than one type of index procedure,
`or received more than one type of pharmacotherapy during index hospitalization. The percentage of female patients
`and the percentage of patients who received an angiotensin-converting-enzyme (ACE) inhibitor or angiotensin-receptor
`blocker (ARB) differed significantly between the prasugrel group and the clopidogrel group (P- 0.02 and P=0.03,
`respectively). NSTEMI denotes non- ST·elevation myocardial infarction (MI), STEM I ST-elevation Ml, CABG coronary(cid:173)
`artery bypass grafting, PCI percutaneous coronary intervention, and LMWH low·molecular-weight heparin. Beta-blocker
`is defined as J3·adrenergic-receptor antagonist, and stalin is defined as hydroxymethylglutaryl- coenzyme A red uctase
`inhibitor.
`t The body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters.
`:~ Race was self-reported.
`' Creatinine clearance was estimated with the use of the Cockcroft-Gault formula.
`, Administration of the study drug before PCI occurred before the first coronary guidewire was placed during the index
`PCI; administration during PCI occurred after the first coronary guidewire was placed or within 1 hour after the patient
`was taken from the cardiac catheterization laboratory; and administration after PCI occurred more than 1 hour after the
`patient was taken from the cardiac catheterization laboratory.
`
`rhage in six patients (2.3%) in the prasugrel group,
`as compared with none in the clopidogrel group
`(P=0.02). As a result, there was a significant inter(cid:173)
`action between a history of cerebrovascular events
`and the degree of net clinical benefit of prasu(cid:173)
`grel as compared with clopidogrel (Table 4), indi(cid:173)
`cating a significant harm from prasugrel among
`patients with a history of cerebrovascular events
`(518 patients), as compared with a significant ben(cid:173)
`efit from prasugrel among patients without such
`a history (13,090 patients). There was also a sig(cid:173)
`nificant interaction between the presence or ab(cid:173)
`sence of any of these three risk factors and the
`degree of net clinical benefit for prasugrel as com(cid:173)
`pared with clopidogrel (P=0.006), though no sig(cid:173)
`nificant harm was evident. Among patients with(cid:173)
`out any of these three risk factors, there was
`greater efficacy with prasugrel (hazard ratio, 0. 74;
`95% CI, 0.66 to 0.84; P<0.001), no significant dif.
`ference in the rate of major bleeding in the pra(cid:173)
`sugrel group and the clopidogrel group (hazard
`ratio, 1.24; 95% CI, 0.91 to 1.69; P=0.17), and a
`substantially favorable net clinical benefit for the
`use of prasugrel (Table 4).
`The rate of serious adverse events not related
`to hemorrhage was similar in the prasugrel group
`and the clopidogrel group (occurring in 22.5% and
`22.8% of patients, respectively; P=0.52). The study
`
`drug was discontinued owing to adverse events not
`related to hemorrhage in 4.7% of patients treat(cid:173)
`ed with prasugrel and in 5.0% of patients treated
`with clopidogrel (P=0.37). The adverse events re(cid:173)
`ported included severe thrombocytopenia in 17
`patients in the prasugrel group (0.3%) and 18
`patients in the clopidogrel group (0.3%) (P=0.86);
`neutropenia in 2 patients (<0.1%) and 10 patients
`(

Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ ChargeStill Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.

This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.

One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site