Therapeutic Area Data Standards User Guide for Cardiovascular Studies Version 1.0 (Provisional) Prepared by the CFAST Cardiovascular Team

Transcription

1 Therapeutic Area Data Standards User Guide for Cardiovascular Studies Version 1.0 (Provisional) Prepared by the CFAST Cardiovascular Team

2 Notes to Readers This is the provisional version 1.0 of the Therapeutic Area Data Standards User Guide for Cardiovascular Studies. It is ready for initial use, but depends on the completion of other standards before it can be considered final. Revision History Date Version Summary of Changes Provisional Draft Draft for Public Review See Appendix F for Representations and Warranties, Limitations of Liability, and Disclaimers Page 2 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

3 CONTENTS 1 INTRODUCTION PURPOSE CARDIOVASCULAR REGULATORY AND CLINICAL GUIDELINES Acute Coronary Syndrome Cardiovascular Endpoints Cardiovascular Endpoints Data Elements ORGANIZATION OF THIS DOCUMENT CONTROLLED TERMINOLOGY CONCEPT MAPS REFERENCING SCTI COMMON DATA ELEMENTS USING DEFINE-XML RELATIONSHIPS TO OTHER STANDARDS KNOWN ISSUES DISEASE CHARACTERISTICS AND ROUTINE DATA DISEASE ASSESSMENTS ACUTE CORONARY SYNDROME Examples for Acute Coronary Syndrome CARDIOVASCULAR ENDPOINTS Adjudication of Events Death Examples for Death Transient Ischemic Attack and Stroke Examples for Transient Ischemic Attack and Stroke Myocardial Infarction Examples for Myocardial Infarction Percutaneous Coronary Intervention Examples for Percutaneous Coronary Intervention Peripheral Vascular Intervention Examples for Peripheral Vascular Intervention Heart Failure Event Examples for Heart Failure Event Unstable Angina Hospitalization Event Examples for Unstable Angina Hospitalization Event APPENDICES APPENDIX A: PROJECT PROPOSAL APPENDIX B: WORK GROUPS APPENDIX C: GLOSSARY AND ABBREVIATIONS Appendix C1: Supplemental Qualifier Name Codes APPENDIX D: QUESTIONNAIRES APPENDIX E: REFERENCES Appendix E1: Works Cited Appendix E2: Further Reading APPENDIX F: REPRESENTATIONS AND WARRANTIES, LIMITATIONS OF LIABILITY, AND DISCLAIMERS FIGURES Figure 1: CDISC Industry-Wide Data Standards... 5 Figure 2: Concept Classification Key for Concept Maps... 9 Figure 3: Referencing CDEs via Define-XML Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 3 Provisional October 17, 2014

4 CONCEPT MAPS Concept Map 1: Acute Coronary Syndrome Concept Map 2: Cardiac Catheterization Concept Map 3: Event Adjudication Process Concept Map 4: Death Concept Map 5: Transient Ischemic Attack and Stroke Concept Map 6: Myocardial Infarction Concept Map 7: Percutaneous Coronary Intervention Concept Map 8: Peripheral Vascular Intervention Concept Map 9: Heart Failure Event Concept Map 10: Unstable Angina Requiring Hospitalization Page 4 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

5 1 Introduction This Therapeutic Area Data Standards User Guide for Cardiovascular Studies (TAUG-CV) is a provisional standard, which means that it has been published for initial use, but is dependent upon completion of other standards and thus may involve risk of upcoming change. This TAUG-CV was developed under the Coalition for Accelerating Standards and Therapies (CFAST) initiative. CFAST, a joint initiative of CDISC and the Critical Path Institute (C-Path), was launched to accelerate clinical research and medical product development by facilitating the establishment and maintenance of data standards, tools, and methods for conducting research in therapeutic areas important to public health. CFAST partners include TransCelerate BioPharma Inc. (TCB), the U.S. Food and Drug Administration (FDA), and the National Cancer Institute Enterprise Vocabulary Services (NCI-EVS), with participation and input from many other organizations. See Appendix B for a description of participating work groups. CDISC has developed industry-wide data standards enabling the harmonization of clinical data and streamlining research processes from protocol (study plan) through analysis and reporting, including the use of electronic health records (EHR) to facilitate study recruitment, study conduct and the collection of high-quality research data. CDISC standards, implementations and innovations can improve the time/cost/quality ratio of medical research, to speed the development of safer and more effective medical products and enable a learning healthcare system. Figure 1: CDISC Industry-Wide Data Standards The goal of the CFAST initiative is to identify a core set of clinical therapeutic area concepts and endpoints for targeted therapeutic areas and translate them into CDISC standards to improve semantic understanding, support data sharing and facilitate global regulatory submission. 1.1 Purpose The focus of this version 1.0 (v1.0) of the TAUG-CV is on Acute Coronary Syndrome (ACS) and Cardiovascular Endpoints. The content of this document requires some familiarity with cardiology: readers who are not familiar with cardiology and the associated terminology and concepts may experience difficulty understanding the concept maps and data examples. The cardiovascular endpoint definitions used in the user guide are applicable to cardiovascular endpoints that occur in other therapeutic areas Thus, the definitions and examples in this user guide will be useful for other therapeutic areas. Guidelines for handling data specific to pediatric studies and from studies for development of devices are not addressed in this version. See Appendix A for the project proposal that was approved by the CFAST Steering Committee. The TAUG-CV describes the most common data needed for ACS or reporting cardiovascular endpoints, so that those handling the data (e.g., data managers, statisticians, programmers) understand the data and can apply standards 2014 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 5 Provisional October 17, 2014

6 appropriately. Descriptions addressed in this TAUG-CV include the clinical situations from which the data arise, and the reasons these data are relevant for cardiovascular disease. The TAUG-CV also strives to define research concepts unambiguously, so that consistent terminology can be used in cardiovascular disease studies to enable aggregation and comparison of data across studies and drug programs. And finally, the TAUG-CV v1.0 describes how to use the following CDISC standards to represent the data: For the Study Data Tabulation Model (SDTM) and the SDTM Implementation Guide for Human Clinical Trials (SDTMIG), these instructions include guidance on which domains and in which other datasets data should be stored in, how variables should be used, and example datasets. These CDISC standards are freely available at It is recommended that implementers consult the Study Data Tabulation Model (SDTM), SDTM Implementation Guide for Human Clinical Trials (SDTMIG), and SDTMIG Medical Devices prior to implementing these cardiovascular disease clinical data standards. It is important to note that the inclusion of concepts in this user guide should not be construed as a requirement to collect data on these concepts in any particular study on cardiovascular disease. The examples included are intended to only show how data of particular kinds can be represented using CDISC standards. Note that certain data items, especially those that are related to safety and other standard items such as demography, medical history, adverse events, hospitalizations, and concomitant medications should also be collected to meet the established standards for data related to these domains. 1.2 Cardiovascular Regulatory and Clinical Guidelines The American College of Cardiology (ACC) and Duke Clinical Research Institute (DCRI) collaboratively contributed to the development of the acute coronary syndrome (ACS) and cardiovascular endpoints common data elements (CDEs) from The engagement and expertise of HL7 members, American Heart Association (AHA), FDA, CDISC and the National Cancer Institute (NCI) also contributed to the development of both groups of CDEs. The ACS CDEs were developed as part of the Cardiovascular Data Standards Project beginning in This project was approved within the Cardiology Special Interest Group (SIG) as a project within the HL7 SIGs. The cardiovascular endpoint data elements were developed by DCRI, ACC, AHA, CDISC, FDA and other sources beginning in CDISC developed the SDTM mappings for the ACS and CV endpoint data elements which are included in this Therapeutic Area User Guide release. Future versions of this TAUG-CV will include additional research concepts that may be informed by other cardiovascular CDEs and relevant inputs Acute Coronary Syndrome The acute coronary syndrome (ACS) data standards were released as part of the HL7 CV DAM 2.1 project. The CDEs are posted on the HL7 website ( Through collaboration with DCRI, the cardiovascular community (e.g., ACC, AHA), Federal Health Organizations, and CDISC jointly developed CDEs for ACS through the NIH funded ACS Data Standards Project. The resulting ACS deliverables represent the first jointly approved CDISC and HL7 standard around a therapeutic indication Cardiovascular Endpoints In March 2009, the FDA initiated interest in cardiovascular and stroke endpoints. In September 2009, the FDA convened a public meeting of all major stakeholders to create The Standardized Data Collection for Cardiovascular Trials Initiative (SCTI) working group and to discuss the definitions for these endpoints that had been developed. Over the next 5 ½ years, the SCTI met numerous times, both publically and internally, to review and refine the cardiovascular and stroke endpoint definitions. The main goals of the SCTI were to: Improve the quality and efficiency of cardiovascular trials Provide endpoint definitions so that events are clearly characterized by objective criteria and reported uniformly Page 6 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

7 Standardize data collection to capture key data elements Simplify analysis of events in drug development programs or among different clinical trials and to more easily identify trend and other safety signals The SCTI created a framework of definitions for cardiovascular and stroke endpoints in clinical trials. These definitions are based on clinical and research expertise, published guidelines and definitions, and current understanding of the specific laboratory tests, diagnostic tests, and imaging techniques used in clinical practice to diagnose these events. It is important to read this publication to understand the detailed definitions of the cardiovascular endpoints. DCRI developed the common data elements for the cardiovascular and stroke endpoint definitions. Key considerations in developing the CDEs were: Standard endpoint definitions are critical, but not sufficient to meet the quality, efficiency or analysis objectives Endpoint data is clinical data, and should be standardized at the source wherever possible Coordinate various cardiology standards efforts to collaboratively produce a single set of work products Standardized definitions of cardiovascular clinical endpoints are needed to objectively and consistently assess patient outcomes, determine responses to therapy, accomplish device surveillance, support aggregate analysis of event data across large clinical trial datasets, expedite the analysis of trends, and identify safety signals and/or estimate event occurrence rates. In contradistinction to the emphasis in EHR solutions on diagnoses as classified by taxonomies including the International Classification of Disease (ICD) and the Systemized Nomenclature of Medicine Clinical Terms (SNOMED-CT), the class of endpoint events represent summative concepts more useful for assessing responses and outcomes. This includes the CDEs comprising endpoint events for the assessment and measurement of process and performance across clinical research and clinical care domains. An endpoint is the occurrence of anything of interest that can be used to qualify or quantify the effectiveness and / or safety of a diagnostic or therapeutic approach. An endpoint can thus be manifested in any number of forms, particularly a clinical change (e.g., a new symptom, finding, diagnosis, or even death) or the unanticipated need for the application of health care resources (e.g., procedure or hospitalization). While the components of an endpoint can be correlated (e.g., an individual can develop new onset chest pain that results in a cardiac catheterization procedure), this is not a requirement hence the need to identify multiple expressions of endpoints to capture all relevant phenotypes. Furthermore, reporting of endpoint phenotypes are variable in the potential for ascertainment and evaluator bias, reliability of measurement, and validity. For some conditions, such as myocardial infarction (MI) or stroke, the occurrence of the event (as defined by conventional criteria) can be considered prima facie evidence of the occurrence of an endpoint. For others, additional rigor is required to qualify the event as an endpoint (e.g., procedures and hospitalization). In these latter cases, additional criteria must be applied to provide consistency and characterize the severity of the conditions before they can be qualified as endpoint events. CDISC and DCRI worked on the standardization of these data elements via the CDISC standards development process Cardiovascular Endpoints Data Elements Approximately 110 consensus cardiovascular endpoint data elements were developed. The CDEs are posted on the ACC website (a link to these CDEs will be posted on the CDISC website when available). Please refer to the CDEs on this website when reviewing this user guide and for updates in the future. Additional data examples on the use of cardiovascular endpoints can be obtained from the ACC website. The CDEs were developed to support each cardiovascular endpoint definition: 1. Death 2. Transient Ischemic Attack and Stroke 3. Myocardial Infarction 4. Percutaneous Coronary Intervention 2014 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 7 Provisional October 17, 2014

8 5. Peripheral Vascular Intervention 6. Heart Failure Event 7. Unstable Angina Hospitalization Event 1.3 Organization of this Document This document is divided into the following sections: Section 1, Introduction, provides an overall introduction to the purpose and goals of the Cardiovascular Disease project. Section 2, Disease Characteristics and Other Routine Data, covers data that are usually collected once at the beginning of a study and background data that are collected in most studies. Section 3, Disease Assessments, covers data that are used to evaluate disease severity, control, or progression. These are usually collected repeatedly during a study, and may be used as efficacy endpoints. Appendices provide additional background material and describe other supplemental material relevant to CV studies. Please refer to the SDTMIG Section 2, Fundamentals of SDTM, in order to understand how the different data types are aligned to the various SDTM domains. A list of domains used in the examples in this document, and the sections in which these appear, is given below: Domains from SDTMIG Section Interventions PR Procedures 3.1.1, , , Events CE Clinical Events 3.1.1, , , , , DS Disposition HO Healthcare Encounters 3.1.1, , , MH Medical History 3.1.1, , Findings DD Death Details EG ECG Test Results 3.1.1, LB Laboratory Test Results 3.1.1, , TU Tumor/Lesion Identification 3.1.1, , TR Tumor/Lesion Results 3.1.1, , MO Morphology 3.1.1, , , QS Questionnaires FA Findings About Events or Interventions Findings About Events or Interventions Domains from SDTMIG-MD* Section DI Device Identifiers * Devices domains are used in an ancillary context , , , , , , Controlled Terminology Terminology applicable to SDTM data presented in this document is either in production or under development by the CDISC Terminology Team at the time of publication of this document. Production terminology is published by the National Cancer Institute s Enterprise Vocabulary Services (NCI EVS) and is available at: Page 8 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

9 CDISC Controlled Terminology is updated quarterly. Because this document is a static publication, it refers readers to the NCI EVS page for CDISC terminology (at the link given above). For the same reason, this document used existing controlled terminology whenever possible, but users must refer to the website above for the most current terminology during implementation. At the time of this publication, the spreadsheet form of the SCTI CV Endpoint CDE definitions (including SDTM mappings) can be found under Cardiovascular Endpoint Initiative on the HL7 site at: Concept Maps This document uses concept maps to explain clinical processes and research concepts. Concept maps, also sometimes called mind maps, are diagrams which include bubbles representing concepts/ideas/things and labeled arrows that represent the relationships between the concepts/ideas/things. They are generally easier to draw and more accessible than more formal modeling diagrams, such as Unified Modeling Language (UML) diagrams. The diagrams in this document use the following coding for classification of concepts. This classification is based on classes in the Biomedical Research Integrated Domain Group (BRIDG) model (see These color-symbol pairs have been used taco highlight kinds of things that occur commonly in clinical data and therefore give rise to common patterns of data. Some concepts are not coded; they have a thinner, black outline, and accompanying symbol. These may include the subject of an observation, as well as characteristics, or attributes, of the coded concepts. In this TAUG-CV v1.0, the purple Terminology boxes contain names of terms found in the CV Endpoints CDEs. Figure 2: Concept Classification Key for Concept Maps 1.6 Referencing SCTI Common Data Elements using Define- XML It is important to understand the SCTI CV ENDPOINTS CDE definitions and permissible value sets as they relate to this TAUG-CV. The reference to these CDEs is accomplished via the Define-XML file produced to access the metadata associated with the CDISC SDTM data standards. In the Define-XML, a reference to the SCTI CV ENDPOINT CV should be provided using an External Codelist. Each version in use within the submission should be referenced. An illustration of an External Codelist definition is shown below. Note that the URL in the href attribute in the XML provides the hyperlink in a Define-XML display Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 9 Provisional October 17, 2014

10 Figure 3: Referencing CDEs via Define-XML For more information about representing External Codelists in the CDISC Define-XML standard, see Relationships to Other Standards This section describes the relationship of this document to other standards. This document does not replace the foundational CDISC standards or their implementation guides. The user should read those standards and implementation guides before applying the advice in this user guide. Certain types of data have existing CDASH and SDTM standards that can be used in CV studies without additional development or customization, and so are not covered in this document. Future versions of this TAUG-CV will include additional CDASH metadata appropriate to CV studies. For the Analysis Data Model (ADaM), the form of guidance has not yet been established, but will also be in future iterations of this document. In order to implement the cardiovascular endpoint CDE s in the CDISC SDTM domain standard, it was necessary to request a number of new SDTM variables. The following variables are being requested as additions in the next release of the SDTMIG. Approved variables as additions to the Events class Variable Name Variable Label Type Role Description --EVAL Evaluator Char Record Qualifier Role of the person who provided an evaluation. Used only for results that are subjective (e.g., assigned by a person or a group). Examples: ADJUDICATION COMMITTEE, INDEPENDENT ASSESSOR, RADIOLOGIST. --EVALID Evaluator Char Variable Used to distinguish multiple evaluators with the same role recorded in -- Identifier Qualifier EVAL. Examples: RADIOLOGIST1, RADIOLOGIST2. --ACPTFL Accepted Record Flag 1.8 Known Issues of --EVAL Char Record Qualifier In cases where more than one assessor provides an evaluation of a result or response, this flag identifies the record that is considered to be the accepted evaluation. Expected values can include Y, N or null. This is not intended to be a statistical censoring flag. Adjudication Data: This TAUG took the following approach to handling adjudicated data. o Separate records were created in the relevant domain in which the data occurred. o The variable --EVAL identifies the evaluator (e.g., INVESTIGATOR, CEC ADJUDICATOR), this can be sponsor-defined since the EVAL codelist controlled terminology is extensible. --EVALID is not used in this TAUG, since there are not multiple evaluators with the same role represented in the data examples. --ACPTFL were used to identify the accepted evaluation. o Users need to be aware of the multiple record approaches to subset data appropriately when summarizing events and interventions. Page 10 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

11 o o The handling of adjudication data in this TAUG was reviewed with the CDISC SDS Extended Leadership Team. Based on the public review comments received on the TAUG-CV, an Adjudication Sub-Team will be formed to provide more information on modeling adjudication data. Additional details on the adjudication process will be addressed in a future CDISC publication. The adjudicated data is sorted in different orders in the document. Some examples are sorted by Visit and others are sorted by Evaluator. Adverse Events vs. Clinical Events: The CV Endpoints Standards Team reviewed the question of whether the cardiovascular events expected in CV endpoint studies should be recorded as an adverse event or a clinical event in SDTM. The team decided they should be clinical events when being evaluated as a CV endpoint, since they are expected to occur in CV endpoint studies. These specific cardiovascular event terms are listed in the SCTI CV endpoints CDE definitions in order to record them consistently for CV endpoint studies. The CV endpoints may be considered adverse events in other types of studies and should follow the sponsor s adverse event reporting rules. Cardiovascular Biomarkers: The CV Endpoint CDEs included the 99% upper reference limit value for certain laboratory data. This value is different from the upper limit of normal, which is typically, though not always, the 95th percentile. The LB domain does not include a variable for 99% upper limit value, so it was placed in a supplemental qualifier (i.e., in the SUPPLB dataset). This relates the 99% upper reference limit values with the related lab record. The CV Endpoint CDEs included value of the concentration of a cardiac biomarker at the 99% upper reference limit from the distribution of values for a subject population who would be expected to have normal values for the lab. The 99% upper reference limit would be supplied by the laboratory. Cardiovascular Lesions: A lesion can be almost any abnormal change involving any tissue or organ, usually due to disease or injury. Classification systems often designate lesions and other abnormalities as one type of lesion such as cysts, calculus, goiters, nodules, polyps, stones and warts. The CV endpoints CDEs describe lesions that occur in main coronary artery segments, which are part of the main coronary arteries or lower extremity artery segments, which are part of the main peripheral arteries. The main arteries are also referred to as vessels in cardiovascular terminology. The CDISC Oncology Sub-Team addressed identification and assessments of lesions which are tumors in the Tumor/Lesion Identification (TU) and Tumor/Lesion Results (TR) domains. The requirements for identifying lesions other than tumors, such as the arterial lesions involved in CV endpoints, were found to be similar to those for tumors. The CDISC SDS Leadership Team decided to expand the scope of the existing TU and TR domains to include non-tumor lesions, rather than to create new domains for nononcology data. The TU and TR domain names will be revised in the next version of the SDTMIG to Tumor/Lesion Identification (TU) and Tumor/Lesion Results (TR). Based on the CV endpoint CDEs lesions and related vessels are identified in the TU domain and lesion using the TULOC variable. The vessel results are represented in the TR domain. Vessel and vessel segment measurements are represented in the Morphology (MO) domain and are part of the SCTI CV Endpoint CDEs. Cardiovascular Judgments: The CV Endpoint CDEs contain a number of clinical judgments which are based on multiple sources of routinely collected data. These clinical judgments are made about clinical events and surgical interventions. Examples are the identification of symptoms, the evaluation of heart failure and unstable angina endpoint events, along with procedure urgency status type and procedure success. The Morphology (MO) and Findings About Events and Interventions (FA) domain are used to record the clinical judgments with the MOLNKID variable and the object variable (FAOBJ) referring to the related clinical event or procedure. This modeling approach is still under evaluation and is subject to change with future releases of the SDTMIG. Clinical Classifications: There are classifications currently represented in FA and MO that may be more suited for a proposed new Clinical Classifications (CC) domain; such cases may be revised in future versions of this document. Examples include Stent Thrombosis, Coronary, ARC Timing and TIMI Flow. Symptom Onset Date: The onset date of symptoms is captured in the SUPPFACE dataset for the FACE examples. This will be updated in subsequent versions of the TAUG-CV, as a new modeling approach for symptom onset data is being developed. Supportive Data: The endpoint definitions are based on the assumption that certain kinds of raw data will be available. Not all potential data may be displayed in all examples, based on the initial interpretation of 2014 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 11 Provisional October 17, 2014

12 the use case. The raw data can generally be handled with existing SDTMIG domains. For instance, if device information was collected, it would be represented in the appropriate Medical Devices domains. 2 Disease Characteristics and Routine Data Subject and disease characteristics generally consist of information about the subject, including events and activities which have affected the subject, prior to or at the start of the study. For CV studies, such information may include the subject s history of CV issues, any family history and/or genetic biomarkers related to CV issues, any past medications or recreational substances, such as tobacco, that could have had negatively impacted the CV system, and prior CV-related procedures. This data may be used to determine eligibility for the study. Study data will include data about the subject s welfare, the safety of the study treatment, and assessments of the subject s condition and their reaction to a treatment. Such routine data are not specific to CV studies, and may include adverse events, healthcare encounters, vital signs, routine observations performed for monitoring purposes, concomitant medications and/or concomitant recreational substance use. This version 1.0 of the TAUG-CV does not include additional guidance for handling data related to subject/disease characteristics and/or routinely collected data beyond that already provided in other standards (see Section 1.6). Later versions of this document may cover such data in more detail. 3 Disease Assessments Cardiovascular disease can cause a variety of problems, but can also be asymptomatic until an acute event such as a heart attack or stroke occurs. Studies of treatments for cardiovascular disease often use the occurrence of one of several major adverse cardiac events (MACE) as the study endpoint. Some studies intended to address risk factors for cardiac events, such as hypertension and hypercholesterolemia, will use test results as their endpoints. However, the relevance of those test results has been established by means of studies with clinical endpoints such as MACE. The definition of MACE can vary from study to study, both in the events included and in the definition of those events. The fact that acute cardiac events occur unexpectedly and can present in widely varying ways means that these events are usually adjudicated by an independent committee, using pre-defined criteria. The Standardized Data Collection for Cardiovascular Trials Initiative has created such criteria for the adjudication of a number of major cardiovascular events. These definitions can be used for studies where cardiovascular events are the study endpoint. They can also be used to examine the safety of treatments of associated diseases, such as diabetes, whose treatments may have effects (positive or negative) on the incidence of cardiovascular events. Page 12 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

13 3.1 Acute Coronary Syndrome Acute coronary syndrome (ACS) is an umbrella term used to cover any group of clinical symptoms compatible with acute myocardial ischemia. Acute myocardial ischemia is defined as an insufficient blood supply to the heart muscle that results from coronary artery disease (also called heart disease). 1 ACS refers to any group of symptoms attributed to obstruction of the coronary arteries. The most common symptom prompting diagnosis of ACS is chest pain, often radiating to the left arm or angle of the jaw, pressure-like in character, and associated with nausea and sweating. Acute coronary syndrome generally refers to one of three etiologies: ST elevation myocardial infarction: If the ECG demonstrates ST segment elevation in anatomically contiguous leads, a new left bundle branch block, or a true posterior MI pattern, this is considered presumptive evidence of an acute ST elevation myocardial infarction (STEMI). To halt the STEMI, thrombolytics may be administered or primary coronary angioplasty may be performed. In the former, medication is injected that stimulates fibrinolysis, dissolving the blood clot in the coronary artery causing the STEMI. In the latter, a flexible catheter is passed via the femoral or radial arteries and advanced to the heart to identify blockages in the coronaries. When the culprit lesion is identified, mechanical intervention is performed using one of a variety of techniques, including aspiration thrombectomy, balloon angioplasty, and / or stent deployment. Data demonstrate that rapid triage and treatment are essential. Per the American College of Cardiology (ACC) guidelines, the target time frame for thrombolytic administration ( door to needle time ) is within 30 minutes, while the time frame for percutaneous coronary intervention ( door to balloon time ) is within 90 minutes. Non ST elevation myocardial infarction: If the ECG does not show ST segment elevation, a non-st segment elevation myocardial infarction (NSTEMI) may be present. The diagnosis requires documentation of myocardial damage via the presence of abnormal elevations of cardiac biomarkers such as troponin or creatine kinase-mb band. The accepted management of NSTEMI includes administration of aspirin, a second platelet inhibitor such as clopidogrel, prasugrel, or ticagrelor, and an anticoagulant such as heparin. Early (but not emergency) referral for cardiac catheterization and coronary intervention are indicated to reduce subsequent morbidity and mortality. Unstable angina: In the absence of STEMI or NSTEMI, the patient presenting with symptoms consistent with myocardial ischemia in an accelerating or unstable pattern likely has unstable angina. Unstable angina is typically characterized by either: o Occurs at rest or minimal exertion, with symptoms lasting less than 20 minutes (if nitroglycerin is not administered) o Occurs with a crescendo pattern (more severe, prolonged, or increased frequency than previously). ACS should be distinguished from stable angina, which manifests as chest discomfort that occurs with exertion and resolves at rest. In contrast with stable angina, unstable angina occurs suddenly, often at rest or with minimal exertion, or at lesser degrees of exertion than the individual's previous angina ("crescendo angina"). New onset angina is also considered unstable angina, since it suggests a new problem in a coronary artery. Though ACS is usually associated with coronary thrombosis, it can also be associated with cocaine use. Cardiac chest pain can also be precipitated by anemia, bradycardias (excessively slow heart rate) or tachycardia (excessively fast heart rate). The Thrombolysis in Myocardial Infarction (TIMI) risk score can identify high risk patients and has been independently validated. Primary prevention of atherosclerosis targets modifiable risk factors, emphasizing healthy eating, exercise, treatment of hypertension and diabetes, avoiding smoking and controlling cholesterol levels; in patients with significant risk factors, aspirin has been shown to reduce the risk of cardiovascular events Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 13 Provisional October 17, 2014

14 These common data elements and definitions for the ACS data elements can be found on the HL7 website. The concept map below shows what happens to a patient experiencing ACS. For example, a patient presents cardiac problems to his doctor that may result in investigating the patient s medical history, symptoms of the problems, cardiac biomarkers, diagnostic procedures and therapeutics. This may result in sending the patient to the emergency room for further evaluation. Based on the applicable cardiac disease guidelines, this may lead to further testing that is assessed with clinical judgment in determining a diagnosis and course of action in correcting the problem. Concept Map 1: Acute Coronary Syndrome Not included in this concept map: Disease Guidelines and Appropriate Use Criteria help to direct what diagnostic tests are performed, what therapies are indicated, and other courses of action. For additional information on myocardial infarction, see Section For examples of therapeutic procedures, see Sections and Cardiac catheterization, which is shown as a surgical intervention in the concept map above, is actually a complex procedure which may combine diagnostic assessments and therapeutic interventions. It is a surgical procedure in which a catheter is threaded from an incision in the groin or wrist through the arteries into Page 14 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

15 the heart. Various instruments may be inserted using the catheter, including diagnostic instruments such as cameras and measuring devices. Therapeutic procedures may be performed from within the coronary arteries, including angioplasty to open coronary arteries narrowed or blocked by atherosclerotic plaque, and the insertion of stents to hold coronary arteries open Examples for Acute Coronary Syndrome Concept Map 2: Cardiac Catheterization Example 1 This ACS use case is based on the HL7 DAM 2 use case in treating an ACS patient and describes how patient care is managed when a patient coming into the emergency department is evaluated and goes through the system as per the ACC/AHA Joint Guidelines for Acute Coronary Syndrome ( Note: Lists of diagnostic tests (lab, ECG, etc.) are intended to be illustrative, but are not comprehensive or exhaustive. Subject presented to the Emergency Department on March 1, 2013 at 5:00 AM for definite symptoms of Acute Coronary Syndrome-chest pain, which began the prior evening. The subject has a history of stable angina. ER ECG findings showed ST Elevation. Cardiac biomarkers taken in the ER were elevated. The facility has on site cardiac catheterization lab and cardiac surgery facilities. The subject was transferred to the cardiac catheterization laboratory for a diagnostic catheterization, which showed a new total occlusion as the culprit lesion prior to treatment which confirmed the STEMI diagnosis. The subject then had a percutaneous coronary intervention (PCI) performed to do a stent implant to correct the stenosis caused by the lesion. Row 2: Shows the subject had chest pain symptoms the evening before going to the emergency room. Shows the subject had stenosis as confirmed by the coronary angiogram Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 15 Provisional October 17, 2014

16 Row 3: Shows confirmation of the STEMI as a clinical event based on the diagnostic tests performed. ce.xpt Row STUDYID DOMAIN USUBJID CESEQ CELNKID CETERM CEDTC CESTDTC CEENDTC 1 STUDY02 CE STEMI-1 CHEST PAIN T05: T23: T07:45 2 STUDY02 CE STEMI-2 STENOSIS T06: T05: T06:00 3 STUDY02 CE STEMI-3 ST ELEVATION MYOCARDIAL INFARCTION T11: T06: T07:45 The subject arrived at the emergency room at 5:00 AM on March 1, Row 2: The subject was transferred to the cardiac catheterization laboratory for diagnostic angiography which resulted in a PCI procedure at 5:30 AM on March 1, Row 3: The subject was admitted to the hospital after the procedure at 8:30 AM on March 1, ho.xpt Row STUDYID DOMAIN USUBJID HOSEQ HOLNKID HOTERM HOSTDTC HOENDTC 1 STUDY02 HO STEMI-1 EMERGENCY ROOM T05: T05:25 2 STUDY02 HO STEMI-2 CARDIAC CATHETERIZATION LABORATORY T05: T08:00 3 STUDY02 HO STEMI-3 GENERAL WARD T08: Row 2: Row 3: Shows the subject s reason for going to the emergency room was chest pain. The subject was sent to the cardiac catheterization laboratory for a diagnostic procedure due to the chest pain. While in the catheterization laboratory the subject had a PCI procedure to implant a stent to treat the blockage caused by the stenosis. The subject was admitted to the hospital after the PCI procedure as a result for the STEMI. suppho.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY02 HO HOSEQ 1 HOINDC Indication CHEST PAIN CRF INVESTIGATOR 2 STUDY02 HO HOSEQ 2 HOINDC Indication CHEST PAIN CRF INVESTIGATOR 3 STUDY02 HO HOSEQ 3 HOINDC Indication ST ELEVATION MYOCARDIAL INFARCTION CRF INVESTIGATOR Shows the subject s history of stable angina. mh.xpt Row STUDYID DOMAIN USUBJID MHSEQ MHLNKID MHTERM MHDTC MHSTDTC 1 STUDY02 MH STEMI-1 STABLE ANGINA Shows the summary (max) ST elevation recorded while in the ER. The result was above the threshold and indicated ST elevation, the criteria for STEMI. eg.xpt Row STUDYID DOMAIN USUBJID EGSEQ EGLNKID EGTESTCD EGTEST EGORRES EGORRESU EGSTRESC EGSTRESN EGSTRESU 1 STUDY02 EG STEMI-1 STELMAX Summary (Max) ST Elevation 4 mm 4 4 mm Page 16 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

17 Row EGMETHOD VISITNUM VISIT EGDTC 1 (cont) 12 LEAD STANDARD 1.1 UNSCHEDULED T5:08:00 Rows 1-4: The cardiac biomarkers results showed evidence of an acute myocardial infarction. lb.xpt Row STUDYID DOMAIN USUBJID LBSEQ LBLNKID LBTESTCD LBTEST LBCAT LBSCAT LBORRES LBORRESU LBORNRLO 1 STUDY02 LB STEMI-1 TROPONI Troponin I CHEMISTRY CARDIAC BIOMARKER 1.1 ug/l 0 2 STUDY02 LB STEMI-1 TROPONT Troponin T CHEMISTRY CARDIAC BIOMARKER 0.7 ug/l 0 3 STUDY02 LB STEMI-1 CK Creatine Kinase CHEMISTRY CARDIAC BIOMARKER 250 IU/L 30 4 STUDY02 LB STEMI-1 CKMB Creatine Kinase MB CHEMISTRY CARDIAC BIOMARKER 15 ug/l 0 Row LBORNRHI LBSTRESC LBSTRESN LBSTRESU LBSTNRLO LBSTNRHI LBNRIND LBNAM LBLOINC LBBLFL VISITNUM LBDTC 1 (cont) ug/l HIGH MEMORIAL HOSPITAL Y T05:15 2 (cont) ug/l HIGH MEMORIAL HOSPITAL Y T05:15 3 (cont) IU/L HIGH MEMORIAL HOSPITAL Y T05:15 4 (cont) ug/l 0 7 HIGH MEMORIAL HOSPITAL Y T05:15 Rows 1-4: Show the upper reference limit of 99% (see Section 1.7) that was supplied by the hospital s laboratory. QEVAL is not populated, since this is an objective result from the laboratory. The CV Endpoint CDEs included the value of the concentration of a cardiac biomarker at the 99% upper reference limit from the distribution of values for a subject population who would be expected to have normal values for the lab. supplb.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY02 LB LBSEQ 1 URLC_99 Upper Reference Limit 99% 0.45 ug/l edt 2 STUDY02 LB LBSEQ 2 URLC_99 Upper Reference Limit 99% 0.08 ug/l edt 3 STUDY02 LB LBSEQ 3 URLC_99 Upper Reference Limit 99% 200 IU/L edt 4 STUDY02 LB LBSEQ 4 URLC_99 Upper Reference Limit 99% 6 ug/l edt Row 2: Shows the diagnostic cardiac catheterization procedure to identify the coronary artery blockage. Shows the stent implantation to correct the stenosis caused by the lesion by PCI. pr.xpt Row STUDYID DOMAIN USUBJID PRSEQ PRLNKID PRTRT PRCLAS VISITNUM VISIT PRSTDTC PRENDTC 1 STUDY02 PR STEMI-1 CARDIAC DIAGNOSTIC 1.1 UNSCHEDULED CATHETERIZATION 01T05:35 01T06:00 2 STUDY02 PR STEMI-2 STENT IMPLANTATION PERCUTANEOUS CORONARY UNSCHEDULED INTERVENTION 01T06:00 01T07:45 Row 2: Shows the target lesion identified in the right coronary artery ostium segment that is causing the blockage using the LESIDENT variable. Shows the main coronary vessel in which the artery segment resides. Lesions and vessels are included in pairs (i.e., the vessel in which the lesion is located), TULNKID=L01 identifies the target lesion and TULNKID=L01-1 identifies the vessel that the lesion is located in (target vessel). The TULNKID is used to link the morphology results found in the MO domain for the target vessel measurements Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 17 Provisional October 17, 2014

18 tu.xpt Row STUDYID DOMAIN USUBJID TUSEQ TULNKID TUTESTCD TUTEST TUORRES TUSTRESC TUNAM 1 STUDY02 TU L01 LESIDENT Lesion Identification TARGET TARGET CARDIAC CATHETERIZATION LABORATORY 2 STUDY02 TU L01-1 VESIDENT Vessel Identification TARGET TARGET CARDIAC CATHETERIZATION LABORATORY Row TULOC TUMETHOD VISITNUM VISIT TUDTC 1 (cont) RIGHT CORONARY ARTERY OSTIUM CORONARY ANGIOGRAPHY 1.1 UNSCHEDULED T11:45 2 (cont) RIGHT CORONARY ARTERY CORONARY ANGIOGRAPHY 1.1 UNSCHEDULED T11:45 Shows the target lesion success indicator results based on the therapeutic PCI procedure. This means that the lesion was successfully treated and met the threshold identified for reduction of stenosis identified in the CV Endpoints CDEs. tr.xpt Row STUDYID DOMAIN USUBJID TRSEQ TRGRPID TRLNKGRP TRLNKID TRTESTCD TRTEST TRORRES TRSTRESC 1 STUDY02 TR TARGET A1 L01 LESSCIND Lesion Success Indicator Y Y Row TRNAM TRMETHOD VISITNUM VISIT TRDTC 1 (cont) CARDIAC CATHETERIZATION LABORATORY CORONARY ANGIOGRAPHY 1.1 UNSCHEDULED T11:45 Rows 1-3: Show the main coronary vessel measurements from the diagnostic cardiac procedure that identifies the stenosis at 100%. The MOLNKID references the vessel identified in the TU domain below. mo.xpt Row STUDYID DOMAIN USUBJID MOSEQ MOGRPID MOLNKGRP MOLNKID MOTESTCD MOTEST MOORRES MOORRESU MOSTRESC 1 STUDY02 MO TARGET A1 L01-1 MEANVDIA Mean Vessel Diameter 2.0 mm STUDY02 MO TARGET A1 L01-1 MINLDIAM Minimum Lumen Diameter 0 mm 0 3 STUDY02 MO TARGET A1 L01-1 PCTDIAST Percent Diameter Stenosis 100 % 100 Row MOSTRESN MOSTRESU MONAM MOLOC MOMETHOD VISITNUM VISIT MODTC 1 (cont) 2.0 mm CARDIAC CATHETERIZATION QUANTITATIVE RIGHT CORONARY ARTERY LABORATORY CORONARY ANGIOGRAPHY 1.1 UNSCHEDULED (cont) 0 mm CARDIAC CATHEERIZATION QUANTITATIVE RIGHT CORONARY ARTERY LABORATORY CORONARY ANGIOGRAPHY 1.1 UNSCHEDULED (cont) 100 % CARDIAC CATHETERIZATION QUANTITATIVE RIGHT CORONARY ARTERY LABORATORY CORONARY ANGIOGRAPHY 1.1 UNSCHEDULED Rows 1-2: Show the angiogram view used to analyze the vessel diameters. The IDVARVAL is listed as the MOTESTCD because the angiogram view applies to all records for each TESTCD for this subject. QEVAL is not populated, since this is an objective result. suppmo.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY02 MO MOTESTCD MEANVDIA AGIO_VW Angiogram View TWO VIEWS edt 2 STUDY02 MO MOTESTCD MINLDIAM AGIO_VW Angiogram View TWO VIEWS edt The RELREC domain defines dataset relationships between these domain records for all subjects. Page 18 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

19 Rows 1-12: Show the dataset relationship between the Healthcare Encounters, Clinical Events, Procedures, Laboratory Test Results, ECG Test Results, Tumor Identification, Tumor Results, and Morphology domains via the --LNKID variables. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 1 STUDY02 HO HOLNKID ONE 1 2 STUDY02 CE CELNKID ONE 1 3 STUDY02 CE CELNKID ONE 2 4 STUDY02 PR PRLNKID ONE 2 5 STUDY02 CE CELNKID ONE 3 6 STUDY02 LB LBLNKID MANY 3 7 STUDY02 CE CELNKID ONE 4 8 STUDY02 EG EGLNKID MANY 4 9 STUDY02 TU TULNKID ONE 5 10 STUDY02 TR TRLNKID MANY 5 11 STUDY02 TU TULNKID ONE 6 12 STUDY02 MO MOLNKID MANY 6 Example 2 Subject presented to the emergency department on April 1, 2013 at 5:00 AM for definite symptoms of myocardial ischemia (shortness of breath). ER ECG findings did not demonstrate ST segment elevation. Cardiac biomarkers were elevated. The facility has on site cardiac catheterization laboratory lab and cardiac surgery facilities. The subject was transferred to the cardiac unit for the management of the symptoms. A blockage was identified that was corrected with a balloon angioplasty. The subject continued to experience bradycardia and required a dual-chamber pacemaker implant to correct the problem. Row 2: Row 3: Shows the subject had shortness of breath upon arrival to the emergency department. When the subject was in the cardiac catheterization laboratory, he was diagnosed with myocardial ischemia which required immediate treatment (see PR domain below). Shows confirmation of the bradycardia as a clinical event based on the diagnostic tests performed. ce.xpt Row STUDYID DOMAIN USUBJID CESEQ CELNKID CETERM CEDTC CESTDTC CEENDTC 1 STUDY02 CE IMPLNT-1 SHORTNESS OF BREATH T01: T05:30 2 STUDY02 CE IMPLNT-2 MYOCARDIAL ISCHEMIA T05: T07:30 3 STUDY02 CE PACE-1 BRADYCARDIA T08: T10:00 Shows the subject s symptoms of myocardial ischemia which was shortness of breath, before the subject went to the ER. face.xpt Row STUDYID DOMAIN USUBJID FASEQ FALNKID FATESTCD FATEST FAOBJ FAORRES FASTRESC 1 STUDY02 FA IMPLNT-2 SYMPINDC Symptom Indicator MYOCARDIAL ISCHEMIA Y Y Row VISITNUM VISIT FADTC 1 (cont) 1.1 UNSCHEDULED Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 19 Provisional October 17, 2014

20 Rows 1: Shows the onset date of symptoms for the FATEST=Symptom Indicator. suppface.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY02 FA FASEQ 1 OSYMPDTC Onset of Symptoms Date T01:00 CRF INVESTIGATOR The subject went to the emergency room due to shortness of breath at 5:00 AM on April 1, HOGRPID is populated for all rows to indicate that the five encounters were part of one visit to the hospital. Row 2: Half an hour later, the subject was transferred to the cardiac surgery facility for diagnostic tests, which required immediate angioplasty (see PR record below). Row 3: The subject was admitted to the general ward for observation 8:30 AM on April 1, Row 4: The subject experienced bradycardia after the initial procedure and was taken to the catheterization laboratory for pacemaker implant surgery, at 8:15 AM on April 2, 2013 (see PR record below). Row 5: The subject was admitted to the general ward for post-operative follow-up and recovery after the pacemaker implant surgery, at 10:30 AM on April 2, 2013 (see PR record below). ho.xpt Row STUDYID DOMAIN USUBJID HOSEQ HOGRPID HOLNKID HOTERM HOSTDTC HOENDTC 1 STUDY02 HO IMPLNT-1 EMERGENCY ROOM T05: T05:25 2 STUDY02 HO IMPLNT-2 CARDIAC CATHETERIZATION LABORATORY T05: T08:00 3 STUDY02 HO GENERAL WARD T08: T08:00 4 STUDY02 HO PACE-1 CARDIAC CATHETERIZATION LABORATORY T08: T10:00 5 STUDY02 HO GENERAL WARD T10: Row 2: Row 3: Row 4: Row 5: Shows the subject s reason for going to the emergency room was shortness of breath. Shows the indication for the transfer to the cardiac catheterization laboratory was due to the myocardial ischemia. Shows the subject was admitted to the hospital for observation. Shows the subject was transferred to the cardiac catheterization laboratory for bradycardia. Shows the subject was admitted to the hospital for post-operative follow-up after the pacemaker implant. suppho.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY02 HO HOSEQ 1 HOINDC Indication SHORTNESS OF BREATH CRF INVESTIGATOR 2 STUDY02 HO HOSEQ 2 HOINDC Indication MYOCARDIAL ISCHEMIA CRF INVESTIGATOR 3 STUDY02 HO HOSEQ 3 HOINDC Indication OBSERVATION CRF INVESTIGATOR 4 STUDY02 HO HOSEQ 4 HOINDC Indication BRADYCARDIA CRF INVESTIGATOR 5 STUDY02 HO HOSEQ 5 HOINDC Indication POST-OPERATIVE FOLLOW-UP CRF INVESTIGATOR Rows 1-4: Show lab results obtained in the emergency room. The cardiac biomarkers were elevated. Page 20 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

21 lb.xpt Row STUDYID DOMAIN USUBJID LBSEQ LBLNKID LBTESTCD LBTEST LBCAT LBSCAT LBORRES LBORRESU LBORNRLO 1 STUDY02 LB IMPLNT-1 TROPONI Troponin I CHEMISTRY CARDIAC BIOMARKER 1.1 ug/l 0 2 STUDY02 LB IMPLNT-1 TROPONT Troponin T CHEMISTRY CARDIAC BIOMARKER 0.7 ug/l 0 3 STUDY02 LB IMPLNT-1 CK Creatine Kinase CHEMISTRY CARDIAC BIOMARKER 250 IU/L 30 4 STUDY02 LB IMPLNT-1 CKMB Creatine Kinase MB CHEMISTRY CARDIAC BIOMARKER 15 ug/l 0 Row LBORNRHI LBSTRESC LBSTRESN LBSTRESU LBSTNRLO LBSTNRHI LBNRIND LBNAM LBLOINC LBBLFL VISITNUM LBDTC 1 (cont) ug/l HIGH MEMORIAL HOSPITAL Y T05:20 2 (cont) ug/l HIGH MEMORIAL HOSPITAL Y T05:20 3 (cont) IU/L HIGH MEMORIAL HOSPITAL Y T05:20 4 (cont) ug/l 0 7 HIGH MEMORIAL HOSPITAL Y T05:20 Rows 1-4: Show the upper reference limit of 99% (see Section 1.7) that was supplied by the hospital s laboratory. QEVAL is not populated, since this is an objective result from the laboratory. The CV Endpoint CDEs included the value of the concentration of a cardiac biomarker at the 99% upper reference limit from the distribution of values for a subject population who would be expected to have normal values for the lab. supplb.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY02 LB LBSEQ 1 URLC_99 Upper Reference Limit 99% 0.45 ug/l edt 2 STUDY02 LB LBSEQ 2 URLC_99 Upper Reference Limit 99% 0.08 ug/l edt 3 STUDY02 LB LBSEQ 3 URLC_99 Upper Reference Limit 99% 200 IU/L edt 4 STUDY02 LB LBSEQ 4 URLC_99 Upper Reference Limit 99% 6 ug/l edt Shows ECG tests result recorded while in the ER, indicating a lack of ST elevation. eg.xpt Row STUDYID DOMAIN USUBJID EGSEQ EGLNKID EGTESTCD EGTEST EGORRES EGORRESU EGSTRESC EGSTRESN 1 STUDY02 EG IMPLNT-1 STELMAX Summary (Max) ST Elevation 0 mm 0 0 Row EGSTRESU EGMETHOD VISITNUM VISIT EGDTC 1 (cont) mm 12 LEAD STANDARD 1.1 UNSCHEDULED T05:08 Row 2: Shows the balloon angioplasty to treat the blockage. A device with identifier (SPDEVID) ABC001 was used in the procedure. Shows the cardiac surgery to implant the pacemaker. A device with identifier (SPDEVID) ABC002 was used in the procedure. pr.xpt Row STUDYID DOMAIN USUBJID PRSEQ PRLNKID SPDEVID PRTRT PRCLAS PRSTDTC PRENDTC 1 STUDY02 PR IMPLNT-2 ABC001 PERCUTANEOUS CORONARY BALLOON ANGIOPLASTY T05: T08:00 INTERVENTION 2 STUDY02 PR PACE-1 ABC002 PACEMAKER IMPLANT CARDIAC SURGERY T08: T10: Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 21 Provisional October 17, 2014

22 The primary purpose of the DI domain is to provide a consistent sponsor-defined variable (SPDEVID) for linking data across Device domains, independent of the level of granularity by which a device might be identified by a sponsor in a study. This eliminates the need to relate the DI domain to other domains via RELREC, since the SPDEVID variable is included in appropriate domains as needed. Rows 1-2: Rows 3-4: Display the device type (balloon) and model for the device with identifier ABC001 used in the balloon angioplasty. Display the device type (pacemaker) and model for the device with identifier ABC002 used in the pacemaker implantation di.xpt Row STUDYID DOMAIN SPDEVID DISEQ DIPARMCD DIPARM DIVAL 1 STUDY02 DI ABC001 1 TYPE Device Type BALLOON 2 STUDY02 DI ABC001 2 MODEL Model PCI STUDY02 DI ABC002 3 TYPE Device Type PACEMAKER 4 STUDY02 DI ABC002 4 MODEL Model DUAL-CHAMBER-1234 Rows 1-10: Show the dataset relationship between the Healthcare Encounters, Clinical Events, Procedures, Laboratory Test Results, and ECG Test Results domains via the --LNKID variables. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 1 STUDY02 HO HOLNKID ONE 1 2 STUDY02 CE CELNKID ONE 1 3 STUDY02 CE CELNKID ONE 2 4 STUDY02 PR PRLNKID ONE 2 5 STUDY02 CE CELNKID ONE 3 6 STUDY02 LB LBLNKID MANY 3 7 STUDY02 CE CELNKID ONE 4 8 STUDY02 EG EGLNKID MANY 4 9 STUDY02 CE CELNKID ONE 5 10 STUDY02 FACE FALNKID MANY Cardiovascular Endpoints The Cardiovascular Endpoints Section of this TAUG-CV is organized by the seven groupings of endpoints of interest, in the order determined by the Cardiovascular Endpoints Working Group: 1. Death 2. Transient Ischemic Attack and Stroke 3. Myocardial Infarction 4. Percutaneous Coronary Intervention 5. Peripheral Vascular Intervention 6. Heart Failure Event 7. Unstable Angina Hospitalization Event Page 22 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

23 The purpose of this user guide it to represent how to handle cardiovascular endpoints whether they occur in a cardiovascular trial or in a non-cardiovascular trial. Other endpoint event information should be modeled per appropriate therapeutic area standards Adjudication of Events An important aspect of CV endpoints is their adjudication. Implementation of adjudicated events in SDTM requires mechanisms to represent multiple opinions about a single event. A number of examples included in this user guide demonstrate how the adjudication records are handled. See Section 1.7 for the new variables approved for the Events class. Clinical events or endpoints in clinical trials are often required to be formally adjudicated. Trials involving adjudication require effective communication and adjudication processes which are enhanced by electronic systems that offer real-time information on patient outcome data. Ideally, communication between sponsors, clinical event committee (CEC) members, medical monitors, data managers, and investigators uses a single system, which allows the CEC to review and rapidly arrive at conclusions about endpoints which are critical endpoint for study decisions. Streamlining adjudications and communication not only allows all relevant patient data to flow quickly to all decision makers, but also keeps the trial timelines intact by managing endpoint target numbers. Adjudication committees have been routinely formed to provide event adjudication and data and safety monitoring services. These include: CECs systematically identify, adjudicate, and classify clinical endpoint events to ensure they are consistent with prevailing standards. Data and Safety Monitoring Boards (DSMB) expertly monitor patient safety and treatment efficacy data to provide a risk-benefit profile of the investigative treatment or procedure throughout the life of the trial. Committee rosters usually include highly accredited, independent interventional cardiologists, non-interventional cardiologists, cardiothoracic surgeons, neurologists, and other specialists as well as biostatisticians. This adjudication process ensures that trial data is consistent, reliable, and of high quality. When data examples in this user guide contain adjudication data, the --EVAL variable will identify the investigator or the adjudicator of the observation. Observations could include the adjudicated event or procedure, as well as findings about the event or procedure. The concept map to the right demonstrates the adjudication process. For example, a patient enters an emergency room (ER) with symptoms that suggest heart problems, and based on the original diagnosis, agrees to enroll in a clinical study which utilizes an Concept Map 3: Event Adjudication Process 2014 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 23 Provisional October 17, 2014

24 adjudication committee. At that point, an investigator identifies a possible CV event, begins collecting relevant data, conducts additional diagnosis activities, and makes various clinical decisions regarding the event. Subject-matter experts on the adjudication committee participate in a re-review of the source data to determine if they agree or disagree with the diagnosis and clinical judgment made by the investigator. See Sections , , , and for examples representing adjudication data Death According to the SCTI criteria, in studies where cardiovascular endpoints are a concern, death should be categorized as follows by the investigator or CEC: 2 Cardiovascular Death includes death resulting from an acute myocardial infarction (MI), sudden cardiac death, death due to heart failure (HF), death due to stroke, death due to cardiovascular procedures, death due to cardiovascular hemorrhage, and death due to other cardiovascular causes (not included in the previous categories, but with a specific known cause peripheral artery disease, for example). Non-Cardiovascular Death is defined as any death with a specific cause that is not thought to be cardiovascular in nature. Permissible values are used to categorize the physiological system associated with the death and can be found in the SCTI CDEs for non-cardiovascular death. Detailed recommendations on the classification of non-cardiovascular causes of death are beyond the scope of this user guide. The level of detail required and the optimum classification will depend on the nature of the study population and the anticipated number and type of non-cardiovascular deaths. Undetermined Cause of Death refers to a death not attributable to one of the above categories of cardiovascular death or to a non-cardiovascular cause. Inability to classify the cause of death may be due to lack of information (e.g., the only available information is patient died ) or when there is insufficient supporting information or detail to assign the cause of death. The appropriate classification and analysis of undetermined causes of death depends on the population, the intervention under investigation, and the disease process. Stent, stroke, and thrombus CDEs (see Section ) are indicated by a value of SSD in the ENDPOINT column of the spreadsheet. The concept map below shows how a death may be caused by either a cardiovascular event/non-cardiovascular event or a cardiovascular procedure, and that cause of death may be cardiovascular, non-cardiovascular, or undetermined. For example, a death related to the cardiovascular endpoint definitions may be related to a specified cardiovascular clinical event. Another cause of death may occur with a specified cardiovascular procedure. Upon review of the details of the cause of death, possibly from a death certificate or autopsy report, it is categorized according to the death endpoint definitions. Page 24 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

25 Examples for Death Concept Map 4: Death More detailed concept maps for PCI and PVI procedures can be found in Sections and Example 1 Deaths that occur during a study are represented as disposition events in the Disposition (DS) domain, as referenced in the current SDTMIG. The cause of death and other details are recorded in the Death Details (DD) domain, as shown below. The example below shows the primary and secondary causes of death for this subject. This example illustrates the use of the SCTI terminology for causes of death. The death would also result in the population of the DTHFL and DTHDTC variables in the Demographics (DM) domain, but a DM record is not included in the example below. The value list for the DDSTRESC values will be included in the define.xml. Shows that the subject left the study on November 27, 2007 when they died due to stroke. ds.xpt Row STUDYID DOMAIN USUBJID DSSEQ DSLNKID DSTERM DSDECOD DSCAT DSDTC DSSTDTC 1 STUDY01 DS DTH-1 Death due to stroke DEATH DISPOSITION EVENT Row 2: Shows the primary cause of death with both the originally reported term and the standardized term taken from the SCTI controlled terminology. The DDRESCAT variable is used to show that this cause of death is classified as cardiovascular. Shows the secondary cause of death, again with both the original term and the standardized term taken from the SCTI controlled terminology. dd.xpt Row STUDYID DOMAIN USUBJID DDSEQ DDLNKID DDTESTCD DDTEST DDORRES DDSTRESC 1 STUDY01 DD DTH-1 PRCDTH Primary Cause of Death DEATH DUE TO STROKE CARDIOVASCULAR: STROKE 2014 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 25 Provisional October 17, 2014

26 Row STUDYID DOMAIN USUBJID DDSEQ DDLNKID DDTESTCD DDTEST DDORRES DDSTRESC 2 STUDY01 DD DTH-1 SECDTH Secondary Cause of Death KIDNEY FAILURE RENAL FAILURE Row DDRESCAT VISITNUM DDDTC 1 (cont) CARDIOVASCULAR DEATH (cont) Rows 1-2: Show the relationship between the Disposition and Death Details domains via the DSLNKID and DDLNKID variables. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 1 STUDY01 DS DSLNKID ONE DSDD 2 STUDY01 DD DDLNKID MANY DSDD Transient Ischemic Attack and Stroke The cardiovascular endpoints of transient ischemic attack and stroke apply to a wide range of clinical trials. The distinction between a transient ischemic attack and an ischemic stroke is the presence of infarction (tissue death). Persistence of symptoms is an acceptable indicator of acute infarction. Thus, duration of symptom persistence that will be used to distinguish between transient ischemia and acute infarction should be defined for any clinical trial in which it is used. Transient ischemic attack is defined as a transient episode of focal neurological dysfunction caused by brain, spinal cord, or retinal ischemia, without acute infarction. 3 Stroke is defined as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction. 4 There are three different types of stroke: Ischemic: An acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of central nervous system tissue. Note: Hemorrhage may be a consequence of ischemic stroke. In this situation, the stroke is an ischemic stroke with hemorrhagic transformation, and not a hemorrhagic stroke. Hemorrhagic: An acute episode of focal or global cerebral or spinal dysfunction caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage. Note: Subdural hematomas are not strokes but intracranial hemorrhagic events. Undetermined: An acute episode of focal or global neurological dysfunction caused by presumed brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction but with insufficient information to allow categorization as either ischemic or hemorrhagic. Stent, stroke, and thrombus CDEs (See Section ) are indicated by a value of SSD in the ENDPOINT column of the spreadsheet. The concept map below shows the transient ischemic attack and stroke CDEs. The cardiovascular endpoint stroke or transient ischemic attack is a combined endpoint, consisting of either a stroke or a transient ischemic attack. Stroke type is based on the SCTI cardiovascular endpoint common data element definitions. The Modified Rankin Scale questionnaire is used to assess the severity of the stroke. Page 26 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

27 Concept Map 5: Transient Ischemic Attack and Stroke For a more detailed description of death see Section Examples for Transient Ischemic Attack and Stroke Example 1 The investigator reported that a subject (USUBJID=40523) had a transient ischemic attack (TIA) on October 15, The clinical event was re-evaluated by the clinical evaluation committee (CEC) and the CEC adjudicator also considered the event to be a TIA. CEGRPID is used to link the investigator and CEC adjudicator records for the one TIA event. Row 2: Shows the subject had a transient ischemic attack on October 15, 2008 as reported by the investigator. Shows the CEC adjudicator s evaluation of the event, approximately one month after the investigator s evaluation. CEGRPID groups the source and adjudicated records. The CEACPTFL=Y indicates that this record is the accepted record. ce.xpt Row STUDYID DOMAIN USUBJID CESEQ CEGRPID CETERM CEDECOD CEEVAL CEACPTFL CEDTC CESTDTC 1 STUDY01 CE TRANSIENT ISCHEMIC ATTACK INVESTIGATOR STUDY01 CE TRANSIENT ISCHEMIC ATTACK CEC ADJUDICATOR Y Example 2 Subject had an ischemic stroke on January 20, The investigator judged the stroke to be ischemic based on the subject s presentation of signs and symptoms, and the criteria identified in the SCTI CV ENDPOINT CDEs. The Modified Rankin Scale (MRS) was administered at an unscheduled visit on January 21, 2009 and the subject was judged to have No Significant Disability Despite Symptoms; Able to Carry Out All Usual Duties and Activities. At the 30-day follow-up visit on February 20, 2009, the patient was administered the Rankin Scale again and had the same result. The subject had a stroke on January 20, This event was not adjudicated, so there is no second record Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 27 Provisional October 17, 2014

28 ce.xpt Row STUDYID DOMAIN USUBJID CESEQ CELNKID CETERM CEDTC CESTDTC CEENDTC 1 STUDY01 CE STRK-1 STROKE The investigator judged the stroke to be ischemic, using the predefined criteria identified in the SCTI CV ENDPOINT CDE.s face.xpt Row STUDYID DOMAIN USUBJID FASEQ FALNKID FATESTCD FATEST FAOBJ FAORRES FASTRESC VISITNUM VISIT FADTC 1 STUDY01 FA STRK-1 STROKTYP Stroke Type STROKE ISCHEMIC STROKE ISCHEMIC STROKE 1.1 UNSCHEDULED Results from the MRS questionnaire are recorded in the QS domain. Refer to the SDTM QS-MRS v1 Public Domain Clinical Outcome Supplement (found on the CDISC website at: for details on implementing the MRS questionnaire. Row 2: Shows the Modified Rankin Scale score at the time of the stroke. Shows the Modified Rankin Scale score at the 30-day follow-up visit. qs.xpt Row STUDYID DOMAIN USUBJID QSSEQ QSTESTCD QSTEST QSCAT QSORRES 1 STUDY01 QS MRS0101 MRS01-MODIFIED RANKIN NO SIGNIFICANT DISABILITY DESPITE SYMPTOMS; ABLE TO CARRY MRS SCALE SCORE OUT ALL USUAL DUTIES AND ACTIVITIES 2 STUDY01 QS MRS0101 MRS01-MODIFIED RANKIN NO SIGNIFICANT DISABILITY DESPITE SYMPTOMS; ABLE TO CARRY MRS SCALE SCORE OUT ALL USUAL DUTIES AND ACTIVITIES Row QSSTRESC QSSTRESN QSEVAL VISITNUM VISIT QSDTC 1 (cont) 1 1 INVESTIGATOR 1.1 UNSCHEDULED (cont) 1 1 INVESTIGATOR 5 30-DAY FOLLOW-UP Rows 1-2: Show the relationship between the Clinical Events and Findings About domains via the CELNKID and FALNKID variables. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 1 STUDY01 CE CELNKID ONE CEFA 2 STUDY01 FACE FALNKID MANY CEFA Myocardial Infarction The cardiovascular endpoint of acute myocardial infarction (MI) is defined as a clinical syndrome where there is evidence of myocardial necrosis (tissue death) in a clinical setting consistent with acute myocardial ischemia (restriction in blood supply). 5 In general, the diagnosis of MI requires the combination of: Evidence of myocardial necrosis (either changes in cardiac biomarkers or post-mortem pathological findings) Supporting information derived from the clinical presentation, electrocardiographic changes, or the results of myocardial or coronary artery imaging Page 28 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

29 The totality of the clinical, electrocardiographic, and cardiac biomarker information should be considered to determine whether or not a MI has occurred. Specifically, timing and trends in cardiac biomarkers and electrocardiographic information require careful analysis. MI may be adjudicated for an event that has characteristics of a MI but which does not meet the strict definition because biomarker or electrocardiographic results are not available. Acute myocardial infarction is classified into 5 different major types. 5 Two types (Types 1 and 2) are related to the disease process and four types (Types 4a, 4b, 4c, 5) are related to procedures being performed to alleviate the cardiovascular problems. Type 3 (death) may be related to either disease progression or a procedure. Type 1: spontaneous: Spontaneous clinical syndrome related to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection, with resulting intraluminal thrombus, and leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis. This classification requires a) detection of a rise and/or fall of cardiac biomarker values (preferably cardiac troponin (ctn)) with at least one value >99th percentile of the upper reference limit (URL) and b) at least one of the following: Symptoms of myocardial ischemia New or presumed new significant ST-segment T wave (ST T) changes or new left bundle branch block (LBBB) on the ECG Development of pathological Q waves on the ECG Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality Identification of an intracoronary thrombus by angiography or autopsy. Type 2: ischemic imbalance: Spontaneous clinical syndrome where a condition other than coronary artery disease contributes to an imbalance between myocardial oxygen supply and/or demand, e.g. coronary endothelial dysfunction, coronary artery spasm, coronary embolism, tachy-/brady-arrhythmias, anemia, respiratory failure, hypotension, and hypertension with or without left ventricular hypertrophy. This classification requires detection of a rise and/or fall of cardiac biomarker values (preferably cardiac troponin (ctn)) with at least one value >99th percentile of the upper reference limit (URL) and b) at least one of the following: Symptoms of myocardial ischemia New or presumed new significant ST-segment T wave (ST T) changes or new LBBB on the ECG Development of pathological Q waves on the ECG Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. Type 3: death, no biomarkers: Death where symptoms suggestive of myocardial ischemia are present, and with (presumed) new ischemic changes or new LBBB on ECG, but where death occurs before cardiac biomarkers can be obtained, or before cardiac biomarker values could rise. Type 4a: PCI Related: PCI Related Myocardial infarction associated with and occurring within 48h of percutaneous coronary intervention, with elevation of cardiac biomarker values to >5x 99th percentile of the upper reference limit (URL) in patients with normal baseline values (<=99th percentile URL), or a rise of cardiac biomarker values >=20% if the baseline values are elevated and are stable or falling. This classification also requires at least one of the following: Symptoms of myocardial ischemia New ischemic ECG changes or new LBBB Angiographic loss of patency of a major coronary artery or a side branch or persistent slow- or no-flow or embolization Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 29 Provisional October 17, 2014

30 Type 4b: stent thrombosis: Myocardial infarction associated with stent thrombosis as detected by coronary angiography or at autopsy, where symptoms suggestive of myocardial ischemia are present, and with a rise and/or fall of cardiac biomarkers values, with at least one value >99th percentile of the upper reference limit. Type 4c: stent restenosis: Myocardial infarction associated with stent restenosis as detected by coronary angiography or at autopsy, occurring more than 48h after percutaneous coronary intervention, without evidence of stent thrombosis but with symptoms suggestive of myocardial ischemia, and with elevation of cardiac biomarker values to >99th percentile of the URL. This classification also requires the following: Does not meet criteria for any other classification of myocardial infarction Presence of a >=50% stenosis at the site of previous successful stent PCI. Type 5: CABG related: Myocardial infarction associated with and occurring within 48h of coronary artery bypass graft surgery (CABG), with elevation of cardiac biomarker values to >10x 99th percentile of the URL in patients with normal baseline cardiac biomarker values (<=99th percentile URL). This classification also requires at least one of the following: New pathologic Q waves or new LBBB on ECG Angiographic new graft or new native coronary artery occlusion Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. Myocardial ischemia CDEs (See Section ) are indicated by a value of MI in the ENDPOINT column of the spreadsheet. The concept map below shows the myocardial infarction CDEs. For example, a myocardial infarction cardiovascular endpoint includes the specific clinical events. The symptoms for acute myocardial ischemia and the history of myocardial infarction are reviewed by the investigator. Specific ECG tests and cardiovascular biomarker lab tests are performed to further evaluate the clinical events. All of this information is reviewed by the investigator in making various clinical judgments determining the MI type. Based on the clinical judgments, it may be determined that a cardiovascular procedure is needed. These procedures produce additional observations that are documented in Sections and Page 30 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

31 Concept Map 6: Myocardial Infarction See Section for details on the PCI procedure Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 31 Provisional October 17, 2014

32 Examples for Myocardial Infarction Example 1 This is an example of a Type 1 myocardial infarction. Subject arrived at the emergency room on June 6, 2010 at 5:00 AM with chest pain that began 4 hours earlier. The subject had had a prior myocardial infarction in September Initial labs were obtained in the emergency room. Initial ECG showed ST segment elevation in the anterior leads. He was taken immediately to the catheterization laboratory for emergency cardiac catheterization and angioplasty (these procedures are not shown in this example, but would be represented in the PR domain See Examples 1 and 2 in Section 3.1.1). The coronary artery thrombus was identified via an angiogram. Subsequent biomarkers were elevated (positive) for myocardial infarction. Rows 1-2: Row 3: Row 4: Show chest pain and acute myocardial ischemia that began four hours prior to the subject coming to the emergency room Shows coronary artery thrombus that was identified in the catheterization lab Shows an acute myocardial infarction that was confirmed by the elevated biomarkers. ce.xpt Row STUDYID DOMAIN USUBJID CESEQ CELNKID CETERM CEDTC CESTDTC CEENDTC 1 STUDY01 CE CHEST PAIN T01: T06:45 2 STUDY01 CE AMI-1 ACUTE MYOCARDIAL ISCHEMIA T01: T06:45 3 STUDY01 CE AMI-2 CORONARY ARTERY THROMBUS T05: T06:45 4 STUDY01 CE MI-1 ACUTE MYOCARDIAL INFARCTION T08: Show the method of event identification for the coronary artery thrombus. suppce.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY02 CE CESEQ 3 MTHDEVID Method of Event Identification ANGIOGRAM CRF INVESTIGATOR Shows the clinical judgment finding of the myocardial infarction type as a Type 1 myocardial infarction. face.xpt Row STUDYID DOMAIN USUBJID FASEQ FALNKID FATESTCD FATEST FAOBJ FAORRES 1 STUDY01 FA MI-1 ACMITYPE Acute Myocardial Infarction ACUTE MYOCARDIAL TYPE 1 MYOCARDIAL Type INFARCTION INFARCTION Row FASTRESC FAMETHOD VISITNUM VISIT FADTC FADUR 1 (cont) TYPE 1 MYOCARDIAL INFARCTION CORONARY ANGIOGRAPHY 1.1 UNSCHEDULED Row 2: Row 3: The subject arrived at the emergency room on June 6, 2010 at 5:00 AM due to the chest pain. The subject was taken to the catheterization laboratory at 5:45 AM and the thrombus was identified and the angioplasty was performed. The subject was admitted to the hospital at 7:00 AM after the angioplasty. Page 32 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

33 ho.xpt Row STUDYID DOMAIN USUBJID HOSEQ HOLNKID HOTERM HOSTDTC HOENDTC 1 STUDY01 HO AMI-1 EMERGENCY ROOM T05: T05:30 2 STUDY01 HO AMI-1 CATHETERIZATION LABORATORY T05: T06:45 3 STUDY01 HO MI-1 HOSPITAL T07: The CV Endpoint CDEs include reason for the healthcare encounter, which is represented as a supplemental qualifier for the healthcare encounter. Row 2: Row 3: The subject came to the ER because of chest pain. The subject was taken to the catheterization laboratory due to the acute myocardial ischemia. In the catheterization lab a coronary artery thrombus was identified and treated The subject was admitted to the hospital for follow-up post-angioplasty. suppho.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY01 HO HOSEQ 1 HOINDC Indication CHEST PAIN CRF INVESTIGATOR 2 STUDY01 HO HOSEQ 2 HOINDC Indication MYOCARDIAL ISCHEMIA CRF INVESTIGATOR 3 STUDY01 HO HOSEQ 3 HOINDC Indication POST-OPERATIVE FOLLOW-UP CRF INVESTIGATOR Shows a prior myocardial infarction in September mh.xpt Row STUDYID DOMAIN USUBJID MHSEQ MHTERM MHDTC MHSTDTC 1 STUDY01 MH MYOCARDIAL INFARCTION Rows 1-2: Show ischemia-related changes in the ECG waveform and elevation of the ST segment. eg.xpt Row STUDYID DOMAIN USUBJID EGSEQ EGLNKID EGTESTCD EGTEST EGORRES EGORRESU EGSTRESC 1 STUDY01 EG AMI-1 AMIEGCHG Acute Ischemia ECG Change Type ISCHEMIC ECG CHANGES ISCHEMIC ECG CHANGES 2 STUDY01 EG AMI-1 STELMAX Summary (Max) ST Elevation 4 mm 4 Row EGSTRESN EGSTRESU EGMETHOD VISITNUM VISIT EGDTC 1 (cont) 12 LEAD STANDARD 1.1 UNSCHEDULED T05:20 2 (cont) 4 mm 12 LEAD STANDARD 1.1 UNSCHEDULED T05:20 Rows 1-4: Show laboratory test results that indicate a myocardial infarction. The labs were initially obtained when the subject arrived in the emergency room. A second set of labs were obtained (nearly seven hours later) following admission to the hospital which showed a rise from previous levels. The results of these cardiac biomarkers when compared to the 99% upper reference limit (represented as a supplemental qualifier in the next table) showed that the subject met the cardiac criterion Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 33 Provisional October 17, 2014

34 lb.xpt Row STUDYID DOMAIN USUBJID LBSEQ LBLNKID LBTESTCD LBTEST LBCAT LBSCAT LBORRES LBORRESU LBORNRLO LBORNRHI 1 STUDY01 LB AMI-1 TROPONI Troponin I CHEMISTRY CARDIAC BIOMARKER 1.1 ng/ml STUDY01 LB AMI-1 CK Creatine Kinase CHEMISTRY CARDIAC BIOMARKER 250 IU/L STUDY01 LB AMI-1 TROPONI Troponin I CHEMISTRY CARDIAC BIOMARKER 2.4 ng/ml STUDY01 LB AMI-1 CK Creatine Kinase CHEMISTRY CARDIAC BIOMARKER 350 IU/L Row LBSTRESC LBSTRESN LBSTRESU LBSTNRLO LBSTNRHI LBNRIND LBNAM LBLOINC VISITNUM VISIT LBDTC 1 (cont) ng/ml HIGH MEMORIAL HOSPITAL UNSCHEDULED T05:10 2 (cont) IU/L HIGH MEMORIAL HOSPITAL UNSCHEDULED T05:10 3 (cont) ng/ml HIGH MEMORIAL HOSPITAL UNSCHEDULED T12:00 4 (cont) IU/L HIGH MEMORIAL HOSPITAL UNSCHEDULED T12:00 Rows 1-4: Show the Upper Reference Limit 99% of the high reference range records. QEVAL is not populated, since this is an objective result from the laboratory. See Section 1.7 and examples in Section for further explanation of the Upper Reference Limit 99%. supplb.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY01 LB LBSEQ 1 URLC_99 Upper Reference Limit 99% 0.45 ng/ml edt 2 STUDY01 LB LBSEQ 2 URLC_99 Upper Reference Limit 99% 200 IU/L edt 3 STUDY01 LB LBSEQ 3 URLC_99 Upper Reference Limit 99% 0.45 ng/ml edt 4 STUDY01 LB LBSEQ 4 URLC_99 Upper Reference Limit 99% 200 IU/L edt Rows 1-8: Show the dataset relationship between the Clinical Events, Healthcare Encounters, Findings About, Laboratory Test Results and ECG Test Results domains via the CELNKID, HOLNKID, FALNKID, LBLNKID and EGLNKID variables. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 1 STUDY01 CE CELNKID ONE CEHO 2 STUDY01 HO HOLNKID ONE CEHO 3 STUDY01 CE CELNKID ONE CEFA 4 STUDY01 FACE FALNKID MANY CEFA 5 STUDY01 CE CELNKID ONE CELB 6 STUDY01 LB LBLNKID MANY CELB 7 STUDY01 CE CELNKID ONE CEEG 8 STUDY01 EG EGLNKID MANY CEEG Example 2 This is an example of both Type 2 and Type 3 myocardial infarctions. Subject had an MI event on June 6, Cardiac biomarkers were elevated (high). The investigator made the following clinical observation: evidence of thrombus on angiogram and new loss of viable myocardium per a non-invasive imaging study. On the basis of this information, the MI type was identified as 'Type 2 - Ischemic Imbalance '. The investigator reported a second MI event on June 29, The subject died; no biomarker tests were performed, but there Page 34 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

35 was an autopsy in which a thrombus was identified. This led the investigator to classify this as a Type 3 MI. All clinical decisions were adjudicated and confirmed by a CEC adjudicator. The subject had a coronary artery thrombus on June 6, 2010 which was identified by angiogram. The thrombus caused the first MI. Row 2: Shows the first acute myocardial infarction, occurring on June 6, 2010 as confirmed by the elevated cardiac biomarkers in the LB domain below. Row 3: Shows the second acute myocardial infarction, occurring on June 29, ce.xpt Row STUDYID DOMAIN USUBJID CESEQ CELNKID CETERM CEEVAL CEDTC CESTDTC CEENDTC 1 STUDY01 CE CORONARY ARTERY THROMBUS INVESTIGATOR T10: T10:45 2 STUDY01 CE AMI-2 ACUTE MYOCARDIAL INFARCTION INVESTIGATOR T10: T10:45 3 STUDY01 CE AMI-3 ACUTE MYOCARDIAL INFARCTION INVESTIGATOR T05: T01:30 Shows the method of event identification for the coronary artery thrombus. suppce.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY02 CE CESEQ 1 MTHDEVID Method of Event Identification ANGIOGRAM edt INVESTIGATOR Row 2: Rows 3-4: Shows the investigator s judgment in typing the first myocardial infarction as a Type 2 myocardial infarction based on the finding of new loss of viable myocardium found in the MO domain below. The elevated cardiac biomarkers in the LB domain below also contribute to this decision. Shows the investigator s judgment in typing the second myocardial infarction. The investigator judged this to be a Type 3 myocardial infarction. This is a separate event, so it has a different value in FAGRPID. Show the same clinical judgments made by the CEC adjudicator. face.xpt Row STUDYID DOMAIN USUBJID FASEQ FAGRPID FALNKID FATESTCD FATEST FAOBJ FAORRES 1 STUDY01 FA AMI-2 ACUTE MYOCARDIAL TYPE 2 MYOCARDIAL ACMITYPE Acute Myocardial Infarction Type INFARCTION INFARCTION 2 STUDY01 FA AMI-3 ACUTE MYOCARDIAL TYPE 3 MYOCARDIAL ACMITYPE Acute Myocardial Infarction Type INFARCTION INFARCTION 3 STUDY01 FA AMI-2 ACUTE MYOCARDIAL TYPE 2 MYOCARDIAL ACMITYPE Acute Myocardial Infarction Type INFARCTION INFARCTION 4 STUDY01 FA AMI-3 ACUTE MYOCARDIAL TYPE 3 MYOCARDIAL ACMITYPE Acute Myocardial Infarction Type INFARCTION INFARCTION Row FASTRESC FAMETHOD FAEVAL FAACPTFL VISITNUM VISIT FADTC 1 (cont) TYPE 2 MYOCARDIAL INFARCTION CORONARY ANGIOGRAPHY INVESTIGATOR 1 BASELINE (cont) TYPE 3 MYOCARDIAL INFARCTION AUTOPSY INVESTIGATOR 1.1 UNSCHEDULED (cont) TYPE 2 MYOCARDIAL INFARCTION CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) TYPE 3 MYOCARDIAL INFARCTION AUTOPSY CEC ADJUDICATOR Y 1.1 UNSCHEDULED Rows 1-2: Show there was new loss of viable myocardium as identified by coronary angiography as reported by the investigator. The CEC adjudicator agreed with this finding Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 35 Provisional October 17, 2014

36 mo.xpt Row STUDYID DOMAIN USUBJID MOSEQ MOLNKID MOTESTCD MOTEST MOORRES MOSTRESC 1 STUDY02 MO AMI-2 NINVIMGC Change in Non-Invasive Imaging Type NEW LOSS OF VIABLE NEW LOSS OF VIABLE MYOCARDIUM MYOCARDIUM 2 STUDY02 MO AMI-2 NINVIMGC Change in Non-Invasive Imaging Type NEW LOSS OF VIABLE NEW LOSS OF VIABLE MYOCARDIUM MYOCARDIUM Row MOLOC MOMETHOD MOEVAL MOAACPTFL VISITNUM VISIT MODTC 1 (cont) RIGHT CORONARY ARTERY CORONARY ANGIOGRAPHY INVESTIGATOR 1 BASELINE (cont) RIGHT CORONARY ARTERY CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE Rows 1-4: Show laboratory test result records obtained after the subject s first myocardial infarction which indicated elevated cardiac biomarkers lb.xpt Row STUDYID DOMAIN USUBJID LBSEQ LBLNKID LBTESTCD LBTEST LBCAT LBSCAT LBORRES LBORRESU LBORNRLO LBORNRHI 1 STUDY01 LB AMI-2 TROPONI Troponin I CHEMISTRY CARDIAC BIOMARKER 1.1 ug/l STUDY01 LB AMI-2 TROPONT Troponin T CHEMISTRY CARDIAC BIOMARKER 0.7 ug/l STUDY01 LB AMI-2 CK Creatine Kinase CHEMISTRY CARDIAC BIOMARKER 250 IU/L STUDY01 LB AMI-2 CKMB Creatine Kinase CHEMISTRY CARDIAC BIOMARKER MB 15 ug/l 0 7 Row LBSTRESC LBSTRESN LBSTRESU LBSTNRLO LBSTNRHI LBNRIND LBNAM LBLOINC LBBLFL VISITNUM VISIT LBDTC 1 (cont) ug/l HIGH MEMORIAL HOSPITAL Y 1 BASELINE T10:10 2 (cont) ug/l HIGH MEMORIAL HOSPITAL Y 1 BASELINE T10:10 3 (cont) IU/L HIGH MEMORIAL HOSPITAL Y 1 BASELINE T10:10 4 (cont) ug/l 0 7 HIGH MEMORIAL HOSPITAL Y 1 BASELINE T10:10 Rows 1-4: Show the Upper Reference Limit 99% of the high reference range records. QEVAL is not populated, since this is an objective result from the laboratory. See Section 1.7 and examples in Section for further explanation of the Upper Reference Limit 99%. supplb.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY01 LB LBSEQ 1 URLC_99 Upper Reference Limit 99% 0.45 ug/l edt 2 STUDY01 LB LBSEQ 2 URLC_99 Upper Reference Limit 99% 0.08 ug/l edt 3 STUDY01 LB LBSEQ 3 URLC_99 Upper Reference Limit 99% 200 IU/L edt 4 STUDY01 LB LBSEQ 4 URLC_99 Upper Reference Limit 99% 6 ug/l edt Rows 1-4: Show the dataset relationship between the CE, MO, FA, and LB domains via the --LNKID variable. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 1 STUDY01 CE CELNKID ONE CEFA 2 STUDY01 FACE FALNKID MANY CEFA 3 STUDY01 CE CELNKID ONE CELB Page 36 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

37 Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 4 STUDY01 LB LBLNKID MANY CELB 5 STUDY01 CE CELNKID ONE CEMO 6 STUDY01 MO MOLNKID MANY CEMO Example 3 This is an example of a Type 5 myocardial infarction. Subject had a CABG procedure on January 16, 2010 at 6:00 AM. The patient was unstable after the procedure. Biomarkers assessed immediately postprocedure were markedly elevated. On January 17, 2010, the day after the CABG, an ECG showed new Q waves in the inferior leads. Based on the ECG results, the investigator judged that the MI (Type 5) was related to the CABG. Shows the CABG procedure record. pr.xpt Row STUDYID DOMAIN USUBJID PRSEQ PRLNKID PRTRT PRCLAS VISITNUM VISIT PRSTDTC PRENDTC 1 STUDY01 PR CABG-1 ARTERIAL GRAFT, CORONARY ARTERY BYPASS UNSCHEDULED FREE GRAFT 16T06:00 16T08:00 Shows the acute myocardial infarction clinical event record with a start date of January 16, 2010 at 10:25 AM following the CABG procedure. ce.xpt Row STUDYID DOMAIN USUBJID CESEQ CELNKID CETERM CEDTC CESTDTC CEENDTC 1 STUDY01 CE CABG-1 ACUTE MYOCARDIAL INFARCTION T10: T12:15 Rows 1-2: Show laboratory test results that are elevated, thus indicating a possible Type 5 myocardial infarction. lb.xpt Row STUDYID DOMAIN USUBJID LBSEQ LBLNKID LBTESTCD LBTEST LBCAT LBSCAT LBORRES LBORRESU LBORNRLO 1 STUDY01 LB CABG-1 TROPONI Troponin I CHEMISTRY CARDIAC BIOMARKER 40 ug/l 0 2 STUDY01 LB CABG-1 CKMB Creatine Kinase MB CHEMISTRY CARDIAC BIOMARKER 95 IU/L 0 Row LBORNRHI LBSTRESC LBSTRESN LBSTRESU LBSTNRLO LBSTNRHI LBNRIND LBNAM LBLOINC VISITNUM VISIT LBDTC 1 (cont) ug/l 0 10 HIGH MEMORIAL HOSPITAL UNSCHEDULED T10:35 2 (cont) IU/L 0 5 HIGH MEMORIAL HOSPITAL UNSCHEDULED T10:35 Rows 1-2: Show the Upper Reference Limit 99% of the high reference range records. QEVAL is not populated, since this is an objective result from the laboratory. See Section 1.7 and examples in Section for further explanation of the Upper Reference Limit 99%. supplb.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY01 LB LBSEQ 1 URLC_99 Upper Reference Limit 99% 0.45 ug/l edt 2 STUDY01 LB LBSEQ 2 URLC_99 Upper Reference Limit 99% 6 IU/L edt 2014 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 37 Provisional October 17, 2014

38 Shows a new pathologic Q wave consistent with myocardial infarction. eg.xpt Row STUDYID DOMAIN USUBJID EGSEQ EGLNKID EGTESTCD EGTEST EGORRES EGSTRESC EGMETHOD VISITNUM VISIT EGDTC 1 STUDY01 EG CABG-1 NEWQWAVE New Q 12 LEAD Y Y 1.1 UNSCHEDULED Wave STANDARD 16T10:45:00 On the next day, the myocardial infarction was judged to be a Type 5 myocardial infarction (See CE record above). face.xpt Row STUDYID DOMAIN USUBJID FASEQ FALNKID FATESTCD FATEST FAOBJ 1 STUDY01 FA CABG-1 ACMITYPE Acute Myocardial Infarction Type ACUTE MYOCARDIAL INFARCTION Row FAORRES FASTRESC VISITNUM VISIT FADTC 1 (cont) TYPE 5 MYOCARDIAL INFARCTION TYPE 5 MYOCARDIAL INFARCTION 1.1 UNSCHEDULED Rows 1-8: Show the dataset relationships between the Procedures and Clinical Events domains via the PRLNKID and CELNKID variables and the Findings About, ECG Test Results and Laboratory Test Results domains via the FALNKID, LBLNKID, and EGLNKID variables. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 1 STUDY01 PR PRLNKID ONE PRCE 2 STUDY01 CE CELNKID ONE PRCE 3 STUDY01 CE CELNKID ONE CEFA 4 STUDY01 FACE FALNKID MANY CEFA 5 STUDY01 CE CELNKID ONE CELB 6 STUDY01 LB LBLNKID MANY CELB 7 STUDY01 CE CELNKID ONE CEEG 8 STUDY01 EG EGLNKID MANY CEEG Percutaneous Coronary Intervention A percutaneous coronary intervention (PCI) * is defined as placement of an angioplasty guide wire, balloon, or other device (e.g., stent, atherectomy catheter, brachytherapy delivery device, or thrombectomy catheter) into a native coronary artery or coronary artery bypass graft for the purpose of mechanical coronary revascularization. 6 The assessment of coronary lesion severity via intravascular ultrasound, coronary flow reserve, or fractional flow reserve are not considered to be a PCI procedure. PCI CDEs (See Section ) are indicated by a value of PCI in the ENDPOINT column of the spreadsheet. * See the NCDR CathPCI Registry v4.4 Coder's Data Dictionary 6, seq. #7020 Page 38 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

39 The concept map below shows the percutaneous coronary intervention CDEs. For example, a PCI procedure may be necessary to correct a variety of cardiovascular events. There are multiple types of PCI procedures, such as angioplasty and stent implantation. A cardiovascular event may be addressed by a PCI or a PCI may precipitate a cardiovascular event. See Section for an example of how a clinical event is diagnosed and what clinical judgment may be made regarding it. A PCI procedure produces additional observations that may involve generating lesion identification, lesion results, and vessel morphology results. Additionally, supplemental procedures, including angiograms, may assist in producing various cardiovascular physiology findings. This information is then evaluated in making clinical judgments of the results of the PCI Examples for Percutaneous Coronary Intervention Concept Map 7: Percutaneous Coronary Intervention See Section for details on myocardial infarction. Example 1 Subject had a PCI with stent implantation in the proximal right coronary artery on March 17, The investigator determined that the procedure status was urgent and that the PCI was successful. Shows the PCI procedure record Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 39 Provisional October 17, 2014

40 pr.xpt Row STUDYID DOMAIN USUBJID PRSEQ PRLNKID PRTRT PRCLAS PRLOC VISITNUM VISIT PRSTDTC PRENDTC 1 STUDY01 PR PCI-1 PERCUTANEOUS STENT PROXIMAL RIGHT WEEK CORONARY 1 IMPLANTATION CORONARY ARTERY 1 T08:10 T09:10 INTERVENTION Row 2: Shows that the investigator considered the procedure to be a success per the SCTI CDE definition of procedure success. The investigator deemed the need for the PCI to be great, hence an urgency status of URGENT. fapr.xpt Row STUDYID DOMAIN USUBJID FASEQ FALNKID FATESTCD FATEST FAOBJ FAORRES FASTRESC FAMETHOD VISITNUM VISIT FADTC 1 STUDY01 FA PCI-1 PRUSTAT Procedure STENT CORONARY WEEK Urgency Urgent URGENT 1 IMPLANTATION ANGIOGRAPHY Status Type 2 STUDY01 FA PCI-1 PRSUCIND Procedure Success Indicator STENT IMPLANTATION Y Y CORONARY ANGIOGRAPHY 1 WEEK Rows 1-2: Show the dataset relationships between the Procedures and Findings About domains via the PRLNKID and FALNKID variables. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 1 STUDY01 PR PRLNKID ONE PRFA 2 STUDY01 FAPR FALNKID MANY PRFA Example 2 This is an example of stent thrombosis. Subject had two stents implanted via PCI (performed within the study) on August 22, 2008; one in the right proximal coronary artery and one in the right posterior descending artery. The subject experienced a thrombosis of the latter stent, and on August 30, 2008, underwent balloon angioplasty to correct the stent thrombosis. Stent thrombosis timing was reported as 'SUBACUTE' on August 30, 2008 by the investigator, and this was confirmed by the CEC adjudicator. The stent thrombosis coronary ARC Grade was reported as 'PROBABLE' on August 30, 2008 by the investigator. The CEC adjudicator disagreed with this finding and thought the ARC Grade should be 'DEFINITE'. This ARC Grade of DEFINITE was accepted and the adjudicator's records were accepted. Rows 1-2: Row 3: Show the original PCI procedure in which two stents were implanted, one in the proximal right coronary artery and the other in the right posterior descending artery with start dates for each stent implantation. Shows the balloon angioplasty procedure to correct the stent thrombosis. pr.xpt Row STUDYID DOMAIN USUBJID PRSEQ PRLNKID PRTRT PRCLAS PRLOC VISITNUM VISIT PRSTDTC PRENDTC 1 STUDY01 PR STC-1 PERCUTANEOUS STENT RIGHT PROXIMAL VISIT CORONARY 1 IMPLANTATION CORONARY ARTERY 1 T08:00 T08:30 INTERVENTION Page 40 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

41 Row STUDYID DOMAIN USUBJID PRSEQ PRLNKID PRTRT PRCLAS PRLOC VISITNUM VISIT PRSTDTC PRENDTC PERCUTANEOUS RIGHT POSTERIOR STENT VISIT STUDY01 PR STC-2 CORONARY DESCENDING 1 IMPLANTATION 1 T08:45 T09:45 INTERVENTION ARTERY 3 STUDY01 PR STC-3 BALLOON ANGIOPLASTY PERCUTANEOUS CORONARY INTERVENTION RIGHT POSTERIOR DESCENDING ARTERY 1 VISIT T08: T09:45 Shows the PCI-related (second stent implant) coronary stent thrombosis. ce.xpt Row STUDYID DOMAIN USUBJID CESEQ CELNKID CETERM CELOC CEEVAL CEDTC CESTDTC CEENDTC 1 STUDY01 CE STC-2 STENT THROMBOSIS, RIGHT POSTERIOR INVESTIGATOR CORONARY DESCENDING ARTERY 30 30T05:00 30T09:45 Rows 1-2: Rows 3-4: Show the investigator s and the CEC adjudicator s judgment for the ARC timing of the stent thrombosis. The adjudication took place roughly two months after the procedure. FAGRPID is used to group records for each evaluator. Show the investigator s and the CEC adjudicator s judgment for the ARC grade of the stent thrombosis. The investigator and the adjudicator disagreed; the CEC adjudicator s record is the accepted record. fapr.xpt Row STUDYID DOMAIN USUBJID FASEQ FAGRPID FALNKID FATESTCD FATEST FAOBJ FAORRES FASTRESC 1 STUDY01 FA STC-2 STCTIMNG Stent Thrombosis, Coronary, ARC Timing STENT IMPLANTATION SUBACUTE SUBACUTE 2 STUDY01 FA STC-2 STCTIMNG Stent Thrombosis, Coronary, ARC Timing STENT IMPLANTATION SUBACUTE SUBACUTE 3 STUDY01 FA STC-2 STCARCGD Stent Thrombosis, Coronary, ARC Grade STENT IMPLANTATION PROBABLE PROBABLE 4 STUDY01 FA STC-2 STCARCGD Stent Thrombosis, Coronary, ARC Grade STENT IMPLANTATION DEFINITE DEFINITE Row FAEVAL FAACPTFL VISITNUM VISIT FADTC 1 (cont) INVESTIGATOR 1 VISIT (cont) CEC ADJUDICATOR Y 1 VISIT (cont) INVESTIGATOR 1 VISIT (cont) CEC ADJUDICATOR Y 1 VISIT Rows 1-4: Show the dataset relationships between the PR, CE, and FA domains via the --LNKID variable. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 1 STUDY01 PR PRLNKID ONE PRCE 2 STUDY01 CE CELNKID ONE PRCE 3 STUDY01 CE CELNKID ONE CEFA 4 STUDY01 FACE FALNKID MANY CEFA Example 3 This is an example of a coronary artery thrombus Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 41 Provisional October 17, 2014

42 Subject had a PCI with angioplasty on January 16, A coronary artery thrombus occurred during the PCI. Thrombolysis in Myocardial Infarction (TIMI) Flow Grade (grading scale to describe coronary epicardial blood flow visualized during angiography) and Coronary Thrombus, TIMI Grade (grading scale to describe coronary thrombus visualized during angiography) were assessed. The angiographic core lab technician agreed with investigator's judgment regarding the thrombus event, TIMI Coronary Thrombus Grade and TIMI Flow Grade, and the adjudicator's records were accepted. Shows the balloon angioplasty PCI procedure on January 16, pr.xpt Row STUDYID DOMAIN USUBJID PRSEQ PRLNKID PRTRT PRCLAS VISITNUM VISIT PRSTDTC PRENDTC 1 STUDY01 PR TM-1 BALLOON PERCUTANEOUS CORONARY UNSCHEDULED ANGIOPLASTY INTERVENTION 16T09:25 16T09:58 Rows 1-2: Show the coronary artery thrombus clinical event record. The event occurred during the PCI procedure. It was adjudicated by the angiographic core lab technician two months later, and agreed with the investigator s initial report. CEGRPID groups the coronary artery thrombus records for the evaluators. ce.xpt Row STUDYID DOMAIN USUBJID CESEQ CEGRPID CELNKID CETERM CEEVAL CEACPTFL CEDTC CESTDTC CEENDTC 1 STUDY01 CE TM-1 CORONARY ARTERY INVESTIGATOR THROMBUS 16 16T09:25 16T09:35 2 STUDY01 CE TM-1 CORONARY ARTERY ANGIOGRAPHIC CORE LAB Y THROMBUS TECHNICIAN 16 16T09:25 16T09:55 Rows 1-4: Show the TIMI flow grade; coronary thrombus, TIMI grade; and coronary artery dominance according to the investigator and the angiographic core lab technician. MOGRPID groups these evaluator records together for the clinical judgment being made. mo.xpt Row STUDYID DOMAIN USUBJID MOSEQ MOGRPID MOLNKID MOTESTCD MOTEST MOORRES MOSTRESC 1 STUDY02 MO TM-1 TIMIFLOW TIMI Flow TIMI GRADE 1 TIMI GRADE 1 2 STUDY02 MO TM-1 CTTIMIGD Coronary Thrombus, TIMI Grade CORONARY THROMBUS CORONARY THROMBUS TIMI GRADE 3 TIMI GRADE 3 3 STUDY02 MO TM-1 CARTDOM Coronary Artery Dominance LEFT DOMINANT LEFT DOMINANT 4 STUDY02 MO TM-1 TIMIFLOW TIMI Flow TIMI GRADE 1 TIMI GRADE 1 5 STUDY02 MO TM-1 CTTIMIGD Coronary Thrombus, TIMI Grade CORONARY THROMBUS CORONARY THROMBUS TIMI GRADE 3 TIMI GRADE 3 6 STUDY02 MO TM-1 CARTDOM Coronary Artery Dominance LEFT DOMINANT LEFT DOMINANT Row MOMETHOD MOEVAL MOACPTFL VISITNUM VISIT MODTC 1 (cont) CORONARY ANGIOGRAPHY INVESTIGATOR 1.1 UNSCHEDULED (cont) CORONARY ANGIOGRAPHY INVESTIGATOR 1.1 UNSCHEDULED (cont) CORONARY ANGIOGRAPHY INVESTIGATOR 1.1 UNSCHEDULED (cont) CORONARY ANGIOGRAPHY ANGIOGRAPHIC CORE LAB TECHNICIAN Y 1.1 UNSCHEDULED (cont) CORONARY ANGIOGRAPHY ANGIOGRAPHIC CORE LAB TECHNICIAN Y 1.1 UNSCHEDULED (cont) CORONARY ANGIOGRAPHY ANGIOGRAPHIC CORE LAB TECHNICIAN Y 1.1 UNSCHEDULED Page 42 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

43 Rows 1-4: Show the dataset relationships between the Procedures and Clinical Events domains via the PRLNKID and CELNKID variables and the clinical events and morphology domains via the CELNKID and MOLNKID variables. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 1 STUDY01 PR PRLNKID ONE PRCE 2 STUDY01 CE CELNKID ONE PRCE 3 STUDY01 CE CELNKID ONE CEMO 4 STUDY01 MO MOLNKID MANY CEMO Example 4 Subject had a previous coronary artery bypass graft surgery. On January 1, 2007, the subject had a PCI with the target lesion (L01) identified in the right coronary artery ostium (within the right coronary artery (L01-1)). The CEC adjudicator agreed with the vessel and lesion identification. Lesion results indicated that the investigator thought there had been a successful index PCI, but the patient returned 24 hours later with ischemic symptoms and underwent a repeat PCI target lesion revascularization (TLR), therefore, target vessel revascularization (TVR), which was defined as target vessel failure. The CEC adjudicator agreed with the investigator s findings. The subject had another diagnostic catheterization on May 1, 2007, that indicated the original index lesion was occluded and the investigator performed a PCI of a non-target lesion in in the graft to the right posterior descending artery (L01-G, within the right coronary artery (L01-G1)), located in the body of the graft, 5 mm from the origin of the graft. The CEC adjudicator disagreed: he thought that the lesion was located 2 mm from the origin of the graft. The PCI procedure data is not presented in this example. (See other examples in this section and in Section for PCI procedure examples). The lesion/vessel pairs below indicate the location of the lesion and the main vessel in which it is related. The location (TULOC) of the lesion within the vessel is the coronary artery segment. Sponsors may choose to use a naming strategy for values in TULNKID in order to imply or preserve associations between lesions, graft lesions, and blood vessels. Rows 1-4: Rows 5-8: Rows 9-12: Show the index target lesion (L01) and target vessel identification (L01-1) according to the investigator and CEC adjudicator. Show the January 2, 2007 target lesion (L01) and target vessel identification (L01-1) according to the investigator and CEC adjudicator that required revascularization. Show the May 7, 2007 non-target graft lesion (NL01-G) and target vessel identification (L01-1) according to the investigator and CEC adjudicator. tu.xpt Row STUDYID DOMAIN USUBJID TUSEQ TULNKID TUTESTCD TUTEST TUORRES TUSTRESC TUNAM 1 STUDY01 TU L01 LESIDENT Lesion Identification TARGET TARGET 2 STUDY01 TU L01 LESIDENT Lesion Identification TARGET TARGET ACME VENDOR 3 STUDY01 TU L01-1 VESIDENT Vessel Identification TARGET TARGET 4 STUDY01 TU L01-1 VESIDENT Vessel Identification TARGET TARGET ACME VENDOR 5 STUDY01 TU L01 LESIDENT Lesion Identification TARGET TARGET 6 STUDY01 TU L01 LESIDENT Lesion Identification TARGET TARGET ACME VENDOR 2014 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 43 Provisional October 17, 2014

44 Row STUDYID DOMAIN USUBJID TUSEQ TULNKID TUTESTCD TUTEST TUORRES TUSTRESC TUNAM 7 STUDY01 TU L01-1 VESIDENT Vessel Identification TARGET TARGET 8 STUDY01 TU L01-1 VESIDENT Vessel Identification TARGET TARGET ACME VENDOR 9 STUDY01 TU NL01-G GRLIDENT Graft Lesion Identification NON-TARGET NON-TARGET 10 STUDY01 TU NL01-G GRLIDENT Graft Lesion Identification NON-TARGET NON-TARGET ACME VENDOR 11 STUDY01 TU L01-1 VESIDENT Vessel Identification TARGET TARGET 12 STUDY01 TU L01-1 VESIDENT Vessel Identification TARGET TARGET ACME VENDOR Row TULOC TUMETHOD TUEVAL TUACPTFL VISITNUM VISIT TUDTC 1 (cont) RIGHT CORONARY ARTERY OSTIUM CORONARY ANGIOGRAPHY INVESTIGATOR 1 BASELINE (cont) RIGHT CORONARY ARTERY OSTIUM CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) RIGHT CORONARY ARTERY CORONARY ANGIOGRAPHY INVESTIGATOR 1 BASELINE (cont) RIGHT CORONARY ARTERY CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) RIGHT CORONARY ARTERY OSTIUM CORONARY ANGIOGRAPHY INVESTIGATOR 1.1 BASELINE UNSCHEDULED (cont) RIGHT CORONARY ARTERY OSTIUM CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 1.1 BASELINE UNSCHEDULED (cont) RIGHT CORONARY ARTERY CORONARY ANGIOGRAPHY INVESTIGATOR 1.1 BASELINE UNSCHEDULED (cont) RIGHT CORONARY ARTERY CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 1.1 BASELINE UNSCHEDULED (cont) RIGHT POSTERIOR DESCENDING ARTERY CORONARY ANGIOGRAPHY INVESTIGATOR 2 VISIT (cont) RIGHT POSTERIOR DESCENDING ARTERY CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 2 VISIT (cont) RIGHT CORONARY ARTERY CORONARY ANGIOGRAPHY INVESTIGATOR 2 VISIT (cont) RIGHT CORONARY ARTERY CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 2 VISIT The CV Endpoint CDEs include additional data collected for coronary graft lesions identified in the TU domain and are populated in SUPPTU as indicated below. These data are listed below with their related standard values. QNAM QLABEL QVAL(s) CAGLL Coronary Artery Graft Lesion Location GRAFT ORIGIN, GRAFT BODY, GRAFT ANASTOMOSIS CAGT Coronary Artery Graft Type from Coronary Artery Graft Type Codelist CAGANAST Coronary Artery Graft Anastomosis from Anatomical Location Codelist OTHLDSC Other Lesion Description <text> Row 2: Row 3: Row 4: Rows 5-8: Shows the target graft lesion s location in the graft body according to the investigator. Shows the target graft lesion s coronary artery graft type according to the investigator. Shows the target graft lesion s coronary artery graft anastomosis according to the investigator. Shows further description of the location of the lesion according to the investigator. Show the adjudication performed by the CEC adjudicator. Note that the CEC adjudicator disagreed with the investigator as to the location and other description of the lesion. supptu.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY01 TU TUSEQ 9 CAGLL Coronary Artery Graft Lesion Location GRAFT BODY CRF INVESTIGATOR 2 STUDY01 TU TUSEQ 9 CAGT Coronary Artery Graft Type SAPHENOUS VEIN GRAFT CRF INVESTIGATOR 3 STUDY01 TU TUSEQ 9 CAGAMAST Coronary Artery Graft PROXIMAL LEFT ANTERIOR Anastomosis DESCENDING ARTERY CRF INVESTIGATOR Page 44 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

45 Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL LESION IS 5MM FROM THE ORIGIN OF 4 STUDY01 TU TUSEQ 9 OTHLDSC Other Lesion Description CRF INVESTIGATOR THE GRAFT Coronary Artery Graft Lesion CEC 5 STUDY01 TU TUSEQ 10 CAGLL GRAFT ORIGIN CRF Location ADJUDICATOR CEC 6 STUDY01 TU TUSEQ 10 CAGT Coronary Artery Graft Type SAPHENOUS VEIN GRAFT CRF 7 STUDY01 TU TUSEQ 10 CAGAMAST Coronary Artery Graft Anastomosis 8 STUDY01 TU TUSEQ 10 OTHLDSC Other Lesion Description PROXIMAL LEFT ANTERIOR DESCENDING ARTERY LESION IS 2MM FROM THE ORIGIN OF THE GRAFT CRF CRF ADJUDICATOR CEC ADJUDICATOR CEC ADJUDICATOR The following results were recorded in the Tumor/Lesion Results (TR) domain: lesion success, lesion revascularization, PCI lesion ischemia, PCI lesion clinical revascularization, PCI lesion failure, and lesion restenosis; along with the corresponding CEC adjudicator s records. The SCTI CDEs provide detailed definitions and criteria for each of the target and non-target lesion result indicators. TRLNKID relates the record back to the lesion and vessel identification value in the TU domain. Rows 1-6: Show the investigator s and CEC adjudicator s index target lesion (L01) and vessel (L01-1) results as a result of the first PCI on January 1, Rows 7-20: Show the investigator s and CEC adjudicator s target lesion (L01) and vessel (L01-1) results from the second PCI revascularization procedure on January 2, Rows 21-26: Show the investigator s and CEC adjudicator s non-target graft lesion (NL01-G) and target vessel (L01-1) results from the May 1, 2007 PCI procedure. tr.xpt Row STUDYID DOMAIN USUBJID TRSEQ TRGRPID TRLNKID TRTESTCD TRTEST TRORRES TRSTRESC 1 STUDY01 TR TARGET L01 LESSCIND Lesion Success Indicator Y Y 2 STUDY01 TR TARGET L01 LESSCIND Lesion Success Indicator Y Y 3 STUDY01 TR TARGET L01 LESFLIND Lesion Failure Indicator N N 4 STUDY01 TR TARGET L01 LESFLIND Lesion Failure Indicator N N 5 STUDY01 TR TARGET L01-1 VSLFLIND Vessel Failure Indicator N N 6 STUDY01 TR TARGET L01-1 VSLFLIND Vessel Failure Indicator N N 7 STUDY01 TR TARGET L01 LESFLIND Lesion Restenosis Indicator Y Y 8 STUDY01 TR TARGET L01 LESFLIND Lesion Restenosis Indicator Y Y 9 STUDY01 TR TARGET L01 LESFLIND Lesion Failure Indicator Y Y 10 STUDY01 TR TARGET L01 LESFLIND Lesion Failure Indicator Y Y 11 STUDY01 TR TARGET L01 LESRVIND Lesion Revascularization Indicator Y Y 12 STUDY01 TR TARGET L01 LESRVIND Lesion Revascularization Indicator Y Y 13 STUDY01 TR TARGET L01 LRISCIND Lesion Revas. Ischemia Indicator Y Y 14 STUDY01 TR TARGET L01 LRISCIND Lesion Revas. Ischemia Indicator Y Y 15 STUDY01 TR TARGET L01 LRVCLIND Lesion Revas. Clinical Indicator Y Y 16 STUDY01 TR TARGET L01 LRVCLIND Lesion Revas. Clinical Indicator Y Y 17 STUDY01 TR TARGET L01-1 VSLRVIND Vessel Revascularization Indicator Y Y 18 STUDY01 TR TARGET L01-1 VSLRVIND Vessel Revascularization Indicator Y Y 19 STUDY01 TR TARGET L01-1 VSLFLIND Vessel Failure Indicator Y Y 20 STUDY01 TR TARGET L01-1 VSLFLIND Vessel Failure Indicator Y Y 21 STUDY01 TR NON-TARGET NL01-G LESSCIND Lesion Success Indicator Y Y 2014 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 45 Provisional October 17, 2014

46 Row STUDYID DOMAIN USUBJID TRSEQ TRGRPID TRLNKID TRTESTCD TRTEST TRORRES TRSTRESC 22 STUDY01 TR NON-TARGET NL01-G LESSCIND Lesion Success Indicator Y Y 23 STUDY01 TR NON-TARGET NL01-G LESFLIND Lesion Failure Indicator N N 24 STUDY01 TR NON-TARGET NL01-G LESFLIND Lesion Failure Indicator N N 25 STUDY01 TR TARGET L01-1 VSLFLIND Vessel Failure Indicator N N 26 STUDY01 TR TARGET L01-1 VSLFLIND Vessel Failure Indicator N N Row TRNAM TRMETHOD TREVAL TRACPTFL VISITNUM VISIT TRDTC 1 (cont) CORONARY ANGIOGRAPHY INVESTIGATOR 1 BASELINE (cont) ACME VENDOR CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) CORONARY ANGIOGRAPHY INVESTIGATOR 1 BASELINE (cont) ACME VENDOR CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) CORONARY ANGIOGRAPHY INVESTIGATOR 1 BASELINE (cont) ACME VENDOR CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) CORONARY ANGIOGRAPHY INVESTIGATOR 1.1 BASELINE UNSCHEDULED (cont) ACME VENDOR CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 1.1 BASELINE UNSCHEDULED (cont) CORONARY ANGIOGRAPHY INVESTIGATOR 1.1 BASELINE UNSCHEDULED (cont) ACME VENDOR CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 1.1 BASELINE UNSCHEDULED (cont) CORONARY ANGIOGRAPHY INVESTIGATOR 1.1 BASELINE UNSCHEDULED (cont) ACME VENDOR CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 1.1 BASELINE UNSCHEDULED (cont) CORONARY ANGIOGRAPHY INVESTIGATOR 1.1 BASELINE UNSCHEDULED (cont) ACME VENDOR CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 1.1 BASELINE UNSCHEDULED (cont) CORONARY ANGIOGRAPHY INVESTIGATOR 1.1 BASELINE UNSCHEDULED (cont) ACME VENDOR CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 1.1 BASELINE UNSCHEDULED (cont) CORONARY ANGIOGRAPHY INVESTIGATOR 1.1 BASELINE UNSCHEDULED (cont) ACME VENDOR CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 1.1 BASELINE UNSCHEDULED (cont) CORONARY ANGIOGRAPHY INVESTIGATOR 1.1 BASELINE UNSCHEDULED (cont) ACME VENDOR CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 1.1 BASELINE UNSCHEDULED (cont) CORONARY ANGIOGRAPHY INVESTIGATOR 2 VISIT (cont) ACME VENDOR CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 2 VISIT (cont) CORONARY ANGIOGRAPHY INVESTIGATOR 2 VISIT (cont) ACME VENDOR CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 2 VISIT (cont) CORONARY ANGIOGRAPHY INVESTIGATOR 2 VISIT (cont) ACME VENDOR CORONARY ANGIOGRAPHY CEC ADJUDICATOR Y 2 VISIT The Morphology (MO) domain includes results for the following measurements of the vessel containing the lesion: mean vessel diameter, two orthogonal views; minimum lumen diameter, two orthogonal views; percent diameter stenosis. These results were reported along with the CEC adjudicator s. The SCTI CDEs provide detailed definitions for the morphology findings. Rows 1-3: Show the investigator s target lesion (L01) vessel segment measurements obtained during the PCI procedure on January 1, The MOLNKID links these vessel segment measurements to the lesion identified in the TU domain. Rows 4-6: Show the investigator s target lesion (L01) vessel segment measurements obtained during the PCI revascularization procedure on January 2, Rows 7-9: Show the investigator s non-target graft lesion (NL01-G) vessel segment measurements obtained during the PCI procedure on May 1, Rows 10-18: Show the vessel segment measurements that were adjudicated by a CEC adjudicator for the results from the Baseline Visit, Unscheduled Baseline Visit and Visit 1. Page 46 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

47 mo.xpt Row STUDYID DOMAIN USUBJID MOSEQ MOGRPID MOLNKID MOTESTCD MOTEST MOORRES MOORRESU MOSTRESC MOSTRESN 1 STUDY01 MO TARGET L01 MEANVDIA Mean Vessel Diameter 3.0 mm STUDY01 MO TARGET L01 MINLDIAM Minimum Lumen Diameter 0.6 mm STUDY01 MO TARGET L01 PCTDIAST Percent Diameter Stenosis 80 % STUDY01 MO TARGET L01 MEANVDIA Mean Vessel Diameter 3.0 mm STUDY01 MO TARGET L01 MINLDIAM Minimum Lumen Diameter 0.3 mm STUDY01 MO TARGET L01 PCTDIAST Percent Diameter Stenosis 90 % STUDY01 MO NON-TARGET NL01-G MEANVDIA Mean Vessel Diameter 5.0 mm STUDY01 MO NON-TARGET NL01-G MINLDIAM Minimum Lumen Diameter 0.5 mm STUDY01 MO NON-TARGET NL01-G PCTDIAST Percent Diameter Stenosis 90 % STUDY01 MO TARGET L01-1 MEANVDIA Mean Vessel Diameter 3.0 mm STUDY01 MO TARGET L01-1 MINLDIAM Minimum Lumen Diameter 0.6 mm STUDY01 MO TARGET L01-1 PCTDIAST Percent Diameter Stenosis 80 % STUDY01 MO TARGET L01-1 MEANVDIA Mean Vessel Diameter 3.0 mm STUDY01 MO TARGET L01-1 MINLDIAM Minimum Lumen Diameter 0.3 mm STUDY01 MO TARGET L01-1 PCTDIAST Percent Diameter Stenosis 90 % STUDY01 MO NON-TARGET NL01-G MEANVDIA Mean Vessel Diameter 5.0 mm STUDY01 MO NON-TARGET NL01-G MINLDIAM Minimum Lumen Diameter 0.5 mm STUDY01 MO NON-TARGET NL01-G PCTDIAST Percent Diameter Stenosis 90 % Row MOSTRESU MONAM MOLOC MOMETHOD MOEVAL MOACPTFL VISITNUM VISIT MODTC 1 (cont) mm RIGHT CORONARY QUANTITATIVE INVESTIGATOR ARTERY OSTIUM CORONARY ANGIOGRAPHY 1 BASELINE (cont) mm RIGHT CORONARY QUANTITATIVE INVESTIGATOR ARTERY OSTIUM CORONARY ANGIOGRAPHY 1 BASELINE (cont) % RIGHT CORONARY QUANTITATIVE INVESTIGATOR ARTERY OSTIUM CORONARY ANGIOGRAPHY 1 BASELINE (cont) mm RIGHT CORONARY QUANTITATIVE ARTERY OSTIUM CORONARY ANGIOGRAPHY INVESTIGATOR 1.1 BASELINE UNSCHEDULED (cont) mm RIGHT CORONARY QUANTITATIVE ARTERY OSTIUM CORONARY ANGIOGRAPHY INVESTIGATOR 1.1 BASELINE UNSCHEDULED (cont) % RIGHT CORONARY QUANTITATIVE ARTERY OSTIUM CORONARY ANGIOGRAPHY INVESTIGATOR 1.1 BASELINE UNSCHEDULED (cont) mm RIGHT POSTERIOR QUANTITATIVE INVESTIGATOR DESCENDING ARTERY CORONARY ANGIOGRAPHY 2 VISIT (cont) mm RIGHT POSTERIOR QUANTITATIVE INVESTIGATOR DESCENDING ARTERY CORONARY ANGIOGRAPHY 2 VISIT (cont) % RIGHT POSTERIOR QUANTITATIVE INVESTIGATOR DESCENDING ARTERY CORONARY ANGIOGRAPHY 2 VISIT (cont) mm ACME VENDOR RIGHT CORONARY QUANTITATIVE CEC BASELINE Y 1 ARTERY OSTIUM CORONARY ANGIOGRAPHY ADJUDICATOR (cont) mm ACME VENDOR RIGHT CORONARY QUANTITATIVE CEC BASELINE Y 1 ARTERY OSTIUM CORONARY ANGIOGRAPHY ADJUDICATOR 12 (cont) % ACME VENDOR RIGHT CORONARY QUANTITATIVE CEC BASELINE Y 1 ARTERY OSTIUM CORONARY ANGIOGRAPHY ADJUDICATOR 2014 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 47 Provisional October 17, 2014

48 Row MOSTRESU MONAM MOLOC MOMETHOD MOEVAL MOACPTFL VISITNUM VISIT MODTC 13 (cont) mm ACME VENDOR RIGHT CORONARY QUANTITATIVE CEC BASELINE Y 1.1 ARTERY OSTIUM CORONARY ANGIOGRAPHY ADJUDICATOR UNSCHEDULED (cont) mm ACME VENDOR RIGHT CORONARY QUANTITATIVE CEC BASELINE Y 1.1 ARTERY OSTIUM CORONARY ANGIOGRAPHY ADJUDICATOR UNSCHEDULED (cont) % ACME VENDOR RIGHT CORONARY QUANTITATIVE CEC BASELINE Y 1.1 ARTERY OSTIUM CORONARY ANGIOGRAPHY ADJUDICATOR UNSCHEDULED (cont) mm RIGHT POSTERIOR QUANTITATIVE CEC ACME VENDOR DESCENDING ARTERY CORONARY ANGIOGRAPHY ADJUDICATOR Y 2 VISIT (cont) mm RIGHT POSTERIOR QUANTITATIVE CEC ACME VENDOR DESCENDING ARTERY CORONARY ANGIOGRAPHY ADJUDICATOR Y 2 VISIT (cont) % RIGHT POSTERIOR QUANTITATIVE CEC ACME VENDOR DESCENDING ARTERY CORONARY ANGIOGRAPHY ADJUDICATOR Y 2 VISIT The CV Endpoint CDEs include additional data collected for CV that are not contained in the MO domain and are populated in the SUPPMO domain as indicated below. The additional data is the angiogram view, which can either be a single view or two views. Rows 1-2: Show the angiogram view records related to all of the measurements for mean vessel diameter and minimum lumen diameter, thus the IDVARVAL is the relevant MOTESTCD. QEVAL is not populated, since this is an objective result. suppmo.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY01 MO MOTESTCD MEANVDIA AGIO_VW Angiogram View TWO VIEWS edt 2 STUDY01 MO MOTESTCD MINLDIAM AGIO_VW Angiogram View TWO VIEWS edt Rows 1-4: Show the relationship between the Tumor Identification, Tumor Results and the Morphology domains via the TULNKID, TRLNKID and MOLNKID variables. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 1 STUDY01 TU TULNKID ONE TUTR 2 STUDY01 TR TRLNKID MANY TUTR 3 STUDY01 TU TULNKID ONE TUMO 4 STUDY01 MO MOLNKID MANY TUMO Example 5 In this example, there are two subjects. Subject had a post-procedure access site hematoma in the left leg as a result of a PCI performed on January 17, Subject had a mid-procedure arteriovenous fistula as a result of a PCI performed on May 23, Rows 1-2: Show the PCI procedures for Subject on January 17, 2010 and Subject on May 23, Page 48 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

49 Shows vascular complication clinical event records. pr.xpt Row STUDYID DOMAIN USUBJID PRSEQ PRLNKID PRTRT PRCLAS VISITNUM VISIT PRSTDTC PRENDTC 1 STUDY01 PR PCI-1 CORONARY PERCUTANEOUS CORONARY UNSCHEDULED ANGIOGRAPHY INTERVENTION 17T11:45 17T12:55 2 STUDY01 PR PCI-1 CORONARY PERCUTANEOUS CORONARY UNSCHEDULED ANGIOGRAPHY INTERVENTION T:08:33 T:09:15 ce.xpt Row STUDYID DOMAIN USUBJID CESEQ CELNKID CETERM CECAT CELOC CELAT CEDTC CESTDTC CEENDTC 1 STUDY01 CE PCI-1 ACCESS SITE VASCULAR LEG LEFT HEMATOMA COMPLICATION 17 17T:12:03 17T12:05 2 STUDY01 CE PCI-1 ARTERIOVENOUS VASCULAR FISTULA COMPLICATION 23 T:08:42 T:08:45 Rows 1-2: Show the vascular complication event timing in relation to the procedures. suppce.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY01 CE CESEQ 1 EVNTTMNG Event Timing POST PROCEDURAL CRF INVESTIGATOR 2 STUDY01 CE CESEQ 1 EVNTTMNG Event Timing INTRA PROCEDURAL CRF INVESTIGATOR Rows 1-2: Show the dataset relationship between the Procedures and the Clinical Events domains via the PRLNKID and CELNKID variables. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 1 STUDY01 PR PRLNKID ONE PRCE 2 STUDY01 CE CELNKID ONE PRCE Example 6 This is an example of a coronary artery abrupt closure. Subject underwent a PCI of the mid right coronary artery beginning at 8:00 AM. During the procedure, at 8:30 AM, an abrupt closure of the coronary artery occurred. A coronary artery dissection Grade E was observed with a reduction in blood flow. As the lesion was treated, no reflow was observed. Shows the PCI procedure on May 15, 2010 from 8:00 AM to 9:00 AM. pr.xpt Row STUDYID DOMAIN USUBJID PRSEQ PRLNKID PRTRT PRCLAS PRLOC VISITNUM VISIT PRSTDTC PRENDTC 1 STUDY01 PR CAAC-1 PERCUTANEOUS MID RIGHT STENT CORONARY CORONARY 1.1 UNSCHEDULED IMPLANTATION 15T08:00 15T09:00 INTERVENTION ARTERY 2014 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 49 Provisional October 17, 2014

50 Shows the coronary artery abrupt closure in the mid right coronary artery, during the procedure at 8:30 AM. ce.xpt Row STUDYID DOMAIN USUBJID CESEQ CELNKID CETERM CELOC CEDTC CESTDTC CEENDTC 1 STUDY01 CE CAAC-1 CORONARY ARTERY ABRUPT MID RIGHT CORONARY CLOSURE ARTERY 15 15T08:30 15T08:30 Shows the event timing in relation to the procedure. The coronary artery abrupt closure occurred during the procedure. suppce.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY01 CE CESEQ 1 EVNTTMNG Event Timing INTRA PROCEDURAL CRF INVESTIGATOR Rows 1-2: Show the lesion and vessel location identification records during the PCI procedure on May 15, tu.xpt Row STUDYID DOMAIN USUBJID TUSEQ TULNKID TUTESTCD TUTEST TUORRES TUSTRESC TULOC 1 STUDY01 TU L01 LESIDENT Lesion Identification TARGET TARGET MID RIGHT CORONARY ARTERY 2 STUDY01 TU L01-1 VESIDENT Vessel Identification TARGET TARGET RIGHT CORONARY ARTERY Row TUMETHOD VISITNUM VISIT TUDTC 1 (cont) CORONARY ANGIOGRAPHY 1.1 UNSCHEDULED (cont) CORONARY ANGIOGRAPHY 1.1 UNSCHEDULED The following lesion evaluation results were recorded in the Tumor/Lesion Results domain: lesion success, lesion failure, and vessel failure. The SCTI CDEs provide detailed definitions and criteria for each of the target lesion result indicators. Rows 1-3: Show the investigator s lesion and related vessel results recorded during the PCI procedure on May 15, tr.xpt Row STUDYID DOMAIN USUBJID TRSEQ TRGRPID TRLNKID TRTESTCD TRTEST TRORRES TRSTRESC 1 STUDY01 TR TARGET L01 LESSCIND Lesion Success Indicator N N 2 STUDY01 TR TARGET L01 LESFLIND Lesion Failure Indicator Y Y 3 STUDY01 TR TARGET L01-1 VSLFLIND Vessel Failure Indicator Y Y Row TRMETHOD VISITNUM VISIT TRDTC 1 (cont) CORONARY ANGIOGRAPHY 1.1 UNSCHEDULED (cont) CORONARY ANGIOGRAPHY 1.1 UNSCHEDULED (cont) CORONARY ANGIOGRAPHY 1.1 UNSCHEDULED Page 50 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

51 The Morphology domain reflects results for the following vessel measurements: mean vessel diameter, two orthogonal views; minimum lumen diameter, two orthogonal views; and percent diameter stenosis. The SCTI CDEs provide detailed definitions for these morphology findings. Rows 1-2: Show the coronary artery dissection grade and coronary artery no reflow on May 15, Rows 3-5: Show the investigator s vessel morphology results during the PCI procedure on May 15, mo.xpt Row STUDYID DOMAIN USUBJID MOSEQ MOGRPID MOLNKID MOTESTCD MOTEST MOORRES MOORRESU 1 STUDY01 MO CAAC-1 CADACCGD Coronary Artery Dissection, CORONARY DISSECTION NHLBI Grade NHBLI GRADE E 2 STUDY01 MO CAAC-1 CANRFIND Coronary Artery No Reflow Indicator Y 3 STUDY01 MO TARGET L01-1 MEANVDIA Mean Vessel Diameter 2.0 mm 4 STUDY01 MO TARGET L01-1 MINLDIAM Minimum Lumen Diameter 0.8 mm 5 STUDY01 MO TARGET L01-1 PCTDIAST Percent Diameter Stenosis 60 % Row MOSTRESC MOSTRESN MOSTRESU MOLOC MOMETHOD VISITNUM VISIT MODTC CORONARY DISSECTION 1 (cont) NHBLI GRADE E MID RIGHT CORONARY ARTERY CORONARY ANGIOGRAPHY 1.1 UNSCHEDULED (cont) Y MID RIGHT CORONARY ARTERY CORONARY ANGIOGRAPHY 1.1 UNSCHEDULED (cont) mm QUANTITATIVE MID RIGHT CORONARY ARTERY CORONARY ANGIOGRAPHY 1.1 UNSCHEDULED (cont) mm QUANTITATIVE MID RIGHT CORONARY ARTERY CORONARY ANGIOGRAPHY 1.1 UNSCHEDULED (cont) % QUANTITATIVE MID RIGHT CORONARY ARTERY CORONARY ANGIOGRAPHY 1.1 UNSCHEDULED The CV Endpoint CDEs include additional data collected for CV that are not contained in the MO domain and are populated in the SUPPMO domain as indicated below. The additional data is the angiogram view, which can either be a single view or two views. Rows 1-2: Show the angiogram view records related to all of the measurements for mean vessel diameter and minimum lumen diameter, thus the IDVARVAL is the relevant MOTESTCD. QEVAL is not populated, since this is an objective result. suppmo.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY01 MO MOTESTCD MEANVDIA AGIO_VW Angiogram View TWO VIEWS edt 2 STUDY01 MO MOTESTCD MINLDIAM AGIO_VW Angiogram View TWO VIEWS edt Rows 1-4: Rows 4-8: Show the dataset relationships between the Procedures and the Clinical Events domains and between Clinical Events and Morphology domains. Show the dataset relationships between the Tumor Identification, Tumor Results and the Morphology domains via the TULNKID, TRLNKID and MOLNKID variables. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 1 STUDY01 PR PRLNKID ONE PRCE 2014 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 51 Provisional October 17, 2014

52 Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 2 STUDY01 CE CELNKID ONE PRCE 3 STUDY01 CE CELNKID ONE CEMO 4 STUDY01 MO MOLNKID MANY CEMO 5 STUDY01 TU TULNKID ONE TUTR 6 STUDY01 TR TRLNKID MANY TUTR 7 STUDY01 TU TULNKID ONE TUMO 8 STUDY01 MO MOLNKID MANY TUMO Example 7 This is an example of a stent thrombosis that occurred during a PCI procedure. Subject developed a stent thrombosis during a PCI with stent implantation. The stent thrombosis occurred at 8:50 AM on February 28, The PCI with stent implantation in the left main coronary artery ostium started at 8:20 AM and ended at 9:10 AM. Shows the PCI procedure on February 28, 2010 beginning at 8:20 AM and ending at 9:10 AM. pr.xpt Row STUDYID DOMAIN USUBJID PRSEQ PRLNKID PRTRT PRCLAS PRLOC VISITNUM VISIT PRSTDTC PRENDTC 1 STUDY01 PR CAT-1 PERCUTANEOUS LEFT MAIN STENT CORONARY CORONARY 6.2 UNSCHEDULED IMPLANTATION 28T08:20 28T09:10 INTERVENTION ARTERY OSTIUM Shows the stent thrombosis that occurred during the procedure on 8:50 AM. ce.xpt Row STUDYID DOMAIN USUBJID CESEQ CELNKID CETERM CECAT CELOC CEDTC CESTDTC CEENDTC 1 STUDY01 CE CAT-1 STENT VASCULAR LEFT MAIN CORONARY THROMBOSIS COMPLICATION ARTERY OSTIUM 28 28T08:50 28T09:00 Shows the event timing in relation to the procedure. The stent thrombosis occurred during the procedure. suppce.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY01 CE CESEQ 1 EVNTTMNG Event Timing INTRA PROCEDURAL CRF INVESTIGATOR Rows 1-2: Show the relationship between the Procedures and the Clinical Events domains via the PRLNKID and CELNKID variables. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 1 STUDY01 PR PRLNKID ONE PRCE 2 STUDY01 CE CELNKID ONE PRCE Page 52 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

53 3.2.6 Peripheral Vascular Intervention Peripheral vascular intervention (PVI) is a catheter-based or open surgical procedure designed to improve arterial or venous blood flow or otherwise modify or revise vascular conduits. 2 Procedures may include, but are not limited to: Percutaneous transluminal balloon angioplasty Aneurysm exclusion Stent placement Treatment of dialysis conduits Thrombectomy Placement of various devices Embolectomy Intravascular thrombolysis or other pharmacotherapies Atherectomy Open surgical bypass or revision Dissection repair In general, the intention to perform PVI is denoted by the insertion of a guide wire into an artery or vein. For the sake of simplicity, this definition applies to the extracranial carotid artery and other non-cardiac arteries and excludes the intracranial vessels, veins, and lymphatics. PVI CDEs (See Section ) are indicated by a value of PVI in the ENDPOINT column of the spreadsheet. The concept map below shows the Peripheral Vascular Intervention CDEs. For example, a PVI procedure may be necessary to correct peripheral vascular related clinical events. Various PVI types, such as a diagnostic procedure, balloon angioplasty, stent implantation, graft, etc. may be performed. Similar observations, findings, and clinical judgments are made based on the clinical event that has occurred. A PVI procedure produces additional observations that may involve generating lesion identification, lesion results and vessel morphology results. This information is then evaluated in making clinical judgments on the PVI status and the PVI success. Concept Map 8: Peripheral Vascular Intervention See Section for clinical event details on myocardial infarction Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 53 Provisional October 17, 2014

54 Examples for Peripheral Vascular Intervention Example 1 Subject had an initial PVI with balloon angioplasty in the left superficial femoral artery on April 12, 2009 and a PVI with stent implantation on April 20, The investigator reported that both procedures were elective, and that the balloon angioplasty failed, but the stent implantation was a success. The CEC adjudicator agreed with the investigator s evaluation on three of the four points, but felt that the stent implantation was urgent. Rows 1-2: Show the initial PVI on April 12, 2009 and second PVI on April 20, pr.xpt Row STUDYID DOMAIN USUBJID PRSEQ PRGRPID PRLNKID PRTRT PRCLAS 1 STUDY01 PR A1 PVI-1 BALLOON ANGIOPLASTY PERIPHERAL VASCULAR INTERVENTION 2 STUDY01 PR A2 PVI-2 STENT IMPLANTATION PERIPHERAL VASCULAR INTERVENTION Row PRLOC VISITNUM VISIT PRSTDTC PRENDTC 1 (cont) LEFT SUPERFICIAL FEMORAL ARTERY 1 BASELINE T07: T08:45 2 (cont) LEFT SUPERFICIAL FEMORAL ARTERY 1 BASELINE T08: T09:30 Procedure urgency and success are recorded as findings about the procedure. The SCTI CDEs provide detailed definitions for these evaluations. FAGRPID groups the FA records according to the related procedure. Rows 1-2: Rows 3-4: Rows 5-6: Rows 7-8: Show the clinical judgment records for the first procedure, the investigator judged the PVI as elective, but not successful. Show the clinical judgment records for the first procedure adjudicated by a CEC adjudicator. The CEC adjudicator agreed with the investigator s judgment. Show the clinical judgment records for the second procedure, the investigator judged the PVI as elective and successful. Show the clinical judgment records for the second procedure adjudicated by a CEC adjudicator. The CEC adjudicator agreed that the PVI was successful, but judged it to be urgent rather than elective. fapr.xpt Row STUDYID DOMAIN USUBJID FASEQ FAGRPID FALNKID FATESTCD FATEST FAOBJ 1 STUDY01 FA PVI-1 PRSUCIND Procedure Success Indicator PERIPHERAL VASCULAR INTERVENTION 2 STUDY01 FA PVI-1 PRUSTAT Procedure Urgency Status Type PERIPHERAL VASCULAR INTERVENTION 3 STUDY01 FA PVI-1 PRSUCIND Procedure Success Indicator PERIPHERAL VASCULAR INTERVENTION 4 STUDY01 FA PVI-1 PRUSTAT Procedure Urgency Status Type PERIPHERAL VASCULAR INTERVENTION 5 STUDY01 FA PVI-2 PRSUCIND Procedure Success Indicator PERIPHERAL VASCULAR INTERVENTION 6 STUDY01 FA PVI-2 PRUSTAT Procedure Urgency Status Type PERIPHERAL VASCULAR INTERVENTION 7 STUDY01 FA PVI-2 PRSUCIND Procedure Success Indicator PERIPHERAL VASCULAR INTERVENTION 8 STUDY01 FA PVI-2 PRUSTAT Procedure Urgency Status Type PERIPHERAL VASCULAR INTERVENTION Row FAORRES FASTRESC FALOC FALAT FAEVAL FAACPTFL VISITNUM VISIT FADTC 1 (cont) NO N LEG LEFT INVESTIGATOR 1 BASELINE (cont) ELECTIVE ELECTIVE LEG LEFT INVESTIGATOR 1 BASELINE (cont) NO N LEG LEFT CEC ADJUDICATOR Y 1 BASELINE (cont) ELECTIVE ELECTIVE LEG LEFT CEC ADJUDICATOR Y 1 BASELINE Page 54 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

55 Row FAORRES FASTRESC FALOC FALAT FAEVAL FAACPTFL VISITNUM VISIT FADTC 5 (cont) Y Y LEG LEFT INVESTIGATOR 2 VISIT (cont) ELECTIVE ELECTIVE LEG LEFT INVESTIGATOR 2 VISIT (cont) Y Y LEG LEFT CEC ADJUDICATOR Y 2 VISIT (cont) URGENT URGENT LEG LEFT CEC ADJUDICATOR Y 2 VISIT Rows 1-2: Show the dataset relationships between the Procedures and Findings About domains via the PRLNKID and FALNKID variables. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 1 STUDY01 PR PRLNKID ONE PRFA 2 STUDY01 FAPR FALNKID MANY PRFA Example 2 Subject had a previous peripheral artery bypass surgery. On February 1, 2007 the subject had a PVI performed. A target lesion (L01) was identified in the infrarenal aorta (within the aorto-iliac vessel (TULNKID = L01-1)). During the same procedure, the subject also had a non-target graft lesion (TULNKID = NL01-G) identified in the left femoro-popliteal graft (L01-G1). The PVI procedure data is not part of this example. See the previous example for a PVI procedure. The graft was a synthetic graft composed of Gore-Tex. The graft lesion location was noted as proximal within the graft anastomosis, "5mm from the origin of the graft, and the anastomosis was in the left femoro-popliteal artery (L01-G1). The CEC adjudicator indicated the location was the 'graft body' but otherwise agreed. Rows 1-2: Show the target lesion located in the infrarenal aorta and within the target aorta-iliac vessel. Row 3: Shows the PVI target limb in which the lesion is located identified by the investigator. Rows 4-5: Show the non-target graft lesion located in the left femoro-popliteal graft and within the non-target femoro-popliteal vessel. Row 6: Shows the PVI target limb in which the graft lesion is located identified by the investigator. Rows 7-8: Show the target lesion and vessel identification records adjudicated by a CEC adjudicator, who agreed with the investigator. Row 9: Show the PVI target limb identified by the CEC adjudicator, who agreed with the investigator. Rows 10-11: Show the non-target graft lesion and non-target vessel identification records adjudicated by the CEC adjudicator, who agreed with the investigator. Row 12: Shows the PVI target limb in which the graft lesion is located identified by the CEC adjudicator. tu.xpt Row STUDYID DOMAIN USUBJID TUSEQ TULNKID TUTESTCD TUTEST TUORRES TUSTRESC TUNAM TULOC 1 STUDY01 TU L01 LESIDENT Lesion Identification TARGET TARGET INFRARENAL AORTA 2 STUDY01 TU L01-1 VESIDENT Vessel Identification TARGET TARGET AORTO-ILIAC 3 STUDY01 TU L01-2 LIMBID Limb Identification TARGET TARGET LEG 4 STUDY01 TU NL01-G GRLIDENT Graft Lesion Identification NON-TARGET NON-TARGET LEFT FEMORO-POPLITEAL GRAFT 5 STUDY01 TU NL01-G1 VESIDENT Vessel Identification NON-TARGET NON-TARGET FEMORO-POPLITEAL 6 STUDY01 TU L01-2 LIMBID Limb Identification TARGET TARGET LEG 7 STUDY01 TU L01 LESIDENT Lesion Identification TARGET TARGET ACME VENDOR INFRARENAL AORTA 2014 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 55 Provisional October 17, 2014

56 Row STUDYID DOMAIN USUBJID TUSEQ TULNKID TUTESTCD TUTEST TUORRES TUSTRESC TUNAM TULOC 8 STUDY01 TU L01-1 VESIDENT Vessel Identification TARGET TARGET ACME VENDOR AORTO-ILIAC 9 STUDY01 TU L01-2 LIMBID Limb Identification TARGET TARGET ACME VENDOR LEG 10 STUDY01 TU NL01-G GRLIDENT Graft Lesion Identification NON-TARGET NON-TARGET ACME VENDOR LEFT FEMORO-POPLITEAL GRAFT 11 STUDY01 TU NL01-G1 VESIDENT Vessel Identification NON-TARGET NON-TARGET ACME VENDOR FEMORO-POPLITEAL 12 STUDY01 TU L01-2 LIMBID Limb Identification TARGET TARGET ACME VENDOR LEG Row TULAT TUMETHOD TUEVAL TUACPTFL VISITNUM VISIT TUDTC 1 (cont) LEFT PERIPHERAL ANGIOGRAPHY INVESTIGATOR 1 BASELINE (cont) PERIPHERAL ANGIOGRAPHY INVESTIGATOR 1 BASELINE (cont) LEFT INVESTIGATOR 1 BASELINE (cont) PERIPHERAL ANGIOGRAPHY INVESTIGATOR 1 BASELINE (cont) PERIPHERAL ANGIOGRAPHY INVESTIGATOR 1 BASELINE (cont) LEFT INVESTIGATOR 1 BASELINE (cont) LEFT PERIPHERAL ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) PERIPHERAL ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) LEFT CEC ADJUDICATOR Y 1 BASELINE (cont) PERIPHERAL ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) PERIPHERAL ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) LEFT CEC ADJUDICATOR Y 1 BASELINE The CV Endpoint CDEs include additional data collected for the peripheral graft lesions identified in the TU domain, which are populated in SUPPTU as indicated below. These data are listed below with their related standard values. QNAM QLABEL QVALs PAGLL Peripheral Graft Lesion Location GRAFT ANASTOMOSIS PROXIMAL, GRAFT BODY, GRAFT ANASTOMOSIS DISTAL PAGT Peripheral Artery Graft Type from Peripheral Artery Graft Type Codelist PAGANAST Peripheral Artery Graft Anastomosis from Anatomical Location Codelist OTHLDSC Other Lesion Description text PAGSM Peripheral Artery Graft Synthetic Material Gore-Tex, POLYTETRAFLUOROETHYLENE (PTFE), POLYESTER, DACRON, POLYURETHANE Row 2: Row 3: Row 4: Row 5: Rows 6-10: Shows the target graft lesion s peripheral artery graft lesion location according to the investigator. Shows the target graft lesion s peripheral artery graft type. Shows the target graft lesion s peripheral artery graft anastomosis according to the investigator. Shows the target graft lesion s other lesion description according to the investigator. Shows the target graft lesion s peripheral artery graft synthetic material. Show the CEC ADJUDICATOR s adjudication results. Note that the CEC adjudicator disagreed with the investigator on the location of the lesion (Row 6). supptu.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY01 TU TUSEQ 4 PAGLL Peripheral Artery Graft Lesion Location GRAFT ANASTOMOSIS PROXIMAL CRF INVESTIGATOR 2 STUDY01 TU TUSEQ 4 PAGT Peripheral Artery Graft Type SYNTHETIC GRAFT CRF INVESTIGATOR Page 56 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

57 Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 3 STUDY01 TU TUSEQ 4 PAGAMAST Peripheral Artery Graft Anastomosis LEFT POPLITEAL ARTERY CRF INVESTIGATOR 4 STUDY01 TU TUSEQ 4 OTHLDSC Other Lesion Description LESION IS 5MM FROM THE ORIGIN OF THE GRAFT CRF INVESTIGATOR 5 STUDY01 TU TUSEQ 4 PAGSM Peripheral Artery Graft Synthetic Material Gore-Tex CRF INVESTIGATOR 6 STUDY01 TU TUSEQ 10 PAGLL Peripheral Artery Graft Lesion CEC GRAFT BODY CRF Location ADJUDICATOR 7 STUDY01 TU TUSEQ 10 PAGT Peripheral Artery Graft Type SYNTHETIC GRAFT CRF CEC 8 STUDY01 TU TUSEQ 10 PAGAMAST Peripheral Artery Graft Anastomosis 9 STUDY01 TU TUSEQ 10 OTHLDSC Other Lesion Description 10 STUDY01 TU TUSEQ 10 PAGSM Peripheral Artery Graft Synthetic Material LEFT POPLITEAL ARTERY LESION IS 5MM FROM THE ORIGIN OF THE GRAFT Gore-Tex CRF CRF CRF ADJUDICATOR CEC ADJUDICATOR CEC ADJUDICATOR CEC ADJUDICATOR The TR domain contains lesion results in which the investigator and adjudicator were in agreement. The SCTI CDEs provide detailed definitions and criteria for each of the target lesion result indicators. TRLNKID relates the record back to the lesion identification value in the TU domain. Rows 1-4: Show the target lesion and vessel result records determined by the investigator. Rows 5-8: Show the non-target graft lesion and non-target vessel result records determined by the investigator. Rows 9-12: Show the target lesion and vessel result records adjudicated by an independent CEC adjudicator. Rows 13-16: Show the non-target graft lesion and non-target vessel result records adjudicated by an independent CEC adjudicator. tr.xpt Row STUDYID DOMAIN USUBJID TRSEQ TRGRPID TRLNKID TRTESTCD TRTEST TRORRES TRSTRESC 1 STUDY01 TR TARGET L01 LESFLIND Lesion Failure Indicator N N 2 STUDY01 TR TARGET L01 LESSCIND Lesion Success Indicator Y Y 3 STUDY01 TR TARGET L01-1 VSLPTIND Vessel Patency Indicator Y Y 4 STUDY01 TR TARGET L01-1 LMBFLIND Limb Failure Indicator N N 5 STUDY01 TR NON-TARGET NL01-G LESFLIND Lesion Failure Indicator N N 6 STUDY01 TR NON-TARGET NL01-G1 VSLPTIND Vessel Patency Indicator Y Y 7 STUDY01 TR NON-TARGET NL01 LESFLIND Lesion Failure Indicator N N 8 STUDY01 TR NON-TARGET NL01 LESSCIND Lesion Success Indicator Y Y 9 STUDY01 TR TARGET L01-1 VSLPTIND Vessel Patency Indicator Y Y 10 STUDY01 TR TARGET L01-1 LMBFLIND Limb Failure Indicator N N 11 STUDY01 TR TARGET L01-G LESFLIND Lesion Failure Indicator N N 12 STUDY01 TR TARGET L01-G1 VSLPTIND Vessel Patency Indicator Y Y 13 STUDY01 TR NON-TARGET NL01-G LESFLIND Lesion Failure Indicator N N 14 STUDY01 TR NON-TARGET NL01-G1 VSLPTIND Vessel Patency Indicator Y Y 15 STUDY01 TR NON-TARGET NL01 LESFLIND Lesion Failure Indicator N N 16 STUDY01 TR NON-TARGET NL01 LESSCIND Lesion Success Indicator Y Y 2014 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 57 Provisional October 17, 2014

58 Row TRNAM TRMETHOD TREVAL TRACPTFL VISITNUM VISIT TRDTC 1 (cont) PERIPHERAL ANGIOGRAPHY INVESTIGATOR 1 BASELINE (cont) PERIPHERAL ANGIOGRAPHY INVESTIGATOR 1 BASELINE (cont) PERIPHERAL ANGIOGRAPHY INVESTIGATOR 1 BASELINE (cont) PERIPHERAL ANGIOGRAPHY INVESTIGATOR 1 BASELINE (cont) PERIPHERAL ANGIOGRAPHY INVESTIGATOR 1 BASELINE (cont) PERIPHERAL ANGIOGRAPHY INVESTIGATOR 1 BASELINE (cont) ACME VENDOR PERIPHERAL ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) ACME VENDOR PERIPHERAL ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) ACME VENDOR PERIPHERAL ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) ACME VENDOR PERIPHERAL ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) ACME VENDOR PERIPHERAL ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) ACME VENDOR PERIPHERAL ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) ACME VENDOR PERIPHERAL ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) ACME VENDOR PERIPHERAL ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) ACME VENDOR PERIPHERAL ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE (cont) ACME VENDOR PERIPHERAL ANGIOGRAPHY CEC ADJUDICATOR Y 1 BASELINE The MO domain reflects results for the following measurements obtained by angiogram: mean vessel diameter single view, minimum lumen diameter single view, and percent diameter stenosis; along with the adjudicator's agreement records. The SCTI CDEs provide detailed definitions for these morphology findings. Rows 1-3: Show the target lesion vessel morphology result records provided by the investigator. Rows 4-6: Show the non-target graft lesion non-target vessel morphology result records provided by the investigator. Rows 7-9: Show the target lesion vessel morphology result records adjudicated by a CEC adjudicator, who agreed with the investigator s findings. Rows 10-12: Show the non-target graft lesion no-target vessel morphology result records adjudicated by a CEC adjudicator, who agreed with the investigator s findings. mo.xpt Row STUDYID DOMAIN USUBJID MOSEQ MOGRPID MOLNKID MOTESTCD MOTEST MOORRES MOORRESU MOSTRESC 1 STUDY01 MO TARGET L01-1 MEANVDIA Mean Vessel Diameter 3.0 mm STUDY01 MO TARGET L01-1 MINLDIAM Minimum Lumen Diameter 0.9 mm STUDY01 MO TARGET L01-1 PCTDIAST Percent Diameter Stenosis 70 % 70 4 STUDY01 MO TARGET NL01-G1 MEANVDIA Mean Vessel Diameter 4.0 mm STUDY01 MO TARGET NL01-G1 MINLDIAM Minimum Lumen Diameter 1.0 mm STUDY01 MO TARGET NL01-G1 PCTDIAST Percent Diameter Stenosis 75 % 75 7 STUDY01 MO TARGET L01-1 MEANVDIA Mean Vessel Diameter 3.0 mm STUDY01 MO TARGET L01-1 MINLDIAM Minimum Lumen Diameter 0.9 mm STUDY01 MO TARGET L01-1 PCTDIAST Percent Diameter Stenosis 70 % STUDY01 MO TARGET NL01-G1 MEANVDIA Mean Vessel Diameter 4.0 mm STUDY01 MO TARGET NL01-G1 MINLDIAM Minimum Lumen Diameter 1.0 mm STUDY01 MO TARGET NL01-G1 PCTDIAST Percent Diameter Stenosis 75 % 75 Row MOSTRESN MOSTRESU MONAM MOLOC MOMETHOD MOEVAL MOACPTFL VISITNUM VISIT MODTC QUANTITATIVE 1 (cont) 3.0 mm INFRARENAL AORTA INVESTIGATOR 1 BASELINE PERIPHERAL ANGIOGRAPHY Page 58 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

59 Row MOSTRESN MOSTRESU MONAM MOLOC MOMETHOD MOEVAL MOACPTFL VISITNUM VISIT MODTC 2 (cont) 0.9 mm INFRARENAL AORTA QUANTITATIVE INVESTIGATOR PERIPHERAL ANGIOGRAPHY 1 BASELINE (cont) 70 % INFRARENAL AORTA QUANTITATIVE INVESTIGATOR PERIPHERAL ANGIOGRAPHY 1 BASELINE (cont) 4.0 mm LEFT FEMORO- QUANTITATIVE INVESTIGATOR POPLITEAL GRAFT PERIPHERAL ANGIOGRAPHY 1 BASELINE (cont) 1.0 mm LEFT FEMORO- QUANTITATIVE INVESTIGATOR POPLITEAL GRAFT PERIPHERAL ANGIOGRAPHY 1 BASELINE (cont) 75 % LEFT FEMORO- QUANTITATIVE INVESTIGATOR POPLITEAL GRAFT PERIPHERAL ANGIOGRAPHY 1 BASELINE (cont) 3.0 mm ACME VENDOR INFRARENAL AORTA QUANTITATIVE CEC PERIPHERAL ANGIOGRAPHY ADJUDICATOR Y 1 BASELINE (cont) 0.9 mm ACME VENDOR INFRARENAL AORTA QUANTITATIVE CEC PERIPHERAL ANGIOGRAPHY ADJUDICATOR Y 1 BASELINE (cont) 70 % ACME VENDOR INFRARENAL AORTA QUANTITATIVE CEC PERIPHERAL ANGIOGRAPHY ADJUDICATOR Y 1 BASELINE (cont) 4.0 mm ACME VENDOR LEFT FEMORO- QUANTITATIVE CEC POPLITEAL GRAFT PERIPHERAL ANGIOGRAPHY ADJUDICATOR Y 1 BASELINE (cont) 1.0 mm ACME VENDOR LEFT FEMORO- QUANTITATIVE CEC POPLITEAL GRAFT PERIPHERAL ANGIOGRAPHY ADJUDICATOR Y 1 BASELINE (cont) 75 % ACME VENDOR LEFT FEMORO- QUANTITATIVE CEC POPLITEAL GRAFT PERIPHERAL ANGIOGRAPHY ADJUDICATOR Y 1 BASELINE The CV Endpoint CDEs include additional data collected for CV that are not currently supported in the MO domain, so they are populated in SUPPMO as indicated below. The additional data is the angiogram view, which can either be a single view or two views; in this case the angiograms were both single view. Rows 1-2: Show angiogram view records. These records are related to all of the measurements for mean vessel diameter and minimum lumen diameter, thus IDVAR is MOTESTCD. QEVAL is not populated, since this is an objective result. suppmo.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY01 MO MOTESTCD MEANVDIA AGIO_VW Angiogram View SINGLE VIEW edt 2 STUDY01 MO MOTESTCD MINLDIAM AGIO_VW Angiogram View SINGLE VIEW edt Rows 1-4: Show the relationship between the Tumor Identification, Tumor Results and the Morphology domains via the TULNKID, TRLNKID and MOLNKID variables. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 1 STUDY01 TU TULNKID ONE TUTR 2 STUDY01 TR TRLNKID MANY TUTR 3 STUDY01 TU TULNKID ONE TUMO 4 STUDY01 MO MOLNKID MANY TUMO 2014 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 59 Provisional October 17, 2014

60 3.2.7 Heart Failure Event A heart failure (HF) event is defined as presentation of the patient for an urgent, unscheduled clinic/office/emergency department visit OR hospital admission, with a primary diagnosis of HF, where the patient exhibits new or worsening symptoms of HF on presentation, has objective evidence of new or worsening HF, and receives initiation or intensification of treatment specifically for HF. 2 Objective evidence consists of at least two (2) physical examination findings OR at least one (1) physical examination finding and at least one (1) laboratory criterion of new or worsening heart failure on presentation. HF CDEs (See Section ) are indicated by a value of HF in the ENDPOINT column of the spreadsheet. The concept map below shows heart failure event CDEs. In order to determine if the clinical event of heart failure meets the cardiovascular endpoint definition, the hospitalization information and symptoms for heart failure are reviewed. Specific cardiovascular biomarker lab tests are performed to determine new or worsening findings related to the heart failure. A physical exam is performed to determine new or worsening findings. Based on the clinical judgments made from this information, a final clinical judgment on classifying the heart failure as a cardiovascular endpoint event is made Examples for Heart Failure Event Concept Map 9: Heart Failure Event Example 1 Subject presented with worsening shortness of breath and edema with a known diagnosis of heart failure. On physical exam, he was found to have 2+ pitting edema with jugular venous distention; laboratory values included an elevated B-type natriuretic peptide (BNP). A decision was made to admit the patient for the management of worsening heart failure including additional diuretic therapy. The investigator reported this was a heart failure endpoint event. Note that the specific symptoms of heart failure and physical exam findings are not included in the data examples below. Shows the subject was hospitalized from February 16, 2011 to February 21, Page 60 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

61 ho.xpt Row STUDYID DOMAIN USUBJID HOSEQ HOLNKID HOTERM HOSTDTC HOENDTC 1 STUDY01 HO HF-1 HOSPITAL T07: T12:30 Shows the reason for the hospitalization was for heart failure. suppho.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY01 HO HOSEQ 1 HOINDC Indication HEART FAILURE CRF INVESTIGATOR Shows the subject had a history of prior heart failure in mh.xpt Row STUDYID DOMAIN USUBJID MHSEQ MHTERM MHDTC MHSTDTC 1 STUDY01 MH Heart Failure Shows the subject was determined to have had a heart failure clinical event on February 16, ce.xpt Row STUDYID DOMAIN USUBJID CESEQ CELNKID CETERM CEDTC CESTDTC CEENDTC 1 STUDY01 CE HF-1 HEART FAILURE The criteria for determining the event are recorded in Findings About. The SCTI CDEs provide detailed definitions for the clinical judgments used to classify heart failure as an endpoint event. Row 2-6: Row 7: Shows that the subject had symptoms of heart failure gives their date with an onset date of February at 11:00 AM. Show clinical judgments made to determine if the heart failure is an endpoint. The healthcare encounter type is important in determining if heart failure is an endpoint event. Shows that the heart failure is considered an endpoint. face.xpt Row STUDYID DOMAIN USUBJID FASEQ FALNKID FATESTCD FATEST FAOBJ 1 STUDY01 FA HF-1 SYMPINDC Symptom Indicator HEART FAILURE 2 STUDY01 FA HF-1 HETYPE Healthcare Encounter Type HEART FAILURE 3 STUDY01 FA HF-1 NWSYMP New or Worsening Symptoms HEART FAILURE 4 STUDY01 FA HF-1 HFPEFNW Heart Failure New/Worsening PE Findings HEART FAILURE 5 STUDY01 FA HF-1 HFLBFNW Heart Failure New/Worsening Lab Findings HEART FAILURE 6 STUDY01 FA HF-1 HFTHERIN Heart Failure Therapy, Intensification HEART FAILURE 7 STUDY01 FA HF-1 ENDPTIND Endpoint Event Indicator HEART FAILURE Row FAORRES FASTRESC VISITNUM FADTC 1 (cont) Y Y (cont) HOSPITALIZATION HOSPITALIZATION Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 61 Provisional October 17, 2014

62 Row FAORRES FASTRESC VISITNUM FADTC 3 (cont) VOLUME OVERLOAD VOLUME OVERLOAD (cont) INCREASING ABDOMINAL DISTENTION OR ASCITES INCREASING ABDOMINAL DISTENTION OR ASCITES (cont) INCREASE IN HEART FAILURE BIOMARKER INCREASE IN HEART FAILURE BIOMARKER (cont) INTRAVENOUS DIURETIC, INOTROPE, OR VASODILATOR THERAPY INTRAVENOUS DIURETIC, INOTROPE, OR VASODILATOR THERAPY (cont) Y Y Rows 1: Shows the onset date of symptoms for the FATEST=Symptom Indicator. suppface.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL QNAM QLABEL QVAL QORIG QEVAL 1 STUDY02 FA FASEQ 1 OSYMPDTC Onset of Symptoms Date T01:00 CRF INVESTIGATOR Shows that B-type natriuretic peptide was elevated, thus indicating a heart failure. lb.xpt Row STUDYID DOMAIN USUBJID LBSEQ LBLNKID LBTESTCD LBTEST LBCAT LBSCAT LBORRES LBORRESU LBORNRLO LBORNRHI 1 STUDY01 LB HF-1 BNP Brain Natriuretic CARDIAC CHEMISTRY Peptide BIOMARKER 510 pg/ml Row LBSTRESC LBSTRESN LBSTRESU LBSTNRLO LBSTNRHI LBNRIND LBNAM LBLOINC VISITNUM VISIT LBDTC 1 (cont) pg/ml HIGH MEMORIAL HOSPITAL UNSCHEDULED T08:00 Rows 1-4: Show the dataset relationships between the Healthcare Encounters, Clinical Events and Findings About domains via the HOLNKID, CELNKID and FALNKID variables. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID 1 STUDY01 HO HOLNKID ONE HOCE 2 STUDY01 CE CELNKID ONE HOCE 3 STUDY01 CE CELNKID ONE CEFA 4 STUDY01 FACE FALNKID MANY CEFA Unstable Angina Hospitalization Event An unstable angina hospitalization event is defined as an unscheduled hospitalization for the management of unstable angina, occurring within 24 hours of the most recent symptoms. 2 Hospitalization is defined as an admission to an inpatient unit or a visit to an emergency department that results in at least a 24 hour stay (or a change in calendar date if the hospital admission or discharge times are not available). This classification requires that 4 separate criteria are met: Worsening ischemic discomfort Unscheduled hospitalization Adapted from J Am Coll Cardiol 2013; 61: Page 62 October 17, Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

63 Objective evidence of myocardial ischemia Negative cardiac biomarkers Note that escalation of pharmacotherapy for myocardial ischemia, while considered supportive evidence, is not sufficient to qualify as an unstable angina hospitalization without objective evidence of ischemia. Admission for suspected unstable angina does not qualify as an unstable angina hospitalization if a non-cardiac or non-ischemic etiology is subsequently identified. An ischemic event meeting the criteria for acute myocardial infarction is not an unstable angina hospitalization. Planned hospitalization or rehospitalization for performance of an elective revascularization procedure (e.g., positive stress test, staged revascularization) is not an unstable angina hospitalization. Hospitalization with revascularization of coronary artery disease identified during elective cardiac catheterization does not qualify as an unstable angina hospitalization. Unstable Angina CDEs (See Section ) are indicated by a value of UA in the ENDPOINT column of the spreadsheet. The concept map below shows the unstable angina hospitalization CDEs. In order to determine if the clinical event of unstable angina meets the cardiovascular endpoint definition, the hospitalization information and symptoms for ischemic discomfort are reviewed. Specific cardiovascular ECG tests and biomarker lab tests are performed to determine various clinical judgments. This information is also reviewed to confirm the event is not a myocardial infarction. Based on the clinical judgments made from this information, a final clinical judgment on classifying the unstable angina hospitalization as a cardiovascular endpoint event is made. Concept Map 10: Unstable Angina Requiring Hospitalization 2014 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 63 Provisional October 17, 2014