Carolinas Cardiogenic Shock Initiative
Conditions: Cardiogenic Shock, Acute; Myocardial Infarction, Complications
Sponsor: Wake Forest University Health Sciences

 
Protocol #: Carolinas CS Initiative 
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TITLE: Carolinas Cardiogenic Shock Initiative 
Protocol #: Carolinas CS Initiative 
LAY TITLE: Carolinas Cardiogenic Shock Initiative 
 
Coordinating Site: 
Atrium Health – Sanger Heart and Vascular Institute 
Carolinas Medical Center 
1000 Blythe Boulevard 
Charlotte, NC 28203 
 
Principal Investigator: 
Glen Kowalchuk, MD 
1000 Blythe Blvd. Charlotte, NC 28203, 704-444-4025 
Glen.Kowalchuk@atriumhealth.org 
 
 
Cone Health Heart & Vascular Center 
 
Daniel Bensimhon, MD, Daniel.Bensimhon@conehealth.org 
Thomas Stuckey, MD, Thomas.Stuckey@conehealth.org  
 
Data Scientist: 
Kamala Swayampakala, PhD 
1540 Garden Terrace Charlotte, Suite 408, NC 28203 
Kamala.Swayampakala@atriumhealth.org   
 
Statistician: 
William Anderson, MS 
1540 Garden Terrace Charlotte, NC 28203, 704-355-0170 
William.Anderson@atriumhealth.org 
 
Study Coordinator: 
 
Melissa Myers 
1001 Blythe Blvd. Charlotte, NC  28203, 704-355-4794 
Melissa.Myers@atriumhealth.org 
 
Data Coordinating Center (DCC) Coordinator:  
Frank Gohs, MS 
1540 Garden Terrace, Charlotte, NC 28203, 704-446-4995 
Frank.Gohs@atriumhealth.org 
 
 

 
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______________________________________________________________________________ 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document whether in 
part or in full to parties not associated with the clinical investigation, or its use for any other 
purpose, without the prior written consent of the Principal Investigator is not permitted. 
Throughout this document, symbols indicating proprietary names (, TM) are not displayed.  
Hence, the appearance of product names without these symbols does not imply that these names 
are not protected.  
 

 
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Version 2 / Date 05/08/2020 
 
PROTOCOL SUMMARY 
Study Title 
Carolinas Cardiogenic Shock Initiative  
Study Design 
 
This is a case series and prospective patient registry  
Study 
Objectives 
 
To determine if deferred or delayed implantation of Impella device based 
on shock severity index is non-inferior with respect to 1 month and 1 year 
mortality compared to standard clinical protocols that do not differentiate 
based on shock severity in adult patients following an initial diagnosis of 
acute myocardial infarction complicated by cardiogenic shock (AMICS). 
 
Study 
Population 
 
The registry will include all eligible subjects from approximately 
5/1/2019 until 4/30/2024, at participating sites. 
Study 
Procedures 
 
Adult patients with a diagnosis of AMICS will have their clinically 
available data contribute to the project registry.  Patients who meet 
criteria for inclusion into the registry will have their chart reviewed 
periodically for the purposes of the registry, for proof of survival at one 
month and one year post-admission. Social Security Death Index (SSDI) 
data will be used to determine mortality at one month and one year if 
unable to confirm using the electronic health record. Patient clinical data 
will be pulled from the medical record and entered or migrated into a 
database for comparison and analysis. All data collected for the study will 
originate in the medical record from clinically available information, from  
a national death database, or from other publically available data sources. 
 
 
 

 
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LIST OF ABBREVIATIONS 
 
ABBREVIATION 
DEFINITION 
AMICS 
Acute Myocardial Infarction complicated by Cardiogenic Shock 
ANT 
Anterior 
CathPCI Registry 
Catheterization and/or percutaneous coronary intervention registry 
CS 
Cardiogenic Shock 
DUA 
Data Use Agreement 
DMP 
Data Management Plan 
eCRF 
Electronic Case Report Form 
ECMO 
Extracorporeal Membrane Oxygenation 
HFrEF 
Heart Failure with reduced ejection fraction 
HFpEF 
Heart Failure with preserved ejection fraction 
IABP 
Intra-aortic balloon pump 
ICU 
Intensive Care Unit 
INF 
Inferior 
LAT 
Lateral 
LBBB 
Left bundle branch block 
MCS 
Mechanical Circulatory Support 
MOP 
Manual of Procedures 
NCDR 
National Cardiovascular Data Registry 
PAPI 
Pulmonary Artery Pulsatility Index 
PCI 
Percutaneous Coronary Intervention 
PI 
Principal Investigator 
RHC 
Right Heart Catheterization 
STEMI 
S-T elevation myocardial infarction 
TIA 
Transient Ischemic Attack 
TTM 
Therapeutic Temperature Management 
 
 

 
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TABLE OF CONTENTS 
 
1 
OBJECTIVES .................................................................................................................................... 6 
 
1.1 Hypotheses ...................... ...............................................................................................................6 
 
1.2 Primary Objectives ..................... ....................................................................................................6 
 1.3 Secondary Objectives..... ..... ..........................................................................................................6 
 
1.4 Exploratory Objective ................ ....................................................................................................6 
2 
BACKGROUND................................................................................................................................. 6 
3 
RATIONALE.......................................................................................................................................7 
4 
INVESTIGATIONAL PLAN ............................................................................................................ 9 
 
4.1 Overall Study Design ...... ...............................................................................................................9 
 
4.2 Subject Selection ...................... ....................................................................................................10 
 4.3 Study Procedures..... .......... ..........................................................................................................11 
 4.4 Statistical Analyses .................. ....................................................................................................11 
5 
DATA SAFETY AND MONITORING PLAN .............................................................................. 15 
 
5.1 Data Quality Assurance . ...............................................................................................................16 
 
5.2 Communication between Sites......................................................................................................16 
6 
STUDY COMPLETION .................................................................................................................. 16 
 
6.1   Completion ...... ...........................................................................................................................16 
 
6.2    Termination ....... ........................................................................................................................17 
7 
RETENTION OF RECORDS ......................................................................................................... 17 
8 
ETHICAL AND LEGAL ISSUES .................................................................................................. 17 
 
8.1    Ethical and Legal Conduct of the Study .......................... ..........................................................17 
 
8.2    Confidentiality .......... .................................................................................................................18 
 
8.3   Disclosure of Data ........... ...........................................................................................................18 
9 
PUBLICATION POLICY................................................................................................................19 
 
REFERENCES..................................................................................................................................20 
 
APPENDICES...................................................................................................................................23 
 
 
 
 

 
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1. OBJECTIVES  
 
1.1. Hypotheses     
 
A standardized clinical protocol that selects patients for MCS based on shock severity, 
will be non-inferior with respect to 1 month and 1 year mortality, compared to standard 
clinical protocols that do not differentiate based on shock severity in adult patients 
following an initial diagnosis of acute myocardial infarction complicated by cardiogenic 
shock (AMICS).  
 
Those patients with shock that is not severe and do not have MCS, have a mortality rate 
that is similar or better than patients who have severe shock and receive MCS.   
 
1.2. Primary Objective  
 
The primary objective of this study is to contribute to the evidence base defining which 
types of patient with AMICS are likely to receive the most benefit from MCS. 
 
1.3. Secondary Objectives 
 
Secondary objectives include: 
a. 
Develop and maintain a patient registry that includes electronic health 
record, administrative and patient reported outcomes data. 
b. 
Classify patients based on shock severity. 
 
  
1.4. Exploratory Objective 
 
Further questions within the scope of the project may be examined using data within the 
registry, as a part of the exploratory analyses. 
 
2. BACKGROUND  
 
Cardiogenic Shock complicating acute myocardial infarction (AMICS) is associated with 
significant mortality, with rates ranging from 40-60% (Kolte et al.; Wayangankar et al., 
2016).  To date, only early mechanical reperfusion has been shown to have a significant 
impact on mortality (Hochman et al., 2001).  Hemodynamic support is commonly 
employed in patients with more severe forms of shock, but there remains considerable 
debate regarding the need, type of device, and timing of deployment.  Moreover, 
approaches in the United States and Europe differ widely (Thiele et al., 2015; O’Neill et 
al., 2017), and randomized trials have yielded results that have failed to clarify the 
optimal strategies, resulting in broad clinical variation in treatment with both cost and 
outcome implications. 
 

 
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In addition to prompt mechanical reperfusion, the most commonly utilized adjunctive 
hemodynamic support include intra-aortic balloon counterpulsation (IABP), the micro-
axial Impella 2.5, CP, and 5.0 systems, and extracorporeal membrane oxygenation 
(ECMO).  Intra-aortic balloon counter-pulsation remains the most widely used device, 
although the hemodynamic effects are quite modest, with limited improvement in cardiac 
output despite diastolic augmentation and afterload reduction (Kern & Sato, 2016).  In 
the IABP Shock II trial, 600 patients were randomized in open label fashion to IABP vs. 
no IABP in addition to mechanical reperfusion.  A majority of patients received IABP 
after reperfusion, and there was no impact on mortality at 30 days or one year (Thiele et 
al., 2012).  Based on the results of this trial, the European guidelines have been updated 
with a Class III recommendation for IABP in cardiogenic shock with the US with a Class 
IIb recommendation (ESC/EACTS, 2014; Levine et al., 2016).   
 
Impella is a trans-catheter axial flow pump that can be delivered percutaneously and can 
provide 2.5-5.0 L/min of forward flow depending upon the device used.   While the use 
of Impella improves the degree of hemodynamic support compared to IABP (Seyfarth et 
al., 2008), in the open label randomized IMPRESS trial in 48 patients, short term 
mechanical circulatory support with Impella did not improve mortality compared to 
IABP, and was associated with multiple complications (Ouweneel et al., 2017).  
However, 92% percent of the patients presented with cardiac arrest and all required 
mechanical ventilation.  In contrast, the USpella registry suggested that early initiation of 
hemodynamic support prior to PCI with Impella is associated with more complete 
revascularization and improved survival in the setting of refractory cardiogenic shock 
complicating acute myocardial infarction (O’Neill et al., 2014).  Moreover, five Detroit 
area centers performed a pilot feasibility analysis to determine whether early routine use 
of mechanical circulatory support with Impella utilized before PCI is possible, and 
whether impact on outcomes could be tracked.  Based on the early encouraging results, 
an algorithm with early MCS with Impella prior to PCI utilizing a structured de-
escalation protocol has been launched as a national initiative (National Cardiogenic 
Shock Initiative). 
 
Current clinical standards do allow for the delay of Impella implantation or based on the 
device materials or FDA approval or IDE marketing application/approval Impella is 
specifically for those with severe shock which outweighs the procedural risks and 
financial burden.  
 
3. RATIONALE 
 
Existing protocols in Europe and the United States vary widely based upon device 
selection and timing of support, a finding that is complicated by the limited data in a 
condition that is difficult to evaluate (Thiele et al., 2015; O’Neill et al., 2014; Diepen et 
al., 2017).  Protocols in Europe suggest the deployment of MCS following 
revascularization, an approach which may underutilize a key pathway to better outcomes 
(O’Neill et al., 2014; Zeymar & Thiele, 2017; Brodie et al., 1999).  In contrast, a 
significant concern for the National Cardiogenic Shock Protocol is that the existing 

 
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protocol may lead to Impella utilization in milder forms of shock when it may not be 
needed, resulting in potentially high artificial survival rates, unnecessarily expensive 
resource utilization, and life-threatening complications.  Moreover, alternative devices, 
such as IABP or ECMO, may be more appropriate in specific clinical situations (small 
femoral anatomy, mitral regurgitation, RV failure, hypoxemia).  
 
A recent American Heart Association Scientific Statement on the contemporary 
management of Cardiogenic Shock advocates for the development of regionalized 
systems of care and outlines future research priorities (Diepen et al., 2017).  The 
statement notes that when, how, and which MCS device should be used remains unclear. 
Thus, outcomes of treatment in specialized cardiogenic shock centers which offer all 
treatment options, should be evaluated further.  
 
The objective of the Carolinas Cardiogenic Shock Initiative will be to evaluate outcomes 
associated with utilization of MCS prior to PCI or delayed implementation in patients 
after reperfusion, based upon shock severity. An algorithm will be utilized which allows 
device variation based upon patient specific factors, employing a protocol driven 
approach to de-escalation in specialized shock centers with access to a variety of 
treatment options.  Whether this can improve upon the protocol adopted by the National 
Cardiogenic Shock Initiative is unknown. However, the initiative addresses specific 
concerns that have arisen, leading to broad variation in the international approach to 
cardiogenic shock. A likely secondary benefit, is that a regionalized protocol should 
reduce center specific provider variation, allowing better outcome analysis and ability to 
execute specific protocol adjustments as a quality improvement initiative. 
 
Previous research suggests that one of the only interventions to show a benefit to patient 
outcomes in adults who present with AMICS, is early mechanical reperfusion, with 
Impella being one of the more commonly used devices for treatment. However, variation 
exists across sites and facilities in patient survival rates and other clinical outcomes. 
Mechanical intervention also comes with its own risk. Implantation of Impella is an 
invasive and possibly risky procedure, with several possible side effects. There is also 
the possibility of the patient’s financial burden from the admission and procedure.  
 
Previous work has been done to identify key treatment elements which could be built 
into a widely accepted and utilized treatment algorithm for individuals who present with 
AMICS.  However, further evaluation of comparing patient outcomes and treatment 
plans based on multiple aspects of the diagnosis, is needed to provide informed advice 
and guidance to patients. This project seeks to examine further diagnosis detail to 
determine if timed or delayed mechanical intervention is appropriate for patients with 
AMICS, based on shock severity. 
 
 

 
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4. INVESTIGATIONAL PLAN 
 
4.1   Overall Study Design 
 
The  Carolinas Cardiogenic Shock Initiative is a clinical pathway and process 
improvement protocol already agreed upon by participating sites, to improve care by 
using a standardized algorithm to treat patients with AMI and CS. This prospective 
registry will capture data from this protocol as a multi-site research project in parallel 
with this standardized non-research clinic workflow protocol.   Participating providers 
will follow the clinical protocol as standard of care for AMICS patients, as clinically 
appropriate.  Patients who have been admitted and diagnosed with AMICS and meet all 
eligibility criteria will have their data entered in this registry.   
 
All eligible patients will be entered into the registry and follow-up via the EMR and/or 
SSDI will occur at 30 days and one year to assess mortality.  No additional provider 
appointments or further testing will be required as a part of this Registry, other than 
what each provider feels is medically necessary and indicated as a part of the patients’ 
care plan.  
 
Treatment decisions and timing will follow an approved clinical protocol and algorithm 
(see Appendix A) based on shock severity classification. The research team at each site 
will capture data generated during standard of care lab tests and clinical procedures, as 
well as data collected during clinical visits from eligible patients. Our target accrual is 
approximately 672 patients, cumulative across all participating sites. 
 
Many of the patient specific outcomes and variables of interest for this study, are already 
submitted to the National Cardiovascular Data Registry (NCDR). Some additional data 
elements, as described in Apendix C, will also be captured. There are no benefits in 
participation other than the scientific knowledge gained, and the only alternative to 
participation is not participating. 
 
 
 
4.1.1 Primary Outcome Variable 
 
 
The primary outcome variable will be 30-day all cause mortality. 
 
 
4.1.2 Secondary Outcome Variable(s) 
 
Key secondary outcome variables for analysis may include but are not 
limited to: 
 
• One year mortality 
• length of ICU care 
• requirement for renal replacement therapy 
• dose and duration of catecholamine therapy 

 
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• requirement for implantation of an active LVAD or referral 
for cardiac transplantation  
• time to support (arrival to tertiary facility to implantation) 
• use of right heart catheterization 
• Attainment of TIMI III flow post reperfusion   
• Attainment of Cardiac power > 0.6 watts after completion 
of therapy 
• Reduction or elimination of vasopressors and inotropic 
agents.   
• blood products during admission 
• hemolysis requiring device discontinuation 
• vascular complication requiring surgery 
 
4.2 Subject Selection  
 
We have no reason to assume the patients who present with AMICS, will not be 
representative of the demographics of the region in which the participating site(s) are 
located. For this reason, we will not prioritize enrollment or recruitment based on 
demographics. Patients who present to the cardiac catheterization lab with AMICS at 
participating sites, and who meet inclusion criteria, will be included in the registry upon 
discharge. Data will be gathered in the usual manner for clinical purposes, for patients 
who die during their admission. The duration of the patient’s enrollment in the registry is 
anticipated to last 1 year from AMICS. Recording of data in the registry is anticipated to 
last approximately five years.  
 
 
4.2.1 Inclusion Criteria 
 
Subjects must meet all the following criteria: 
• Symptoms of acute myocardial infarction (AMI) with ECG and/or 
biomarker evidence of S-T elevation myocardial infarction (STEMI) or 
non-S-T elevation myocardial infarction (NSTEMI)  
• Systolic blood pressure < 90mm at baseline or use of inotropes or 
vasopressors to maintain SBP > 90  
• Evidence of end organ hypoperfusion  
• Patient undergoes PCI  
 
 
4.2.2 Exclusion Criteria 
 
Subjects must not meet any of the following criteria: 
• Evidence of Anoxic Brain Injury  

 
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• Unwitnessed out of hospital cardiac arrest or any cardiac arrest in which return 
of spontaneous circulation (ROSC) is not achieved in 30 minutes  
• IABP placed prior to Impella  
• Patient is already supported with an Impella  
• Septic, anaphylactic, hemorrhagic, and neurologic causes of shock  
• Non-ischemic causes of shock/hypotension (pulmonary embolism, 
pneumothorax, myocarditis, tamponade, etc.)  
• Active bleeding for which mechanical circulatory support is contraindicated  
• Recent major surgery for which mechanical circulatory support is 
contraindicated  
• Mechanical complications of AMI (acute ventricular septal defect (VSD) or 
acute papillary muscle rupture)  
• Known left ventricular thrombus for which mechanical circulatory support is 
contraindicated  
• Mechanical aortic prosthetic valve  
• Contraindication to intravenous systemic anticoagulation  
• Receipt of thrombolytics with this event 
 
4.3 Study Procedures 
 
All inpatient data on eligible patients will come from the hospital inpatient records. Once the 
patient is deemed eligible, their clinical data will be entered or migrated into the research 
registry. Additional data will be collected at approximately one month and one year following 
AMICS, using the EMR and the SSDI.  
 
The following are some of the variables which will be collected and recorded within the 
registry: 
 
• 
Demographics 
• 
Medical history 
• 
Admission characteristics  
• 
Diagnostic values  
• 
Procedure dates and times  
• 
Procedure characteristics  
• 
Post-procedure information  
• 
Discharge survival  
• 
Survival at 1 month from AMICS  
• 
Survival at 12 months from AMICS  
• 
Additional Quality Metrics 
 
4.4 Statistical Analysis 
 
4.4.1. Exploratory analysis. Variable distributions will be examined using summary 
measures, tables, and graphics, such as histograms and scatter plots, where appropriate. 
Variables will initially be used as they were obtained; however, transformation may be 

 
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necessary or prove more informative. For example, continuous variables may be 
categorized, using common category boundaries found in the literature or based on 
percentiles of the variable distribution, in order to stratify the data. Student’s t-test or the 
Wilcoxon rank-sum and chi-square statistics will be used to examine simple associations. 
For event history outcomes, we will primarily rely on survival analysis (i.e., event history 
modeling) to investigate if and when the event has occured (Singer & Willett, 1993). For 
this study, the time scale for mortality will be recorded in discrete time intervals (i.e., 
baseline, one month, one year); therefore, the underlying continuous time-to-event process 
will be modeled using discrete time.  
 
A major consideration will be the nested organization of the data. Patients (level-1) are 
nested within sites (level-2). When hierarchical data are analyzed without regard to the 
interdependence of the data type-I error rates are inflated (aggregation) or deflated 
(disaggregation) resulting in incorrect significance tests and invalid conclusions (Hox, 
2002). While multilevel modeling methods explicitly account for the nested structure of 
data, this approach is not feasible because we do not have sufficient number of sites to treat 
these effects as random (Hox & Roberts, 2010; Roberts, Monaco, Stovall, & Foster, 2011). 
Therefore, each site will be evaluated for differences in multiple group analyses. If the site 
differences are trivial, we will collapse the data across sites (Little, 2013). Non-trivial 
differences will require a grouping variable for site in subsequent analyses. 
 
4.4.2. Analytic strategy. Insights gained from the exploratory data analysis will then be 
used to fit appropriate statistical models to the data. Within the context of survival 
analyses, we will begin by modeling the unconditional model (no covariates) in order to 
establish a baseline model. Next, we will add covariates with time-varying 
(nonproportional hazard odds) effects. Using model constraints, we will then fit a 
proportional hazard odds model and compare. Finally, we will probe for hypothesized 
effects. 
  
Specifically, our goal is, first, to examine the degree to which a standardized clinical 
protocol that selects patients for MCS based on shock severity will be non-inferior with 
respect to mortality when compared with a standard clinical protocol that does not 
differentiate based on shock severity among adult patients following an initial diagnosis of 
AMICS. Second, our goal is to determine the degree to which mortality rates of patients 
with AMICS differ on MCS exposure.  
 
Missing Data  
Censoring will be assumed to be noninformative (i.e., the distribution of censoring times is 
independent of event times, conditional on the set of observed covariates). Missing data 
will be described in detail, including comparisons among participants that remained in the 
study to those that dropped out across demographic and outcome variables using t-tests, 
Little’s MCAR test, or logistic regression (Nicholson, Deboeck, & Howard, 2015). 
Sensitivity analyses will be used to gauge the stability of inferences (Enders, 2010). When 
possible, we will use full-information maximum likelihood (FIML) estimation under the 
MAR missing data assumption (corresponding to the assumption of noninformative right 

 
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censoring) estimation option in the Mplus 7.3 software program to deal with missing data 
related to censoring and time-varying covariates with measurement intervals that do not 
correspond to the precision with which event times are measured. When appropriate, the 
robust standard error option, and the corresponding Satorra-Bentler correction for chi-
square difference tests to evaluate site-level difference, will be used to correct for non-
normality (Muthén & Masyn, 2005; Singer & Willett, 2003; Wang & Wang, 2012).  
 
4.4.2.1. Hypothesis 1.  
Approach 
To evalaute this hypothesis, we will use a discrete time survival analysis (DTSA) within 
the structural equation modeling (SEM) framework (Muthén & Masyn, 2005; Raykov, 
Gorelick, Zajacova, & Marcoulides, 2017). This approach offers substantively important 
extensions to conventional DTSA models (e.g., logistic regression) that more accurately 
reflects the complexity and interconnectedness of survival (i.e., event history modeling) 
processes (Masyn, 2014). This more general approach includes the ability to model 
unobserved population heterogeneity (frailty) in the event history process, latent variable 
predictors of event history (e.g., health-related quality of life) including possible mediators 
and moderators, recurring events, competing risks, parallel and sequential growth 
processes (i.e., between-person variability in within-person change over time), onset-to-
growth models, parallel event history processes, measurement error on event occurrence, 
hazard risk set matching, handling multilevel data structures, and time-varying covariate 
effects (non-proportional hazard) among other advantages (Masyn, 2013, 2014). Figure 1 
presents an exemplary DTSA within the context of SEM (simplified for ease of 
presentation). In this example, three binary indicators (1, event occured; 0, event not 
occured) corresponding to the j = 3 proposed measurement occasions (𝑒𝑗). In this analysis 
the hazard probability for a given measurement occasion will be defined as the probability 
of mortality in that occasion, provided that patient is alive. The hazard probability will then 
be related to time-varying (𝑤𝑗) and time-invariant (x) covariates through a logit link 
function to parameterize the effect of a particular covariate on the log hazard odds of 
mortality during a given time interval. We will then describe covariate effects in terms of a 
hazard odds ratio (hOR). For example, if clinical protocol is coded 1 for typical and 0 for 
being based on a shock serverity score, were estimated to have a hOR of 2.0 at 30 days, we 
would note that the odds of mortality at 30 days for those without a shock severity protocol 
was twice the odds of mortality at 30 days for those with a shock severity protocol. This 
model can be written as: 𝑙𝑜𝑔𝑖𝑡(𝑃𝑟(𝑒𝑗= 1)) = 𝛼𝑗+ 𝛽𝑗𝑥+ 𝛾𝑗𝑤𝑗, where 𝛼𝑗 is the log 
hazard odds (with all covariates set to 0), 𝛽𝑗 is the difference in the log hazard odds and 
𝑒𝑥𝑝(𝛽𝑗) is the hazard odds ratio (hOR) for a positive one unit differece in x (controlling 
for covariates 𝑤𝑗), and 𝛾𝑗 represents a time-varying covariate effect for the difference in 
log hazard odds. The assessment of non-inferiority will be performed by comparing hazard 
odds ratio confidence intervals to the non-inferiority margin (Althunian, Boer, Groenwold, 
& Klungel, 2017). Specifically, since lower is better, non-inferiority will be concluded 
when the actual hazard ratio is less than the clinically acceptable ratio of 1.2. 
 
 

 
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Power 
With respect to the 30-day primary end point of death, we estimated that an overall sample 
size of 672 patients would provide 80% power (at a one-sided alpha level of 0.025) to 
show the  noninferiority of a standardized clinical protocol that selects patients for MCS 
based on shock severity to a standard clinical protocol that does not differentiate based on 
shock severity  assuming the proportion of subjects observed with the event (death) during 
the study is 39.7% for the control group and 41.3% for the treatment group (Thiele et al., 
2005; Thiele et al., 2013). The power was computed for the case when the actual treatment 
group proportion is 31%. The test statistic used is the one-sided Z test (unpooled).  
 
Expected results 
We expect a standardized clinical protocol that selects patients for MCS based on shock 
severity, will be non-inferior with respect to 1 month and 1 year mortality compared to 
standard clinical protocols that do not differentiate based on shock severity in adult 
patients following an initial diagnosis of acute myocardial infarction complicated by 
cardiogenic shock (AMICS).  
 
Potential problems and alternatives 
The issue of multiple testing that is involved in evaluating the p-values associated with a 
large set of covariates, is not addressed through the use of SEM. To address this concern, 
we will use the Benjamini–Hochberg (BH) procedure that is based on the false discovery 
rate concept, and has been shown to be more powerful than conventional multiple testing 
procedures (Benjamini & Hochberg, 1995; Benjamini & Yekutieli, 2001; Raykov, 
Lichtenberg, & Paulson, 2012). The inclusion of time-dependent covariates introduces 
reciprocal causation (Singer & Willett, 2003). We will address this issue by modeling 
covariate effects with a time-lag (Brown, 2012; Little, 2013). Model comparisons based on 
the Wald statistic test (dividing a parameter estimate by its standard error), may be 
influenced by non-normal concentration distributions (Little, 2013). To address this, we 
will use the adjusted likelihood ratio test statistic (i.e., Chi-Square Difference Test) using 
the log likelihood values and scaling correction factors obtained with the “MLR” estimator 
in Mplus, the default maximum likelihood estimator for binary and ordinal outcomes 
(Wang & Wang, 2012). In the event of unforeseen problems related to the proposed 
models, we will simplify our approach by modeling single-occurrence events in discrete-
time with observed predictors using a multivariate logistic regression to model conditional 
model-estimated hazard probabilities and corresponding survival probabilities (Masyn, 
2014; Muthén & Masyn, 2005). In this case, noninferiority will be calculated with the use 
of the Com–Nougue approach to estimating the z statistic for the Kaplan–Meier failure 
rates, with standard errors estimated by means of Greenwood’s formula (Com‐Nougue, 
Rodary, & Patte, 1993). 
 
4.4.2.2. Hypothesis 2.  
 
Approach 
To evaluate this hypothesis, we will conduct a prevalence analysis using a multilevel 
regression model to obtain site-level prevalence estimates of participant mortality using the 

 
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general equation: 𝑙𝑜𝑔𝑖𝑡(𝑝𝑖𝑗) = 𝑋′𝛽+ 𝛼𝑖 , where 𝑥𝑖𝑗= (𝑥𝑖𝑗1 … 𝑥𝑖𝑗𝑞)′ is a vector of q 
covariates, 𝛽= (𝛽1 … 𝛽𝑞)′ is a vector of fixed effects and 𝛼𝑖 is the random effect for site 
(Raudenbush & Bryk, 2002). The model will include demographic variables (e.g., race, 
gender, age, etc.), as well as site-level data and cross-level interactions. The prevalence 
estimates will be calculated from the predictors in the multilevel regression where: 𝑝̂𝑖𝑗𝑘=
𝑒𝑝𝑟𝑒𝑑𝑖𝑐𝑡𝑜𝑟1 + 𝑒𝑝𝑟𝑒𝑑𝑖𝑐𝑡𝑜𝑟
⁄
. A follow-up evaluation will determine site-level prevalence 
rates by factors such as MCS and risk status categories, with the formula: 𝑝̂𝑖𝑗𝑘=
∑
𝑛𝑖𝑗𝑘𝑙
𝑛𝑖𝑗𝑘
𝑗
𝑝̂𝑖𝑗𝑘𝑙 , where 𝑝̂𝑖𝑗𝑘 is the estimated prevalence of mortality in site i of risk status j at 
time k, 𝑛 𝑖𝑗𝑘𝑙 is the number of participants in site i that are of MCS (or risk status type) j, at 
time k and belong to demographic group l (i.e., a particular age, gender, race group), 𝑛 𝑖𝑗𝑘 
is the total population in site i of risk status type j, at time k and 𝑝̂𝑖𝑗𝑘𝑙 is the estimated 
prevalence of patient mortality in site i that are of risk status type j at time k and belong to 
demographic group l. We will compare these rates using risk difference and rate ratios 
(Agresti, 2013).  
 
Expected results 
We expect patients with shock that is not severe and do not receive MCS, have a mortality 
rate that is similar or better than patients who have severe shock and receive MCS.  
 
Potential problems and alternatives 
In the event of unforeseen problems related to the proposed models, we will simplify our 
approach by comparing the odds of mortality between groups using a multivariate logistic 
regression to model conditional model-estimated hazard probabilities and corresponding 
survival probabilities 
(Masyn, 2014; Muthén & Masyn, 2005).  
 
 
5. DATA AND SAFETY MONITORING PLAN 
Data collected by the participating sites will be entered into case report forms, then stored and 
managed in a secure REDCap database hosted by Atrium Health. REDCap (Research Electronic 
Data Capture) is a secure, web-based application, designed to support data capture for research 
studies. The REDCap database which will be used for the registry, was built solely for the 
purposes of this project, and includes only those data elements deemed relevant for measuring 
and analyzing the objectives of interest.  
 
The protocol and recorded data will be monitored in accordance with the Data Coordinating 
Center’s monitoring plan, and will operate under standard operating procedures set forth by both 
the Office of Clinical and Translational Research and the Center for Outcomes Research and 
Evaluation at Atrium Health. 
 
Due to the nature of this project, participation in the registry presents no more than minimal risk 
to subjects. According to the FDA Guidance for Clinical Sponsors: Establishment and 

 
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Operations of Clinical Trial Data Monitoring Committees, this study does not require oversight 
by a Data and Safety Monitoring Committee.  
 
 
5.1. Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the study protocol, 
standard operating procedures (SOPs) set forth by the Office of Clinical and Translational 
Research and the Center for Outcomes Research and Evaluation at Atrium Health, the FDA, 
and other applicable regulations and guidelines (e.g. GCP).  
 
Data will be collected on electronic Case Report Forms (eCRFs). 
 
The protocol and recorded data will be monitored in accordance with the Data Coordinating 
Center’s monitoring plan. This monitoring will be done by comparing source documentation 
to the eCRFs.  
 
The study database will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures. Data queries 
requiring clarification will be generated and addressed by the appropriate research 
teammates, including the Project Coordinator and/or Principal Investigator. Only authorized 
personnel will make corrections to the project database, and all corrections will be 
documented in an electronic audit trail. 
 
Any variation between the two data sets will be discussed with the site’s Project Coordinator 
and Principal Investigator. 
 
5.2. Communication Between Sites 
The project steering committee and/or research team will meet on at least a monthly basis, or 
more frequently as needed. The meetings will take place to discuss any encountered issues, 
discuss project progress, and to address other project related topics, as appropriate.  
 
Participating sites will be required to report any problem that could affect the 
validity/integrity of the study data to the Principal Investigator and the Data Coordinating 
Center. Any problem should be communicated to the Principal Investigator and the Data 
Coordinating Center as soon as possible. 
 
6. STUDY COMPLETION 
6.1   Completion 
The study will be considered complete upon the determination of the Principal Investigator 
or the Institutional Review Board.  

 
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6.2    Termination 
The study will be terminated upon completion of the enrollment period, or once the risk-
benefit ratio becomes unacceptable owing to, for example, results of parallel studies or if the 
study conduct (e.g. data quality, protocol compliance) does not suggest a positive 
contribution toward the study objectives. 
 
The Principal Investigator has the right to close the study at any time. Closures should only 
occur after consultation between involved parties and all affected institutions must be 
informed as applicable according to local law. 
 
 
7. RETENTION OF RECORDS 
Essential protocol documentation, including all IRB correspondence, will be retained for at least 
2 years after the investigation is completed. Documentation will be readily available upon 
request. 
 
8. ETHICAL AND LEGAL ISSUES 
8.1    Ethical and Legal Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Investigator abide by 
Good Clinical Practice (GCP) guidelines and under the guiding principles detailed in 
the Declaration of Helsinki. The study will also be carried out in keeping with the 
applicable local laws and regulation(s). 
 
Documented approval from appropriate agencies (e.g. IRB) will be obtained before 
the start of the study, according to GCP, local laws, regulations, and organizations.  
 
Strict adherence to all specifications laid down in this protocol is required for all 
aspects of study conduct; the Investigators may not modify or alter the procedures 
described in this protocol. 
 
Modifications to the study protocol will not be implemented without consulting the 
Principal Investigator and the IRB, as applicable. The Principal Investigator must 
assure that all study personnel, including sub-investigators and other project staff 
members at external sites, adhere to the study protocol and all applicable regulations 
and guidelines regarding research both during and after study completion. 
 
The Principal Investigator will be responsible for assuring that all the required data 
will be collected and properly documented. 
 

 
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8.2    Confidentiality 
Subject confidentiality will be maintained by the Principal Investigator, the 
Investigator’s associates and co-workers. Confidentiality will be maintained 
according to ICH E6; 4.8.10, part O: “Records identifying the subject will be kept 
confidential and, to the extent permitted by the applicable laws and/or regulations, 
will not be made publicly available. If the results of the study trial are published, 
the subject’s identity will remain confidential.” 
 
Participation in the project registry presents no risk, other than breach of 
confidentiality. To mitigate this risk, only necessary patient identifiers will be 
captured, and all data used for the project will be stored in a secure REDCap 
database.  
 
8.3   Disclosure of Data 
 
The Principal Investigator, his or her associates and teammates, and the appropriate 
regulatory agencies may use the information and data included in this protocol as 
necessary for the conduct of the study. Information contained in this study, and data 
and results from the study are confidential and may not be disclosed without the 
written permission of the Principal Investigator.  
 
Local Site Investigators and their research teams will only be able to access PHI 
from their own patients. However, Lead site teammates and other Project Team 
and Steering Committee Members may have access to the full registry data, 
inclusive of external site patient information, as appropriate for the purposes of 
data accuracy and project oversight. The following project team members will 
have access to patient medical information, and any necessary information for the 
completion of the project as outlined in the MOP and this protocol. Data Use 
Agreements will also be completed for participating sites external to the 
Coordinating Site’s Healthcare System.  
 
Atrium Health:  
• PI  
• Co-Investigator(s) 
• Data Manager(s)  
• Research Nurse(s) 
• Data Coordinator(s) 
• Statistician(s) 
• Other Administrative Teammates such as Steering Committee or 
Project Team Members 
 
External Sites: 
• Local PI  
• Sub-Investigator(s) 

 
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• Research Nurse(s) 
• Data Coordinator(s)  
 
9.     PUBLICATION POLICY 
There is no planned interim analysis of the data. A final analysis is planned, for the 
purpose of presentation and submission for publication of all data at the end of the study 
enrollment and follow-up periods.  
 
Manuscript(s) and abstract(s) prepared from the data collected during this study will be 
prepared by the Principal Investigator and select members of the research team.  Local 
Site Investigators will not publish or present results, for reasons beyond site care and 
quality improvement, without written consent of the Lead Principal Investigator, per the 
site DUA. Investigators will provide the Principal Investigator with publication or 
presentation materials (including slides, text of oral or written presentations, and 
electronic media), at least 30 days in advance of publication/presentation, to allow for 
review and comment as a means of ensuring confidentiality, accuracy, and objectivity. 
 
 
 
 
 
 

 
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APPENDICES 
APPENDIX A: Cardiogenic Shock Algorithm 
 
 
            
                
SEVERE SHOCK CRITERIA  
(as above plus): 
SBP less than 80 mm on arrival in cath 
lab  
or 
High dose pressor (any one of the 
following): 
• 
More than one pressor 
• 
Dopamine >10 ug /kg / min 
• 
Norepinephrine >10 ug/ min 
• 
Epinephrine > 5ug/ min 
• 
Neosynephrine > 40ug /min  
or 
SBP less than 90 with LVEF <20% pre-
PCI 
or  
Cardiac index <2.0 or  
Cardiac Power Output < 0.6  
SHOCK CRITERIA: 
SBP less than 90mm for more than 30 
mins 
or 
Use of Vasopressors/Inotropes for 
support 
 
 
EXCLUSION CRITERIA: 
• 
Anoxic Brain Injury 
• 
Cardiac Arrest with ROSC 
>30 mins 
• 
Non-Cardiac Shock 
Sepsis 
• 
Non-ischemic causes of 
shock/hypotension 
• 
IABP inserted pre-PCI 
• 
CPO = MAP x CO/451 
• 
PAPI = sPAP – dPAP/RA