Wake Forest University long‐term follow‐up of type 2 myocardial infarction: The Wake‐Up T2MI Registry

Abstract Background The Wake‐Up T2MI Registry is a retrospective cohort study investigating patients with type 2 myocardial infarction (T2MI), acute myocardial injury, and chronic myocardial injury. We aim to explore risk stratification strategies and investigate clinical characteristics, management, and short‐ and long‐term outcomes in this high‐risk, understudied population. Methods From 1 January 2009 to 31 December 2010, 2846 patients were identified with T2MI or myocardial injury defined as elevated cardiac troponin I with at least one value above the 99th percentile upper reference limit and coefficient of variation of 10% (>40 ng/L) and meeting our inclusion criteria. Data of at least two serial troponin values will be collected from the electronic health records to differentiate between acute and chronic myocardial injury. The Fourth Universal Definition will be used to classify patients as having (a) T2MI, (b) acute myocardial injury, or (c) chronic myocardial injury during the index hospitalization. Long‐term mortality data will be collected through data linkage with the National Death Index and North Carolina State Vital Statistics. Results We have collected data for a total of 2205 patients as of November 2018. The mean age of the population was 65.6 ± 16.9 years, 48% were men, and 64% were white. Common comorbidities included hypertension (71%), hyperlipidemia (35%), and diabetes mellitus (30%). At presentation, 40% were on aspirin, 38% on β‐blockers, and 30% on statins. Conclusion Improved characterization and profiling of this cohort may further efforts to identify evidence‐based strategies to improve cardiovascular outcomes among patients with T2MI and myocardial injury.


| INTRODUCTION
Myocardial necrosis due to myocardial ischemia is designated as myocardial infarction (MI). Recognizing the heterogeneity inherent to this entity, in 2007 and 2012, the ESC/ACCF/AHA/WHF Task Force for the Universal Definition of MI released expert consensus documents redefining MI into five types. 1 This classification system was recently further refined with the Fourth Universal Definition of MI. 2 Type 1 myocardial infarction (T1MI) refers to acute coronary syndrome (ACS) caused by atherosclerotic plaque rupture, ulceration, fissure, or erosion leading to intraluminal thrombus formation and obstructed coronary blood flow. Type 2 myocardial infarction (T2MI) was defined as myocardial ischemia, not due to plaque rupture but secondary to an imbalance between myocardial oxygen demand and/or supply due to an underlying cause. 2 In defining presence of MI, a critical characteristic is presence of myocardial ischemia; this may be manifested by symptoms, changes on electrocardiography, or evidence for loss of myocardial function. Patients with evidence of elevated troponin with at least one value above the 99th percentile upper reference limit (URL) and 10% coefficient of variation without overt myocardial ischemia are classified as having myocardial injury. 2 This injury may be acute or chronic, depending on the pattern of cTn elevation and in appropriate clinical contexts.
T2MI and myocardial injury are commonly encountered in clinical practice. In smaller studies, T2MI has been found to be responsible for 2% to 37% of all elevated troponin results in unselected hospitalized patients and 5% to 71% in an unselected emergency department setting. [3][4][5][6][7] Similarly, myocardial injury has been reported in up to 70% of unselected patients. 8,9 The heterogeneity in reported frequencies across studies is likely due to differences in biomarkers cut-offs, selected populations, variation in adjudication processes, and challenges in clinically distinguishing myocardial injury from infarction.
Relatively few studies are available comprehensively characterizing the longitudinal profile, medical and interventional management, and short-and long-term clinical prognosis of patients with T2MI or myocardial injury. 26 There is a lack of consensus on the optimal therapeutic approach to this heterogeneous cohort of patients, including whether they benefit similarly from guideline-based ACS therapies (as T1MI). 30 Although select studies have characterized patients with T2MI, patients with myocardial injury have been infrequently studied.
Few studies have leveraged linked national and state death records to facilitate more complete mortality estimates.
Our study has the following objectives: (a) to explore clinical characteristics of patients with T2MI and myocardial injury; (b) to investigate the differences in presentation, stratified by age, sex, and race; (c) to characterize utilization of noninvasive and invasive ischemic evaluation strategies in this population; (d) to determine the rates and burden of obstructive CAD; (e) to determine differences in medical and interventional management of T2MI and myocardial injury; (f) to investigate causes of cardiovascular and noncardiovascular mortality in T2MI and myocardial injury; (g) to identify predictors of in-hospital, 180-days, 1-year, 5-year, and 7-year outcomes.

| METHODS
The Wake-Up T2MI Registry is a registry of adults (age ≥ 18 years) who were hospitalized at Wake Forest University Medical Center in a 2-year period between 1 January 2009 and 31 December 2010, and had T2MI or myocardial injury as defined by the Fourth Universal Definition of MI. 2 Figure 1 provides an outline of the study design and patient selection.

| Identification of study population and patient selection
Patients with elevated cTnI >40 ng/L from 1 January 2009 to 31 December 2010 were identified using data extracted from CTSI.
Due to the absence of International Classification of Disease, Ninth Revision (ICD-9) code for T2MI and myocardial injury and since administrative coding for T2MI in ICD-10 were only available in October 2017, ascertainment of T2MI will rely on primary chart review. To limit patients with presumed T1MI, those with ICD-9 diagnosis of acute MI (410.xx, 411.1) have been excluded from the initial inclusion criteria. The study will exclude patients with prehospital cardiac arrest, patients who were transferred from an outside hospital more than 24 hours after the presentation (to limit selection of patients requiring higher levels of care to minimize the transfer of incomplete or inaccurate information), T1MI diagnosed by discharging physician, traumatic brain injury, readmission, one troponin I level, and significant missing data to sufficiently adjudicate T2MI vs myocardial injury. Data of patients who met the inclusion criteria will be entered into a secure, customized electronic adjudication system for review.

| Presentation
Emergency department notes or admitting physician's notes will be the source of information on the initial presentation of patients ( Figure 2). Further information on variables collected during the hospital course, traditional comorbidities and risk factors, baseline medications, laboratory testing variables are provided in Appendix S1.

| Adjudication of T2MI and myocardial injury
A team of trained study physicians will review all records and utilize the Fourth Universal Definition to classify patients into (a) T2MI, (b) acute myocardial injury, and (c) chronic myocardial injury 2 ( Figure 3). All diagnoses will be adjudicated by two independent adjudicators with disagreements settled by a third adjudicator. All reviewers will have access to all available electronic patient medical records from the index admission described above. To fulfill the biomarker criteria of T2MI, an elevated cTnI of at least >40 ng/L along with an evidence of rise and/or fall of cTnI will be required. If the biomarker criteria is met, clinical conditions with potential to trigger overt ischemia along with any one of the following will be required to be

| Study endpoints
Causes of death will be classified in 1 of 3 categories (1) CV death (secondary to MI, heart failure, sudden cardiac death, stroke, CV procedure, and other CV causes such as pulmonary embolism or peripheral artery disease), (2) non-CV death, and (3) undetermined cause of death (Appendix S2). Name, social security numbers, and date of birth will be used to match patients with the NDI/North Carolina State Vital Statistics to identified deaths at follow-up. The definition of CV death will be adapted from the 2014 American College of Cardiology/American Heart Association key data elements and definitions for CV endpoints in clinical trials. 32 No formal sub-studies are planned in this study.

| Data management
All study-related patient data will be stored on REDCap (Research Electronic Data Capture) tools hosted by Wake Forest CTSI. REDCap is a secure, encrypted, web application for building and managing the online database. REDCap is a Health Insurance Portability and F I G U R E 1 Scheme of the Wake-Up T2MI Registry design Accountability Act compliant. This web serves as an intuitive interface to enter data with real-time validation (automated data type and range checks). This platform offers easy data manipulation with audit trails and reports for monitoring and querying of participant records. 33

| Statistical analysis
Continuous variables will be reported as means or medians and compared with t tests, Wilcoxon rank-sum, or analysis of variance, as appropriate. Categorical variables will be reported as proportions and frequencies and will be compared with chi-square or Fisher exact tests.
Ordinal variables will be compared with a trend test. Cox proportional hazards modeling will be performed for time-to-event analyses. All analysis will be performed on de-identified data. All analysis was performed using SAS software, version 9.4 (SAS Institute, Inc., Cary, North Carolina).

| Baseline clinical profile of T2MI or myocardial injury
We plan to collect data from a total of 2846 patients, who met our inclusion criteria over a period of 1 January 2009 to 31 December 2010. As of November 2018, we have collected data for a total of 2205 patients. The baseline characteristics of this initial cohort are detailed in Table 3. The mean age was 65.6 ± 16.9 years, 52.2% were women, and 64% were white. Over two-thirds (71%) had hypertension, 35% had hyperlipidemia, 30% had diabetes mellitus, and 18.5% had chronic kidney disease at baseline (Table 3). At the time of hospital admission, 40% were on aspirin, 38% were on β-blockers, 30% were on statins, 29% were on angiotensin-converting enzyme inhibitors, and 9% were on angiotensin II receptor blockers (Table 3).

| DISCUSSION
The increasing sensitivity of troponin assays, their wide ranging use, and heightened recognition by clinicians have contributed to an increase in diagnoses of T2MI and myocardial injury. These clinical entities have drawn more attention largely related to challenges in their management and poor short-and long-term outcomes. To date, there have been few randomized clinical trials available to determine the effects of investigational strategies in these cohorts. 34,35 As such, observational studies defining the epidemiology of these disease entities are of great importance. In the CASABLANCA study 26

| Conclusions
The Wake-Up T2MI Registry will collect a large cohort of patients with T2MI and myocardial injury. By linking robust electronic health record system administrative coding, detailed chart review with independent adjudication, and national and state death records, we will obtain comprehensive data that will allow us to characterize differences in the presence and treatment of risk factors, as well as short-and long-term outcomes. More granular data regarding T2MI and myocardial injury are needed to guide treatment strategies in these at-risk populations. Note: Continuous variables measured as mean (SD); categorical variables measured by frequency (%).