Aspirin Professional Labeling Proposed Changes Citizen Petition McNeil Consumer 81Specialty Pharmaceuticals



Summary of Aspirin Efficacy Information


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Table of Contents

INTRODUCTION ......................................................................................................... 1 .I. Background .............................................................................................................. 1.2. Efficacy Conclusions Supported ............................................................................

5 5 7

2. 3.

DESCRIPTION OF ISE FORMAT . . . . . . . . . . . . . . . . . . . . . . . . . . . ..~..~..........~....~............................... 8 METHODOLOGY ........................................................................................................ 3.1. Literature Search Methodology .............................................................................. 3.2. Efficacy Summary Methodology ........................................................................... 3.21. Key Publication.. ............................................................................................... Publications .................................................................................... 3.2.2. Supporting 3.2.3. Publications Providing Additional Efficacy Information ...................................... OVERVIEW OF RELEVANT PUBLISHED STUDIES AND STUDY POPULATION CHARACTERISITCS ................................................................................................. 4.1. Key Publication ...................................................................................................... 4.1 .I. Antithrombotic Trialists’ Collaboration, 2002 ..................................................... 4.2. Supporting Publications ....................................................................................... 4.2.1. Posada et al., 1999.. ......................................................................................... 4.2.2. Taylor et al.,, 1999 ............................................................................................. 4.2.3. Peters et al., 2003 ............................................................................................. 4.2.4. Top01 et al., 2003 .............................................................................................. 4.2.5. Algra and van Gijn, 1996 .................................................................................. 4.2.6. Johnson et al., 1999 ......................................................................................... 4.3. Publications Providing Additional Efficacy Jnformation ..................................... 9 9 12 15 16 19


19 19 19 21 22 22 23 25 25 26 27


SUMMARY OF SUBJECT ACCOUNTABILITY AND EXTENT OF EXPOSURE.......2 7 27 5.1. Key Publication ...................................................................................................... 5.1 .I. Antithrombotic Trialists’ Collaboration, 2002 ..................................................... 27 28 5.2. Supporting Publications ....................................................................................... 30 5.2.1. Posada et al., 1999.. ......................................................................................... 30 5.2.2. Taylor et al., 1999 .............................................................................................. 30 5.2.3. Peters et al., 2003 ............................................................................................. 30 52.4. Top01 et al., 2003 .............................................................................................. 31 52.5. Algra and van Gijn, 1999 .................................................................................. 31 5.2.6. Johnson et al., 1999 ......................................................................................... 5.3. Publications Providing Additional Efficacy Information ...................................... 31



Aspirin Prafessionaf Labeling Proposed Changes Citizen Petition McNeil Consumer & Specialty Pharmaceuticals


SUMMARY OF EFFlCACY INFORMATION .............................................................. 6.1. Key Publication ...................................................................................................... 6.1 .I. Antithrombotic Trialists’ Collaboration, 2002 ..................................................... 6.2. Supporting Publications ....................................................................................... 6.2.1. Posada et al., 1999.. ......................................................................................... 6.2.2. Taylor et al., 1999 ............................................................................................. 6.2.3. Peters et al., 2003 ............................................................................................. 6.2.4. Top01 et al., 2003 .............................................................................................. 6.25. Algra and van Gijn, 1996 .................................................................................. 6.2.6. Johnson et al., 1999 ......................................................................................... 6.3. Publications Providing Additional Efficacy Information .....................................

31 31 31 33 34 35 37 38 39 40 40 ’

7. 8.

41 OVERALL SUMMARY AND CONCLUSIONS . . . . . . . . ..~.......~.~.~~.~...~..~.“..~.~.~.........~....~.. REFERENCES .......................................................................................................... 8.1. Key Publication ...................................................................................................... 8.2. Supporting Publications ....................................................................................... 8.3. Publications Providing,Additional “Efficacy Information ..................................... 8.4. Cited, Not Reviewed .............................................................................................. 43 43 43 43 52

APPENDIX 1 TABLE OF STUDIES - PUBLICATIONS PROVlDlNG -ADDiTIONAL EFFICACY INFORMATION . . . . ..~....~,...,..~...“.~,..,..,,**~,,,.....*,~..~.,,*.......,...,.....,.,........,...53 APPENDIX 2 SUMMARY OF,EFFICACY RESULTS - PUBLICATIONS PROVIDING ADDITIONAL EFFICACY INFORMATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..~.......... 79

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List of Abbreviations ACS ARR ATC BID BRAVO CABG CAD Cl CURE ECG ESPS FDA GP Ilb/llla HR ISIS-2 Ml N ns NS NSAlDs PAF PCI PTCA PVD QOD RR RRR SALT SAPAT SE TIA TIMI acute coronary syndromes absolute risk reduction Antithrombtic Trialists’ Collaboration twice daily Blockade of the Glycoprotein Ilb/llla Receptor to Avoid Vascular Occlusion Trial coronary artery bypass grafting coronary artery disease confidence interval Clopidogrel in Unstable Angina to Prevent Recurrent *Events Trial electrocardiogram European Stroke Prevention Study Food and Drug Administration glycoprotein Ilb/lila receptor hazard ratio Second International Study of Infarct Survival myocardial infarction number not specified not significant non-steroidal anti-inflammatory drugs primary atrial fibrillation percutaneous coronary intervention percutaneous transluminal coronary angioplasty peripheral vascular disease every other day relative risk relative risk reduction Swedish Aspirin Low-dose Trial Swedish Angina Pectoris Aspirin Trial standard error transient ischemic attack Thrombolysis in Myocardial Infarction

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1. 1.1.


Aspirin for the treatment of acute myocardial infarction (Ml) and for the secondary prevention of MI, chronic stable and unstable angina pectoris, transient ischemic attacks (TIA), and ischemic stroke is one of the most important therapies available to reduce cardiovascular morbidity and mortality. Since the initial proposed rule of November 16, 2988 [53 FR 462041 for aspirin professional labeling, the Food and Drug Administration (FDA) has expanded the vascular indications and refined aspirin dosage instructions in the subsequent Federal Register notices of June 13, 1996 [61 FR 300021 and the Final Rule of October 23, 1998 [63 FR 568021. Since the 1998 Final Rule, new data have become available that support the need to reconsider the safety and efficacy profiles of the recommended doses of aspirin for these vascular indications. Since 1988, the FDA has reviewed the safety experience associated with the use of aspirin over a broad range of effective doses (i.e., 50 to 1500 mglday).’ In the 1988 Federal Register [53 FR 5 462311, FDA concluded that aspirin at a dose of 1300 mg/day was safe and effective for reducing the risk of recurrent TlAs or stroke in men. For secondary MI prevention, the notice [53 FR 3 462321 stated in part: “Dosage and administration: Although most of the studies used dosages exceeding 300 milligrams, 2 trials used only 300 milligrams, and pharmacologic data indicate that this Therefore, 300 milligrams, or a conventional dose inhibits platelet function fully. 325 miNgram aspirin dose is a reasonable, routine dose that would minimize gastrointestinal adverse reactions. W To expedite the approval process for aspirin in the treatment of acute Ml, FDA published a Notice of Proposed Rulemaking on June 13, 1996 [61 FR 30002]. Regarding the findings from the Second International Study of Infarct Survival (ISIS-2) study (ISIS-2 Collaborative Group, 1988) that proposal [61 FR 30006] stated in part: “The Agency has determined that the ISIS-2 study supports the use of aspirin at a dose of 162.5 mg/day, started as soon as possible afier an infarction and continued for at least 30 days, to reduce the risk of fatal and non-fafal cardiovascular and cerebrovascular events in subjects with a suspected MI. V The proposal [61 FR 300061 continues, “After the 30-day recommended treatment with aspirin for acute MI, physicians should consider further therapy based on fhe labeling for dosage and administration of aspirin to prevent recurrent MI (reinfarction).”



Aspirin Professional Labeling Proposed Changes Citizen Petition McNeil. Consumer & Specialty Pharmaceuticals

In the October 23, 1998 Final Rule [63 FR 568021, FDA codified the acute Ml indication and refined its evaluation of the dose needed for secondary prevention as new data and FDA considered data from the Antiplatelet Trialists’ analyses were made available. Collaboration (1994), the United Kingdom-TIA study (UK-TIA Study Group, 1988), the Danish Very Low Dose study (Boysen et al., 1988), the Swedish Aspirin Low-dose Trial (SALT Collaborative Group, 1991), European Stroke Prevention Study-2 (ESPS-2) for TIA or stroke prevention (Diener et ai., 1996), and the Swedish Angina Pectoris Aspirin Trial (SAPAT) in chronic stable angina (Juul-Moller et al., 1992). The Agency provided the following summary [63 FR 568061 regarding support for a lower dose of aspirin: “In summary, there is clinical trial support for a lower dose of aspirin for subjects with a history of T/A or cerebral ischemia and considerable evidence in p&ients with MI. It is also c/ear that the effect of aspirin on platelet functions is complete at lower doses. The positive findings at lower dosages (e.g., 50, 75 and 3OO.mg dailyl along with the higher incidence of side effects expected at the higher dosage (e.g., ?300 mg daily) are sufficient reason to lower the dosage of aspirin for subjects with T/A and stroke.” Given that the SAPAT study used a dose of 75 mglday for cardiovascular indications, FDA also recommended that the dose range for secondary prevention. of Ml be changed from 300-325 mglday to 75-325 mg/day. Furthermore, in the 1998 Final Rule, FDA stated in part: I‘. specific doses for specific uses of aspirin, supported by appropriate data, are necessary . for an optimal benefit to the user and, in general, that a minimum eff&tke dose established for a given indication should be used to minimize dose.related adverse effects.” FDA’ statement thereby allows the opportunity for further refinement of the aspirin dose s that provides optimal benefit for a given indication, while minimizing adverse effects. Since the 1998 Final Rule notice, the approved monograph for professional labeling of aspirin was used to form the basis for the New Drug prescription labeling of buffered aspirin approved as an independent drug product co-packaged with PRAVACHOLB (pravastatin sodium). This product, PRAVIGARDTM PAC (NDA 21-387), was approved by the FDA on June 24, 2003. The aspirin component of that labeling was consi.stent with the 1998 Final Rule and provides physicians with information appropriate to the use of buffered aspirin when used in conjunction with PRAVACHOL@. FDA’ approval of PRAVIGARDTM PAC was s consistent with the monograph professional labeling’ of aspirin. However, the FDA review resulted in modification of the aspirin component of that labeling. McNeil’ proposal s includes a request to modify the current professional labeling to ‘ consistent with FDA’ be s aspirin evaluation during the PRAVIGARDTM PAC review.



Aspirin Professional Labeling Proposed Changes Citizen Petition McNeil Consumer & Specialty Pharmaceuticals

McNeil’ Petition proposes to modify the current monograph professional labeling (21CFR s 330.11) based on data that has become available since the 1998 Pinal Rule. In addition, McNeil’ proposed changes are also reflective of the NDA-approved tabeting of the aspirin s component of PRAVIGARDTM PAC under 21CFR 31454. The proposed aspirin labeling provides professional labeling information appropriate to the use of aspirin doses 75-150 mglday for secondary cardiovascular prevention and 50-150 mg/day for secondary cerebrovascular prevention. An annotated version of the proposed professional labeling for aspirin is provided in Attachment 1. McNeil considers that all the material and methods used by the FDA to reach the scientific and regulatory conclusions enunciated in the Federal Register notices of 1988, 1996, and 1998 (Section 2.1 .I), as well as the NDA 21-387 approval of new labeling for buffered aspirin (Section 2.1 .I), provide the critical background information for consideration of new post-1998 aspirin data, particularly safety data. Using the FDA process to establish the safe and effective dose of aspirin for secondary vascular prevention under 21 C.F.R. $j 343.80 Professional Labeling and the new post-1998 aspirin data, McNeil requests that the professional labeling for aspirin specify the more favorable benefitirisk profile of aspirin dose of 75-150 mg/day for secondary cardiovascular prevention and 50-150 mg/day for secondary cerebrovascular prevention to provide effective treatmem and minimize major bleeding events, particularly gastrointestinal (GI) bleeding. These conclusions are reflected in the Clinical Studies, Warnings, Adverse ReactionsControlled Trials, and Dosage and Administration sections of the new proposed labeling submitted in the subject Citizen’ Petition for FDA’ review. The scientific basis regarding s s the benefit/risk profile of aspirin at doses <I50 mgfday versus >I 50 mg/day follows. 1.2. Efficacy Conclusions Supported

Data from the publications discussed in this aspirin efficacy summary are consistent with the FDA’ previous conclusions [63 FR 568063: s

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Doses of aspirin within the range of 50-150 mg daily are equally effective for the prevention of serious vascular events (non-fatal MI, non-fatal stroke, and vascular death). The recommended aspirin dose for chronic administration is 50-150 mg daily, which is safe and effective far prevention of recurrent MI, ischemic Stroke and TIA and for treatment of unstable angina pectoris or chronic stable angiha pectoris. Aspirin is recommended for patients who undergo revascurarization procedures, such as coronary artery bypass grafting, angioplasty, or carotid endarterectomy, if there is a pre-existing Therapy should be continued condition for which aspirin is atready indicated. indefinitely. DESCRIPTION OF EFFICACY SUMMARY FORMAT



A discussion of the general methodology used to identify articles included in this aspirin efficacy summary is presented in Section 3. This includes a description of the initial literature search that was performed, as well as a description of the criteria ‘ that were developed to identify and group articles containing relevant efficacy: data. Section 3 also includes a brief description of the articles in each publfcation grouping and the order of presentation. In Section 4, information on study design and patient populations, including study objectives, key inclusion and exclusion criteria, patient characteristics (age, sex, and if available, relevant medical conditions at study entry), efficacy endpoints, and a brief description of statistical methodology is presented. In Section 5, a summary of subject accountability and extent of exposure to aspirin is presented, including the number of patients exposed to specific doses and duration of exposure. Efficacy data from each of the publication groupings are presented in Section 6. In publications where the primary focus included comparisons between another antiplateiet medication plus aspirin versus placebo plus aspirin, only data for placebo plus aspirin (i.e., aspirin alone) is presented. A publication that substantiates the reduced antiplatelet effect co-administered with ibuprofen is presented and discussed in Section 7. of aspirin when

Finally, Section 8 provides a summary of efficacy and a discussion of overall conclusions, and Section 9 provides a bibliographical list of references.



Aspirin Professional Labeling Proposed Changes Citizen Petition McNeil Consumer & Specialty Pharmaceuticals

3. 3.1.

METHODOLOGY Literature Search Methodology

Three literature searches were conducted for aspirin-related publications for the time period from 1996 through 2004 and included both the MEDLINETM and EMBASETM databases. The following search strategies were used:

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Search #I : 8
Set Sl Items Description

s2 s3 54 s5 S6 s7 S8 s9 SIO Sll S12

24401 35847 314831


DE = descriptor; MAJ = major descriptor; DT = document type; ENG = English language; RD = remove duplicates

Search #2:
Set Sl Items Description

s2 s3 s4 s5 S6 s7 S8

24428 35858 375012


s12 s13 s14 s15 S16 s17 S18 S19 DE = descriptor; MAJ = major descriptor; DT = document type; ENG = English language; RD = remove duplicates




Aspirin Professional Labeling Proposed Changes Citizen Petition McNeil Consumer & Specialty Pharmaceuticals

Search #3:

s2 s3


Items 24428 35858 375012


Of note, three additional publications that did not- meet the criteria defined in the above searches were identified and are also included in this submission for safety information purposes (Serebruany et al., 2QO4; Serebruany et al., 2005 fin~pre$s$ Blot and McLaughlin, 2000). A total of 850 articles were reviewed in detail for relevant content. The 850 articles were classified as follows. Articles were separated whether or not they described the use of aspirin in a cardiovasculqr Articles that described the use of aspirin in a indication. cerebrovascular indication were further classified into those that. from a clinical trial, meta-analysis, or other study and those that review articles, editorials, letters, commentaries, etc. into groups according to and/or cerebrovascular cardiovascular and/or presented primary data were considered to be

For articles that described the use of aspirin in a cardiovascular and/or cerebrovascular indication and presented primary data from a clinical trial, meta-ar$aljrsis or other study, the following information was summarized:



AspiriwProfessional Labeting Proposed Changes Citizen Petition McNeil Consumer & Specialty Pharmaceuticals

Type of article (i.e., clinical trial, metalanalysis, etc.) Indication(s) being addressed by the publication Patient population Number of patients Mean age (or median age) Sex breakdown Treatment groups investigated (including non-aspirin treatment groups) Treatment duration Endpoints Efficacy data Safety data Conclusions Comments Article keywords Articles describing studies that used aspirin in a non-cardiovascular and/or cerebrovascular indication were summarized in the same way and used for safety information purposes if they captured data on bleeding events associated with aspirin. Otherwise, these articles were considered not relevant and were not summarized. For articles that involved the use of aspirin in a cardiovascular and/or cerebrovascular indication that were considered to be review articles, editorials, letters, and commentaries, etc., the following information was summarized:

Type of article (i.e., review, letter, etc.) Conclusions Comments Keywords Efficacy Summary Methodology

0 0


Figure I represents a flowchart of the process used for categorizing articles for the purposes of the efficacy summary.

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1 Flowchart

of Literature Search Methodology

- Efficacy Data

Total Aspirin Articles Reviewed N=850 Not in a Cardiovascular or Cerebrovascular Indication Cardiovascular or Cerebrovascular Indication N=587 Review Article, Editorial, Letter, etc. N=233 --i r Primary Data or Meta-anatysis N=354

Aspirin Dose Unspecified


with Another Agent

* The Supporting Publications grouping also includes publications that did not compare>1 aspirin-alone treatment group within the dose range of 50 to 325 mglday. ** These publications were not considered Key Publications primarily due to study design issues.



Aspirin Professional Labeling Proposed Changes Citizen Petition McNeil Cansumer 8 Specialty Pharmaceuticals

Of the 850 articles reviewed, a total of 587 described the use of aspirin in a cardiovascular and/or cerebrovascular indication. Of these 587 articles, 354 presented primary data from a clinical trial, meta-analysis, or other study. These 354 articles were categorized based on . whether the aspirin dose was specified (264 articles) or unspecified .(90 articles). Articles in which the aspirin dose was specified were further categorized based on whether or not they reported data when aspirin was administered alone (171 articles). or in combination with other agents (93 articles). Finally, the 171 articles that included an’aspirin-alone treatment group were categorized based on whether they presented ciinically relevant efficacy outcome information, resulting in a total of 106 articles. Articles reporting no efficacy data or reporting only efficacy findings ,based on laboratory assessments are not included in this aspirin efficacy summary (65 articles). Per the FDA’ 1998 Final Rule for the Professional tabeling of Aspirin, the current Dosage s and Administration recommendations identify aspirin doses within the range of 50325 mg/day for the following cardiovascular and cerebrovascufar indications: ischemic stroke and TIA, suspected acute MI, prevention of recurrent Ml, unstable angina pectoris, chronic stable angina pectoris, CABG, and percutaneous transtuminai coronary angioplasty (PTCA). For the purposes of this aspirin efficacy summary, we sought to further identify the aspirin dose(s)‘ within the range of 50-325 mg/day that confer the most favorable efficacy profile for aspirin. The 106 articles included in this ISE are classified into three major.groupings. The first two groupings include articies that reported efficacy outcome information for more than one aspirin-alone treatment group, allpwing for a dose-by-dose cornparis& of safety. The first of these two groupings is comprised of 1 article summarizing the results of a meta-analysis in which direct comparisons of efficacy outcome data were made between at least two aspirin-alone treatment groups that fell within the dose range of 50 - 325 mglday (i.e., Key Publication). This grouping forms the basis of this ISE.and the proposed labeling change in the recommended aspirin dose, from 50 - 325 mglday to 75 -199 mglday. The second grouping (i.e., Supporting Publications) is comprised of 6 articles summarizing the results of clinical trials or meta-analyses that either (I) compared -efficacy outcome data for at least two aspirin-alone treatment groups that fell within the dose range of 50 - 325 mglday but, due to study design issues, were not considered Key Publications, or (2) did not compare efficacy outcome data between at least two aspirin-atone treatment groups that fell within Finally, the third grouping is comprised of 99 articles the dose range of interest. summarizing the results of clinical trials, meta-analyses, or other,studies in which efficacy outcome data were presented for a single aspirin-alone treatment group, thereby not allowing for direct comparisons between aspirin doses (i.e., Publications Providing Additional Efficacy Information). The inclusion of this third publication grouping in this submission serves to ensure that all aspirin-related efficacy data in cardiovascular and/or

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cerebrovascular indications published since 1996 are presented; however, it is important to note that these studies were conducted in a wide variety of indications, many of which are not directly relevant for this submission.


Key Publication

The Key Publication presenting efficacy data relevant to the proposed labeling change in the recommended aspirin dose, from 50 - 325 mg/day to 75 - 199 mglday, is the Antithrombotic Trialists’ Collaboration (2002), a large meta-analysis in which direct:comparisons of efficacy outcome data were made between at least two aspirin-alone treatment groups that fell within the dose range of 50 - 325 mglday. Results from the ATC form the bpsis. of this ISE. This meta-analysis included a total of 212,000 patients from 267 randomized trials who were at increased risk of occlusive vascular events. Aspirin was the most widely studied antiplatelet drug in this analysis. Comparisons of different aspirin doses comprise some of the most convincing data to date that low daily doses of aspirin (75 - 150 m&day) are at least as effective as higher daily doses (>ZUO mg‘ /day) in reducing the incidence of non-fatsil Ml, nonfatal stroke, and vascular death. Study features of the ATC meta-analysis are presented in Table 1.

Table 1 Table of Studies - Key Publication
Total Subject s Patient Population Treatme nt Type of Treatment Groups @I) Duration Article Antiplatelet vs. control Not Meta-analysis3


212,000 Patients at IAntithrombotic Trialists’ high risk of (135,000) specified2 Collaboration. occlusive Collaborative metavascular Different antiplatelet analysis of randomised regimens (77,000) trials of antiplatelet events therapy for prevention of death, myocardial Aspirin dose: (~7.5mg infarction, and stroke in to 1500 mg/day)’ high risk patients. British Medical Journal. iI 12002;324(7329) 71-86. I 1. Doses of antiplatelet therapies and controls used in indivjdual studies include! in:the AK m&a-analysis were not specified. Exposure data for each trial included in the ATC meta-anaiysis can be found at www.bmj.com. Of note, aspirin was the most widely studied antiplatelet drug. 2. Duration of treatment of antiplatelet therapies used in studies included in the ATC meta-analysis was not specified iu the article. Exposure data for each trial included in the ATC meta-analysis can be found at bmj.com. Of note, trials that included oral antiplatelet regimens were eligible far inclusion in the metaanalysis only if they had assessed >I day of treatment. Trials of parenteral administration of antiplatelet regimens of any duration were included. 3. Only studies that were believed to have used a randomization method and that contained two randomized groups that differed only with respect to the antiplatelet comparison of interest Were incfuded in the ATC meta-analysis. Details regarding study design for each trial included in the ATC meta-analysis can be found at www.bmj.com.



Aspirin Professional Labeling Proposed Changes Citizen PetStion McNeil Consumer & Specialty Pharmaceuticals




The Supporting Publications grouping is comprised -of 6 articles that either (I) compared efficacy outcome data for at least two aspirin-alone treatment groups that fell within the dose range of 50 to 325 mglday but, due to study design issues, were not considered Key Publications, or (2) did not compare efficacy outcome data between at least two aspirinalone treatment groups that fell within the dose range of interest. Nonetheless, since these publications present efficacy data for more than one aspirin-alone treatment group, they allow for a dose-by-dose comparison of efficacy. Table 2 summarizes the six publications included in this study grouping, as well as the order of presentation throughout the efficacy summary. Table 2. Table of Studies - Supporting Publications

1999;138(lpt.l):137-143. Ferguson SackettDL, ThorpeiE, GG, SimardD, SilverFL, Hachinski V, ClagettGP, BarnesR, SpenceJD. Low-dose high-dose and acetylsalicylic acid for patientsundergoing carotid endarterectomy: randomised a

PetersRJG,MehtaSR, Fox KAA,Zhao F, LewisBS, KopeckySL, Diaz R, Commerford ValentinV, Yusuf S. PJ, Effectsof aspirindosewhen used’ alone or in combination clopidogrel with in patientswith acutecoronary syndromes: observations the from Clopidogrel UnstableAnginato in PreventRecurrent Events(CURE) study.Circulation. 2003;108( 168214): 1687.

Aspirin?01-199mglday+ Clopidogrel Aspirin-alone vs. (3109)2 Aspirin2200 mgldayc Clopidogrel vs. Aspirinalone (43IO)2 Aspirindose:75325 mglday; median:150tqglday3 Clopidogrel: mg loadingdose 300 followedby 75 mgfday

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Aspirin ProfessionalLabeling ProposedChanges

Citizen Pstition McNeil Consumer & Specialty Pharmaceuticals

rable 2. Table of Studies - Supporting


Pkicebo+ Aspirin(4590) (oudstaalPJ, TherouxP, Vande Werf F, SigmonK, PieperK, ValleeM, JVillerson Randomized, JT. doubleolind,placebo-controlled, international Lotrafiban: or 50 mg BID5 30

protection cerebral after ischaemia. Journal Neurology, of Neurosurgery and Psychiatry. 1996;60(2):197-199.

Abbreviations: transient TIA: ischemic attack;ACS: acutecoronary syndrome; PAF:primary’ fibritlation; atrial QOD:everyother day;CAD:coronary arterydisease;BID:twicedaily;ns: not specified 1. Patients all 4 treatment in groupsalsoreceived placebo. 2. Patients the CUREstudywererandomized receiveclopidogrel placebo a$@. In the analysisby Peterset in to or plus al. included this table,patients the CUREstudyweredividedinto treatment in from groupsby aspirindose(<lOO, 101-l99, and2200 mglday)(totalof 6 treatment groups).The numberof patients we+ onlygivenfor the combined treatment groupsat eachaspirindose(e.g.,clopidogrel aspirin1100 mgldayvs. aspirinalone). Number patients + of for the aspirinalonetreatment groups werenot included the article. in 3. The exactdoseof aspirinpatients received determined the Investigator. was by 4. Information obtained the original from publication the CUREtrial:CURETrial Investigators. of Effectsof clopidogrel in addition aspirinin patients acutecoronary to with syndromes withoutST-segment elev&tic?n. England New Journalof Medicine. 2001;345(7):494-502. 5. The doseof lotrafiban dependent ageand creatinine was on clearance. 6. Datafromthe following studieswereincluded the meta-analyses bothAlgraandyan Gijn, 1996andJohnson al., in by et 1999:SALT(1991),UK-TIA(1988,19!31),, Danish Cooperative Study(1983), AlTlA (19771, Canadian Cooperative Study (1978),Reuther Dorndorf and (1978), Swedish the Cooperative Study(IQW), andAlC&A(1983). 7. Number patientsrepresents combined of the numberreceiving aspirinor control.

For this publication grouping, efficacy data from publications of four clinical trials are presented first in each section of the ISE followed by data from two small meta-analyses.

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The publication of the placebo-controlled study by Posada et al. (19$9), which examined the protective effects of low-dose aspirin therapy against cerebrovascular disease when taken daily versus every other day, is presented first. This publication was not considered a ‘ Key Publication’ because, although this study examined the effect of two aspirin dose regimens (every day vs. every other day), the 125 mg dose was used in both regimens. In addition, several study design limitations, including small sample size due to early termination of the study and lower than expected incidence of stroke, confound the results of this study. The second publication in this grouping is that of a controlled trial b,y Taylor et al. (1999), which investigated the relationship between lower versus higher daily doses of aspirin and perioperative complication rates in patients undergoing carotid endatterectomy. Although this trial compared aspirin doses of 81, 325, 650, and 1300 mg/day, the primary analysis of this study was the comparison between the two low-dose groups combined (81 and 325 mg/day) versus the two high-dose groups combined (650 and 1300 mglday). Comparisons between the 81 and 325 mg/day doses and between the 650 and 1300 mglday doses were performed as secondary analyses, but the data were not presented in the publication. In the remaining two clinical trial publications, which include a post-hoc analysis of the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial (Peters et al., 2003) and a summary of efficacy data from the Blockade of .the Glycoprotein Ilb/llla Receptor to Avoid Vascular Ccclusion (BRAVO) trial (Top01 et al., 2003), aspirin combined with another antiplatelet medication (CURE) or a glycoprotein IlblWa antagonist (BRAVO) was the primary comparison of interest. In both trials, control groups included patients who received aspirin alone, allowing the effect of a range of aspirin doses on cardiovascular and cerebrovascular outcomes to be evaluated. However, subjects enrolled in both the CURE and the BRAVO trials were not randomized to different aspirin doses, but rather received aspirin at a dose determined by the Investigator, thereby limiting their usefulness in assessing the efficacy of aspirin. Finally, efficacy data from publications of two meta-analyses are presented. In the analysis presented by Algra and van Gijn (1996) the effect of different aspirin doses on the composite endpoint of vascular death, stroke, or Ml was evaluated using data from patients in IO randomized studies, most of which were placebo-controlled. Johnson et al. (1999) performed a similar analysis using a similar patient population from. I ? randomized, placebocontrolled studies to evaluate the dose-response relationship between aspirin and stroke. It should be noted that significant overlap in trials included in then two meta-analyses exists including data from SALT (1991), UK-TIA (1988, 1991) Danish Cooperative Study (1983), Aspirin in Transient lschemic Attacks (1977), Canadian Cooperative Study (1978) Reuther and Dorndorf (1978), the Swedish Cooperative Study (1987) and Bousser et al. (1983).

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Furthermore, the majority of trials included in these two analyses wore also included in the much larger ATC meta-analysis and are, therefore, considered to be “Supporting Publications.” 3.2.3. Publications Provic#ing Additional Efficacy lnformatiqn

The publications providing additional efficacy information include 99 articles summarlsing the results of primary data from a clinical trial, meta-analysis, or other study in which efficacy data are presented for a single aspirin-alone treatment group. These articles describe a wide range of studies including clinical trials, meta-analyses, case studies, retrospective studies, population studies, follow-up studies and observational studies. A summary of study and patient characteristicsifor the publications included in this grouping is presented in the Table of Studies in Appendix 1. A discussion of the efficacy data from the publications included in this grouping is provided in Section 6.3 and a tabular presentation of the efficacy data is provided in Appendix 2 of this ISE. However, it is important to note that meaningful comparisons of efficacy across the different publications are difficult, primarfly due-to differences in the methods of deriving and presenting efficacy data across studies (e.g., incidence rates, relative risks, annualized event rates, odds ratios, hazard ratios, etc.), differences in study-specific endpoints (e.g., a variety of individual and composite endpoints), and differences in treatment durations. The inclusion of this publication grouping in this submission serves to ensure that all aspirinrelated efficacy data in cardiovascular and/or cerebrovascular indications .published since 1996 are presented; however, it is important to note that these studies were conducted in a wide variety of indications, many of which are not directly relevant for this submission.






This section provides a brief overview of publications included in this ISE in terms of study design characteristics (patient population, study objectives, inclusion and exclusion criteria, treatment groups) efficacy endpoints, and statistical methodology. All descriptions were derived directly from the methods section of each publication; 4.1. 4.1.1. Key Public&ion Antithrombotic Trialists’ Collaboration, 2002

The Antithrombotic Trialists’ Collaboration (2002) meta-analysis was based on data from 212,000 patients in 287 randomized studies. The primary objective of the analysis was to determine the effects of antiplatelet therapy among patients at high annual risk (over 3% a

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year) of vascular events based on evidence of pre-existing disease (previous occk~sive event or predisposing condition). Relevant trials were identified by searching electronic databases (MEDLINETM, EMBASETM, DERWENTTM, SCISEARCHTM, and BIOSISTM) and the trial registersof the Cochrane Stroke and Peripheral Vascular Disease Groups. Trials were also identified by manual searching of journals, abstracts, and meeting proceedings, as well as reference zlists of trials; and review articles, and by inquiry among colleagues. The goal was to identify all trials, published or otherwise, that were available by September 1997 and that cqmpared an antiplatelet regimen with a controt or a different antiplatelet regimen. All studies included in the analysis were believed to have used a randomization method that precluded prior-knowledge of the next treatment to be .allocated and wet-e “unconfounded” (i.e., contained two randomized groups that differed only with respect to the antiplatelet comparison of interest). Trials involving oral antiplatelet regimens were eligible only if they had assessed more than, one day of treatment, but trials of parenteral antiplatelet regimens of any duration were included. Details about method of randomization, blinding of treatment allocation, duration of treatment, .and duration of follow-up (if different) were obtained f6r all potentially eligible trials. In addition, a tabular summary of the number of patients originally allocated to each treatment group (without any post-randomization exclusions) and the number of patients experiencing particular outcomes during the scheduled follow-up pe&d were obtained. For trials that had randomized 2200 patients, individual patient data (baseline characteristics, dates of randomization, follow-up, and any vascular events that had occurred) were collected. Analyses were based on data from 197 studies involving 135,000 patients where antiplatelet therapy was compared to a non-antiplatelet control group, and from 90 studies involving 77,000 patients where comparisons were made between different ‘ antiplatelet therapies. Aspirin was the most widely studied antiplatelet drug. The primary measure of outcome was a “serious vascular event” (i.e., non-fatal mydcardial infarction, non-fatal stroke, or death from a vascular or unknown cause [most deaths in high risk patients are likely to be due to Deaths were divided into those with a vascular cause (cardiac, vascular causes]). cerebrovascular, venous throrpboembolic, hemorrhagic, .other vascular, or unknown cause) and those that were considered to be definitely non-vascular in nature. Strokes were subdivided irito intracranial hemorrhages (intracerebral, subdural, subarachnoid, and extradural hemorrhages) and strokes of ischemic or unknown etiology.



Aspirin’ Professional Labeling Proposed Changes Citizeri Petition McNeiI Consumer & Specialty Pharmaceuticals

No demographic data were presented for the patients included in the meta-analysis. Information regarding patient characteristics can be obtained from jndividual trials included in the analyses and referenced in th,e ATC publication. Proportional and absolute effects of antiplatelet treatment were determined. Analyses were stratified by trial to avoid direct comparisons between individuals in different studies. The typical odds ratio for these trials was calculated by the one step method from b = (0-E)N, either as exp(b) or, for rare events, as (2 + b)/(Z-b). Additional details regarding study design and statistical meta-analysis can be found in the original publication. 4.2. Supporting Publications methods employed in this

In addition to the brief description of study design for this grouping of publications, patient characteristics, including patient population, age, and sex are summarized in Table 3 below. The data presented in Table 3 represent patients exposed- to aspirin atone. ,
Table R. . Sllmmsrv nf Patinnt Char~&xkticn - Suannrtina Publicatinnn


_. - .Abbreviations: TIA: transient ischemic attack;ACS: acutecoronary syndrome; PAF:primaryatria1 fibrillation; CAD:

coronary arterydisease; not specified ns: 1. Medianagewas 69 yearsin all 4 treatment groups. 2. Represents totalnumberof patientsrandomized the placebo aspirin-alone) the to (Le., treatment groupperthe originalpublication the CUREtrial:CURETrial Investigators. of Effectsof ctopidogrel additionto aspirinin patients in with acutecoronary syndromes withoutST-segment elevation. England New Journalof Medidine. 2001;345(7):494502. 3. Meanagewas not specified the analysisby Peterset al., 2003,andwas obtained in from the.original CUREstudy. 4. Includes patients randomized aspirinplusplaceboor aspirinplusclopidogrel. to



Aspirin Professional Labeling Proposed Changes Citizerr Petition McNeil Consumer & Specialty Pharmaceuticals


Posada et al., 1999

The study by Posada et al. (1999) was a multicenter, randomized, placebo-controlled study of open-label aspirin in adult patients with ,primary atrial fibriltation (PAF). Patients were evaluated over a mean period of 550 days. The primary objective of the study was to evaluate the cardiovascular and cerebrovascular protective effects of low-dose aspirin (I 25 mg) administered daily versus on alternate days. There were a total of 285,patients enrolled in the study. Not included were patients who had general contraindications for the use of aspirin (peptic ulcer, symptomatic hiatus hernia, aspirin hypersensitivity), an accepted indication for the use of oral anticoagulants (vascular prosthesis, cardiac intracavity thrombus, spontaneous echoes), or an indication for antiplatelet treatment before entry into the study, such as previous,episodes of angina, Ml, or TIA. Patients were randomly assigned to one of three treatment groups and received 125 mg aspirin daily, 125 mg on alternate days, or placebo. There was a slightly higher percentage of males than females among patients taking 125 mg of aspirin baly compared to those taking 125 mg every other day (QOD) or placebo. Mean age &as approximately 66 to 67 years across the treatment groups. As expected, 80% or more of patients in al treatment groups had constant atrial fibrillation and approximately 50% had arterial hypertension. Approximately 7-l I % of patients in each group had an implanted pacemaker.> Endpoints included the following: (I) global and cardiovascular mortality rates across the 3 treatment groups; (2) cerebrovascular accident of any kind, including thrombotic, embolic, or hemorrhagic (severity was classified according to the criteria of .the European Stroke Prevention Study; ESPS Group, 1987); (3) other embolic events, including acute episodes of mesenteric ischemia or peripheral embolism; and (4) MIS, the need for coronary surgery, or admissions to the hospital due to episodes of unstable angina. .The incidence of stroke, MI, cardiovascular death, and the need for coronary surgery, were considered as a composite of major cardiovascular events. Data from the three treatment groups were compared by actuarial curves. The Wilcoxon test and chi-square distribution log rarik test were used for the analysis of significance in the differences observed. The data were analyzed with the intention-to-treat method. 4.2.2. Taylor et al., 1999

The study by Taylor et al. (1999) was a multicenter, randomized, double-blind, controlled trial of aspirin at doses of 81, 325, 650, and 1300 mg/day in adult patients who were scheduled to undergo carotid endarterectomy for arteriosclerotic” djsease. Patients were treated with aspirin prior to and for three months following surgery.’ The primary objective of

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the study was to evaluate differences in the occurrence of penoperative complications (stroke, Ml, and death) at 30 days and three months after surgery among patients receiving four different doses of aspirin. The study also evaluated the safety of aspirin at the above doses by assessing bleeding complications. A total of 2804 patients were enrolled (2800 patients planned) at 74 canters in the United States (48), Canada (19), Australia (4), Italy (I), Argentina (I), and,Finland (1). Patients who were taking aspirin or any other antiplatelet medication that could not be stopped, had had a recent disabling stroke, or had undergone cardiac surgery in the previous 30 days were excluded from the study. Prior to randomization, a medical history was taken and patients underwent physical, neurological, and functional-status assessments. A randomization schedule stratified by center and balanced every i2 .patients was used to assign patients to one of four aspirin treatment groups. Patients received 81’ 325, 650, or , 1300 mg/day aspirin, plus placebo. Almost all patients in each of the, four aspirin treatment groups (81, 325, 650, or 1300 mg/day) were Caucasian (95%) and approximately 70% of patients were male. The median age in all treatment groups was .69 years. Approximately 46% of patients (1292 of 2804) in each dose * group had had ischemic carotid-territory symptoms in the preceding 6 months and 54% (1512 of 2804 patients) were symptom-free. The effect of aspirin dose on perioperative complication rates wes measured by the occurrence, of strokes, MIS, and death. Neuroiogical assessments were performed on discharge from the hospital and at 30 days and three months after.surgery. Cross-sectional brain imaging was performed if cerebrovascular events were suspected, at the discretion of the neurologist and surgeon. All reports of these events were assessed by an adjudication committee masked to treatment” group and. chaired by the prinoipal study neurologist. Deaths were assessed for underlying cause. Strokes were assessed for territory, type, severity, and duration. Stroke severity was based on the modified Rankin scale (scores: 1, mild; 2,,moderate; 3, severe) (de Haan et al., 1995) at the final 3-month follow-up assessment. The planned composite endpoints were as follows: all strokes, MIS, and deaths; all strokes and deaths; and ipsilateral strokes and deaths. The primary analysis compared the two high dose groups (650 and 1300 mglday) with the two low dose groups (81 and 325 mg/day) with Pearson’ x2 test, Comparisans between s the 81 and 325 mg/day doses and between the 650 and 1309 mglday doses were performed as secondary analyses. All reported p-values were two-Wed. 4.2.3. Peters et al., 2003

This post-hoc observational analysis of the CURE study presented by Peters et al. (2003) was a randomized, double-blind, placebo-controlled study’ that was’ designed to evaluate the


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benefits and risks of adding clopidogrel to different- doses of aspirin in patients with acute coronary syndromes (ACS). A total of 12,562 patients from 28 countries were enrolled in the study. To be included in the study, patients had to have symptoms indicative of ACS within 24 hours of study entry without ST-segment elevation >I mm on the electrocardiogram (ECG). In addition, ECG evidence of new ischemia or concentrations of cardiac’ enzymes (including troponin) at two times the upper limit of normal was required. Patients were excluded. if they had New York Heart Association class IV heart failure, if they had undergone percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in the previous three months, if they had contraindications to antithrombotic or antiplatelet therapy, if they had previous disabling or hemorrhagic stroke or intracranial hemorrhage, if they’ had clinically severe thrombocytopenia, if they used or required oral anticoagulants pr nonstudy antiplatelet agents, or if they had received a glycoprotein Ilb/llla receptor (GP Ilb/llta) inhibitor fewer than 3 days prior to randomization. Patients were assigned to receive clopidogrei or placebo. A loading dose of 300 mg oral clopidogrel or placebo was given, followed by ,75 mg/day clopidogret or placebo. Aspirin was coadministered with both clopidogrel and placebo. The dose of aspirin was left to the discretion of the Investigator but a 75-325 mglday dose was recommended per the protocol. Patients were treated for an average of three to 12 months (mean: 9 months). The percentage of males in the three aspirin dose groups ranged from 58.8 to 65.4% and mean age was 64.2 years. Over 50% of patients had hypertension. In each dose group, approximately one-third of patients had a previous Ml and 10 to 15% had a history of CABG. The first co-primary endpoint was the combined incidence of cardiovascular death, Ml, or stroke. The second co-primary endpoint was the composite of cardiovascular death, MI, stroke or refractory ischemia. The risk of major and minor bleeding was also assessed. For analysis, patients were divided into three groups based on daily aspirin dose at the time of randomization (<lOO, 101-199, or 2200 mglday). All hazard ratios (HRs) and 95% Cls for primary and secondary outcomes comparing clopidogrel and placebo were derived by use of the Cox proportional hazards model. Efficacy HRs were adjusted for sex, weight, hypertension, components of the Thrombolysis in Myocardial Infarction (TIMI) risk scores (Rao et al., 1988), and rates of angiogrephy, PCI, and CABG,



Asp+ Professional Labeling Proposed Changes Citizen Petition McNe’ Consumer & Specialty Pharmaceuticals il


Top01 et al,, 2003

The BRAVO study presented by Top01 et al. (2003) was a randomized, double-blind, placebo-controlled, study of lotrafiban, an oral GP llblllla antagonist, in patients with coronary and cerebrovascular disease. A total of 9190 patients from 23 countries were enrolled in the study* Patients were included if they had prior Ml or unstable angina-within 14 days of Baseline, ischemic stroke 5-30 days after the acute event, a TIA within 30 days, or “double bed” vascul,ar disease defined as documented peripheral vascular disease (PVD) combined with either coronary or cerebrovascular disease. Patients were not eligible for the study if they had a predisposition to bleeding, suboptimal blood pressure control, intolerance or allergy to aspirin, recent use of an intravenous GP Ilb/llla antagonist, or need for therapy with watfarin or a thienopyridine drug. At the time of enrollment, almost 50% of patients had-cardioVascul,ar disease (Ml and unstable angina), approximately 36% had cerebrovascular disease (TIA and stroke), about 1 +I% had PVD and cardiovascujar disease, and 5% had PVD and cerebrovascular disease. The majority of patients who participated in the study were Caucasian (93.5%) and 71.2% were male. Mean age was approximately 62 years. Patients were assigned to receive lotrafiban or placebo. The dose of lotrafiban was either. 30 or :50 mg twice daily (BID) depending on age and creatinine clearance. Aspirin at doses of 75-325 mg/day was administered concomitantly, with the exact dose determined by the Investigator. Follow-up was for up to two years. The primary efficacy endpoint was the composite of death, Ml, stroke, ,recurrent ischemia requiring hospitalization, and urgent revascularization. The incidence of serious bleeding, any bleeding, or any transfusion was also assessed. No statistical methods from the publication of the BRAVO study ,are included in the ISE since only incidence of efficacy endpoints is discussed. 4.2.5. Algra and van Gijn, 1996

Algra and van Gijn (1996) conducted a meta-analysis of stroke that included data from IO randomized trials (these trials were among the 18 studies included in the second cycle of the Antiplatelet Trialists Collaboration, 2002). The purpose of the an’ alysis was to evaluate the relative efficacy of low (<IO0 mg/day), medium (300 mglday), ‘ and high (1900 mglday) doses of aspirin in patients following a TIA or non-disabling stroke. Trials in which aspirin-only was compared with -control treatment were selected for the analysis. The IO studies contributed a total of 6171 patients to the analysis and all of the studies were placebo-controlled with the exception of the Toulouse’ TiA trial. The mean age



Aspirin Professional Labeling Proposed Changes Citizen Pefifion McNeil; Gansumer & Specialty Pharmaceuticals

of patients across the studies ranged from 59-68 years. Information on sex was not presented in this publication. The percentage of patients with a TIA at ‘ baseline ranged from O-l 00% across studies. The primary efficacy measure was the composite’ outcome of vascular death, stroke, or Ml. The relative risk and corresponding relative risk reduction [(I - rejative risk) x 100) were used as the effect measure. Data from the different trials were combined by means of the Mantel-Haenszel method. Cumulative meta-analysis by date of publication was performed according to methods referenced in the original pubkcation. Poisson regression was used to test for statistically significant differences in the efficacy of low, medium, and high doses of aspirin. 4.2.6. Johnson et al., 1999

Johnson et al. (1999) conducted a meta-regression analysis of stroke using’ data from I I published randomized, placebo-controlled secondary prevention trials. The primary. objective of the analysis was to evaluate the dose-response relationship between aspirin and stroke in high risk patients. Regression methods were used toevaluate the stroke risk reduction per milligram of aspirin across a broad range of doses (50-1500 mg/day). Relevant trials were identified by Medline searches and by consulting reference lists of reviews to identify additional articles. All studies included in the analysis had an aspirin-only treatment arm, reported the occurrence of stroke alone, and were .pubiished through April 30, 1996. The 11 studies contributed a total of 9629,patients to the analysis with 5228 randomized to aspirin-only treatment groups (50-1500 mg/day) and 4401 randomized to placebo only. Ten of the studies included only patients who had :a history of at least one recent TIA or stroke. In the remaining study 94% of the patjents Iin both the aspirin and placebo treatment arms had had a previous TIA or stroke. Consequently all 11 studies were considered secondary prevention trials. Data on demographics, inclusion and exclusion criteria, treatment ( regimen, duration of follow-up, and stroke were abstracted from published data only, and from aspirin-only andplacebo-only treatment arms. A total of 63.3% of patients were male and mean age across the studies was 63 years (range: 59-73 years). Detailed information an the number of patients’ with stroke was also obtained. Stroke was diagnosed #n part on the: basis of symptoms, with most of the studies requiring symptoms of at least 24 hours duration. Information was abstracted from the studies to conduct an intentionto-treat meta-regression analysis, the primary analysis in most of the published studies. Accordingly, outcome data represent the number of patients who experienced an outcome of interest among all randomized subjects. Most studies attempted to follow-up all patients,for the duration of the

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study regardless of whether patients experienced an event of interest or withdrew for another reason. Events that occurred after study withdrawal or medjcation discontinuation were included in the meta-analysis whenever reported. The average follow-up period was 32 months. Risk ratios for stroke were estimated by constructing contingency tables based on the number of patients randomized and the number of patients experiencing events. Summary effect estimates adjusted for study with the Mantel-Haenszel estimator and 95% Cls were Weighted least-squares linear regression was used to evaluate variation calculated. between studies, to model, the risk ratio as a function of aspirin dose in milligrams, to test for trends, and to graph the predicted dose-response curve. The dependent variable for the regression was the natural log of each study-specific RR for stroke, weighted by the inverse of its variance. 4.3. Publications Providing Additional Efficacy Information

The 99 publications included in this grouping describe a wide range-ofstudies (clinical trials, meta-analyses, case studies, retrospective studies, population s&dies, follow-up studies and observational studies) in a variety of patient populations. In general, the patient populations consisted of males and females who were diagnosed with various cardiovascular and/or cerebrovascular conditions or who were considered to be at risk for such conditions. The studies also included patients in a wide array of’ age groups, ranging, from children aged between seven months and <+l8 years to elderly patients aged 175 years. A summary of general study and patient characteristics for the publications included in this grouping is presented in the Table of Studies in Appendix 1.

5. 5.1. 5.1.1.

SUMMARY OF SUBJECT ACCOUNTABILiTY Key Publication Antithrombotic Trial&is’ Collaboration, 2002


The publication of the ATC meta-analysis included data from comparisons of several different antiplatelet medications and treatment regimens. Table 4 represents exposure data for the comparisons relevant to this aspirin efficacy summary. These include meta-analyses using data from,clinical trials in which different aspirin doses were compared to controls or meta-analyses using data from clinical trials in which more than one aspirin dose was investigated. Data presented in the table were derived directly from figures presented in the ATC publication and include information for patients exposed to aspirin only.

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Table 4. Summary of Subject Acqountability
Reference ATC, 2002 N’ 29,652 Aspirin Doses*

and Exposure to Aspirin - ATC, 2002
Numberof Patients Exposed’ Durationof Exposure

ns ~75mglday 18272 75-150 mglday 33702 160-325 mglday 13,2402 500-I500 mglday 12,21526767 275 mgldayvs. 75-325mglday3 17954 17754 ns 500-1500 mgldayvs. 75-325mgldap 25884 16084 Abbreviations: not specified; versus ns: vs.: 1. Exposure presented from 2 separate data are comparisons presented the ATC. fie first included in m&a-analyses usingdatafrom clinicaltrialsin whichdifferent aspirindoseswerecompared controls(N=29,652). second to The included meta-analyses datafromclinicaltrialsin whichmorethanone aspirindosewas investigated using ’ (N=6767).Datapresented represents patients exposed aspirinonly. to 2. Patientsmay havecontributed morethan 1 dosecomparison. to 3. Includes trialscomparing 2 75-325 ~75 mgldayand 1 trial of 500-1500 475 mglday. vs. vs. 4. Represents number patients eachaspirintreatment of in regimen (e.g,,275 mgldayvs.75-325mglday). 5. Includes1 trial comparing 1400vs. 350mgldayand another (excluding patients acutestroke)comparing with 1000vs. 300mgldayamongpatients werealso givendipyridamole. who

In the meta-analyses using data from clinical trials in which differentaspirin doses were compared to controls, a total of ,29,652 patients from 65 trials were exposed. to doses of aspirin that ranged from ~75 to 500-1500 mglday, as shown in Table 4. Neta-analyses using data from clinical trials in which more than one aspirin dase was investigated included a total of 6767 patients from IO’ clinicaf trials. These patients wereexposed to aspirin doses 275 mg/day versus 75-325 mgtday or 500-I 500 mglday versus 75-325 mg/day. 5.2. Supporting Publications

A brief description of subject accountability and exposure to aspirin is presented for each publication and summarized in Table 5 below. The data presented in the.table represent patients exposed to aspirin alone, unless noted otherwise.

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Table 5. Summary of Subject Accountability Publications

and Exposure to Aspirin - Supporting

and continued for

815 1200mglday 232 1300mglday 282 1500niglday .. I .+. . a-..* . .. Aoarevlatlons: not specrnea; ns: uuu: everyotnerclay I. Represents totalnumber patients the of randomized the placebo aspirin-alon&) to (i.e., freatment groupperthe originalpublication the CUREtriat CURETrialInvestigators. of Effectsof clopidogrel,in,additionaspirinin to patients acutecoronary with syndromes withoutST-segment elevation. Engtan$l New Journalof Medicine. 2001;345(7):494-502. 2. The number patients of exposed aspirindosewas not presented the publicatioh Peterset al, 2003. by in by Patients represented the aspirintreatment in groupsinclude thosewhoweretakiqg!spirin aloneand aspirinplus clopidogrel. exactdoseof aspirinpatientsreceived at the discretion the Inv&iga!or. Dosesin the range The was of of 75-325 wererecommended the studyprotocol. mg in 3. Duration exposure the originalpublication the CUREtrial:CURETrialOnve@$$ors. of per of Effectsof clopidogrel in addition aspirinin patients acutecoronary to with syndromes withoutST-segmeti~elavation. England New ’ Journalof Medicine. 2001;345(7):4&l-502. 4. Patients the BRAVOstudyreceived in placebo plusaspirin lotrafiban aspirin.The exactdoseof aspirin or plus patientsreceived at the discretion the ‘ was of investigator (75-325 mglday).

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Posada et a!., 1999

Patients participating in the study were exposed to 125 mg aspirin daily (N=104) or on alternate days (N=90) for a mean evaluation period of 510 and 600 days, respectively. 5.2.2. Taylor et al., 1999

Patients were exposed to 81 mg (698 patients), 325 mg 1697 patients), 650 mg (703 patients), or 1300 mg (706,patients) daily for a duration of 3 months. Compliance was >90% at the 30-day assessment and ranged from 86 to 89% at the 3-month assessment. Of note, approximately two-thirds of patients in each ,treatment group were taking ~650 mglday of aspirin prior to study entry and 11% to 14% of patients in each ,aspirin dose group were taking 2650 mglday. 5.2.3. Peters et al., 2003

Patients included in the post-hoc observational analysis of the CURE study data were exposed to a median aspirin dose of 150 mglday. The CURE study recruited patients from 482 centers in 28 countries (2001). Aspirin dosing varied among” regions with the highest dose (2200 mglday) most common in North and South America. Use of the medium dose (101-199 mglday) was common in Australia and New Zealand, and use of the lowest dose (5100 mg/day) was common in Eastern and Western Europe. Within each center, the variation in aspirin dose was small. An average of 89% of all patients per center used a dose of aspirin within 50 mg of the most frequently used dose. Aspirin dose per patient varied little during the course of the study. Only 14% of patients used a-dose that differed by at least 50 mg from the initial dose for >50% of the duration of follow-up (mean: 9 months; CURE, 2001). As noted previously, data presented for each aspirin dose group in Table 5 represents patients taking aspirin alone and aspirin plus clopidogrel. 5.2.4. Top01 et al., 2003

A total of 4589 patients in the placebo plus aspirin treatment groups of the BRAVO study were exposed to doses of aspirin that ranged from 75-32.5 mg/day’ for up to two years (75162 mg/day: 2410 patients; >I62 mglday: 2179 patients). A dose reduction was required in 4.6% of patients in this treatment group and 22.9% of patients ,prematurely discontinued study medication. Reasons for premature discontinuation included major (1.6%) and minor (2.6%) bleeding. The length of follow-up was 366 days (median) (includes patients in both the placebo plus aspirin and lotrafiban plus aspirin treatment groups; 25* and 75’ h percentiles, respectively were 279 and 463 days in the placebo plus aspirin treatment groups).

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Algra and van Gijn; 1999

In the meta-analysis presented by Algra and van Gijn (1999) a to@t of 3482 patients from * 10 trials received <IO0 mg/day (N=826), 300 mg/day (N=806), or 29QO mglday (N=1850) of aspirin, as presented in Table 5. Duration of exposure for each aspirin dose was not specified in the meta-analysis but is available from publications of the individual studies referenced in the article. 5.2.6. Johnson et al., 1999

Among the 5228 patients from II trials included in the meta-analysis presented by Johnson et al. (I 999), exposure to aspirin alone ranged from a low of 50 mg/day to a high of 1500 mglday, as outlined in Table 5. The average follow-up was 32 months. 5.3. Publications Providing Additional Efficacy .lnformatkm

The publications providing additional efficacy information -included a wide range of study sizes and treatment durations. For the individual studies included In this grouping, the total number of subjects exposed ranged from a small case study of eight patients (Derksen et al., 2003) to a large clinical trial of 21,106 patients (Chinese Acute Stroke Trial [CAST] Collaborative Group, 1997). For the meta-analyses included in this grouping, the ‘ total number of subjects exposed ranged from 1002 patients in seven trials (Tangelder et al., 1999) to a large meta-analysis of 55,462 patients in 16 trials (He et :al., $998). Aspirin doses utilized in the individual studies or in the studies included in the meta-analyses ranged from 50 to 990 mg/day with a duration of treatment (where specified} ranging from a mean of one day up to 12 years. Summaries of subject accountability and extent of exposure for the studies included in this grouping are presented in the Table of StudBees Appendix I. in

6. 6.1. 6.1.1.

SUMMARY OF EFFICACY INFORMATION Key Publication Antithrombotic Trialis&? Collaboration, 2002

As noted previously, this aspirin efficacy summary and the efficacy data relevant to the proposed aspirin dose labeling change from 75-325 mgtday+. to 75-150 mglday for cardiovascular protection and from 50-325 mglday to 50-150 mg/day for cerebrovascutar protection are primarily based on the findings from the ATC metaranalysis, which included data from 212,000 patients in 287 randomized trials who were at increased risk of occlusive vascular disease. The overall objective of the analysis was to evaluate the effectiveness of


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various antiplatelet regimens in ‘ preventing serious vascular events {non-fatal MI, non-fatal stroke, and vascular death). Aspirin was the most widely studied antiplatelet drug in the Because the efficacy of low-dose aspirin in cardiovascular and ATC meta-analysis. cerebrovascular indications is the focus of this Petition, only data generated from comparisons of one aspirin regimen versus another aspirin regimen (~75 mg/day vs. 275 mg/day and 75-325 mg/day vs. 500-1500 mgiday) or different aspirin doses versus no aspirin (controls) (~75 mglday, 75-15O.mg/day, are discussed in this aspirin efficacy summary. Comparison of Aspirin Doses Across Studies Comparison of the incidence of vascular events across 65 trials (59,395 patients) in which different aspirin doses were compared to controls (no aspirin) .reve,aled that no particular range of aspirin dose 275 mg/day was preferable for the prevention of serious vascular events, as shown in Table 6. The proportional reduction (% odds reduction)’ in vascular events was similar for doses of 75-I 50 mglday (32%), 160-325 mg/day (26%), and 5001500 mglday (19%), suggesting that there is no difference in the,oscurrence of vascular events in patients treated with lower versus higher doses of aspirin. At doses ~75 mglday, the incidence of vascular events was higher and the proportional reduction was lower (13%), suggesting that doses of aspirin below 75 mg/day may be lesseffective in preventing vascular events. It should be noted that data generated for the 475 mglday aspirin dose were derived from only three studies. 366-325 mglday, ‘ and 500-1500 mglday)

Abbreviations: standard SE: error 1. Includes from high-risk data patients exceptthosewith acutestroke. Onlymeta-analyses involving patients 500 or moreare represented the table. in 2. Controlsincludepatients did nbt receiveaspirin. who 3. Sometrialscontributed morethan 1 comparison. to

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Direct Comparison of More Than One Aspirin Dose Within Studies A separate meta-analysis was also conducted using data from clinical trials in which more than one aspirin dose was investigated and the results are presentgd .in Table 7. Data from 3570 patients in three trials showed that there wa&also no sigMicant difference in the incidence of vascular events when doses of aspirin 175 mg/day (14.2%) were directly compared with doses ~75 mg/day (13.2%). Similar results were ,bbserved when 5001500 mglday (14.1%) doses were directly compared with 75-325 mglday doses (14.5%) using data from 3197 patients in seven trials. As expected, the proportional reduction in vascular events was small in both comparisons (3% and -8%, respectively). More importantly, this small proportional reduction in events strongly suggests that the lower doses of aspirin used in these comparisons are as efficacious as higher doses in this patient population. Table 7. Incidence and Proportional, Reduction in Vascular Ewnts From Comparisons of Different Aspirin Regimens’ - ATC, 2002

500-I500 vs. 75-325 mglday3

Subtotal 10

(14:5%) 46513364 (13.8) -3 (7)

48113403 (14.1)

Abbreviations: versus is.: I, Includesdatafrom high-riskpatientsexceptthosewith acute stroke. Only nieta-a@ysesinvolving500 patients or moreare represented the table. in 2. Includes trials comparing 2 75-325 vs. c75 mgldayand I trial of 500-1500vs. ~75 mglday. 3. Includes1 trial comparing1400vs. 350 mgldayand another(excluding patientsti;th acute stroke)comparing 1000vs. 300 mgldayamongpatientswho were also givendipyridamole.

In conclusion, the resultsof these analyses from the.ATC verify that lower doses of aspirin (50-I 50 mg/day) are as effective as higher doses in preventing :serious vascular events among high-risk patients. 6.2. Supporting Publications

A by-publication summary of efficacy results from the four clinical trials and two meta-analyses that provide other relevant efficacy data to suppprt the .proposed aspirin labeling change from 75-325 mglday to 75-150 mg/day for cardiovascular protection and from 50-325 mglday to 50-150 mg/day for cerebrovascular protection are discussed below.

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Posada et al., 1999

The placebo-controlled study presented in the publication, by Posada et al. (1999) examined the protective effects of low-dose aspirin therapy (125 mg) whentaken daily versus every other day in a high-risk population of patients with PAF. Table 8 summarizes absolute and relative risk reductions for daily and alternate-day aspirin dosing in this study.

Table 8 Absolute and Relative ,J%isk Reductions for Daily and qlternate Day Aspirin Dosing - Posada et al., 1999 ’

Abbreviations: QOD: everyotherday; ARRi absoluterisk reduction; RRR:relativerisk re&otion; $3: not significant I. Majorcardiovascular eventsincludea composite stroke,MI, cardiovascular of death,tid need-forcoronary surgery. 2. P-valuefor trendshowingsurvivalfree from each corresponding event.

A total of 19 deaths occurred these deaths were considered groups were compared using observed in the alternatelday cardiovascular mortality.

during the 550-day (mean) evaluation period. Thirteen (13) of to be of cardiovascular origin. When data from the treatment actuarial curves, a reduction in the overall mortality rate was dosing group compared to placebo because of a decrease in

There was an 80% relative reduction in cardiovascular mortality when patients taking aspirin on alternate days (1 .I%) were compared to placebo (6.6%) (p=O.O2), as shown in Table 8. The trend for survival free from cardiovascular mortality demonstrated no difference between the aspirin daily and alternate-day dosing groups (p=O.6). No difference in the cardiovascular mortality rate was observed between the dally dosing (4.8%) and placebo treatment groups (6.6%).

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Four (4) patients taking aspirin’ daily (3.8%), 1 patient (I .?%) taking aspirin. on alternate days, and 3 patients (3.3%) taking placebo suffered a stroke. There was a significant difference in the occurrence of stroke in the alternate-day dosing. group compared to placebo (p=O.O5). The trend for survival free from stroke demonstrated no difference between the aspirin daily and alternate-day dosing groups {p=O,4). When the composite endpoint of occurrence of cardiovascul& events (stroke, Ml, cardiovascular death, and need for coronary surgery) was compared across, the treatment groups, there was an 80% relative reduction among patients taking 125 mg on alternate days (2.2%) compared with those taking placebo (I 1.0%; p=O;OOl). There was no difference in occurrence of major cardiovascular events between patjents taking aspirin daily (7.7%) and placebo (11 .O%). The trend for survival free from major oardiovascular events demonstrated no difference between the aspirin daily and alternate-day dosing groups (p=O.8). Based on these analyses, the authors conclude, that 125 mg aspirin taken every other day appeared to be effective in preventing major cardiovascular events -$mong high-risk patients with PAF. However, these results should be interpreted carefully for several reasons. First, the authors’ conclusions, are based on comparisons between aspirin and placebo treatment groups which demonstrate a significant reduction in cardiovascular mortality, stroke, and major cardiovascular events among patients taking aspirin on alternate days. When the more relevant comparisons of alternate versus daily dosinglwere performed, no statistically significant difference between the treatment groups was observed for any of these endpoints. The study also has limitations due to the relatively small -sample size, resulting from early termination of the study, and the low incidence of stroke that occurred over the 2-year treatment period, making it difficult to draw meaningful-: conclusions from data comparisons. A 12% incidence of stroke was expected; however the observed incidence was only 3.3% among patients receiving placebo .after 12 months. Thus, the study population was at intermediate rather than at high risk of stroke. 6.2.2. Taylor et al., 1999

In the study presented by Taylor et al. (1999), the relationship, between low (81 and 325 mg/day) versus high (650 and 1300 mglday) doses of aspirin and perioperative complication rates in 2804 patients undergoing carotid endarte$eotomy was examined. Treatment with aspirin was started prior to surgery and continueo for three months postsurgery. Table 9 summarizes failure rates at ,30 days and, three months after carotid endarterectomy for the efficacy analysis population and for all patients by dose of aspirin.



Aspirin Professional Labelina Proaosed Chanaas . C&err Petition McNeil Consumer & Specialty Pharmaceuticals

Table 9, Failure Rates at 30 Days and Three Months after Caroiid Endarterectomy Aspirin Dose - Taylor et al., 1999


All Patients Numberof patients Any stroke,MI, or death: 30 days 75 (5.4%) 3 months 87 (6.2%) Abbreviations: myocardial Ml: infarction

99 (7.0%) 118 (8.4%)

0.07 0.03

The efficacy analysis was performed using data from 566 ,patients in the @w-dose and Patients taking 550 patients in the high-dose treatment groups (N=l116 patients). 2650 mg/day aspirin prior to randomization, and patients. randomized within one day of surgery were excluded from this analysis. In the efficacy population, strokes occurred in 18 patients (3.2%) taking low-dose aspirin compared to 38 patients,,(6.9%) taking high-dose aspirin. Similarly, five patients (0.9%) in the low-dose aspirin group and 18 patients (3.3%) in the high-dose aspirin group had an Ml, and nine patients (1.6%) taking low doses of aspirin compared to 12 patients (2.2%) taking high doses of aspirin died. As shown in Table 9, when the combined rate of stroke, MI, and death were examined in patients included in the efficacy analysis, event rates were found tu’ lower in the low-dose be aspirin group at both the 3O-day (low-dose: 21 patients [3.7%]; high-dose: 45 patients [8.2%]; p=O.O02) and 3-month (low-dose: 24 patiepts [4.2%]; high-dpse: 55 patients [lO.O%]; p=O.O002) assessments. Similar results were observed for the combi,ned endpoint for all patients at 30 days (low-dose: 75 patients [5.4%]; high-dose: 99 patients f7.0%]; p=O.O7) and three months (low-dose: 87 patients [6.2%]; high-dose: 118 patients [8.4%]; ~~0.03)

Secondary analyses were also petiormed to probe for potential differences between the 81 and 325 mglday doses and between the 650 and 1300 mglday doses. Although no data are presented in the publication, the authors make a point of noting that no significant differences were observed in either of these analyses. These results provide additional evidence that low doses of aspirin are as effective as higher aspirin doses in preventing perioperative complications in this patient population. In conclusion, the risk of stroke, MI, and death within 30 days and three months of carotid endarterectomy is lower for patients taking 81 or 325 mglday of aspirin than for those taking



Aspirin,Professional Labeling Proposed Changes Citizen Petition McNeil. Cdnsumer &‘ Specialty Pharmaceuticals

650 or 1300 mg/day. Additionally, there were no ,significant differencxxs observed between the 81 and 325 mg/day aspirin treatment groups (the dose range of interest) in any of the analyses. 6.2.3. Peters et al, 2003


The post-hoc observational analysis of the CURE study data presented in the publication by Peters et al. (2003) evaluated the benefits and risks of adding cfopidogrel to a range of aspirin doses (5100, 101-l 99, and 2206 mg/day) in the treatment of patients with ACS. For the purposes of this aspirin efficacy summary, only data from the control groups, which included patients who received aspirin alone, were evaluated following an average treatment duration of nine months. Table IO summarizes the ,combined incidence of cardiovascular death, MI, and stroke by aspirin dose. Table IO. Incidence of Cardiovascular et al., 2003 Death, Ml, and Stroke by CA&p&in Dose - Peters

usted HR for IOIAbbreviations: hazardratio;vs.: versus HR: Note:numberof patientsin the publication Peterswas givenby aspirindosebu! includedpatientsreceiving by aspirin plus clopidogrel, well as aspirinalone as 1. Adjustedfor sex, weight,hypertension, componentsofthe TM risk score,ratesof aigiography,PCI and CABG

The incidence of cardiovascular death, Ml, and stroke among patients, taking 1100 mg/day (10.5%), 101-199 mg/day (9.8%), and 2200 mglday (13.6%) for .an average duration of 9 months was similar. As shown in Table IO, the adjusted hazard ratio (95% confidence interval [Cl]) was 1 .O (0.82-1.23) when the medium (lot-199 mg/day) and lowest (<I 00 mg/day) aspirin doses were compared, and 1.3 (1.08-1.52) when the highest (~~200 mglday) and lowest (21‘ mg/day) doses were compared. 00 Similar results were observed in the incidence of the second co-primary endpoint (the composite of cardiovascular death, non-fatal MI, stroke, and refractory ischemia), which was 18.2% (5100 mg/day), 17.2% (101-199 mglday), and 20.7% (2200 mg/day) :across the three dose groups. In this large, international trial, the dose $of aspirin prescribed was at the discretion of the Investigator and strongly dependent on the center at which the patient was treated. Further, the choice of dose by the center was associated with geographic location. That is, a patient


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was more likely to receive 2200 mg/day aspirin at centers in North ‘ South America than at or centers in Australia/New Zealand/South Africa or EasternNVestern, Europe where doses of 101-199 mglday and <IO0 mg day, respectively, were most‘ commonly used. Under these circumstances, any argument seeking to establish causality between aspirin dose and efficacy outcome measures must account for the confounding effects of site and geography. In conclusion, aspirin doses 5199 mglday appeared to be 8s. effective as doses

2200 mg/day, either alone or in combination with clopidogrel, in reducing cardiovascular death, Mi, and stroke in patients with ACS. However, these results, it should be noted that patients were not randomly assigned Rather, the dose of aspirin was prescribed by individual lnvestigatorsand dependent on both study center and-geographic location. ’ 6.2.4. Top01 et al., 2003

the occurrence of when interpreting to aspirin groups. was also strongly

The BRAVO study presented in the publication by Top01 et al. (2003) evaluated the effect of the platelet GP llblllla antagonist, lotrafiban, in 9190 patients with “coronary artery disease (CAD) or cerebrovascular disease. Similar to the subanalysis of the CURE trial data, this study also included control patients who received aspirin alone at a. dose determined by the Investigator. Thus, for the purposes of this aspirin efficacy summary,: the effect of low-dose (75-162 mg/day) (N=2410) and higher doses of aspirin (>I62 mg/day) (N=2179) were compared. The duration of treatment was 52 years or a median of 366 days (25’ and 75” h percentiles were 279 and 463 days, respectively). Of note, the. trial was terminated prematurely because of a statistically significant excess of mortality in the lotrafiban ,group, Table 11 summarizes the incidence of the composite endpoint and individual components of the cpmposite endpoint by dose of aspirin. Table II. Incidence of ,the Composite Endpoint and Individual, Components Composite Endpoint by, Aspirin Dose Y Toljot et al., 2003 Outcomesby AspirinDose
Outcome Primaryendpoint’ Death,Ml, stroke Death MI Stroke Urgenthospitalization 1Urgentrevascularization I Abbreviations: myocardial Ml: infarction

of the

Low Dose (75-162 mglday) fN=2410) 16.4% 6.2% 2.8% 2.0% 2.1% 9.6% 7.3%

High-Dose(d62 mglday) fN=2179) 18.6% 6.1% 1.7% 2.1% 2.8% 10.6% 10.0%

The primary endpoint was a composite of all-case mortality, MI, stroke, ,recorrent ischenja requiring hospitalization, and urgent revascularization.

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Doses of aspirin >I62 mglday (18.6%) were associated with an increased risk of the primary composite endpoint compared with lower doses of aspirin (16.4%). These results reflect the higher incidence of stroke (low dose: 2.1%; high dose: 2.8%), urgent hospitalization (low dose: 9.5%; high dose: 10.6%), .and urgent revascularization (low dose: 7.3%; high dose: 10.0%) among patients taking >162 mg/day of aspirin, as shown ‘ Table Il. in Death occurred at a higher incidence in the low-dose (2.8%) compared to the high-dose (1.7%) aspirin group, and no between treatment group differences were observed in the incidence of Ml (low dose: 2.0%; high dose: 2.1%). In conclusion, aspirin doses of 75-162 mglday appeared to be at,least as effective as doses >I62 mglday in reducing the incidence of stroke, recurrent ischemia requiring . hospitalization, and urgent revascularization in’ patients with CAD or cerebrovascular disease, but not total mortality. The fact that patients were not randomly assigned to aspirin treatment groups, but received a dose of aspirin determined by an Investigator, should be considered when interpreting the results of this study. 6.2.5. Algra and van Gijn, 1996

The meta-analysis presented in the publication by Algra and van Gijn (1996),, evaluated the efficacy of various doses of aspirin (5190, 300, and 2900 mglday) in patients who had suffered a TIA or non-disabling stroke. Table 12 presents the number of vascular events and the corresponding relative risk reduction in the composite outTome of vascular death, stroke, and Ml by dose of aspirin. Table 12. Relative Risk Reduction in Vascular Events (Composife &Death, Stroke, and Ml) by Aspirin Dose - Algra and van Gi‘ 1996 jq : RRR (95% Cl) Aspirin Dose 1Number of Vasculaf Events 1 I 184 T3% (-3 to 27) <I00 mg/day (N=826)



300 mglday (N=806)


352 2900 mg/day (N=l850) Overall effect estimate - all trials 710 Abbreviations: RRR: relative risk reduction; Cl: confidence interval

9% (-9 to 24) 14% (2 to 24) 13% (4 to 21)

Results of the analysis showed that all aspirin dose groups had similar efficacy in preventing vascular events. The overall relative risk reductions (95% Cl) were 13% (-3 to 27), 9% (-9 to 24), and 14% (2 to 24) for the 1100, 300, and 2900 mg/day,dosing regimens. Following statistical testing, no significant-differences in efficacy across any of the three aspirin dose groups was observed. The overall relative risk reduction (95% C!) for the combined data from all 10 trials was 13% (4 to 21). In conclusion, based on the results of this meta-analysis, doses of:aspirin 5100 mg/day are as efficacious as higher doses (up to 1500 mg/day) in the secondary ,prevention of vascular

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events following cerebral ischemia. As noted in Section 32.2, clinical trials included in the current meta-analysis overlap significantly with the meta-analyses presented by both the ATC (2002) and Johns& et al. (1999), an important consideration when evaluating primary data. ’ 6.2.6. Johnson et al., 1999

The meta-analysis presented by Johnson et al. (1999) evaluated the dose-response relationship between aspirin (175, 300, 650, and >900 mg/day) and stroke in patients who had suffered a recent TIA or stroke. Results of the analysis of study-specific risk ratios using weighted linear regression revealed no linear dose-response effect of aspirin therapy on stroke risk reduotion during the average follow-up period of 32 months. ’Risk ratio estimates were similar across the doses used in the trials, which ranged from as low as 50 to as high as 1500 mgldky. No evidence of a linear dose-response trend (p=O.49), or quadratic dose-response trend (p=O,85), was observed. When risk ratios were summarized across all ‘ studies, aspirin was found to reduce the risk of stroke by approximately 15% (risk ratio, 95% Cl: 0.85, 0.77-0.94). In conclusion, based on the results of this meta-analysis, aspirin reduces the risk of stroke by 15%, an effect that is uniform across a wide range of doses from: 50-I 500 trig/day. As noted above, there is considerable overlap in. clinical studies included in the current meta-analysis and those performed by both the ATC (2002) and Algra and van Gijn (1996). 6.3. Publications Providing Additional Efficacy Informatkk

A summary of efficacy findings from the studies included in this grouping is presented in Appendix 2. As discussed in’ Section 3.2.3 above, meaningful ‘ comparisons of efficacy across the different studies in this grouping are difficult, primarily due to differences, in the methods of deriving and presenting efficacy data across studies (e,g., incidence rates, relative risks, annualized event rates, odds ratios, hazard ratios, etc.), differences in studyspecific endpoints, and differences in,treatment durations. For example, in the Coumadin Aspirin Reinfarction Study (CARS), treatment with aspirin 160 mg/daay was associated with a one-year life table estimate of 8.6% for the composite. of, firsts occurrence of nonfatal death (CARS myocardial reinfarction, nonfatal ischemic stroke, or cardiova&ular Investigators, 1997). Treatment with aspirin at a dose of 325.mglday was associated with a 12.4% incidence of the combined endpoint of nonfatal acute Ml, nonfatal stroke, or vascular death in a study by Matias-Guiu et al. (2003). White the two composite events are similar, the differences in the methods of reporting the rates of these events (one-year life table estimate versus incidence) as well as the differences in the duration of treatment/follow-up~in the two studies (14 months versus one to three years) do not allow for a direct comparison of the efficacy at different aspirin doses between these two studies.

,* : Aspirin Professional Labeling Proposed Changes Citizen Petition McNeil Consumer & Specialty Phatynaceuticals

Similarly, in the CAST study, aspirin at a dose of 160 mg/day was associated with a 5.3% incidence of the combined endpoint of death or nonfatal stroke, qnd a 3.2% incidence of fatal and nonfatal recurrent strokes (CAST Collaborative Group, lQQ7). On the other hand, in the Stroke Prevention in Atrial Fibrillation III study (SPAF-III), the annualized rate of the primary events of ischemic stroke and non-CNS emboli associated with the use of aspirin 325 mg/day was 2.2%, and for all deaths was 1.8% (SPAF Ill Writing-Committee, 1998). In this case, the differences in the study-specific endpoints evaluated in teach of the studies do not permit a direct comparison of the efficacy at different aspirin doses between these two studies. In addition, in some studies the efficacy- results for aspirin were reported relative to a comparator agent rather than placebo or control. For example; in the CARS study mentioned above, the relative risk of a primary event associated with the use of aspirin 160 mg/day of 1.03 was reported relative to the comparator treatment group (warfarin plus aspirin), thereby not allowing for comparisons of efficacy with ot.her studies that reported efficacy results for aspirin relative to placebo or control. Therefore, due to the difficulties encountered in making comparisons between different studies, across-publication efficacy conclusions could not be made from this group of studies. The inclusion of this publication grouping in this submission serves.tiotoensure that all aspirinrelated efficacy data in cardiovascular and/or cerebrovasGu\ar indications published since IQ96 are presented; however, it is important to note that these studies were conducted in a wide variety of indications, many of which are notdirectly relevant for this Peition. OVERALL SUMMARY AND C@NCLUSiONS


The proposed labeling changes in <the recommended aspirin dose from 75-325 mg/day to 75-150 mg/day for secondary cardiovascular prevention, and from 50-325 mg/day to 50150 mglday for secondary cerebrovascular prevention is supported, by published safety data (particularly bleeding data). These data demonstrate that. low-dose aspirin results in fewer bleeding complications than higher aspirin doses (>I 50 mglday) and published efficacy data demonstrate that doses of aspirin within the range of 50-150 mgMay are,equally effective for the prevention of serious vascular events. Clinical studies as well as meta-analyses, substantiate the modifications to the, professional labeling for aspirin. These benefit/risk data were identified following an extensive search and review of the literature published between 1996-2004. The proposed labeling change in the recommended aspirin dose,, from 50-325 mglday to 50-150 mg daily, is also supported by published efficacy data demonstrating that doses of aspirin in the range of 50-150 mg/day are equally effective for the prevention of serious cerebrovascular events (non-fatal stroke). and doses of aspirin.‘ the range of 75-150 in



Aspirin professional Labeling Proposed Changes Citizen Petition McNeii consumer & specialty Pharmaceuticals

mg/day are equally effective for the prevention of serious cardiovascular events (non-fatal MI and vascular death). In particular, the Antithrombatic Trialists’ Collaboration (ATC) meta-analysis demonstrates that the reduction in the occurrence of serious vascular events across a range of aspirin doses from less than 75 mglday, 75-150 mg/day, and 5001500 mg/day in patients at risk of occlusive vascular disease, is similar. Cardiovascular and cerebrovascular disease benefit is no greater at aspirin doses above 150 mg or below 150 In addition, the small proportional reduction in events observed in direct mglday. comparisons of doses less than 75 mg/day versus greater than or equal to 75 mglday demonstrates that lower doses of aspirin used in these comparisons are as efficacious as higher doses in this patient population. Efficacy Conclusions

Doses of aspirin within the range of 50-150 mg daily are equally effective for the prevention of serious vascular events (non-fatal Ml, non-fatal stroke, and vascular death). The recommended aspirin dose for-chronic administration is 50-150 mg daily, which is safe and effective for prevention of recurrent MI, ischemic stroke and TIA and for treatment of unstable angina pectoris or chronic stable angina pectoris. Aspirin is recommended for patients who undergo revascularization procedures, such as coronary artery bypass grafting, angioplasty, or carotid endarterectomy, if there is a pre-existing condition for which aspirin is already indicated.. Therapy should be continued indefinitely.


Aspirin ~Professional Labeling Proposed Changes Citizen Petition McNeil ~Consumer & Specialty Pharmaceuticals


REFERENCES Key Publication


Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis .,of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, ,and stroke in high risk patients. British Medical Journal. 2002;324(7329):71-86. 8.2. Supporting Publications

Algra A, Van Gijn J. Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia. Journal of ‘ Neurology Neurosurgery and ‘ Psyqhiatry. 1996;60(2):197199. Johnson ES, Lanes SF, Wentworth CE, Satterfield MH, Abebe BL, Dicker LW. A metaregression analysis of the dose-response effeef of aspirin :on stroke. Archives of Internal Medicine. 1999;159(11):1248-1253.~ Peters RJG, Mehta SR, Fox KAA, Zhao F, Lewis BS, Kopecky SL, Diaz R, Commerford PJ, Valentin V, Yusuf S. Effects of aspirin dose when used alone .or in combination with clopidogrel in patients with acute coronary syndromes: observationa from the Glopidogrel in to Prevent Recurrent Events ~(CURE) ‘ study. _ Circulation. Unstable Angina 2003; 108( 14): 1682-l 687. Posada IS, Barriales V. Alternate-day dosing of aspirin in atrial fibrillation. American Heart Journal. 1999;138(1 1):137-143. Taylor DW, Barnett HJ, Haynes RB, Ferguson GG, Sack&t Dt, Thorpe KE, Simard D, Silver FL, Hachinski V, Clagett GP, Barnes R, Spence JO- Low-dose and:high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised ,controlled trial. ASA and Carotid Endarterectomy (ACE) Trial Collaborators. Lancet. 1999;353(9171):2179-2184. Top01 EJ, Easton D, HarringtonRA, Amarenco P, Califf RM;Graffagnino C, Davis S, Diener H-C, Ferguson J, Fitzgerald D, Granett J, Shuaib A, Koudstaal PJ, Theroux P, Van de Werf F, Sigmon .K, Pieper K, Vallee M, Willerson JT. Randomized; gouble-blind, placebocontrolled, international trial of the oral Ilb/llla antagonist lotrsfihan in coronary and cerebrovascular disease. Circulation. 2003; 108(4):399-406. 8.3. Publications Providing +dditional Effkacy Informafin

Akaike M, Azuma H, Kagawa A, Matsumoto K, Hayashi I, Tamura K, Nishiuchi T, luchi T, Takamori N, Aihara KI, Yoshida T, Kanagawa Y, Matsumoto T. EffeGt’ aspirin treatment on of serum concentrations of lipoprotein(a) in patients” with atherosclerotic diseases. Clinical Chemistry. 2002;48(9):1454-1459. Ariyo A, Hennekens CH, Stampfer MJ, Ridker PM. Lipoprotein (a), l@ds, aspirin, and risk of myocardial infarction in the Physician’ Health Study. Journal <of- Cardiovascular Risk. s 1998;5(4):273-278. Aronow WS, Ahn C, Kronzon I, Gutstein H, Effect of warfarin versus aspirin on the incidence of new thromboembolic stroke in older.persons with chronic atriai: fibrillation and abnormal



Aspirin Professional Labeling Proposed Changes Citizen Petition McNeif’ Consumer & Specialty Pharmaceuticals

and normal left ventricular 2000;85(8):1033-1035.







Atrial Fibrillation investigators. The efficacy of aspirin in patients with atrial fibrillation. Analysis of pooled data from 3 randomized trials. Archives. of Internal Medicine. 1997;157(i1):1237-1240. Bar Dayan Y, Levy Y, Amital H, Shoenfeld Y, Aspirin for preventionof myocardial infarction. A double-edge sword. Annales de,Medecine Interne. 1997;148(6):430433. Bartorelli AL, Trabattoni D, Montorsi P, FabbiocGhi F, Galli S, Ravagnani P, Grancini L, Cozzi S, Loaldi A. Aspirin alone antiplatelet regimen after intracoronary placement of the Carbostent: The Antares study. Catheterization and Cardiovascular Interventions, 2002;55(2):150-156. Bath PM, Lindenstrom E, Boysen G, De Deyn P, Friis P, Leys D, :Marttifa R, Olsson J, O’ Neill D, Orgogozo J, Ringelstein 9, van der Sande J,, Turpie AG. Tinzaparin in acute stroke (TAIST): a randomised aspirin-controlled trial. Lancet. ischaemic 2001;358(9283):702-710. Berge E, Abdelnoor M, Nakstad PH, Sandset PM.. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atriai fibrillation: a double-blind randomised study. HAEST Study Group. Heparin in Acute Emboiic Stroke Trial. Lancet. 2000;355(9211):1205-1210. Bhatt DL, Chew DP, Hirsch AT, Top01 EJ. Clopidogrel reduced recurrent ischaemic events in patients with previous cardiac surgery more than aspirin. Evidence-Based Medicine. 2001;6(4):114. Bhatt DL, Hirsch AT, Ringleb PA, Hacke W, Top01 EJ. Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. American Heart Journal. 2000; 140( 1):67-73. Bhatt DL, Marso SP, Hirsch AT, ,Ringleb PA, Hacke W, Top01 EJ. Amplified benefit of Clopidogrel versus Asp,irin in patients with diabetes meflitus. American Journal of Cardiology. 2002;90(6):625-628. Brouwer MA, van den Bergh PJPC, Aengevaeren WRM, Veen G; Luijten HE, Hertzberger DP, van Boven AJ, Vromans RPJW, Uijen GJH, Verheugt FWA. Aspirin plus coumarin versus aspirin alone in the prevention of reocclusion after fibrinotysis for acute myocardial infarction: results of the Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis (APRICOT)-2 Trial. Circulation. 2002;106(6):659-665, Budaj A, Yusuf S, Mehta SR, Fox KAA, Tognoni G, Zhao F, Chroilavidus S, Hunt D, Keltai M, Franzosi MG. Benefit of clopidogrel in patients with acute coronsry syndromes without ST-segment elevation in various risk groups. Circulation. 2002;l OS(i 3):1622-l 626. Cannon CP. Effectiveness of clopidogref versus aspirin in .preventing acute myocardial infarction in patients with symptomatic atherothrombosis (CAPRIE trial). American Journal of Cardiology. 2002;90(7):760-762.



, Aspirin Professional Labeling Proposed Changes Citizen .Petition McNeil Cokumer & Specialty Pharmaceuticals

CAPRIE Steering Committee (Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events). A randomised, blinded, trial of clopidogrel vers.us aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 3996;348(9038):1329-1339. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: Randomised placebocontrolled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet. 1997;349(9066): 1641-I 649. Castilio J, Leira R, Moro MA, Lizasoain I, Serena J, Davalos A. Neuroprotective effects of aspirin in patients with acute cerebral infarction. Neuroscience Le$ters. 2003;339(3):248250. Cesarone MR, Belcaro G, Nicolaides AN, Incandela L, De San&is, MT, Geroulakos G, Lennox A, Myers KA, Moia M, lppoiito E, Winford M. Venous thrombosis from air travel: The LONFLlT3 study: Prevention with aspirin vs low-moiecutar-weight heparin (LMWH) in highrisk subjects: A randomized trial. Angiology. 2002;53(1): 1-6. Cesarone MR, Laurora G, DeSanctis MT, Incandela L, Fugazza L, Girardello R, Poli A, Peracino L, Ambrosoli L, Belcaro G. Effects of triflusal on arteriosclerosis progression assessed with high-resolution arterial ultrasound. Angiology. 1999;5Q(6):455-463. Chan K-L, Dumesnil Jean G, Cujec B, Sanfilippo Anthony J, Jue J, Turek Michele A, Robinson Trevor I, Moher D. A randomized trial of aspirin on the risk of embolic’ events in patients with infective endocarditis. Journal of the American ~Coilege of Cardiology. 2003;42(5):775-780. Chen ZM, Sandercock P, Pan HG,,Counsell C, CoIlins.R, Liu LS, Xie JX, Warlow C, Peto R. Indications for early aspirin use in acute ischemic stroke : A combined analysis of 40 000 randomized patients from the Chinese acute stroke trial and the ihternational stroke trial. Stroke. 2000;31(6):1240-I 249. Collaborative Group of the Primary Prevent/on Project (PPP). Low-dose aspirin and vitamin E in people at cardiovascular risk: A randomised trial. in -g&era1 practice. Lancet. 2001;357(9250):89-95. Cook NR, Hebert PR, Manson J,E, Buring JE, Hennekens CH. Self-selected post-trial aspirin use and subsequent cardiovascular-disease and mortality in the Physicians’ Health Study. Archives of Internal Medicine. 2QOO;160(7):921-928. Coumadin Aspirin Reinfarction Study (CARS) Investigators. Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Lanceti i997;350(9075):389396. Creager MA. Results of the CAPRIE trial: efficacy and safety of clopidogrel. Vascular Medicine. 1998;3(3):257-260. Cruz Fernandez JM, Lopez GAV, Marfil Montoya F, Pabon Osuna P, Navarro Salas E, Garcia-Dorado D, Lopez-Bescos L. Managing acute myocardial infarction: Ciinical implications of the TIM study. European Heart Journal. 1,999;Supplement 1(F):Fl2-F18.



Aspirin Pr?fessional Labeling Proposed Changes Citizen Petition f&Neil Consumer & Specialty Pharmaceuticals

Cruz-Fernandez JM, Lopez-Bescos L, Garcia-Dorado 0, Lopez Garcia-Aranda V, Cabades A, Martin-Jadraque L, Velasco JA, Castro-B&ras A, Torres F, Mat-fit F, Navarro E. Randomized comparative trial of triflu@ and aspirin following acute niyocardial infarction. European Heart Jpurnal. 2000;21(6)i457-465. CURE Trial Investigators (Clopidogrel In Unstable.Angipa To Prevent Recurrent Events). Effects of clopidogrel in addition’ to aspirin in patients with acute coronary syndromes without ST-segment elevation. New England Journal of Medicine. 2001;345(7):494-502. Derksen RHWM, De Groot PGi Kappelle LJ. Low dose- aspirin after ischemic stroke associated with antiphospholipid syndrome. Neurology. 2003;61(1):11-1-114. Diener C, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal. A. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevent& of stroke. Journal of the Neurological Sciences. 1996;143(1-2): 1-l 3. Diener HC, Darius H, Bertrand-Hardy JM, Humphreys M. Cardiac safety in the European Stroke Prevention Study 2 (ESPS2). International Jourrial, of Clinical Practice. 2001;55(3):162-163. Droste DW, Sonne M, Siemens HJ, Kaps M; Asymptomatic circulating cerebral emboli and cerebral blood flow velocity under aspirin and ticlopidine in patients with cerebrovascular disease. Neurological Research 1996;18(5):449-453. ’ Evans A, Perez I, Yu G, Kalra L. Should stroke subtype influence anticoagulation decisions to prevent recurrence in stroke patients with atria! fibrillation? Stroke. 2001;32(12):28282832. Ferro M, Crivello R, Rizzotti M. Comparison of subcutaneous .calcium heparin and acetylsalicylic acid in the prevention of ischemic events and de&h. after myocardial infarction: a randomized trial in a consecutive -series of 90 patients. Heart Disease. 2000;2(4):278-281. Fiore LD, Ezekowitz MD, Brophy MT, Lu D, Sacco J, Peduzzi P,:,C@partment of Veterans Affairs Cooperative Studies Program Clinical Trial comparing comBned warfarin and aspirin with aspirin alone in survivors of acute myocardial infarction: primary results of the CHAMP study. Circulation. 2002; 105(5):557-563. Forbes CD. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of -stroke. “International Journa! of Clinical Practice. 1997;51(4):205-208. FRISC Study Group (Fragmin During Instability in Coronary Artery Pisease). Low-molecularweight heparin during instability in coronary artery disease. Lancet. 1996;347(9001):561568. Garcia Rodriguez LA, Varas C, Patron0 C. Differential effects of aspirin. and non-aspirin nonsteroidal antiinflammatory ‘ drugs in the prima@ prevention of myocardial infarction in ’ postmenopausal women. Epidemiology. 2OOO;l I (4):382-387.

Aspirin Profassional Labeling Proposed Changes Citizen‘ Petition McNeil,Consumer & Specialty Pharmaceuticals

Goertier M, Baeumer M, Kross R, Blaser T, Lutze G, Jost S, Wallesch CW. Rapid decline of cerebral microemboli of arterial origin after it?ravenous acetylsalicylic acid. Stroke. 1999;30( I)%-69. Goldstein RE, Andrews M, Hall WJ, Moss AJ. Marked. red,uction in long-term cardiac deaths with aspirin after a coronary, event. Journal of the American :%&llege of Cardiology. 1996;28(2):326-330. Gorelick PB, Richardson D, Kelly M, Ruland S, Hung E, et al. Aspirin and ‘ ticlopidine for prevention of recurrent stroke in black patients: a randomized trial., JQurnal of the American Medical Association. 2003;289(22):2947-2957. Grotemeyer KH, Evers S, Fischer M, Husstedt IW. Piracetarq versus acetylsalicylic acid in secondary stroke prophyfaxis. A double-blind, randomized, parallal group, 2 year fpllow-up study. Journal of the Neurological Sciences. 2000;181(1-2):65-72. Gullov AL, Koefoed BG, Petersen-P, Pedersen TS, Andersen ED, Godtfredsen J, Boysen G. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial. Fi@illation, Aspirin, and Anticoagulation Study. Archivesof Internal Medicine. 1998;158(1~4):1513-1521. Hall P, Nakamura S, Maiello L, ftoh A, Blengino S, Martini G, Femaro M, Colombo A. A randomized comparison of combined ticlopidine and aspirin theraey versus aspirin therapy alone after successful ,intravascular ultrasound-guided stent implantation. Circulation. 1996;93(2):215-222. Harker LA, Boissel JP, Pilgrim AJ, Gent M. Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE. CAPRIE Steering Committee Andy Investigators. Clopidogrel versus aspirin in patients at risk of ischaemiq events. Drug Safety. 1999;21(4):325-335. Hart RG, Benavente 0, McBride R, Pearce LA. Antithrombcitic therapy to prevent stroke in Annals ii Of Internal Medicine. patients with atrial fibrillation: a meta-analysis. 1999a;131(7):492-501. Hart RG, Halperin JL, McBride R, Benavente 0, Man-Son-Hing ,M, Kronmal RA. Aspirin for the primary prevention of stroke. and other major vascular events: meta-analysis and hypotheses. Archives of Neurology. 2000;57(3):326-332. Hart RG, Pearce LA, McBride R, Rothbart RM, Asinger RW. ‘ ,Factors associated with ischemic stroke during ~aspirintherapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. Stroke. 1$9>b;30(6):1223-I 229. He J, Whelton PK, Vu B,,Klag MJ. Aspirin and risk of hemorrhagic stroke: a meta-analysis of Association. controlled triats. Journal of the American‘ Medical randomized I 998;280(22): 1930-I 935. Hebert PR, Hennekens CH. An overview of the 4 randomized trials of aspirin therapy in the primary prevention of vascular disease. Archives of Internal Medicine. 2000;160(20}:31233127.

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Aspirin Professional Labeling Proposed Changes Citizen’ Petition McNeiF Cansumer & Specialty Pharmaceuticals

Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP. Effect of medical treatment in stroke patients with patent foramen ovale: Patent foramen oval@ in Cryptogenic Stroke Study. Circulation. 2002; 105(22):2625-2631. Hop JW, Rinkel GJ, Algra A, Berkelbach van der Sprenkel JW, van Gijn J. Randomized pilot trial of postoperative aspirin in subarachnoid hemorrhage. Neurologv. 2000;54(4):872-878, Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin,. aspirin, or both after myocardial infarction. New England Journal of Medicine. 2002;347(1,3):969-974. Huynh T, Theroux P, Bogaty P, Nasmith J, Solymoss S. Aspirin, wacarin, or the combination for secondary prevention of coronary events in patients with acute Coronary syndromes and prior coronary artery bypass surgery, Circulation. 2001; 103(25):3069-3074. lshikawa K, Kanamasa K, Hama J, ,Ogawa I, Takenaka T, Naito T, Yamamoto T, Nakai S, Oyaizu M, Kimura A, Yamamoto K, Katori R. K. Aspirin plus? e&her dipyridamole or ticlopidine is effective in preventing recurrent myocardial infarction. Japanese Circulation Journal. 1997;61(1):38-45, IST Collaborative Group (International Stroke Trial). The International Stroke Trial (IST): A randomised trial of aspirin, subcutanepus heparin, both, or neither among 19 435‘ patients with acute ischaemic stroke. Lancet. 1997;349(9065):1569-1’ 581. Johnson WC, Williford WO. Benefits, morbidity, and mortality assqciated with long-term administration of oral anticoagulant therapy to patients with peripheral arterial bypass procedures: a prospective randomized study. Journal of Vascular Surgery. 2002;35(3):413421. Julian DG, Chamberlain DA, Pocock SJ, Bernard R, Chamberlain D, Bothwick I, Irving J, Murdoch W, Pohl J, Wood D, Penny J, Millar-Craig M; Robson D, Valiance B, Hine K, Powell-Jackson J, Varma M, Joseph S, Greenwood T, et al. A cqmparison of aspirin and anticoagulation following thrombolysis for myocardiat infarction (the AFTER study): a clinical Medical randomised trial. British Journal. multicentre unblinded 1996;313(7070):1429-1431. Kalra L, Perez I, Smithard DG, Sulch D. Does prior use of aspirin affect outcome in ischemic stroke? American Journal of Medicine. 2000; 108(3):205-209. Klootwijk P, Meij S, Melkert R, Lenderink T, Simoons ML. Reduction of recurrent ischemia with abciximab during continuous ECG-ischemia monitoring in patier@ with unstable angina refractory to standard treatment (CAPTURE). Circulation. 1998;98( $4): 1358-l 364. Knottenbelt C, Brennan Patrick J, -Meade Tom W. Antithrombotic treatment incidence of angina pectoris. Archives of Internal Medicine. 2002;162(8):881-886. and the

Lee TK, Chan KW, Huang ZS,. Ng SK, Lin RT, PO HL, Yuan RY; Lai ML, Chang TW, Yan SH, Deng JC, Liu LH, Lee KY, Lie SK, Sung SM, Hu HH. Effectivfaness of low-dose ASA in prevention of secondary ischemic stroke, the ASA Study Group in Taiwan. Thrombosis Research. 1997;87(2):215-224.

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Leon MB, Bairn DS, Popma JJ, Gordon PC, Cutlip DE,. Ho KK, Giamb&tolomei A, Diver DJ, Lasorda DM, Williams DO, Pocock SJ, Kuntz RE. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. New England Journal of Medicine. 1998;339(23):1665-1671. Ma J, Hennekens CH, Ridker PM, Stampfer MJ. A prospective study of fibrinogen and risk of myocardial infarction in the Physicians’ Health Study. Journal of the American College of Cardiology. 1999;33(5):1347-1352. Mangano DT. Aspirin and mortality from coronary bypass surgery. <New England Journal of Medicine. 2002;347(17):1309-1317. Mas JL, Arquizan C, Lamy C,, Zuber M, Cabanes L, Derumeaux G, Caste 3, Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. New England Journal of Medicine. 2001;345(24); 1740-I 746. Matias-Guiu J, Ferro Jose M, Alvarez-Sabin J, Torres F. Comparison of triflusal and aspirin for prevention of vascujar events in patients after cerebral infarc$on: the TACIP Study: a randomized, double-blind, multicenter trial. Stroke. 2003;34(4):840-848. Meade TW, Brennan PJ, Wilkes HC, Zuhrie SR. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose’ aspirin in the primary men. at inGreased risk. Lancet. prevention of ischaemic heart disease in 1998;351(9098):233-241. Meade TW, Brennan PJ. Determination of who may derive most benefit from aspirin in primary prevention: subgroup results from a randomised controlled trial. British Medical Journal. 2000;321(7252):13-17. Mehran R, Aymong ED, Ashby. DT, Fischell T, Whitworth Jr H, Siegel. Safety of an aspirinalone regimen after intracoronary stenting.with a heparin-coated atent: Final results’ the of HOPE (HEPACOAT and an antithrombotic regimen of aspirin alone) study. Circulation. 2003;108(9): 1078-I 083. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis ,.BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA. Effebs of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. .Lancet. 2001;358(9282):527-533. Miller VT, Pearce LA, Feinberg WM, Rothrock JF, Anderson DC, Hart RG. Differential effect of aspirin versus warfarin on clinical stroke types in patients with atriai fibrillation. Neurology. 1996;46( 1):238-240. Mohr JP, Thompson JL, Lazar RM, Levin B, Sacco RL, Furie KL, Kistler JP, Albers GW, Pettigrew LC, Adams HP, Jackson CM, Pullicino P. A comparison of -war-f&n and aspirin for the prevention of recurrent. ischemic stroke. New- England Journal of Medicine. 2001;345(20):1444-1451. Morais J. Insights from CURE: using clopidogrel Cerebrovascular Diseases. 2002;13(Suppl 1):17-21. on top of standard therapy.



Aspirin Professional Labeling Proposed Changes Citizen Petition McNeil~Censumer & Specialty Pharmaceuticals

O’ Connor CM, Gattis WA, Hellkamp AS, Langer A, Larsen RL, H,ariington RA, Berkowitz SD, O’ Gara PT, Kopecky SL, Gheorghiade M, Daly-R, Caiiff RM, ,Gu@er V. Comparison of two aspirin doses on ischemic stroke in post-myocardial infarction patients iv Ihe warfarin (Coumadin) Aspirin Reinfarction Study (CARS). American Journal of Cardiology. 2001a;&8(5):541-546. O’ Connor FF, Shields DC, Fitzgerald A, Cannon CP, Braunwald E, Fitzgerald DJ. Genetic variation in glycoprotein Ilb/tlla (GPllb/llla) as a determinalit of the responses to an oral GPllb/llla antagonist in patients with unstable coronary syndromes. Blood. 2001 b;98(12):3256-3260. Obialo CI, Conner AC, Lebon LF. Maintaining patency of tunneled hemodialysis catheters Efficacy of aspirin compared to warfarin. Scandinavian Journal of Wrofogy and Nephrology. 2003;37(2):172-176. Oosterga M, Anthonio RL, De Kam PJ, Kingma JH, Crijns HJGM, Van .Gilst WH. Effects of aspirin on angiotensin-converting enzyme inhibition and teft ventricular dilation one year after acute myocardial infarction. American Journal of Cardiology. 199$81(10): 1178-I 181. Ryglewicz D, Baranska-Gieruszczak M, Czlonkowska ‘ Lechow&z W, Hier DB. Stroke A, recurrence among 30 days sutiivors of ischemic stroke in a pros@ective community-based study. Neurological Research. 1997; ‘ l9(4):377-379. Sanmuganathan PS, Ghahra,mani P, Jackson PR, Waltis EJ, Ramsay:LE. Aspirinfor primary prevention of coronary heart disease: safety and absolute benefit: r&ated to coronary risk derived from meta-analysis of randomised trials. Heart. 2001;85(3):265-271. Sarac TP, Huber TS, Back MR, Ozaki CK, Carlton’ LM, Flynn TC, Sbeger JM. Watfarin improves the outcome of infrainguinai vein bypass grafting at high risk for failure. Journal of Vascular Surgery. 1998;28(3):446-457. Scrutinio D, Cimminiello C, Marubini E, PitzaliS MV, Di .Biase M, Riizon P. Ticlopidine versus aspirin after myocardial infarction (STAMI) trial. Journal of Xhe American College of Cardiology. 2001;37(5):1259-1265. Second SYMPHONY Investigators. Randomized trial of aspirin, qibrafiban, or both for secondary prevention after acute coronary syndromes. Circulation. 2001;Z03(13):17271733. Sivenius J, Cunha L, Diener HC, Forbes C, Laakso M, Lowenthal A, Smets P, Riekkinen P. Second European Stroke Prevention Study: antiplatelet therapy i$ effective regardless of age. ESPS2 Working Group. Acta neurologica Scandinavica. 1999;@(1):54-60. SPAF III Writing Committee (Stroke Prevention ‘ Atrial Fibrillation). Patients with in nonvalvular atrial fibrillation at tow risk of stroke during treatment with aspirin: Stroke Prevention in Atrial Fibrillation 111Study. Journals of the American Medical Association. 1998;279( 16): 1273-I 277. SPlRlT Study Group. A randpmized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Annals of Neurology. 1997;42(6):857-865.

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Aspirin.P&fessional Labeling Proposed Changes Citizen Petition McNeUConsumer & Specialty Pharmaceuticals

Srinivasan AK, Grayson AD, Pullan DM,.Fabri BM, Dihmis WC. Effeot of preoperative aspirin use in off-pump coronary artery bypass operations. Annals of Thoracic Surgery. 2003;76(1):41-45. Strater R, Kurnik K, Heller C, Schobess R, Luigs P, NowaklGottl U. Aspirin versus fow-dose low-molecular-weight heparin: Antihrombotic therapy in pediatric istihemic stroke patients: A prospective follow-up study. Stroke. 2001;32(11):2554-2558. SYMPHONY Investigators. Comparison of sibrafiban with aspirR for prevention of cardiovascular events after acute. coronary syndromes: a randomised trial. Lancet. 2000;355(9201):337-345. Tangelder MJ, Lawson JA, A@a A, Eikelboom BC. Systematic. review of randomized controlled trials of aspirin and oral anticoagulants in the prevention of graft occlusion and ischemic events after infrainguinal bypass surgery. Journal ’ of Vascular Surgery. 1999;30(4):701-709. Taylor FC, Cohen H, Ebrahim S. Systematic review of long -term anticoagulation or atrial fibrillation. BMJ. antiplatelet treatment in patients with non-rheumatic 2001;322(7282):321-326. van Es RF, Jonker JJC, Verheugt FWA, Deckers JW, Grobbee DE-Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet. 2002;360(9327):109-113. WASID Study Group (Watfarin-Aspirin Symptomatic Intracranial 1Disease). Prognosis of patients with symptomatic vertebral or basilar artery stenosis. Stroke. 1998;29(7): 13891392. Weisman SM, Graham DY. Evaluation of the benefits and risksof low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events. Archives of Internal Medicine. 2002;162(19):2197-2202. Westrich GH, Haas SB, Mosca P, Peterson M. Meta-analysis of thromboembolic prophylaxis after totat knee arthroplasty. Journal of Bone and Joint Surgery. 2000;82(6):795-800, Wilterdink JL, Easton JD. Dipyridamole plus aspirin in cerebrovascular disease. Archives of Neurology. 1999;56(9): 1087-I 092. Yasue H, Ogawa H, Tanaka H, Miyazaki S, Hattori R, Saito .M;-lshikawa K, Masuda Y, Yamaguchi T, Motomiya, T, Tamura Y. Effects of aspirin and trapidii on cardiovascular events after acute myocardial infarction. Japanese Antiplatelets Myooardiat Infarction Study (JAMIS) Investigators. American Journal of Cardiology. 1999;83(9):,l308-1313. Young B, Moore WS, Robertson JT, Toole JF, Ernst CB, Cohen SN., Broderick JP, Dempsey RJ, Hosking JD. An analysis of perioperative surgical mortality and morbidity in the asymptomatic carotid atherosclerosis study,. Stroke. 1996;27(12):2216-2224. Yusuf S, Mehta SR, Zhao F, Gersh BJ, Commerford. PJ, et al. IEarly and late effects of clopidogrel in patients with acute coronary syndromes. Circulation. 2003; 107(7):966-972.

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Total 1 Treatment Duration 6300 A meta-analysis 6 studiesthat were of randomized, placebo-controked interventions an aspirin-only with with arm, low-doseaspirindefinedas daily dosesof Sot0325 mg. Aspirindosesinvestigated theseE in studiesincluded50, 75, 300 and 325 mglday(n=3127) Placebo(n&73) rreatment duration fadedacrossthe 6 &dies andwas not specifically reportedin his meta-analysis.

1 Reference WeismanSM, GrahamDY. 2002. Evaluation the benefitsand risksof lowof doseaspirinin the secondary prevention o cardiovascular cerebrovascular and ever& Archivesof Intemaffvtedicine 162(19):2197-2202 Wkterdink EastonJD. 1999. JL, Dipyridamole aspirinin plus cerebrovascuiar disease.Archivesof Neurology 56(9):1087-1092.

Type of Article Aeta-analysis

(n=6602): II ,919 ESPS-2trial: Patientswho had expeiienced ESPS-2trial treatments Aspirin59 mglday TIA or ischemicstrokewithinprevious3 SMained-release dipyridamole niogths 400 mglday Antiplatelet Trialists’ Collaboration Trials: Aspirin50 mglday+ dipyridamole Includes14 trialsaGross patientpopulations m,,/dav .4nn Placebo Antiplatelet Trialists’ Collaboration trial tfeatments (n=5317): Aspirinalone(dosages variedfrom 15%1300 mglday;medianaspirin dose=975 mgfday) Aspirin+ dipyridamole tablets (medianaspirindose=225 day) mgf

Vestmentduration icrossthe studiesnot rpe&iedin the article


3 3

1Atrial Fi~rj~la~on lnva~~gat~rs. The $997, efficacyof aspirinin patientswith atnal, fibrillation: analysisof pooleddata from 3 randomized trials.Archivesof Internal Medicine157(1 237-l240. I):1


AFASAK:aspirin75 mgldayor Poofedi~~iv~duai patientdatafrom 3 randomized hisf!s: tlie.AtnatFibrillation, 'placei (n=S72) Aspirin,Anticoagulation Stu~y~(~FASAK), EMT: aspkin300 mgldayor the European Atria!Fibrillation (EAFl placebo(n=762) Trial SPAFI: aspirin325mgldayor and the StrokePrevention Atrial in placebo(n=ll20) Fibrillation Study(SPAFI) 1

‘ reatmentdurationnot ~pedffied the’ in article ,”


APPENDIX I. Reference

TABLE OF STUDIES - PUBLICATIONS PROVIDING ADDITIONAL EFFICACY INFORMATION Total 1 Subjects Patient Population I treatment Aspirin75 mgldayor placebo (n=21,330) Aspirin325 mg QODor placebo {n=22,071) Aspirin500 to 650 mgldayor placebo(n=8850) I Treatment Duration Type of Article

Hart RG, HalperinJL, McBrideR, Benavente Man-Son-Hing Kronmal 0, M, RA. 2000.Aspirinfor the primary prevention strokeand othermajor of vascularevents:meta-analysis and hypotheses. Archivesof Neurology 5?(3):326-332

52,251 Primaryprevention highrisk patients in

Averagefollow-upperioc ineta-analysis of 4.6 years

51,085 Healthymalephysicians (PHS,BDT),high HebertPR, Hennekens 2000.An CH. -~ risk men - top 20% of risk scoredistribution overview the 4 randomized of of, trials releaseof 4 to 6 years (TPT),men/ womenwith hypertension and Aspinn75 mg/day-con~olled aspirintherapyin the primaryprevention of diastolicBP 100to 115mmHg(HOT) vasculardisease.Archivesof internal Medicine160(20):3123-3127.


Sanmuganathan Ghahramani PS, P, Jacks& PR, WailisEJ, RamsayLE. 2001. Aspirinfor primaryprevention coronary of heartdisease:safetyand absolutebenefit relatedto coronaryrisk derivedfrom metaanalysisof randomised trials.Heart (British CardiacSoci@y) 85(3)!265-271. ‘ TayltirFG, CohetiH, Ebr’ S. 2001. akm SyStema&rgviewbf longterm anticoagulation afitiplatelet or treatmentin patientswith non-rheumatic atrial fibrillation. 322(7282):321-326. BMJ

Aeta-analysid e of the four trialsdid not include In the one trial that did enroll rangedfrom 4 to 6 years

(AFASAK1, AFASAK2, SFAF Ii, SIFA, PATAFfin patientswithAF

‘ Reference Total 1 Subjects] I Patient Population I Type of Article

40,090 A subsetof patientswith acuteischemic ChenZM, Sandercock Pan HC, P, Counsel1 CollinsR, Liu LS, Xie JX, C, strokewho had beenenrolledinto the ChineseAcuteStrokeTrial (CAST)or WarlowC, PetoR. 2000.indications for International StrokeTrial (IST) earlyaspirinuse in acuteischemicstroke: a combinedanalysisof 40 000 randomized patientsfrom the ChineseAcuteStroke Trial andthe International StrokeTrial. Stroke31(6):1240-1249. 5022 A prospective longitudinal and studyof 5065 Aspirinup to 650 rug/daywithin Mangano 2002.Aspirinand mortality DT. patientsundergoing coronarybypass 48 hours afterrevascularization from coronarybypass,surgery. New surgery,of whom5022survivedthe first 48 (n=2999) England Journalof Medicine347(17):1309. hoursfollowingsurgery 1317. No aspirin(n=2023)


332 Patientswith refractory unstableangina. Klootwijk‘ Meij S, MelkertR, Lenderink P, T, This was a sub-study the CAPTURE of SimoonsML. 1998.Reduction recurrent of study. ischemia abciximab with duringcontinuous EGG&hernia monitoring patientswith in unstable anginarefractory standard to treatment (CAPTURE). Circulation 98(14):1358-1364. A of trials Treatmentduration Hart RG, Eenavente McBrideR, Pearce 8856 ‘ meta-ana!ysis 16 randomized 0, testtiiglongterm,(>3months)use of LA. W9a. ~~~r~rn~~~,#~rapy to ,28 months.across the ‘ ~~~rornboi~e agentsh patientswithatrial rjn @-jj&& &se for an,l&JR trials includedin this preventstrekeinp~ients-~th atrial fibrillation ~bdlla~on: me&analysis.Annalsof a of 2.0-2.6for primaryprevention me&analysis Internal Medicine13$(7):492-501. trials;adjusted INR of2.9 for the to one secondary prevention trial) versusplacebo(n=2900) Warfannto INR 2.2 to 3.1 versus Aspirin75-325mglday(n=2837)

Durationof aspirin Iinical Trial treatmentnot specified; the trialendpointswere collectedduringthe hospitalization, lasting ‘ to 30 days up Aspirinminimumdailydose of Follow-up occurredfor Iinical Trial 50 mgldayf Abciximab0.25 mglkg 30 days bolusfollowedby a continuous infusionof IO mglmin(n=169) Aspirinminimumdailydose of ,60mglday+ Placebo(n=163) ileta-analysis

]APPENDIX 1. TABLE OF STUDIES - PUBLICATIONS PROVIDING ADDITIONAL EFFICACY INFORMATION Total Subjects TreatmentDuration TreatmentGroups (n) .I457 All patientswith a diagnosis acute of Aspirinmediandailydoseof 75 mg, Treatmentdurationnot rangeof 75 to 300 mglday. specifiedin the article. hemispheric strokein a White,largely middleclass,suburban population South Aspirinwas usedregularlybefore in East England. the strokeby 650 (45%)of patients. 340 Patientswho underwent off-pumpcoronary Aspirin75 to 300 mglday{n=170) Treatment durationnot arterybypassbperation (OPCAB) the Nonaspirin for specifiedin the article. us&s (n=170) first time betweenJanuary1998and Septeniber 2001 366 Ischemicstrokepatients&tmittedto a Shouldstrokesubtypeinfluence anticoagulation decisionsto prevent recurrence strokepatientswith atriat in fibrilfation? Stroke3?(12):2828-2832. Xnical Trial G, Zbao F, Chrolavicius Hunt 0, S, changesor elevationin serumlevelsof clopidogrel75 mglday(n=6259) Aspirin75 to 300 mglday(n=172) Pat&& we& treated Patient Population Type of Article Jopulation3asedStudy

utcomein ischemicstroke?American

ietrospective study


Aspirin75-325mglday+ Placebo

1 APPENDIX 1. TABLE OF STUDIES - puf3LiC~~l0NS Reference Total iubjects


Type of Treatment Duration Article Subjectswere Iinical Trial MehtaSR, YusufS, PetersRJG, Bertrand 2658 pretreated aspirin with ME, LewisBS, Natarajan MalmbergK, MK, and studymedication for Rupprecht Zhao F, Chrolavicius H, S, a medianof 6 days CoplandI, Fox KA. 2001.Effectsof beforePCI duringthe pretreatment clopidogrel aspirin with and initialhospitaladmission followedby long-term therapyin patients and for a medianof IO undergoing-percutaneous coronary days overall. After PCI, intervention: PCI-CURE the study.Lancet mostsubjectsreceived 358(9281):52?-533. open-label study medication for, approximately weeks, 4 afterwhichstudydrug was restarted a mear for of 8 months. Iinical Trial atientswho presented withinpast 24 hours Clopidogrel loadingdoseof 300 mg Averagetreatment MoraisJ. 2002.Insightsfrom CURE:using 12,562 ‘ followedby 75 mg/day+ Aspirin75- duration=9 months rf onsetoffhe,mostrecentepisodeof clopidogrel top of standardtherapy. on 325 mglday(n=6259) (rangeof 3 to schemic chestpain~symptoms with Cerebrovascular diseases13(Suppl1):1712 months) suspected acuteCOrOf’ syndrome te~ WithOUt Placabo+ Aspidn 75-325 mg/&y 21. ST-segment elevation>I mm fn=6303) loadingdoseof 300 mg Averagedurationof IinicatTrial 12,562 ‘ atientshospitalized within 24 hoursafter Clopidogrel YusufS, MehtaSR, ZhaoF, GershBJ, administered immediately followed treatment=9 months r&et of symptoms(patients ECG with Commerford et al. 2003,Earlyand late PJ, by 75 mglday+ Aspirin75 :hanges elevationin seium levelsof or effectsof clopidogrel patientswith acute in )ardiaC e~z~~);~~out ST-segment ~3~~‘ ~day-~~~6259) ~~~~ s~~~rnes. CircutatEon elevation (CURETrial). 107(7):966-972. Placebo+ Aspirin7%325,mglday . TreatmentGroups (n) subjects symptomsindicative acute Double-blind with of phase: mglday+ Aspirin nronarysyndrome non-ST-segment Clopidogrel300 and 75-325mglday(n=l313) :levation >l mm on ECG of Placebo+ Aspirin75-325mglday (n=1345) Openlabelphase(afterPCI): Clopidogrel ticlopidine or (Dose unspecified) Aspirin(Doseunspecified)

CastilloJ, LeiraR, MoroMA, LizasoainI, SerenaJ, DavalosA. 2003. Neuroprotective effectsof aspirinin patientswith acutecerebralinfarction. Neuroscience Letters339(3):248-250. ’


durationwas IinicalTrial +bjects with a first episodeof hemispheric Aspirin75-500mgldayat the time of Treatment strokeonset(n=63) not relevantin this study ;chemicstrokeof less than 24 hours luration.Thesesubjectsformedpart of a No aspirinat the time of stroke argergroupof 270 subjectsincludedin a onset(n=175) rrospective studyassociated with neurological deterioration,

Aspirin Piofessional Labeling Proposed Changes Citizen Petition McNeil Consumer 8. Specialty Pharmaceuticals

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Reference Forbes 1997.European CD. Stroke Prevention Study2: dipyridamole and acetylsalicylic in the secondary acid prevention stroke.International of Journal of ClinicalPractice 51(4):205-208. lshikawa Kanamasa HamaJ, Ogawa K, K, I, Takenaka NaitoT, Yamamoto Naka T, T, S, OyaizuM, Kimura Yamamoto A, K, KatoriR. 1997. Aspirinpluseither dipyridamole ticlopidine effectivein or is preventing recurrent myocardial infarction. Japanese Circulation Journal 61(1):38-45. Sivenius CunhaL, DienerHC, ForbesC, J, LaaksoM, Lowenthal SmetsP, A, Riekkinen 1999.SecondEuropean P. StrokePrevention Study:antiplatelet therapy effective is regardless age. of ESPSZWorking Group. Acta neurologica Scandinavica 99(1);54-60. FRISCStudyGroup(Fragmin During Instability Coronary in ArteryDisease). 1996. low-rnot~~~~ar-we~ht heparinduiin$ instabiiity coronary in arterydisease. Lancet347(9001):561-568.

Total iubjects

TreatmentGroups(n) Follow-up period=2 6602 Patients a TIA or ischemic with strokewithin Aspirin5o mg’ (n=164g) day ’ Dipyridamole mglday(n=1654) years 400 the preceding months 3 Aspirin50 mglday+ Dipyridamole 400 mglday(n=1650) Placebo (n=1649)



Type of Article Clinical Trial


618 Patients a priorMl with

Aspirin50 mglday+ dipyridamole Not specified; mean 150mglday(n=113) observation periodof Aspirin50 mglday+ ticlopidine 12.5months 200mglday(n=253) Aspirin50 mgfdayor dipyridamole 150mgldayor ticlopidine 200mgldayalone(n=252) No antiplatelet treatment (n=465)

Iinical Trial

Follo$-up periodwas 2 6602 Patients a recentTIA or strokeenrolledAs@rin mg’ with 5o day Dipyridamole modified-release yearsregardlesc nf in the ESPS-2Study 400 mglday medication con, Aspirin50 mglday+ Dipyridamole 400mglday Placebo
I I 1

Clinical Trial

1506 Subjects unstable with CAD(unstable angina non-Q-wave (Fragmin or Ml) During l~stabi~it~ Coronary in ArteryDiseaseStudy [FRISCj).

Daltepa& 120IUlkgbddyweight Treatment duration: 40- Iinical Trial 10,000IU) BID SC for 6 50 days (maximum days;subjects,then received ~oitow-~p: monks 5-7 75110 @Idayfor the next35-45days (n=746) Placebo (n=760) All subjects received initial an 300mg doseof aspirinand 75 mgldaythereafter.Betablockers, well as calcium as antagonists organic and nitrates, werealsoadministered needed. as





- PUBLICATIONS Total Iubjects 5499




INFORMATION Treatment Duration Type of Article

Patient Population

Treatment Groups (n)

Knottenbelt Brennan MeadeTW. C, PJ, 2002.Antithrombotic treatment the and incidence anginapectoris. of Archivesof Internal Medicine 162(8):881-886.

articipants were IinicalTrial Malesubjects wereat increased of Aspirin75 mgldaycontrolled who risk releaseF‘ up + Warfarin (Started 25’ at mglday Rollowed for a median coronary heartdisease andadjusted INR 1.5)(n=1269) Crf 6.8 yearsfor major to Crutcomes or (MI Warfarin placebo + (n=1260) Ccoronary death). Aspirin75 mgldaycontrolled release follow-up for nnedian + placebo (n=1252) inquiry.about s ;ystematic Doubleplacebo (n=1259) ir lcident anginawas 5 rears Y Iinical Trial of releasenAedian 6.8 years as MeadeTW, Brennan WilkesHC, Zuhrie 5085 Menidentified beingin the top 20%on Aspirin75 mgldaycontrolled PJ, + placebo warfarin {n=l268) the IHD risk scorederivedfromthe SR. 1998.Thrombosis prevention trial: Northwick HeartStudy. Criteria Park based Warfadn meanstablelNR of 1.47 randomised of low-intensi~ trial oral on smokinghistory, familyhisW, BMI,BP, 14.1mg/day] + piac&o aspirin anticoagulation warfarin low-dose with and cholesterol fibrinogen and levels,and aspirinin the primaryprevention of (n=l268) plasma factorVII coagulant activity ischaemic heartdisease men at in Warfarin meanstableINR of 1.47 increased Lancet351(9098):233-241. risk. [4.1mglday]+ Aspirin75 mglday controlled release(n=1277) Placebo warfarin placebo + aspirin (n=1272) MeadeTW, Brennan 2000. PJ. Determination whomay derivemost of benefit from aspirinin primaryprevention: subgroup resultsfroma randomised controlled BritishMedicalJournal trial. 321(7252):13-17.

3 4

Menconsidered be at increased of Aspirin75 mgldayin a controlledto risk, coronary heartdisease(i.e.,thosein the top refease formulation warfarin ’ 2.5 mgldaywithmonthly dose 20 or 25% basedon a risk score) adj~s~~~ to an tNR of 1.5 Warfarin placebo plus Aspirinplusplacebo DoublePlacebo

ireatment duration not rpecified the article. in

Iinical Trial

Reference Total iubjects I Patient Population rreatment Groups (n) Treatment Duration Type of Article


BrouwerMA, van den BerghPJPC, Aengevaeren WRM,VeenG, LuijtenHE, Hertzberger van BovenAJ, Vromans DP, RPJW,UijenGJH,VerheugtFWA. 2002. Aspirinpluscoumarinversusaspirinalone in the prevention reocclusion of after fibrinolysis acutemyocardiai for infarction: resultsof the Antithrombotics the in Prevention Reocclusion Coronary of In Thrombolysis (APRICOT)-2 Trial. Circulation 106(6):659-665. HuynhT, TherouxP, BogatyP, NasmithJ, SolymossS. 2001.Aspirin,warfarin,or the combination secondary for prevention of coronary eventsin patientswith acute coronary syndromes priorcoronary and arterybypasssurgery. Circulation 103(25):3069-3074. ’

274 Patientsreceivingaspirinand heparinwho had a patentinfarct-related artery(TIMI grade3 flow) <48 hoursafterfibrinolysis for acuteMl

Aspirin mgldayfor 3 months+ 80 5months leparin[heparin stoppedwithin48 lours] (n=139) bpirin 80 mg/day+ heparin[until NR 2.03.01followedby Coumarin or 3 months(n=l35)

‘ linicalTrial

135 Enrolled subjectshad unstableanginaor non-ST-segment elevationMI with prior CABGand werepoorcandidates a for revascularization procedure

lspirin 80 mglday(n=46) Narfarin INR of 2.0 to 2.5 (n=45) to Narfarin INR of 2.0 to 2.5 + to bpirin 80 mglday(n=44f ‘ okowingthe 12-month treatment jeriod,open-label aspirin l25 mgldaywas prescribed all for subjects

-herewas a l-month allow-upafter administration the of tpen-label aspirin+


[Oosterga AnthonioRL, De Kam PJ, M, KingmaJH, CrijnsHJGM,Van Gilst WH. ~ 1998.Effectsof aspirinon angiotensinconverting en@meinhibitionand Ieft ven~culerdilationone yearafter acute myocardial infarction, AmericanJournalof Cardiology 81(10~:1178-1181. .

298 Maleand femalepatientswith a first anterior ihe Captopril Thrombolysis and wall Ml who originallyenteredthe Captopril study(CATS)was a comparison and Thrombolysis Study(CATS) retween captopriland placeboafter :ompletion s~ept~in?s~infusion; of I rowever, paperlookedat the this rffectof low doseaspirin(dosenot lpecitied) takenpriorto the eventon Icute(infarctsize)and longterm LV dilation)outcomes followinga rst anteriorwall MI. Patientswere *eated aspirin(80-100mglday) with lfferthe eventat the discretion of le ihvestiaator

Iurationof aspirin linicalTrial Fxposure to prior enrollment reported. not Lspirin. at taken iscretionof investigator allowing enrollment isted for the 28-day tudy duration

Aspirin Professional Labeling Proposed Changes Citizen Petition McNeit Consumer & Specialty Pharmaceuticals

Vol 1 Pg 205


TABLE OF studies

- PUBLICATIONS PROVIDING ADDITIONAL EFFICACY INFORMATION Total iubjects Patient Population ( keatment Groups (n) Qpirin 100mg suppositories (n=24) 21 days ‘ lacebo (n=26) Treatment Duration Type of Article >linical Trial

HopJW, RinkelGJE,AlgraA, Berkelbach van der Sprenkel van Gijn J. 2000. JW, Randomized trial of postoperative pilot inn in subarachnoid hemorrhage.

50 Subjects aneurysmal with subarachnoid hemorrhage had undergone who surgery within4 days afterthe subarachnoid hemorrhage 466 Patientswho had a first non-cardiogenic stableischemicstroke(including lacunar infarction) reversible or ischemic neurological deficitand werehospitalized in 1 of 13 participating hospitalsin Taiwan / from October1992to April 1995

lspirin 100mglday,initiatedwithin 3 Aspirin(Meanfollow-up Iinical Trial o 6 weeksafterthe onsetof stroke of 612 days) :n=222) Nicametate citrate Jicametate citrate50 mglday, (Meanfollow-upof 625 nitiatedwithin3 to 6 weeksafterthe days) Insetof stroke(n=244) :ase Study

women.Epidemiology 11(4):362-387.

iis d

BernardR, Chamberlain Bothw@k D, L, IrvingJ, MurdochW, PohlJ, WoodD, PennyJ, Millar-Craig RobsonD, M, VallanceB, Hine K, Powell-Jackson J,

1,013 Femalesubjectswith first validatedcaseof !spirin:0150mgldayor MI identified Tom a cohortof women ~150mglday(300mglday registered the GeneralPracticeResearch accounting closeto 90% of this in for Database betweenJanuary1991and iose category) December 1995who had no historyof MI, Jonaspirin NSAID:low-/mediumothercoronaryheartdisease,stroke, fose or high-dose categories neoplasms, coaguiopathies, vasculitis, and alcohol-related diseases /Patientswith Ml who received anistreplase lspirin 150mglday(n=519) Aspiringiven thrombolysis I ~~agu~a~on therapy(1000l&r immed!ate!y &er If I.V. heparinfollowedby >warfarin anrstreptase then and )r otheroral anticoagulant; heparin dailYfor 3 months discontinued INR>2 and when Hepadngiven6 hours naintained between2-2.5)(n=517) afteranistreplase; warfarinor other anticoagulant given within24 hoursafter anistreplase 3 for months I

Iinical Trial










Type of TreatmentDuration Article /ariable(l-l 5 months) IinicalTrial

Total iubjects PatientPopulation Reference of the 1014 Substudy OPUS-TIMI- examining O’ Connor ShieldsDC, Fitzgerald FF, A, safetyandefficacyof orbofiban patients in Cannon Braunwald Fitzgerald CP, E, DJ. Nithunstable coronary syndromes. 2001 Genetic b. variation giycoprotein in llb/llla (GPllb~llia) a determinant the as of responses an oral GPllbllllaantagonist to in patients unstable with coronary syndromes. Blood98(12):3256-3260.

BergeE, Abdelnoor Nakstad M, PH, Sandset 2000.Lowmolecular-weight PM. heparin versusaspirin patients in with acuteischaemic strokeandatrial fibrillation: double-blind a randomised study,HAESTStudyGroup.Heparin in AcuteEmbolic StrokeTrial.Lancet 355(921 I):12051210. CAST(Chinese AcuteStrokeTrial) Collaborative Group.1997.CAST:’ randomised, placebo-controlled of early trial aspirinusein 2O;OOO patients acute with ischaemic stroke.Lancet349(9066):16411649. Couinadin AspirinReinfarction Study

TreatmentGroups(n) Orbofiban 50130 groupf50 ma mg orbofiban for 30 daysfoilowedy bid by 30 mg bid + aspirin150-I62 mg daily)(n=353) Orbofiban 50150 group(50 mg mg orbotiban for 30 daysfollowed bid by 50 mg bid + aspirin150-l62 mg dailvl (n=308) Pla&&ogroup(placebo aspirin + 150-I62 mg daily)(n=353) i4 days(range:II-17 with strokeandAF Aspirin160mglday+ placebo 449 Subjects acuteischemic lays)or untilearlier ampules BID (n=225) SC Daiteparin IUlkgSC BID + 100 lischarge placebo tablets(n=224)

Iinical Trial

I weeks

Xinical Trial

2 4 3 8 -4

(CARS)Investigators. 1997.Randomised double-btind of fixedlow-dose trial warfarin with aspirinaftermyocardial infarction. Lancet 350(9075):389-396.

*hemedianfollow-up who daysprior Aspirin160mglday(n=3393j 8863 Subjects hadhadan Mt 3~21 was Warfarin mg + Aspirin80 mglday tertod 14 months 1 to enroltment. (n=2028) Warfarin mg + Aspirin80 mglday 3 (n=3382) The doseof warfarin reduced was if la subject‘INR was above3.5 s

Xinical Trial











Total PatientPopulation iubjects Reference TreatmentGroups(n) after infarction Aspirin160mglday(n=1206) HurlenM, Abdelnoor SmithP, Erikssen 3630 Patients acutemyocardial M, Warfarin INR 2.8-4.2 to (n=1216) - J, AmesenH. 2002.Warfarin, aspirin, or Aspirin75 mglday+ Warfarin INR to bothaftermyocardial infarction. New 2.0-2.5(n=l208) England Journal Medicine 13):969of 347( 974. 5421 Subjects hadan Ml 3-21dayspriorto Aspirin 160 mg/&y (nz3393) who O’ Connor GattisWA, Hellkamp CM, AS, ; enrollment. Langer LarsenRL, Harrington A, RA, Warfarin mg + Aspirin80 mglday 1 Berkowitz O’ PT, Kopecky SD, Gara SL, Gheorghiade DalyR, CaliffRM, Fuster M, V. 2001a.Comparison two aspirindoses of on ischemic strokein post-myocardial infarction patients the warfarin in (Coumadin) AspirinReinfarction Study (CARS). American Journal Cardiology of 88(5):541-546. 1470 Survivors acuteMl (AMI)treated of with Scrutinio Cimminiello Marubini D, C, E, Aspirin160mglday(n=736) thrombolysis PitzalisMV, Di BiaseM, RizzonP. 2001. Ticlopidine mglday(n=734) 500 Ticlopidine versusaspirinaftermyocardial infarction (STAMI) Journalof the trial. Amencan College Cardiology of 37(5):1259-1265. 6637 PatbItS Within 7 daysOfan acuteCoronaryAspifin 160 mg/day (nz2231) Second SYMPHONY Investigators. 2001. syndrome werestablefor at least 12 who Randomized of aspirin, trial sibrafiban, or Aspirin160mglday+ Low-dose hourswithoutsignsof active&hernia, bothfor se~~da~.preve~~o~ acute after sibraliiban [3.0;4.5,or 6.0 mgiday hem~ynamicinstability, Fillip class or Goronary syndromes. Girc~lation basedon weightandserum greater 2 than 103(23):1727-1733. creatinine) (n=2232) High-dose sibrafiban 4.5,or (3.0‘ 6.0 mgldaybasedon weightand serumcreatinine) ln=2174)


Type of Article

1:he median follow-up leriodwas 14 months

:oliow-up period=6 nonths

Iinical Trial

neanfollow-up period01 ZnicalTrial approximately days 95

APPENDIX 1. TABLE OF STUDIES - PUBLICATIONS PROVIDING ADDITIONAL EFFICACY INFORMATION Total Patient Population Subjects Reference 9233 Patientswith MI or angina SYMPHONY investigators. 2000. Comparison sibrafiban aspirinfor of with prevention cardiovascular of eventsafter acutecoronarysyndromes: randomised a trial.Lancet355(9201):337-345. TreatmentGroups (n) Aspirin160mglday(n=3089) Treatment Duration 90 days Type of Article ClinicalTrial

FioreLO,Ezekowitz BrophyMT, Lu 0, 50% MD, SaccoJ, PeduzziP. 2002.Department of Veterans AffairsCooperative Studies Program ClinicalTrial comparing combined warfarin aspirinwith aspirinalonein and survivors acutemyocardial of infarction: primaryresultsof the CHAMPstudy. Circulation 105(5):557-563. AriyoA, Hennekens StampferMJ, CH, RidkerPM, 1998.Lipoprotein lipids, (a), aspirin,and risk of myocardial infarctionin the Physician’ s HealthStudy,Journalof

Long-ternl follow-Up patientswho had an Aspirin 162 mg/&y Of (nz2537) Ml within 14 daysof originaladmission and Aspirin81 mglday+ Warfarin[INR who were not beingtreatedwith high-dose 1.5-2.5IU])(n=2522) ASA or NSAlDs

Medianpatientfollow-up ClinicalTrial PeriodwaS2.7 Years. The studylasteda total of 6 years(1992-1997). Person-years followof up was 6940yearsin the aspiringroupand 6789yearsin the aspirin + warfafingroup.

Aspirin325 mg QOD (n=255)









TreatmentDuration Type of Article treatment duration tc Ibserv-ational up I2 years study

Reference CookNR, HebertPR, Manson Buring JE, JE, Hennekens 2000.Self-selected CH. post-trial aspirinuseandsubsequent cardiovascular disease mortality the and. in Physicians’ HealthStudy.Archivesof Internal Medicine 160(7):921-928. Ma J, Hennekens RidkerPM, CH, Stampfer 1999.A prospective MJ. study01 fibrinogen risk of myocardial and infarction in the Physicians’ HealthStudy.Journalof theAmencan College Cardiology of 33(5):1347-1352.

Total PatientPopulation Subjects 18,496 Apparently healthymalephysicians

TreatmentGroups (n) Aspirin325mg QOD

, 398

Nestedwithinthe Physicians’ HealthStudy Aspirin325 mg QODversusplacebc qpproximatelyyears 5 (PHS),this analysis involved bloodsamples Aspirinassignment casesubjects in takenfrom 199physicians who was 32%;aspirinassignment in subsequently developed myocardial controlsubjects 46% was infarction 5 yearsof follow-up.Each after Subjects werealso randomly casewas matched a samplefrom a with assigned takeQODbetato subjectfreeof MI carotene mg) in a 2 X 2 factorial (50 desian Aspirin100mg/day@=I) wereadmitted the hospital to because of unstable anginaor Ml
I With 8


Y. 1997. Aspirinfor prevention of myocardial infarction. double-edge A sword.Annales Medecine de lnterne 148(6):430-433.

Aspirin 4 q/kg body Weight per

135 Whitechildren mOllthS t0 1118 7 )WrS Strater KurnikK, HellerC, Schobess R, R, first episode an ischemic of stroke Luigs P, Nowak-Got8 2001.Aspirin U. versuslow-dose low-molecular-weight heparin: Antithrombotic therapy pediatric in ischemic strokepatients: prospective A follow-up study.Stroke32(11):2554-2558.

day;range,2 to 5 mglkg(n=49) Low-dose tow-mo~~ular weight (LMWH) heparin (enoxaparin to [? 1.5 mglkgbodyweightper day]or dalteparin to 125anti-XaU/kg j75 bodvwt oerdavhh-r=861

Jnknown: subjects 4 :I month:4 subjects I monthto 1 year:1 subject ~1year:6 subjects rreatmentfor 6 to 14 nonths ‘ oilow-up 8 to 48 for nonths

:ase Study

Iinical Trial

IAPPENDIX 1. TABLE OF STUDIES - PUBLICATIONS PROVIDING ADDITIONAL EFFICACY INFORMATION Type of Treatment Duration Article TreatmentGroups (n) Aspirin300 mglday(n=491) 1486 Jatientsadmittedto the hospitalin 10 Treatment durationup tc ClinicalTrial BathPM, Lindenstrom BoysenG, De E, European countries a clinicalsyndromeTinzaparin with IO days DeynP, Friis P, LeysD, MarttilaR, Olsson high-dose anti(175 If a strokeif they wereaged 18-90years Xa Wkg daily)(n=487) J, O’ D, Orgogozo Ringelstein var Neill J, B, andcouldbe treatedwithin48 hoursof der SandeJ, TurpieAGG. 2001.Tinzaparir Tinzaparin medium-dose anti(100 ;trokeonset in acuteischaemic stroke(TAIST):a Xa IU/kgdaily)(n=508) randomised aspirin-controlled Lancet trial. 358(9283):702-710. Reference Total iubject: Patient Population Cesarone LauroraG, DeSanctisMT, MR, Incandela Fugava L, GirardelloR, Poli L, A, Peracino AmbrosoliL, BelcaroG. L, 1999.Effectsof friflusalon arteriosclerosis ssionassessed high-resolution with al ultrasound. Angiology50(6):45543 ‘ atientswith subclinical atherosclerotic Aspirin300 mg QD (n=22) esionsas classifiedby ultrasound arterial Triflusal300mg BID (n=21) norphology enteredthe study. Patients I&I significant cerebrovascular or :ardiovascular disordersrequiring treatmeni vereexcluded. ;ubjer%s hospitalized within24 hoursof AMI Aspirin300 mgiday(n=ll40) rymptom onsetwere randomized TriRusal600 mglday(n=1135) Two-week placeborun- ClinicalTrial in followedby 12 months of treatment



Theprimaryand secondary endpoints Meremeasured 35 at daysafterAM1



‘ atientswith confirmed acuteMl, within24 Aspirin300 mglday(n=1140) toursof onsetof symptoms Tnftusal600 mg/day@=I135)



iit 4 c;rp

NavarroE. 2000.Randomized comparative trial of triflusaland aspirinfollowingacute myocardial infarction. EuropeanHeart Journal21(6):457-465.


IONAL EFFICACY INFORMATION TreatmentGroups (n) Aspirin300mg QD for 2 weeks followedby ticlopidine mg BID 250 for 2 weeks(n=26) Treatment schemereversed(n=27) Treatment Duration I4 days of the first nedication followedby I4 days of the second nedication Type of Article Iinical Trial

53 Inpatients admittedto the hospitalfor cerebralischemiaand outpatients witi varyingdegreesof carotidstenosis

Rapiddeclineof cerebralmicroemboli of arterialoriginafterintravenous acetylsalicylic Stroke30(1):66-69. acid.

9 Patientswith TIA or minorstrokes attributable the territoryof the midd to cerebralartery(nondisabling cerebral ischemiaof probabte arterioembofic in o and had not.startedon antiplatelet or anticoagulant medications Sincethe a et of symptoms) 677 Patientswith nonvalvular chronicatria

Aspirin500 mg i.v. bolusinto the Jot specified antecubital followingl-hour of vein continuous microembolic signals (MES)monitoring. Aspirin300 mgldayp.o. was started the day afterthe i.v. bolus Aspirin300 mglday(n=169) \pproximately years 3 Warfarin1.25mglday(n=167) Warfarin1.25mglday+ aspirin 300 mglday(n=171) Adjusteddosewarfarinto INR 2.0 to 3.0(n=170)

Iinical Trial

Iinical Trial

J, BoysenG. 1998.Fixedminidose warfarinand aspirinaloneand in combination adjusted-dose vs warfarinfor strokeprevention atrialfibrillation: in SecondCopenhagen Atrial Fibrillation, Aspirin,andAnticoagulation Study. Archives internalMedicine of

2 Y tQ

19,435 ISubjectswith evidenceof an acuteisc rmic Aspirin300 mglday(n=9720) strokewithonset ~48hoursof studyE ‘ No aspirin(n=9715) Ynd no evidence intracranial of hemorrhag ,ns Unfractionated heparin(5000IU no clearindications or contraindic: for, aspirin,subcutaneous heparin,both,or [low-dose] 12500IU [mediumor to, heparinor aspirin. neitheramong19 435 patientswith acute dose]SC BID) (n=9717) emit stroke.Lancet349(9065):1569No heparin(n=9718)

“reatment to was ontinuefor 14 days or until discharge prior

Iinical Trial










Reference MasJL, Arquizan LamyC, ZuberM, C, Cabanes Derumeaux CosteJ. 2001. L, G, Recurrent cerebrovascular events associated patent with foramen ovale,atria septalaneurysm, both.New England or Journal Medicine of 345(24):1740-1746. Rygtewicz Baranska-Gieruszczak D, M, Czlonkowska Lechowicz HierDB. A, W, 1997.Strokerecurrence among30 days survivors ischemic of strokein a prospective community-based study. Neurological Research 19(4):377-379. Aronow Ahn C, Kronzon Gutstein WS, I, H. 2000.Effectof warfarin versusaspirinon the incidence newthromboembolic of strokein olderpersons chronicatrial with ~brilla~on abnormal normalfeft and and ventricular ejection fraction. American Journal Cardiology of 85(8):1033-1035. Bartorelli Trabattoni Montorsi AL, D, P, Fabbiocchi GalliS, Ravagnani F, P, Grancini CozziS, LoaldiA. 2002.Aspirin L, aloneantiplatelet regimen after intracoronary placement the Carbostent: of TheAntares study.Catheterization and Cardiovascular Interventions 55(2):150-

Total iubjects

TreatmentGroups(n) (18-55 years)andwho had Aspirin300mglday 581 Eligiblepatients an ischemic stroke(defined a as Patients withoutatrialseptal neurological deficitthatlastedmorethan24 abnormalities (n=304) hours)withinthe preceding threemonthsfor Patientswith atrialseptal whichno definite causehadbeenidentified abnormalities (n=277) aftera standardized work-up


TreatmentDuration Meanfollow-up 37.8 of months

Type of Article :ollow-up itudy

of who 30 209 A cohortof patients survived days Aspirin300mgldayin 134(64%)of Only81 (38.7%) patients continued after‘ first-ever-in-lifetime-ischemic-stroke’ patients antiplatelet therapy for werefollowed 1 yearfor recurrent for stroke thewholeyear.

lopuiationbased Study

with in 350 Patients chronicatrialfibrillation a long-term healthcarefacility

Aspirin325mglday(n=209) Warfarin 2.0-3.0, (INR meanratio 2.4)@=141)

Follow-up averaged 36 months




Aspirin325mg/dayalonein all aspirin treatment was Patients undergoing intracoronary continued indefinitely Carbostent implantation a Milanhospital patients at (aspirin mg i.v. was 500 administered immediately beforethe afterthe procedure procedure the patienthad not if beenpretreated aspirinj with


s -L

/APPENDIX Reference




- PUBLICATIONS Total ,Subjects I




INFORMATION Treatment Duration Type of Article

Patient Population

ITreatment krouw Inl

Aspirin325mglday(n=9546) with disease BhattDL, HirschAT, RinglebPA, HackeW, 19,099 Subjects atherosclerotic manifested recentischemic as strokeor Ml Clopidogrel75 mg/&y (n=g553) Top01 2000.Reduction the needfor EJ. in or symptomatic PAD hospitalization recurrent for ischemic eventsandbleeding clopidogrel with instead aspirin. of American HeartJournal 140(1):67-73. BhattDL.,ChewDP, HirschAT, Top01 EJ. 2001,Clopidogrel reduced recurrent ischaemic eventsin patients previous with cardiac surgery morethanaspirin. Evidence-Based Medicine 6(4):? 14 BhattDL, MarsoSP, HirschAT, Ringleb, PA, HackeW, Top01 2002.Amplified EJ. benefit Clopidogrel of versusAspirinin patients diabetes with mellitus.American Journal Cardiology of 90(6):625-628. 1480 Subgroup analysis the CAPRIEstudy: Aspirin325mglday(n=705) of PathItS With recentischemic stroke,MI, OF CIopidogref 75 mg/&y (n=775) peripheral arterydisease alsohad who cardiacsurgery 3866 In this retrospective subanalysis the of CAPRIEdata,patients a historyof with diabetes mellitusat enrollment were identified the original from CAPRIEstudy population Aspirin325mglday(n=1952) Clopidogrel75 mgiday(n=l914)

l-3 years

Clinical Trial

I to 3 years

CommentaryTreatment Guideline

i -3 years

2etrospective Subanalysis

19,185 Patients symptomatic with atherosclerosis Aspirin325mglday(n=9586) Cannon 2002.Effectiveness CP. of manifested recentischemic as stroke,MI, or Clopidogref 75 mg/&y (n=g5gg) dopidogrel versusaspirinin preventing peripheral arterydisease acutemyocardial infarction patients in with symptomatic atherothrombosis (GAPRIE trial).American Journal Cardiology of ’ 19,185 Patients symptomatic with atheroscierosis Aspirin325mglday(n=9586) mg/day (nzg5gg) manifested recentischemic as stroke,MI, or Clopidogrel75 peripheral arterydisease(CAPRIE Trial)

l-3 years(meanfollow-. ?etrospective rp of 1.9 years) ?\nalysis

to 3 years

Xnical Tria!


Total Subjects Patient Population Treatment Groups (n) Treatment Duration Type of Article



ChanK-L, Dumesnil CujecB, JG, Sanfilippo Jue J, Turek MA, Robinson AJ, TI, MoherD. 2003.A randomized of trial aspirinon the risk of emboliceventsin patientswith infectiveendocarditis. Journal of the AmericanCollegeof Cardiology

with between Aspirin325 mglday(n=60) 115 Patients infectiveendocarditis 16 and 80 yearsof age Placebo(n=55)

1 weeks

Iinical Trial

with atherosclerosis Aspirin325 mglday(n=9586) CreagerMA. 1998.Resultsof the CAPRIE 19,185 Patients symptomatic nanifestedas recentischemicstroke,Ml, or Clopidogrel75 trial:efficacyand safetyof ctopidogrel. mg/day(n=9599) peripheral arterydisease(CAPRIETrial) Vascularmedicine3(3):257-260. FerroM, CrivelloR, RizzottiM. 2000. Comparison subcutaneous of calcium heparinand acetylsalicylic in the acid prevention ischemiceventsand death of aftermyocardial infarction: randomized a trial in a consecutive seriesof 90 patients. HeartDisease2(4):278-281 Goldstein AndrewsM, Hall WJ, Moss RE, AJ. 1996.Markedreduction long-term in cardiacdeathswith aspirinaftera coronary event.Journalof the AmericanCollegeof Cardiology 28~2):326-330. 90 Patients discharged a coronary from care unitafteracutemyocardial infarction Aspirin325 mglday(n=46) Aspirin325 mglday+ Calcium heparin12,500IU daily (n=44)

l-3 years


Aspirin(6 months) 2linicalTrial Calcium heparin+ aspirin(heparinfor 3 nonthsfollowedby %spirin mgldayfor 3 325 nonths) Zollow-up occurredfor ietrospective sn averageof 23 Study nonths. A totalof 695 )f the 751 regularaspirin lsers ~n~~~~ their egularaspirinuse. Of hese 695 patients,676 ook 250 mg or 325 mg aspirin QD. Aspirin foses ~250 mg were aken by relatively few latients

936 FromtheMulticenterStudyof Myocardial lschemia (patients afteran acuteMI or mstableangina)

Patients takingaspirinregularly (n=751): dosingat baseline: 325mglday(n=585) 250mglday(n=93) 160mgiday(n=6) 80 mgtday(n=29) 325 mg QQD(n=ll) Otherdosingpatterns(n=27) Patients takingaspirinregularly not jn=185)

1 APPENDIX 4. TABLE OF STUDIES - PUBLICATIONS PROVIDING ADDITIONAL EFFICACY INFORMATION Total Subjects Patient Population TreatmentGroups (n) Aspirin325 mglday(n=lO3) Ticlopidine mg BID + Aspirin 250 325mglday(n=123) Treatment Duration Aspiringroup: indefinitely. Ticlopidine aspirin + group:ticlopidine 1 for monthand aspirinfor 5 days Follow-up: months 2 1 to 3 years Type of Article YinicalTrial


aftersuccessful intravascular 226 Patients ultrasound-guided implantation stent A. 1996.A randomized comparison of combined ticlopidine aspirintherapy and versusaspirintherapyaloneafter successful intravascular ultrasound-guided t implantation. Circulation 93(2):215-

with atherosclerosis Aspirin325 mglday(n=9586) 19,185 Patients symptomatic manifested recentischemicstroke,MI, or Clopidogrel75 as mgiday(n=9599) symptomatic peripheral arterydisease Thisstudywas a pooledanalysisof the data r\spirin325 mglday(n=1722) iromthe SPAF l-111 whichenrolled trials, 19spirin mg/day+ Warfarin 325 3atients documented with sustained or Imeandailydosewas 2.1 mg) *ecurrent fibrillation withoutmitral [n=290) atrial (AF) jtenosisor prosthetic cardiacvalvesfrom 25clinicalsites 630 ‘ atients who had experienced ischemic stroke withinthe previous30 days bpirin 325mglday(n=318) JVarfarin mglday(n=312) 2

Xnical Trial

Follow-up: years 2


RM, AsingerRW. 1999b.Factors associated ischemicstrokeduring with aspirintherapyin atrialfibrillation: analysis of 2012participants the SPAF l-111 in

Treatment durationup 2 years

Iinical Trial

wale in Cryptoganic StrokeStudy. Circulation 105(22):2625-2631. d J 2 h) 7n” 831 morbidity, mortalityassociated and with long-term administration oral of anticoagulant therapyto patientswith %rbjects underwent who peripheral arterial aspirin3’ mglday(n=413) 25 ypass surgery. lspirin 325 mglday+ Warfarin j mgldaywith a targetINRof i.4!.8 (n=418) Prosthetic bypass (Average follow-up Pedod=36.6 months) Vein bypass(Average follow-upperiod=39.3 months.) Iinical Trial










TreatmentDuration 10 days Type of Article Iinical Trial

Total iubjects LeonMB, BairnDS, PopmaJJ, Gordon PC, CutlipDE, Ho KKL,Giambartolomei A, DiverDJ, Lasorda WilliamsDO, DM,

aspirin prevention vascular for of eventsin patients cerebral after infarction: TAClF the Study:a randomized, double-blind, multicenter Stroke34(4):840-848. trial.

TreatmentGroups(n) 1653 Patients enrolled werethosewith single- ’Aspirin325mglday(n=557) vesselor multivessel disease native of Aspirin325mglday+ Heparin to i-v. coronary arteries weresuccessfully an aPTTof 40 to 60 seconds, who treated a high-pressure, with balloonsubstituted oralwarfarin with once expandable stent an INR of 2.0 to 2.5 was reached) (n=550) Aspirin325mglday+ Ticlopidine 500mglday(n=546) 2107 Patients yearswho hadsuffered TIA Aspirin325mglday(n=1052) WO a Of nondisabling strokeWithin the previous Tnftusal600 6 m&day (n=1055) mon#s I

Patient Population

Treatment duration ranged from 1 to 3 years. Meanfollow-up: 30.1 months The articlestatesthat aspirinwas taken through hospital discharge

Xinical Tritil

200 Patients evidence ischemia with of or lesionsin nativecoronary vessel


Clinical Trial

(HEPACOAT an antithrombotic and regimen aspirinalone)Study.Circuiation of 108(9):1078-1083. _ Rothrock Anderson HartRG. 1996 JF, DC Differential effectof aspirin on clinicalstroketypesin p 49 Patients enrolled the SPAFII studywho in suffered ischemic an strokeduringthe trial pirin325mglday[n=545) rfarinadjusted to maintain lNR ,2.0to 4.5 (n=555) Trial Duration treatment %nical of the development of strokenot specified in the article .
prior t0

iii d 2 f? 45










Total Reference MohrJP, Thompson LazarRM, Levin JL, 8, SaccoRL, FurieKL, KistlerJP, Albers GW,Pettigrew AdamsHP, Jackson LC, CM,PullicinoP. 2001.A comparison of warfarin aspirin the prevention and for of recurrent ischemic stroke.NewEngland Journal Medicine of 345(20):1444-1451. ObialoCl, Conner LebonLF. 2003. AC, Maintaining patency tunneled of hemodialysis catheters Efficacyof aspirin compared warfarin. to Scandinavian Journal Urology Nephroiogy of and 37(2):172-176. SaracTP, HuberTS, BackMR, OzakiCK, Canton FlynnTC, Seeger 1998. LM, JM. Werfarin improves outcome the of in~ainguinal bypass vein graftingat high riskfor failure.Journal Vascular of Surgery 28(3):446-457. SPAFiii WritingCommittee (Stroke Prevention AtriaiFib~ila~on). in 1998. Patients nonvaivuiar tibriltation with atiial at low risk of strokeduringtreatment with aspirin: StrokePrevention Atriai in Fibrillation Study.Journal the Iii of American Medical Association 279(16):1273-1277.
I Subjects

TreatmentGroups (n) 2206 Eligible patients were30 to 85 yearsold, Aspirin325mglday(n=1103) wereconsidered acceptable candidates Warfann mg/day to lNR 1.4 to for 2 warfarin therapy, an ischemic had stroke 2.8(n=I103) withinthe previous daysandhas scores 30 of 3 or moreon the Glasgow Outcome Scale


TreatmentDuration ! years

Type of Article Ziinical Trial

Yellow-up period=120 Iinical Trial 63 Patients cuffedtunneled with hemodiaiysis Aspirin325mglday(n=21) lays catheters awaiting maturation their of Warfarin (dose-adjusted INRof 2. to . arteriovenous fistuiae 3) (n=ll) Control (neither aspirinor warfarin) (n=31) 56 Patients hadundergone who infrainguinai arterial bypassgrafting autogenous with veinwhowereat highrisk for graftfailure, defined suboptimal as venousconduit, poor arterialrunoff,or redoinfrainguinai bypass grafting Aspirin325mglday(n=24) Aspirin325mglday+ Warfarin to INR 2 to 3 + heparin15 units/kg (n32) i to 5 years Iinical Trial

zi -L 2 Y 00

892 Patients a~ial~fibrillation with categorized Aspirin325mglday as “lowrtsk” basedon the‘ absence 4 of prespecitied ~~rnb~e~~c rtskfactors (recentcongestive heartfailureor left ventricular fractional shortening 25%or of less,previous thromboembolism, systolic bloodpressure greater -160 than mmHg,or femalesex at ageolderthan75 years)

‘ atients weretreated Iinical Trial ,ndfollowed a mean for f2years




htrospective study

TreatmentDuration TreatmentGroups(n) atientswith symptomatic stenosis (50%to Aspirin(nospecificdoserequired ‘ or atientsweretreated 68 ‘ VASlDStudyGroup(Warfarindspirin nd followed a for 19%) a majorintracranial of artery(carotid specified; of 26 patients 21 were Qmptomatic Intracranial Disease). 1998. treatedwith at least325 mglday) iedianof 13.8months iphon;anterior, middle,or posterior ‘ rognosis patients symptomatic of with (n=26) erebralartery;vertebral artery;basilar lertebral basilararterystenosis.Stroke or Irtery; pOStf?riOr inferior Or cerebellar artery) Warfarin specific dose required (no !9(7):1389=1392. or specified; warfarin therapywas typicallyadjusted maintain to prothrombin timesin the rangeof 1.2to 1.6timescontrol(n=42) It shouldbe notedthatnoneof the investigational centerswereusing prothrombin international time normalized for measuring ratio levelsof anticoagulation duringthe studyperiodof 1985to 1991) 325 Treatment duration not atientsaftertotalkneearthroplasty from Aspirinbetween and Vestrich HaasSB, MoscaP, Peterson 6001 ’ ‘ GH, specified the article in 650mglday 13 studies A.2000.Meta-analysis thromboembolic of Irophylaxis totalkneearthroplasty. after Warfarin or 10 mg on the evening 5 ‘ ournat Boneand JointSorgeryof beforeor nightof operation with 12(6):795-800. dailydoseson the first or second day afferoperation PT time with keptat 1.3to 1.5of normal low Molecular WeightHeparin ’Intermittent pneumatic compressjon startedduringor aherthe operation. Treatment duration for Aspirin325mglday 825 Therewere 1662subjects 260% with ‘ oungB, MooreWS, Robertson Toole JT, aspirin not given, was in carotidstenosis enrolled the in F, ErnstCB, CohenSN, Broderick JP, All subjects the ACASalso in thecurrentstudy Asymptomatic Carotid Atherosclerosis Iempsey Hosking 1996.An RJ, JD. underwent aggressive factor risk Study(ACAS). Subjects the current in analysis perioperative of surgicalmortatity reduction studyincluded thosefromACAS nd morbidity the Asymptomatic in Carotid uherosclerosis Study.Stroke27(12):2216randomized the surgical of the study to arm i224. (underwent carotidendarterectomy) Zeference


Iinical Trial

APPENDIX 1. TABLE OF STUDIES - PUBLICATIONS PROVIDING ADDITIONAL EFFICACY INFORMATION Reference Cesarone BelcaroG, Nicolaides MR, AN, lncandela De SanctisMT, Geroulakos L, G, LennoxA, MyersKA, Moia M, lppolitoE, WinfordM. 2002.Venousthrombosis from air travel:The LONFLIT3 study:Prevention with aspirinvs low-molecular-weight heparin(LMWH)in high-risksubjects:A randomized Angiology53(l):%6. trial. Grotemeyer EversS, FischerM, KH, HusstedtIW. 2000.Piracetam versus acetylsalicylic in secondary acid stroke prophylaxis. double-blind, A randomized, parallelgroup,2 yearfollow-upstudy. Journalof the Neurological Sciences 781(1-2):65-72. Total !Subjects Patient Population TreatmentGroups (n) Aspirin400 mgldayx 3 days starting 3 daysfor aspiringroup; Iinical Trial 12 hoursbeforethe beginning the 1 day for LMWHgroup of flight LMWH(enoxaparin) 1,000IU per 10 kg bodyweightinjectedbetween2-4 hoursbeforethe flight Control( no prophylaxis) Aspirin200 mg TID (n=307) Piracetam 1600mg TID (n=256) 2 years :linicalTrial Treatment Duration Type of Article


at 300 Subjects highrisk for DVT

afterstrokeas confirmed by 563 =atients amputed tomography or magnetic (CT) ‘ esonance imaging(MRI)

Aspirin Professional Labeling Proposed Changes Citizen Petition McNeH Consumer & Specialty Pharmaceuticals

t 2 i 5 : : . ! i .
i ! I I i 1 i i t i

spirinin the secondary revention cardiovascular of

Stroke:0.8 risk ratio(95%Cl 0.7-l .O;p=O.O7); risk reduction 20% MI was reported 5 of the 6 studies,while strokewas reportedin only 2 studies. To in includeall-studies, authorscreatedthe eventcategory‘ the vascularevents’ to summarize reportsof Ml, stroke,and other vasculareventsincludingvasculardeath. all

999.Dipyridamote plus spirinin cerebrovascular isease.Archivesof Neurology 6(9):1087-1092.

3 trials involvingpatientswith cerebrovascular disease: NonfatalMl -7%; nonfatalstroke17%;vasculardeath-6X, all vascularevents6%; nonvascular death-26%; totaldeaths-12% ESPS2 trial plus the 14 trialsfrom the Antiplatelet TrialistsCollaboration: NonfatalMl -4%; nonfatalstroke23%;vasculardeath-3%, all vascularevents10%; Collaboration treatments nonvascular triat death-14%; total deaths-6% (n=5317): ESPS-2trial plus the 3 cerebrovascular trials: Aspirinalone(dosages varied NonfatalMl -6%; nonfatalstroke25%;vasculardeath-I%, aft vascularevents18%; from 150-I300 mglday; nonvascuiar death-11%: totaldeaths-5% medianaspirindose = 975 (medianaspirindose= 225 mglday)

I4PPENDIX 2. F leference

SUMMARY OF EFFI’ 4CY RI Type of Total Article Subjects itrial Fibrillation Investigators. F Aeta2574 997.The efficacyof aspirinin i rnalysis Fatients atrialfibrillation: with analysis pooleddatafrom 3 of andomized trials.Archivesof nternai Medicine ~ I):1 237-l240. 57(1

;ULTS - PUBLICATIONS PROVIDING ADDITIONAL EFFICACY INFORMATION TreatmentGroups(n) \FASAK:aspirin75 mglday lr placebo(n=672) EAFT: aspirin300 mg/dayor llacebo (n=782) IPAFI: aspirin325mglday lr placebo(n=ll20) Efficacy Data Aspirintherapy seemedparticularly effectivein younger patientsand in patients with hypertension SPAF’ but not in the other2 studies. Whenall patients in i, were combined, thosewith a historyof hypertension a statistically had significant relative 36% reduction the risk of strokeassociated aspirintherapy(p=O.O09). in with However, the interaction between historyof hypertension aspirintherapy(p=O.O8) not reach a and did conventional statisticalsignificance, did the interaction any othervariables nor of with aspirinefficacy. The overallrelativerisk reduction aspirintherapywas 21% (95%Cl: 0% to 38%; with p&0.05).Disabling strokeoccurrence decreased 17%(95%Cl: -12%to 38%; was by p=O.23) nondisabling and strokeoccyrrence 27% (95%Cl: -7% to 51%;p=O.lO).In by SPAFI andEAFT,the frequency stroke,MI, or vascular of deathwas 13.5%in the controlgroupand 10.8%in the aspiringroup(relative reduction, [95%CI: 1% risk 19% to 34%;p=O.O4]). AFASAKstudydid not consider an outcomeevent. The MI Aspirintherapy not efficacious patientswithoutrisk factorsfor stroke(increasing was in age,historyof hypertension, previous strokeor TIA, anddiabetes).It did appearto be moreeffectivein patients clinicalrisk factors(relative reduction, [95%CI: with risk 28% 7% to 44%;p=O.Ol]), although interaction the between presence thesefactors the of andaspirintherapywas not significant (p=O.lO).A secondary analysisin patients a with previous strokeor TIA, the strongest factor,showeda relativerisk reduction risk with aspirinuse bf 19%(95%Ct: -7% to 39%;pEO.13) thi?se in patients. In patients a with historyof hypertension diabetes with no previous or but strokeor TIA, the relativerisk reduction aspirinusewas 54% (95%Cl: 17%to 74%;p=O.O09; with interaction term, p=0.02).Exceptfor patientsyounger 65 years,the absolute of strokewith than risk aspirintherapydid not decrease below3.0%per yearfor any of the risk strata.

SUMMA1 I OF EFFI Type of Article Reference netaHart RG, Halperin McBride JL, analysis R, Benavente Man-Son0, HingM, KronmalRA. 2000. Aspirinfor the primary prevention strokeand other of majorvascularevents:metaanalysisand hypotheses. Archivesof Neurology APPENDIX 2.
57(3):326-332. --




Total iubjects

HebertPR, Hennekens CH.
2000. An overview the 4 of


randomized of aspirin trials therapyin the primary prevention vasculardisease of Amhivesof Internal Me~i~ina
160~20):3123-3~~7, 2 -L

Efficacy Data TreatmentGroups (n) rspirin75 mgldayor placebo Aspirintherapywas associated modestincreases the rateof all stroke(includes with in ischemicand hemorrhagic) the BDT, USPHS,and ETDRS,a decrease the MRCin in 1=21,330) TPT, and no appreciable effectin the HOT,but was not statistically significant any in rspirin325 mg QODor individual clinicaltrial or theirpooledresults(relativerisk [RR], I .08;95% Cl: 0.95-l .24). (n=22,071) PNlacebo with reduction Ml-inthesetrials,with an overallRR in PLspirin to 650 mgldayor This contrasted a highlysignificant 500 reduction Ml of 26% (RR: 0.74;95% Cl: 0.68-0.82; in pcO.001).Pooledanalysisof all 5 llacebo(n=8850) trialsrevealeda RR of 0.93 (95%Cl: 0.83-I.03)for deathscategorized vascularand as 0.94 (95%Cl: 0.87-1.01) all causemortality. for No net effectof aspirintherapyon strokewas notedin the clinicaltrials of participants with vascularrisk factors(i.e.,HOT, MRS-TPT,and ETDRS)(RR=1.02; Cl: 0.8695% 1.21)compared a small increasein the 2 trialsof men withoutrisk factors(i.e., to USPHSand BDT){RR: 1.20;95% Cl: 0.96-I.49), Pooledexperience participants in with manifestvasculardisease(i.e., high risk)by the ATC yieldeda 27% RR reduction in stroke(RR:0.73;95% Cl: 0.67-0.79) antiplatelet by therapy. This effectwas incompatible the effectof aspirintherapyin the 5 clinicaltrials of primaryprevention with (p=O.OOl). contrast,the effectof aspirintherapyfor prevention Ml is similarfor In of thosewith vs. withoutvasculardisease(about25%)and for participants vs. without with vascularrisk factorsin the 5 primaryprevention clinicaltrials (23% vs. 26%reductions, respectively). L 51,085 Aspirin75 mgldayor placebo Subjectswho receivedaspirintherapyhadsignificantreductions 32% (95%Cl: 21%of 41%)for nonfatalMl and 13%(95%Cl: 5%-19%) any importantvascularevent. No for ,(n=l8,790) Aspirin 75 mg/day~ntrolled significant difference betweentreatment groupsin the risk of ischemicstrokewas release or placebo (n=5085) observed (RR: 1.01,95X Cl: O.79-1.30). Aspirin325 mg QODor placebo(n=Z2,07l) Aspirin500 mgidayor openlabelcontrol(n=5139)

P (1 P T

APPENDIX 2. SUMMARY OF EFFlCl 4CY RE ;ULTS - PUBLICATIONS PROVIDING ADDITIONAL EFFICACY INFORMATION Reference letaSanmuganathan PS, nalysis Ghahramani JacksonPR, P, WalksEJ, RamsayLE. 2001. Aspirinfor primaryprevention of coronaryheartdisease: safetyand absolutebenefit relatedto coronaryrisk derived from meta-analysis of randomised trials.Heart
85(3):265-271. Type of Article Total Efficacy Data Subjects Treatment Groups (II) Aspirinfor primaryprevention significantly reducedthe annualrisk of all CV eventsby 48,540 bpirin 75 mglday(TPT, 15%(95%Cl, 6 to 22) and MISby 30% (95% Cl, 21 to 38) and non-significantly 1=1268)(HOT,n=9399) \spirin 162.5mg/day(pHS) reducedall deathsby 6% (95%Cl, -4 to 15). Aspirinnon-significantly increased the

n=l1,037) \spirin500 mglday(BDT) n=3429) ‘ lacebo(n=23,407)

annualrisk of strokeby 6% (95%Cl, -24 to 9).

TaylorFC, CohenH, Ebrahim rletaS. 2001.Systematic reviewof Inalysis longterm anticoagulation or antiplatelet treatment in patientsv&h non-rheumatic atrialfibrillation. BMJ


3 8.A 2

ChenZM, Sandercock Pan fletaP, HC, Counsel1 CollinsR, Liu :nalysis C, LS, Xie JX, WarlowC, Peto R. 2600.,lndi~~~nsfor e&y aspirinuse in acuteischemic stroke:a combined analysisof 40 000 randomized patients from the Chinese AcuteStroke Trial and the International StrokeTrial. Stroke

40,090 ST (Aspirin300 mglday ersus hostel) (n=l9,435~

Reference .

Type of Article Total Subjects Treatment Groups (n) Efficacy Data

Mangano 2002.Aspirin ClinicalTrial DT. andmortality from coronary bypasssurgery.New England Journal Medicine of 347(17):1309-1317.

Klootwijk Meij S, MelkertR, ClinicalTrial P, Lenderink SimoonsML. T, 1998.Reduction recurrent of ischemia abciximab with duringcontinuous ECGischemia monitoring patients in withunstableanginarefractory to standardtreatment (CAPTURE). Circulation 98(14):1358-1364.

Patientsreceivingaspirinwithin48 hoursafterrevascularization a significantly had 5022 Aspirinup to 650 mglday within48 hoursafter reducedmortality(1.3%)compared patientsnot receivingaspirin(4.0%,p<O.OOi). to revascularization (n=2999) Aspirintherapysignificantly reducedthe incidence MI (2.8%vs. 5.4%,p<O.OOl), of congestive heartfailure(5.8%vs. 11.O%%, p<O.OOl), deathfrom cardiaccauses(1.1% No aspirin(n=2023) vs. 3.1%,p<O.OOl), stroke(1.3%vs. 2.6%‘ p=O.Oi), encephalopathy (0.4%vs. 2.4%, p<O.OOl), deathfrom cerebral and causes(0.2%vs. 0.8%,p=O.O2). An analysisof fatal and non-fatal eventsby aspirindose (for dosesfrom 75 mg to 325 mg) was performed (datanot provided); doseeffectwas found. no 332 Aspirinminimumdailydose Patientsweremonitored from startof treatment through6 hoursaftercoronary of 50 mglday+ Abciximab intervention.Recurrent ischemiawas detectedin 31 (18%)of the 169 abciximab in and 0.25 mglkgboiusfollowedby 37 (23%)of the 163placebopatients(p=O.34).Excluding time periodof the PTCA the a continuous infusionof IO and the stay in the catheterization laboratory, 9 (5%)of abcitimabversus22 (14%) only mglmin (n=169) of placebopatientshad22 ST episodes. Similarly,only 5 (3%)of abciximab versus‘ I5 patients r3 ST episodes(p=O.O2). had Aspirinminimumdailydose (9%)of placebo‘ Symptomatic episodes occurredin 5 (3%)of abciximab 13 (8%)of placebopatients(p=O.O5). patients and of 50 mglday+ Placebo In with ischemia,abciximab significantly reducedtotal ischemicburdenparameters (as (n=163) definedby the durationof ischemiaper patient,the sum of the areaunderthe curveof the ST vectormagnitude duringST episodes, sum of.theareaunderthe ST trend the curveof all leadsinvolved, the sum of the areaunderthe curveof all I2 leadsduring or ST episodes.Thus , patientsreceivingabciximab significantly frequentand had less fewersevereischemicepisodes.

Zeference Type of Article Total Efficacy Data Subjects Treatment Groups (n) AspirinversusPlaceboTrials(N=6) 8856 Aspirinfrom 50 to 1300 mgldayversusplacebo Meta-analysis 6 trials(average of follow-up1.5 yearsper patient)showedthat aspirin (n=3119) reducedthe incidence strokeby 22% (95%Cl, 2% to 38%).On the basisof these of was Warfarin(adjusted dosefor 6 trials,the absoluterisk reduction 1.5%per year (numberneededto treat [NNTj, an INR of 2.0 - 2.6 for primary 67) for primaryprevention 2.5%per year (NNT,40) for secondary and prevention. prevention trtals;adjustedto Althoughall 6 trials showedtrendstowardreducedstrokethat were associated with aspirin,this resultwas statistically significant only 1 study. Whendisablingstroke in INR of 2,9 for the one strokeseveritywas considered, aspirinuse was secondary prevention trial) from the 3 largesttrialsthat reported associated a relativerisk reduction 13%(95% Cl, -19%to 36%). Whenonly with of versusplacebo(n=2900) ischemicstrokeswere considered the 3 largesttrials,aspirinresultedin a 23% from Warfarinto INR 2.2 to 3.1 reduction (95%Cl, 0% to 40%). According datafrom 4 trials,all-causemortalitywas to versusAspirin75-325mglday not signiticantly reducedby aspirin(RRR 16%,95% Cl: -5% to 33%). (n=2837) Warfarin versusAspirinTrials(N=5) Theeffectof warfarinon strokecompared that of aspirinvariedwidelyamongthese with 5 trials(meanfollow-up2.2 yearsper patient). No statistically significant heterogeneity was seen (p=O.O9), meta-analysis and showedthatadjusted-dose warfartnreduced overallrelativerisk for all strokeby 36% (95%Cl, 14%to 52%)compared aspirin. with Whenonly ischemicstrokeswereconsidered, adjusted dosewarfartn associated was with a 46% (95%Cl, 27% to 60%) relativerisk reduction compared aspirin.This with difference relativerisk reduction-all strokescompared only ischemicstrokesin with ~was mostlycausedby the higherabsoluterisk for intracranial hemorrhage during warfarintherapyin 1 study. On the basisof datafrom 4 studies,all-causemortality was similarin patientswho receivedadjusted-dose warfarinand thosewho received aspirin (RRR,95% Cl: 8%, -21% to 30%).

Metaiart RG, Benavente 0, McBride PearceLA. 1999a. analysis R, Uithrombotictherapyto rrevent strokein patientswith rtrialfibrillation: metaa nalysis.Annalsof Internal dedicine131(7):492-501.


I /Reference

Type of Article



Treatment Groups (n)

Efficacy Data

KalraL, PerezI, SmithardDG, PopulationSulchD. 2000.Doesprioruse BasedStudy of aspirinaffectoutcomein ischemic stroke?American Journalof Medicine 108(3):205-209.

1457 Aspirinmediandailydoseof 75 mg, rangeof 75 to 300 mglday. Aspirinwas used regularly beforethe strokeby 650 (45%)of patients.

Srinivasan Grayson AK, AD, RetroPullanDM, FabriBM, Dihmis spective Study WC. 2003.Effectof preoperative aspirinuse in offpumpcoronaryarterybypass operations. Annalsof Thoracic Surgery 76(1):41-45.

340 Aspirin75 to 300 mglday (n=170) Nonaspirin users(n=170)

Use of aspirinpriorto strokewas associated lower4-weekmortalitycompared with with no aspirinuse priorto stroke(14%versus20%, p<O.Ol) (relativerisk, 95% Cl: 0.7,0.6 to 0.9). Beneficial effectsof prioraspirinuse on 4-weekmortalitywere seenin patients with atherosclerotic strokes(15%versus21%,~~0.05)and with cardioembolic strokes (21%versus34%,~‘ 0.05) but not amongpatientswith strokesdue to small vessel occlusion(10%versusII%, p=O.8).Prioraspirinuse was also associated lower with mortalityin patientsin whomthe causeof ischemicstrokecouldnot be determined (15%versus22%,pc10.01). difference mortalitybetweenthe aspirinand The in nonaspirin groupcontinued be significant, to evenwhenpatientswith hemorrhagic and otherstrokeswere included(14%versus21X). The effectof prioraspirinuse on mortalitywas independent age,gender,otherrisk factors,and use of other of medication. Amongpatientswho had first time off-pumpcoronaryarterybypassoperation, there were no significant differences betweenaspirinand nonaspirin usersin in-hospital mortalityrate(1.2%versus1.8%) stroke(0.6%versus0), and MI (2.4%versus1.2%). Therewas a statistically significant difference post-operative in lengthof stay,although the medianwas the samein bothgroups(7 versus7 days,pcO.001).


Reference Type of Article Total Subjects Treatment Groups (n) Efficacy Data

EvansA, PerezI, Yu G, Kalra ClinicaiTrial L. 2001.Shouldstrokesubtype influence anticoagulatidn decisions prevent to recurrence strokepatients in withatrialfibrillation? Stroke 32(12):2828-2832.

386 Aspirin75 to 300 mg/day (n=l72) Warfarinto INR 2.0 to 3.0 (n=214)

Annualrecurrent strokerate (% and 95% Cl) in ischemicstrokepatientsfor warfarin versusaspirin;p-value: l All strokes:4.9 (2.9-7.0)versus9.5 (6.3-12.7);P (0.02 a lschemicStroke:4.2 (2.3-6.2)versus9.2 (6.1-12.4);p<O.Ol l FatalStrokes/Strokes Leadingto MajorDisability: (0.02-I .8) versus3.9 (I$0.9 6.0);~~0.01 l Total Deaths:6.5 (4.1-8.8)versus8.1 (5.1-l 1.1);p=NS o VascularDeaths:4.0 (2.2-5.9)versus5.9 (3.4-8.4);p=NS l Cerebral Deaths(stroke):0.4 (O-l ,I) versus2.0 (0.5-3.4);p=NS l CardiacDeaths:2.5 (1.0-3.9)versus3.1 (1.3-4.9);p=NS Annualrecurrent strokerate (% and 95% Cl) in ischemicstrokepatientsby initialstroke subtypefor warfarinversusaspirin;p-value:

M, Franzosimg. 2002.Benefit of clopidogrel patientswith in acutecoronary syndromes withoutST-segment elevation in variousrisk groups, circulation106(13): 1622-1626.

Low-riskgroup(TIMIscore0 to 2),4.1% vs. 5.7%(RR, 95% Cl: 0.71,0.52-0.97;

High-risk group(TIMIscore5 to 7j, 15.9%versus20.7%(RR, 0.73;95% Cl, 0.60-0.90;


Type of Article Total Subjects Treatment Groups (n) Efficacy Data

leference :URE Trial Investigators

Iopidogrel In Unstable ngina To PreventRecurrent ,vents). 2001.Effectsof lopidogrel additionto in spirinin patientswith acute oronary syndromes without ;T-segment elevation. New :ngland Journalof Medicine 45(7):494-502.

ClinicalTrial (CURE)

12,562 Aspirin75-325mglday+ Clopidogrel300 loading mg dosefollowedby cloptdogrel 75 mglday(n=6259) Aspirin75-325mglday+ Placebo(n=6303)

Outcomes The first primaryoutcome(deathfrom cardiovascular causes,nonfatalMl, or stroke) occurredin 9.3%of patientsin the clopidogrel groupand 11.4%of patientsin the placebogroup(RR, 95% Cl: 0.80,0.72-0.90; p<O.OOl). secondprimaryoutcome The (composite first primaryoutcomeor refractory of ischemia) occurredin 16.5%of patientsin the clopidogrel groupand 18.8%of patientsin the placebogroup(RR, 95% Cl: 0.86,0.79-0.94; p<O.OOl). rateof each component thesecomposite The of outcomesalsotendedto be iower in the clopidogrel group. The clearestdifference was observed the ratesof Ml (clopidogrel: in 5.2%;placebo:6.7%;RR, 95% Cl: 0.77, 0.67-0.89).Lessof a difference observed CV death(clopidogrel: was for 5.1%; placebo:5.5%;RR, 95% Cl: 0.93,0.79-l.08)and stroke(clopidogrel: 1.2%;placebo: 1.4%;RR, 95% Cl: 0.86,0.63-1.18).With respectto refractory ischemia,the diierence was observed primarilyin first eventsthat occurredduringthe initialhospitalization (clopidogrel: 1.4%;placebo: 2.0%;RR, 95% Cl: 0.68,0.52-0.90; p=O.O07) Significantly fewerpatientsin the,clopidogret groupthan in the placebogrouphad severeischemia(2.8%versus3.8%,respectively; 95% Cl: 0.74,0.61-0.90; RR, p=O.O03), recurrent or angina(20.9%versus22.9%,respectively; 95% Cl: 0.91, RR, 0.85-0.98; p=O.Ol). Radiologic evidenceof heartfailurewas foundin fewerpatientsin the clopidogrel group versusthe placebogroup(3.7%versus4.4%,respedvely; RR, 95% Cl: 0.82,0.69 -0.98;pt0.03).

TernDorA Trends
The rateof the first primaryoutcomewas lowerin the clopidogrel groupbothwithinthe first 30 daysafterrandomization between30 days and the end of the study. and Furtheranalysis~n~~~t~ that the benefitof ~iopidogrei apparentwithina few was ,hours afterrandomization, the rateof deathfrom car~ovas~ul~r” with causes,nonfatal Ml, stroke,or refractory severeischemiasignificantly or lowerin the clopidogrel group by 24 hoursafterrandomization (clopidogrel: 1.4%;placebo:2.1%;RR, 95% Cl: 0.66, 0.51-0.86).

PrPPENDlX 2. _- - ---------







._ _ _-__- _______.____ __-.. EFFICACY _ INFORMATION

ii leference k lehtaSR,YusufS, Peters

Type of Total Article Subjects TreatmentGroups(n) Efficacy Data ClinicalTrial 2658 Double-blind phase: EventsbeforePCI FIJG,Bertrand LewisBS, (PcI-CURE) ME, Clopidogrel300 mg/day+ Significantly fewerpatients clopidogrel on placebo an Ml (3.6%versus on than had latarajan Malmberg MK, K, Fi 5.1%,respectively; p=O.O4) the composite Ml or refractory or of ischemia (12.1% versus Aspirin75-325 mglday H, Fkrpprecht ZhaoF, (n=1313) 15.3%, respectively; p=O.OOS). S, I, C:hroiavicius Copland Fox Placebo Aspirin75-325 + Eventsfrom PCI to 30 davs KA. 2001.Effectsof mglday(n=1345) The percentage subjects the primary of with endpoint cardiovascular of death,Ml, or with Pretreatment clopidogrel urgentrevascufarization 30 daysafterPCI was signiticantly within lowerin the followed longby and aspirin open labelphase (afterPC!): clopidogrel(4.5%) in the placebo than group(6.4%)(RR,0.70;95%Cl, 0.50-0.97; in tf3rmtherapy patients p=O.O3). deathswithinthe first 30 dayswerecardiovascular All deathsandweresimilar Clopidogrel ticlopidine or percutaneous undergoing between two groups(approximately the 1.O%).Patients clopidogrel significantly on had (Doseunspecified) oronary intervention: PCIthe fewerMIS(dopidogrel: 2.1%;placebo 3.8%)andQ-wave (clopidogrel: MIS 0.8%; : URE study.Lancet Aspirin(Doseunspecikd) placebo 2.4%)thanpatients placebo. on 358(9281):527-533, Eventsfrom PCI to endof follow-up Fromthe timeof PC1to the endof follow-up (mean8 monthsafterPCI),significantly fewersubjects cardiovascular had deaths,MIS,or anyrevascularization clopidogrel with (18.3%) placebo than (21.7%) (p=O+O3). percentage subjects experienced The of who cardiovascular deathswas similarbetween two groups(2.4%versus2.3%)but the therewere.significantly MISamongsubjects fewer treated clopidogrel with (4.5%) than placebo (6$4%) to a difference Q-wave (clopidogrel: due in MIS 1.5%;placebo 3.5%). WheneventsbeforeandafterPCI wereconsidered, was a highlysignificant there difference the percentage subjects suffered cardiovascular in of who a deathor Ml between clopidogrel(8.8%) ptacebo the and (12.6%) groups(p=0.002). DuringPCI, significantly fewersubjects treated clopidogrel(20.9%) placebo with than (26.6%) rotein ,llb/lllainhibitors duringPCI (RR,0.79;95%Cl, 0.69a secondrevasculan”zation alsolowerin the was ebogroup(14.2%versus17.1%, respectively; 0.82; RR,

Reference Type of Article Total Subjects Treatment Groups (n) Efficacy Data


MoraisJ. 2002.Insights from ClinicalTrial CURE:usingclopidogrel on (CURE) top of standard therapy. Cerebrovascular diseases 13(Suppll):l7-21.

loadingdoseof i 2,562 Clopidogrel 300 mg followedby 75 mglday+ Aspirin75-325 mglday(n=6259) Placebo+ Aspirin75-325 mglday(n=6303)

The incidence the first primaryendpointof cardiovascular of death,MI, or strokewas 9.3%in the clopidogrel groupand 11.4%in the placebogroup,corresponding a to relativerisk reduction 20% in favorof clopidogrel(95% 72 - 90%;p<O.OOl). of Cl, Moreover therewas a consistent benefitof clopidogrel placebofor the individual over outcomes cardiovascular of death,MI, and stroke. A similarlevelof benefitwas observed boththe secondprimaryendpointcomposite for of CV death,Ml, strokeor refractory ischemia(relativerisk reduction14%;95% Cl, 79 94%;p<O.OOl) refractory and ischemiaalone.

Leference Type of Article Total Subjects Treatment Groups (II) Efficacy Data

‘ S, MehtaSR, Zhao F, ClinicalTrial usuf ;ershBJ, Commerford et (CURE) PJ, I. 2003.Earlyand late effects #f clopidogrel patientswith in cutecoronarysyndromes. :irculation 107(7):966-972.

12,562 Clopidogrel loadingdoseof 300 mg administered immediately followedby 75 mglday+ Aspirin75-325 mgtday(n=6259) Placebo+ Aspirin75-325 mglday(n=6303)

Efficacyof clopidogrellaspirin relativeto placebo/aspirin the first 24 hoursafter in randomization: ratio(95%Cl): Risk l CV death/Ml/stroke: (0.48-1.32) 0.80 l CV death/Ml/stroke/refractory ischemia:0.76 (0.53-1.09) l CV death/Ml/stroke/severe ischemia:0.66 (0.51-0.86) Efficacyof clopidogrellaspirin relativeto placebo/aspirin between0 to 7 daysafter randomization: ratio (95%Cl): Risk l CV death/Ml/stroke: (0.65-I.04) 0.82 l CV death/Ml/strokelrefractory ischemia:0.82 (0.69-0.98) o CV death/Ml/stroke/severe ischemia:0.77 (0.67-0.89) Efficacy of clopidogrellaspirin relativeto placebo/aspirin between8 to 30 days after randomization: ratio (95%Cl): Risk 0 CV death/Ml/stroke: (0.61-0.94) 0.76 m CV death/Ml/strokelry ischemia:0.83 (0.71-0.98) l CV death/Ml/stroke/severe ischemia:0.86 (0.73-I.Ol) Efficacyof clopidogrellaspirin relativeto placebo/aspirin between0 to 30 daysafter randomizatiqn: ratio (95%Cl): Risk l CV death/Ml/stroke: (0.67-0.92) 0.79 l Refractory &hernia: 0.86(0.72-1.03) Severeischemia: 0.75 (0.63-0.88) l CV.death/Mllstroke/refractory ischemia:0.83 (0.73-0.93) 0 CV dea~/Ml/s~oke~n-hos~tal severeischemia: 0.81 (0.73-0.90) Efficacyof clopid~rel/aspi~n relativeto placebo/aspirin between31 days to 1 yearafter rand~ization: Risk raQo,(95% Cl): GV dea~~Ml/s~oke~ (0.70-0.95) 0.82 Refractory ischemia:0.98(0.84-I.15) Severeischemia:Not applicable CV death/~l/stroke/refracto~ ischemia:0.90 (0.80-I.Ol) l CV death/~l~stroke~in-hospital ischemia: applicable severe Not Overall,9.3%of patientsexperienced death,MI, or strokesin the clopidogrel CV group

Reference Type of Article Total Subjects Treatment Groups (n) Efficacy Data

CastilloJ, LeiraR, MoroMA, ClinicalTrial Lizasoain SerenaJ, Davalos I, A. 2003.Neuroprotective effectsof aspirinin patients with acutecerebralinfarction. Neuroscience Letters 339(3):248-250.

238 Aspirin75-500mgldayat the time of strokeonset(n=63) No aspirinat the time of strokeonset(n=175)



Cerebral spinalfluid glutamate concentrations higherin subjectsnot takingaspirin were (8.9+ 5.2 PM/L)thanin subjectstakingaspirin(4.9+ 3.1 @l/L) (p<O.OOOl). No correlation betweendoseof aspirinand glutamatelevelswas observed.Early neurological deterioration eighttimesmorefrequentin subjectswho did not take was aspirin, The frequency earlyneurological of deterioration not significantly was different betweensubjectstaking>200mgldayof aspirin(9.7%)and thosetaking~200mglday (5.6%). Aspirintreatment strokeonsetshoweda 97% reduction risk of early at in neurological deterioration adjustment significant after for factorsassociated with progressing stroke. Aspirineffectremainedunchanged a furtheradjustment after for glutamate concentrations,


Type of Article Total Subjects Treatment Groups (n) Efficacy Data

ie J, WheltonPK, Vu B, Klag MetaAJ.1998.Aspirinand risk of analysis temorrhagic stroke:a metaanalysis randomized of :ontrolled trials.Journalof the rmerican MedicalAssociation !80(22):1930-1935.

55,462 Aspirin75-1500mglday Absoluterisk reduction (95%Cl; p-value)associated aspirinuse and the following with (Meandose = 273 mglday) clinicaloutcomes: l All-causemortality:120110,000 persons(77-l 62; p<O.OOl) Cardiovascular mortality:97110,000 persons(59-l 35; p<O.OOl) l l TotalMl: 137/l0,000persons(107-l67; p<O.OOl ) FatalMl: 36110,000 persons(16-55;p<O.OOl) l l Totalstroke:31/10,000 persons(5-57;p=O.O2) l lschemicstroke:39/10,000 persons(17-61;pcO.001) l Fatalstroke:4/10,000persons(8-‘ p-0.50) l6; The proportional reduction (relativerisk, 95% Cl; p-value)in clinicaloutcomes associated aspirintreatment as follows: with was l All-causemortality:15% (0.85,0.80-0.90; pcO.001) l Cardiovascular mortality:16%(0.84,0.79-0.90; p~~O.001) l Total MI: 32% (0.68;0.62-0.74; p<O.OOl) l FatalMl: 22% (0.78;0.68-0.90; pcO.001 l Totalstroke:12%0.88,0.76-l.02; p=O.O8) c lschemicstroke:18%,(0.82,0.73-0.92 l Fatalstroke:(1.07,0.85-l.35;p=O.60) The numberneededto treatto preventone eventwas as follows: l Total Ml: 73 o FatalMl: 278 l lschemicstroke:256 Treatment aspirinwas also associated an increase 12 (95%Cl: 5-20) with with of ~~rn~h~ic strokesper ~0,~~ personsor an 84% increase the risk of this stroke in subtype(relativerisk,~95% I .84, 1.24-2.74; Cl: p<O.OOl).


Type of Article Total Subjeds Treatment Groups (n) Efficacy Data


:linicalTrial anticoagulants versusaspirin aftercerebralischemiaof presumed arterialorigin. 42(6):857-865. therapyversus6 on aspirin(3 intracranial, fatal). The bleeding 1 Anticoagulant group(Target duringanticoagulant incidence increased a factorof 1.43(95%Cl: 0.96-2.13) each 0.5 unit increase by for o INR valueof 3.0 to 4.5 the achievedhternationalNormalized Ratio(INR). The HR for deathfrom all causes significant difference the in was 2.4 (95%Cl: 1.3-4.4).Therewas no statistically occurrence majorischemicevents. of Phenprocoumon the was preferred anticoagulant.)

2 IL 2

DerksenRHWM,de GrootPGI :aseStudy KappelleLJ. 2003.Low dose aspirinafterischemicstroke associated with an~pho~pholipid syndrome, Neurology61(1):1~1-114. DienerHC, CunhaL, Forbes linicalTrial C, SiveniusJ, SmetsP, .SPS-2) Lowenthal 1996.European A. S~~.Prev~~ Study2, Dipyrtdamole and acetylsalieylic in the acid secondary prevention of stroke.Journalof the Neurological Sciences143(l2):1-13.

syndrome (APS),hada periodfrom the time of the

6602 Aspirin50 mglday(n=l649) Dipyridamole mglday 400 (n=l654) Aspirin50 mglday+ Dipyridamole mglday 400 (n=1650) Placebo(n=l649)

The numberof strokes,strokesor deaths,and deathsthat occurredduringthe 2 year follow-up periodfor the aspirinalone,dipyridamole alone,combination therapy,and placebotreatment groupswas as follows: * Totatstrokes:266;2i-I, -157,and 250 0 Strokesor deaths:330,32?,286,and 378 0 Deaths:182,188,185,and 202 The 24month strokeratewas 12.9%in the aspirinalonegroup,13.2in the dipyridamole alonegroup,9.9%in the combination group,and 15.8%in the placebo group. Survivalcurvesshoweda clear,progressive divergence the curvesfor stroke of and strokeand deathcombined, demons~a~ng higherprobability endpoint-free a of survivalwith the combination treatment aspirinand dipyridamole of regimenthaneither medication alone. IStrokerisk was reducedby 18.1%(p=O.O13) aspirinalone,by 16.3%(p=O.O39) with

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Type of Article

Total Subjects


Efficacy Data * with dipyridamole alone,andby 37.0%(pcO.001) combination with therapy, when compared placebo.The relativerisk reductions the combined with for endpoint stroke of or deathwere 13.2%(p=O.O16) aspirin,15.4%(p=O.O15) dipytidamole, with with and 24.4% (p<O.OOl) the combination. with Noneof the treatments significantly reduced the risk of deathaloneor of fatalstroke. The number eventsavoided 1,000patients of per treated 2 yearsfor aspirinalone, over dipyridamole alone,andcombination therapy whencompared placebo as to was follows: 0 Stroke: 29,26, and58 l Strokeor death:30,35, and56 * Death:13,9, and 10 Factorial analysisalsodemonstrated highlysignificant a effectof aspirin(p<O.Ol) and dipyridamole (~~0.01) preventing with a risk reduction 21.9%and 18.3%, for TIA, of respectively. risk reduction the combination 35.9%compared placebo The for was with (p<O.OOl). number patients hada TIA duringthe 2 yearfollow-up The of who period was 206,215,172, 267for the aspirinalone,dipyridamole and alone,combination therapy, placebo and treatment groups. The occurrence othersecondary of endpoints theaspirinalone,dipyridamole for alone, combination therapy, placebo and treatment groupswas as follows: * Ml: 39,48,35, and45 (notsignificant) l Othervascular events(lungembolism, DVT,obstruction peripheral of arteries, and retinalarteryocclusion): 38,35,21,54 (p<O.OZ) l lschemicevents(strokeand/orMI and/orsudden death:266,271,206, 307 and

Reference Type of Article Total Subjects Treatment Groups (n) Efficacy Data

ClinicalTrial DienerHC, DariusH, Bertrand-Hardy JM, (ESPS-2) Humphreys 2001.Cardiac M. safetyin the European Stroke Prevention Study2 (ESPS2). lntemationai Journalof Clinical ractice55(3):162-163.

6602 Aspirin50 mglday(n=1649) Dipyridamole mglday 400 (n=16!54) Aspirin50 mglday+ Dipyridamole mglday 400 (n=l@O) Placebo(n=1649)

In this post-hocanalysisof ESPS2,patientswith coronaryheartdiseaseor MI at entry who receiveddipyridamole (includes dipyridamole and dipyridamole aspirin oniy + groups)werecompared thosewho did not receivedipyridamole with (includesaspirin only and placebogroups). Similarly,all patientstreatedwith aspirin(includesaspirin only and aspirin+ dipyridamole groups)were compared those not receivingaspirin with (includes dipyridamole and placebogroups). only Therewas a trendtowardfewerMISin patientswho wereon aspirinthan in thosewho were not on aspirin(74 [2.2%]vs.’ [2.8%],respectively); 93 however,this difference was not statistically significant.Therewas no difference all-causemortalityin patients in

orbesCD. 1997.European trokePrevention Study2: pyridamole and :etylsalicylic in the acid zondary prevention of rake. International Journalof linicalPractice51(4):205-

compared placebo. The combination aspirint to of deathby 15.4%(p=O.O15) dipyndamole resultedin a significantly greaterrisk reduction termsof stroke(37.0%; in p=O901)and-stroke or-death (24.4%;p=O.OOl) compared piacebo. Combintition to treatment also superiorto eitheragentalonein reducing relativerisk of stroke was the (p<O,Ol all comparisons). treatment for No significantly reducedthe + dipyridamole)

I OF EFFll KY RESULTS - PUBLICATIONS PROVIDING ADDITIONAL EFFICACY INFORMATION Total Type of Efficacy Data Subjects TreatmentGroups (n) Article Reference Cardiaceventrates(nonfatal recurrentMI, fatal recurrentMI, deathby congestive hear 618 Aspirin50 mglday+ Iinical Trial lshikawaK, Kanamasa K, failure,and suddendeath)in patientstreatedwith aspirinalone,dipyridamole alone,an dipyridamole mglday 150 HamaJ, OgawaI, Takenaka ticlopidine alonewere 5.5%,7.6%,and 2.8%,respectively.Combined treatment with (n=113) T, NaitoT, Yamamoto Naka T, aspirinpluseitherdipyridamole ticiopidine or resultedin significantly lowercardiac S, Oyairu M, KimuraA, Aspirin50 mglday+ events(1.9%)thandid treatment aspirin,dipyridamole, ticlopidine with or alone(p<O.O! YamamotoK, KatoriR. K. ticlopidine mglday 200 OR, 95% Cl: 0.39,0.15-l.Ol). 1997.Aspirinpluseither (n=253) dipyridamole ticlopidine or is Aspirin50 mgldayor effectivein preventing dipyridamole mgldayor 150 recurrent myocardial infarction ticlopidine mgldayalone 200 Japanese Circulation Journal fn=252) 61(1):38-45. No antiplatelet treatment I (n=465) Whenthe incidence stroke,strokeand/ordeath,and vasculareventswere analyzed of 6602 bpirin 50 mglday SiveniusJ, CunhaL, Diener XinicalTrial by age group(~65 years,65-74years,275 years)the greatestbenefitwas observed in HC, ForbesC, LaaksoM, IipyridamolemodifiedESPS-2) patientsreceivingaspirinplus dipyridamole combination (DP) therapy. Lowenthal SmetsP, A, elease400 mglday Riekkinen 1999.Second P. In patients~65 years,factorialdesignanalysisshowedthat aspirinhad a significant hpirin 50 mglday+ European StrokePrevention effecton ait endpoints, while DP produced significantreduction vascularendpoints a in )j~~damole’ mglday 400 Study:antiplatelet therapyis only. In pairwisecomparisons aspirin,DP, or combination (i.e., therapyversus ‘ lacebo effectiveregardless age. of placebo), the combination only therapywith aspirinplus DP produceda significant ESPS2WorkingGroup.Acta reduction stroke,strokeand/ordeath,or vascularevents. in neurologica Scandinavica In the 65-74year age group,bothaspirinand DP produced significant a reduction in 99(1),5&60. mostendpoints,In this agegrouponly combination therapywas also shownto be superiorto placeboin pairwisecomparisons. Amongpatients275 yearsof age,factorialdesignana~ysis,show~ aspirinand DP to bi equallyeffective.The pakwisecomparisons this age groupshowedthat combination in therapywas significantly superiorto placeboin reducingthe incidence all endpoints. of Aspirinalonesigntficantly reducedthe incidence strokeand/ordeathcompared of to placebo, while DP alonehad no significant effecton any endpoint. Thus,combination therapyis superiorto eitheraspirinor DP alonein all threeage groups. Combination therapyalso providesa statistically significant reduction the in incidence eachendpointin each age groupcompared placebo. of with APPENDIX 2. SUMMA


LPPENDIX -2m SUMMARY _. OF EFFICACY RESULTS - PUBLICATIONS __ * -. _-__- ---__... ._ -~ Type of Total Article Subjects Treatment Groups (n) leference





Efficacy Data

RISCStudyGroup(Fragmin ClinicalTrial luringInstability Coronary (FRlSC) in ,rtery Disease). 1996.Lowdecular-weight heparin uringinstability coronary in rterydisease. Lancet 47(9001):561-568.

1506 Dalteparin IUlig body AcutePhase 120 weight(maximum 10,000IU) Duringthe first 6 days,the rateof deathandnew Ml was lowerin the dalteparin group BID SC for 6 days;subjects (1.8%)thanin the placebo group(4.8%)(RR,95%Cl: 0.37,0.20-0.68; p=O.OOl). thenreceived 7500lU/dayfor Separately, rateof Ml (dalteparin: the 1.4%;placebo: 4.4%)(RR,95%Cl: 0.31,0.16the next35-45days.(n=746) 0.60;p=O.OOl), death(dalteparin: and 0.9%:placebo: .I%) (RR,95% Cl: 0.88,0.321 2.48;p=O.8) werelowerin the dalteparin groupthanthe placebo group. Ratesof urgent Placebo (n=760) All subjects received initial revascularization an (dalteparin: 0.4%;placebo: 1.2%)(RR,95% Cl: 0.33,O.lO-l.lO; and (dalteparin: 3.8%;placebo: 7.7%)(RR,95% Cl: 0.49, 300mg doseof aspirinand p=O.O7) needfor i.v. heparin 0.32-0.75; p=O.OOl) alsolowerin the dalteparin were treatment groupwhichindicated a 75 mgldaythereafter.Betabloc&s, as well as calcium reduction refractory in angina.Whencombined a compoite as endpoint (death, MI, revascularization, i.v. heparin), absolute or the reduction daiteparin 4.9%and with was antagonists organic and the relative reduction 48%duringthe acutephase. was nitrates, werealso administered needed. as Treatment Phase At 40 days,the ratesof deathor Ml as well as the composite endpoint remained lower in the DP groupthanin the placebo group(dalteparin: 20.5%;placebo: 25.7%;RR, 95% Cl: 0.79,0.66-0.95; p=O.Ol The rateof the individual I). endpoints (dalteparin: Ml 6.7%; placebo: 9.7%)(RR,95% Cl: 0.69,0.49-0.98; p=O.O4), revascularization (dalteparin: 12.1%; placebo: 15.5%) (RR,95% Cl: 0.77,0.60-0.99; p=O.O4), i.v. heparin and (dalfeparin: 8.4%;placebo: 13.6%) (RR,95% Cl: 0.61,0.46-0.82; p=O.OOl), not but death(dafteparin: 2.6%;placebo: 3.0%)(RR, 95%Cl: 0.85,0.47-1.54; p=O.59), were alsosignificantly lowerin the datteparin treatment group. Subgroup analysis suggested thatthe effectsof dalteparin confined nonsmokers were to (80%of the sample) to and patients non-Q-wave with Ml. Follow-Up Phase At the ~oflow-up 4-5 monthsafterthe endof treatment, visit therewereno significant differences the occurrence death,new Ml, or revascularization in of (composite as or separate endpoints) between two groups.The rateof heparin the infusionremained lowerin the dalteparin group(dalteparin: 11.9%; placebo:16.7%) (RR,95%Cl: 0.71, 0.55-0.91; p=O.OOS).


RE SUMMAf ?Y OF EFkACY Total Type of hblects Article Reference :linical Trial 5499 Knottenbelt Brennan C, PJ, 2.

Meade 2002. TW. Antithrombotic treatment and the incidence angina of oectoris. Archives Internal of Medicine 162(8):881-886,

‘ I .5) (n=1269) NR wereconsidered, stableandunstable, i.e., warfarin Aspirin mgldaycontrolled Whenall casesof angina 75 nonsignificantly reduced casesby 11%(95%Cl: -17-32)whileaspirinsignificantly *etease placebo + (n=1252) increased incidence anginaby 33% (95%Cl: -77-O) the of (p=O.O5). Double placebo (n=1259) Warfarin reduced coronary total heartdiseaseevents(thecombination coronary of death,nonfatal infarction, angina) 18%(95%Cl: 4 to 30; p=O.Ol), and by resulting from the largedecrease majorfatalevents,alongwith warfarin’ in s possible effecton angina cant)reduction majornonfatal in events. For aspirin, therewas Ionin totalcoronary heartdiseaseof approximately (95%Cl: 8% It of the reduction to aspirinin majornonfatal due events,the creasein fatalevents,andthe apparent increase angina. in 5085 lschemic HeartDisease (IHD) All: 71 (8.7),83 (10.3), (10.2);107(13.3) 83 Fatal:24 (3.0) 19 (2.4) 36 (4.4) 34 (4.2) l Non-fatal: (5.8) 64 (8.0) 47 (5.8) 73 (9.0) 47 * 6 Placebo warfarin placebo o + aspirin (n=l272) e * All: 29 (3.6) 22 (2.7) 18 (2.2),26(3.2) Fatal:12 (1.5) 5 (0.6) 2 (0.2) 1 (0.1) Thrombotic: (1.4),15 (1.9) 10 (1.2) 18 (2.2) 11 Hemorrhagic: (0.9) 1 (0.1) 2 (0.2) 0 7 Sub-arachnoid:(0.2),3 (0.4),1 (O.l),2 (0.2) 2 Unknown: (I,?), 3 (0.4) 5 (0.6),6 (0.7) 9

IinicalTrial MeadeTW, Brennan PJ, WilkesHC, ZuhrieSR. 1998. TPT) Thrombosis prevention trial: randomised of lowtrial intensity anticoagulation oral with warfarin low-dose and aspirinin the primary prevention ischaemic of heart disease menat increased in risk.Lancet351(9098):233241. 2 .mb

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