Emergency Medical Services (EMS) Telehealth to Speed STEMI Reperfusion (THOR)
Conditions: STEMI - ST Elevation Myocardial Infarction
Sponsor: Wake Forest University Health Sciences

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Study Title: EMS Telehealth to Speed STEMI Reperfusion (THOR) 
 
Simon Mahler, MD MS Principal Investigator 
 
Co-investigator(s): 
Jason Stopyra, MD MS  
James Winslow, MD, MPH 
Nicklaus Ashburn, MD, MS 
Anna Snavely PhD  
 
Sponsor or funding source: Genentech  
 
Background, Rationale and Context 
STEMI is the most severe type of heart attack and carries a 30-day mortality of nearly 8%.1 
Reperfusion therapy is the mainstay of treatment for STEMI, either by percutaneous coronary 
intervention (PCI) or fibrinolytics.2 Delays in reperfusion are associated with negative health 
outcomes. Specifically, each 30-minute delay in reperfusion corresponds to a 7.5% decrease in 
1-year survival.3 The current body of literature clearly shows that rural EMS agencies often have 
longer transport times, which makes the 90-minute first medical contact (FMC) to PCI time goal 
difficult to achieve.4 Approximately 16% of Americans live more than an hour from a PCI-
capable facility, reinforcing the need for timely therapies in rural prehospital settings to 
decrease heart muscle damage (disability) and mortality.5-7 Recently, our team conducted an 
analysis of a large national EMS database, which showed that FMC to PCI times were longer for 
patients treated by rural EMS agencies even after these times were adjusted for distance to 
destination hospital.8In addition, our preliminary data for Cherokee Tribal EMS, who serves the 
Eastern Band of Cherokee Indians on the Qualla Boundary and its surrounding communities, 
show that none of their patients who called 9-1-1 for a STEMI received reperfusion within the 
AHA time goal. The American College of Cardiology and AHA support prehospital fibrinolytics 
when timely PCI cannot be performed.9 Preliminary data from our HRSA project demonstrates 
the feasibility of using telehealth to guide care for a patient calling 9-1-1 for acute chest pain 
and suggests successful expansion to patients with acute STEMI. In Europe, telemedicine 
programs, which connect EMS providers with expert physicians to assist in EKG interpretation, 
have improved quality of care and decreased healthcare costs.10 In addition, these European 
programs have demonstrated that telehealth can improve STEMI reperfusion times in rural 
settings.11 However, STEMI telehealth programs have yet to be implemented and tested in the 
United States. 
Current Therapies and Unmet Medical Need Related to STEMI Care 
Rural Americans are much less likely than their urban counterparts to receive timely reperfusion. For 
example, since January 1, 2020 there were 37 patients with a STEMI cared for by Cherokee Tribal EMS 
(CTEMS), of which none (0% 0/37) received reperfusion within the American Heart Association 
recommended time goal. These delays in care are associated with excess mortality and high rates of 

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long-term morbidity from congestive heart failure and recurrent heart attacks. Eliminating this rural 
disparity is a top public health priority both nationally and locally.  STEMI guidelines from the American 
College of Cardiology and American Heart Association (AHA) recommend reperfusion within 90 
minutes of a patient’s first-medical-contact (FMC) with emergency medical services (EMS). In most 
cases, reperfusion is accomplished with percutaneous coronary intervention (PCI; formerly known as 
angioplasty with stent) at tertiary care hospitals that offer this advanced capability. However, rural 
patients often live great distances from PCI centers and therefore have less than a 1/8th odds of timely 
access to PCI compared to their urban counterparts. It has been estimated that at least 16% of 
Americans live in rural areas over an hour drive away from a PCI-center, which makes achieving PCI 
within 90-minutes very difficult. For those expected to have delayed PCI, guidelines recommend 
administration of fibrinolytics (“clot busting medication”). However, despite these recommendations 
and evidence suggesting fibrinolytic administration can reduce reperfusion times, few rural EMS 
agencies currently administer fibrinolytics. For example, over the past four years, Cherokee Tribal EMS 
has never given fibrinolytics.  
 
The major barrier to fibrinolytic use in rural EMS systems is a lack of robust medical control to ensure 
the safe use of this medical reperfusion treatment. Due to bleeding risk, most community emergency 
physicians are hesitant to order fibrinolytics without being able to evaluate the patient. Although 
telehealth programs are gaining popularity across the United States and successfully connecting 
physicians with EMS systems, including one in Wilkes County, no EMS telehealth STEMI-specific 
programs have been initiated in rural America to our knowledge. To overcome the main barrier to 
fibrinolytic use and eliminate rural disparities in STEMI care, implementation of a sustainable and 
scalable EMS telehealth STEMI program is needed. 
 
Our team at the Wake Forest University School of Medicine (WFUSM), led by Drs. Mahler and Stopyra, 
have experience implementing a collaborative cardiovascular rural EMS telehealth project to improve 
rural patient access to expert cardiovascular care with Health Resources and Services Administration 
(HRSA) funding. This telehealth service aims to improve the care of patients who call 9-1-1 for chest 
pain or shortness of breath, by assisting with early risk stratification to appropriately align patient risk 
and resource use.  Thus, we have successfully established a telehealth workflow between a rural EMS 
service and a team of Wake Forest physicians. At the request of Cherokee Tribal EMS we now seek to 
expand our existing telehealth program to this service to improve STEMI care by facilitating timely 
reperfusion either through PCI or thrombolysis. Patients will be considered for thrombolytics if the 
patient meets clinical inclusion to receive the drug, the transport time is greater than 60 minutes, and 
the patient is transported by CTEMS via ambulance and not by helicopter transport. (See Screening 
Tool, Appendix 3) This proposal, which is supported by Duke Endowment and seeks drug from 
Genentech, is a clinical implementation and will become the local standard of care. We aim to collect 
data to evaluate the impact of implementation of this EMS Telehealth STEMI program on health 
outcomes. 
Tenecteplase (TNKase→) is a modified form of human tissue plasminogen activator (tPA) that 
binds to fibrin and converts plasminogen to plasmin.  In vitro studies demonstrated that in the 
presence of fibrin, tenecteplase conversion of plasminogen to plasmin is increased relative to 
its conversion in the absence of fibrin.  This fibrin specificity decreases systemic activation of 

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plasminogen and the resulting degradation of circulating fibrinogen compared with a molecule 
lacking this property, which could potentially decrease the incidence of bleeding. 
Refer to the Tenecteplase Investigator's Brochure for details on nonclinical and clinical studies. 
Approved Indication 
In the United States (US), TNKase→ (tenecteplase) is indicated to reduce the risk of death 
associated with acute ST elevation myocardial infarction (STEMI).  In Canada, TNKase→ 
(tenecteplase) is indicated to reduce the mortality associated with acute myocardial infarction 
(AMI).  Outside US and Canada, Metalyse→ (tenecteplase) is indicated in more than 90 countries 
for the thrombolytic treatment of AMI. 
OVERVIEW OF CLINICAL DEVELOPMENT 
Tenecteplase has been previously developed in other indications and has been approved for 
the treatment of AMI.   
Completed and ongoing clinical studies of tenecteplase are summarized in the Tenecteplase 
Investigator’s Brochure.  
Acute Myocardial Infarction Clinical Development 
Tenecteplase is indicated for use in the reduction of mortality associated with AMI and has 
been approved since 2000.  Completed and ongoing clinical studies of tenecteplase are 
summarized in the Tenecteplase Investigator’s Brochure.   
Objectives 
 
Objective 1: The primary aim is to assess the impact of implementation of an EMS STEMI 
telehealth program on patient reperfusion times.  
 
We seek to improve consistent achievement of the reperfusion time goals from 0% to over 75% 
among STEMI patients in the Qualla Boundary. In Y1 we will begin measuring the project's      
impact on time from FMC to reperfusion. This will be measured using electronic health records 
from CTEMS and WFUSM and compared to the AHA time goal of reperfusion within 90 minutes. 
These times are routinely and reliably documented in the health records, and we have 
experience abstracting them in prior clinical trials. The baseline proportion of STEMI patients 
meeting the AHA reperfusion time goal in Qualla Boundary is 0%. In Y2 and Y3 we anticipate 
achieving the AHA time goal for reperfusion in at least 75% of STEMI encounters.  
 
Objective 2: Assess program uptake/adoption by Cherokee Tribal EMS paramedics.  
 
Our goal is to establish a successful telehealth connection in 90% of CTEMS STEMI calls. Telehealth 
communication will be conducted using Pulsara, a HIPAA compliant platform that can connect the EMS 
agency to a trained Physician 24/7/365 through a video, voice call, or chat. The EMS agency will be 
trained on the workflow after identification of patients and when to notify a physician for a further 

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patient evaluation and medication administration support.  We will review electronic health records 
from CTEMS and WFUSM for STEMI calls and determine if a telehealth connection was made.  
 
Methods and Measures 
 
Design 
We propose a pre-post evaluation of a planned clinical implementation of an EMS STEMI 
telehealth program.  To Improve the care for STEMI patients, a tele-health program will be 
implemented to provide an additional resource for Paramedics. The administration of 
Fibrinolytics is in the EMS formulary and considered standard of care. We will collect data from 
patients to assess the impact of the program and perform quality assurance. 
 
Setting 
During this initial phase of this telehealth program implementation, participation will be limited 
to patients in Cherokee, NC who receive 9-1-1 care from Cherokee Tribal EMS, in the future this 
may be scaled to additional counties.  
 
Subjects selection criteria 
Project participants will receive standard/usual care and will be identified for participation in 
electronic quality surveillance retrospectively. For patients identified for participation in this 
project/quality surveillance, minimal risk is expected from participation beyond that 
encountered in daily clinical practice, as these participants will receive standard care. 
● Inclusion Criteria 
All patients calling 9-1-1 in Qualla Boundary with possible STEMI as determined by 
the on scene paramedics will be included in the data. 
● Exclusion Criteria 
As this is a Quality Surveillance study, subjects will not be excluded.  
● Sample Size 
 Within the Qualla Boundary we estimate 20-25 patients with EMS calls for possible 
STEMI will be accrued each year. Our estimated sample size that is treated with 
TNK is 35 total patients.  
 
Interventions and Interactions 
For quality assurance data collection, participants will be identified retrospectively and data will 
be collected electronically using the EHR (EMS records, and WFBH medical records).  
A telehealth program will be implemented to support EMS in their care of patients with STEMIs 
including use of fibrinolytics if indicated. Fibrinolytics are in the North Carolina Office of EMS 
(NCOEMS) formulary and standard of care at Wilkes EMS.  
 
Outcome Measure(s) 
The primary outcome, FMC to reperfusion, will be measured using electronic health records from 
CTEMS and WFUSM. Patient reperfusion times will also be compared to the AHA time goal. 
Reperfusion times are routinely and reliably documented in both the EMS and hospital electronic 
health record. Our data team has ample experience collecting these measures in prior clinical trials.  

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For each STEMI patient in Qualla Boundary, we will obtain their FMC to reperfusion time and their sub-
component times (e.g., FMC to EKG time, EKG to activation time, activation to reperfusion [by 
fibrinolytic or PCI] time) and these will be recorded in a study database. Data will be aggregated from 
patients before (baseline) and after EMS telehealth STEMI program implementation. FMC to 
reperfusion time will be reported as a mean with standard deviation and as a median with interquartile 
range.  
● Qualla Boundary has a population greater than 5,000 with a local non-PCI 
hospital within its locality that serves locals and surrounding communities. 
Closest PCI centers utilized by CCTEMS are greater than 50 miles and 70 minutes 
away depending on dispatch location.  
● The expected end of the study is defined as the completion of the project, year 
of 2025. In addition, the Investigator may decide to terminate the study at any 
time. 
● The total length of the study, from screening of the first patient to the end of the 
study, is expected to be approximately 23 months.  
 
Analytical Plan 
 
Results will be analyzed initially using descriptive statistics. We anticipate time data to be non-
normally distributed, therefore reperfusion times pre- and post-implementation will be 
compared using Wilcoxon Rank Sum tests. In addition, a linear regression model will be used to 
quantify the association between telehealth program implementation and FMC to reperfusion 
time while adjusting for the patient’s demographics (sex, race, age, and ethnicity) and their 
distance from the tertiary care center. The proportion of patients meeting the AHA time goal 
will be reported in percentages with associated 95% confidence intervals before and after 
implementation. These proportions will be compared using a Chi-squared test. In addition, 
logistic regression models will assess association between telehealth program implementation 
and meeting AHA time goals while adjusting for potential confounders (as above). 
 
Human Subjects Protection 
 
Informed Consent 
 
Written informed consent will not be obtained.  This is a quality surveillance study and the risk 
of harm or discomfort that may occur as a result of taking part in this research study is not 
expected to be more than in daily life or from routine physical or psychological examinations or 
tests.  The rights and welfare of study will be protected through the use of measures to 
maintain the confidentiality of study information.  Study results will be presented or published 
in lieu of providing individual subjects additional information regarding the study. Patients will 
receive standard care (which following implementation in 2024 will include an EMS STEMI 
telehealth program). Data will be collected from paramedic records and the WFBH EMR. 
However, we are interested in publishing the findings of this implementation project. 
Therefore, this project meets the definition of human subjects’ research. 
 

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Request of a waiver of consent: 
1) The research involves no more than minimal risk to participants. The risk of harm or 
discomfort that may occur as a result of taking part in this research is not expected to be 
more than in daily life or from routine physical or psychological examinations or tests. 
Patients identified for participation in this study/quality surveillance will receive 
standard care. Administration of fibrinolytics is within the Scope of Practice and 
Protocols of Cherokee Tribal EMS. Therefore, the primary risk of participation is a 
breach in privacy and confidentiality. 
 
2) The waiver of informed consent will not adversely affect the rights and welfare of the 
participants.  The rights and welfare of participants will be protected through the use of 
measures to maintain the confidentiality of project information.   
 
3) The research could not practical     ly be carried out without the waiver of informed 
consent.  To determine the effect of the telehealth program it must be utilized in a “real 
world” prehospital chest pain patient population. Performing informed consent would 
threaten the validity of this evaluation by introducing a significant selection bias. 
Furthermore, having paramedics obtain consent in the field is not practical or safe as 
this would prolong transport time and delay patient care, potentially leading to a 
worsening of clinical outcomes. In addition, ambulance transport for patients with acute 
chest pain is anxiety provoking. These patients are usually very concerned about having 
a heart attack and thus may not be in the appropriate frame of mind to ethically 
participate in informed consent during emergency transport.  
 
4) Participants will give verbal consent for both the conversation with the Physician and the 
use of the platform Pulsara. Verbal consent for the use of the Pulsara platform will be 
obtained by the EMS provider. Once the physician is connected there will be a second 
verbal consent obtained for the conversation between the physician, EMS provider, and 
participant.   
 
5) Whenever appropriate, the subjects will be provided with additional information after 
participation.  Project results will be presented or published (if possible) in lieu of 
providing individual subjects additional information regarding the project.  
 
Confidentiality and Privacy 
Confidentiality will be protected by collecting only information needed to assess study 
outcomes, minimizing to the fullest extent possible the collection of any information that could 
directly identify subjects, and maintaining all study information in a secure manner.  Access to 
individually identifiable private information will be limited to those people required to access 
this information in order to conduct this project. This includes project team members, IRB, 
adjudication committee, and data monitors. 
 
The project database will contain a limited amount of individually identifiable private 
information in the form of whole date elements and medical record numbers. Each participant 

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will be assigned a unique sequential project identifier that will be linked to the participant’s 
research record and source documents through a log housed locally. Access to the entire 
project database will be limited to project team members at WFBMC who are involved in the 
trial management activities, including project team members, the institutional review board 
(IRB), adjudication committee, and data monitors. 
 
The full electronic database will contain the participant’s unique project identifier, full date 
elements, and medical record numbers, but will otherwise be clean of identifiers. A key will link 
the project identifier to participants’ personal identifiers. This key will be housed in the project 
binder or electronically in a secure project folder behind the medical center firewall. Access to 
data containing personal identifiers will be restricted to the project team members, IRB, 
adjudication committee, and data monitors. Data entry will be performed by trained research 
staff with valid confidentiality agreements. 
 
Our project team members have experience implementing an electronic process using a secure 
web-based data entry system for data collection and participant tracking. For this proposal, we 
will leverage forms and processes already in existence, along with our existing web 
infrastructure, REDCap. 
      
The web-based system allows research personnel to interact with data using web forms. The 
website will be designed with input from the research staff so that the workflow follows the 
protocol and is in line with how the quality surveillance will be conducted. Website activity will 
be monitored and audited for security purposes. Users may view detailed tracking and 
management information for each participant and/or by assessment time point. Once logged 
in, research staff may run reports, enter data into forms, and review and edit data. As data are 
entered, validations rules are applied before data are saved. Inconsistencies are noted for staff 
to resolve. Research staff can resolve many queries immediately, comparing the screen to the 
source, often cleaning the entire database record on the spot. For queries not immediately 
resolvable, warnings are displayed whenever the data entry screen is recalled.   
All access to the website will be logged and stored for auditing purposes.   
 
Following data collection subject identifying information will be destroyed at the earliest 
opportunity, consistent with data validation and study design, producing an anonymous 
analytical data set.  Data access will be limited to study staff.  Data and records will be kept 
locked and secured, with any computer data password protected.  No reference to any 
individual participant will appear in reports, presentations, or publications that may arise from 
the study. 
 
Data and Safety Monitoring 
The principal investigator will be responsible for the overall monitoring of the data and safety 
of study participants.  The principal investigator will be assisted by other members of the study 
staff. 
 
Safety 

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The safety plan for patients in this study is based on clinical experience with tenecteplase in 
completed and ongoing studies.  The anticipated important safety risks for tenecteplase are 
outlined below.  Please refer to the Tenecteplase Investigator's Brochure for a complete 
summary of safety information.  
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  Patients 
will undergo safety monitoring during the study, including assessment of the nature, frequency, 
and severity of adverse events.  In addition, guidelines for managing adverse events are 
provided below. 
Measures will be taken to ensure the safety of patients participating in this study, including the 
use of stringent inclusion and exclusion criteria and close monitoring of patients during the 
study.  Administration of tenecteplase will be performed in a monitored setting in which there 
is immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.   
Risks Associated with Tenecteplase 
Standard management of myocardial infarction should be implemented concomitantly with 
tenecteplase treatment.   
 
Arterial and venous punctures should be minimized.  Noncompressible arterial puncture must 
be avoided, and internal jugular and subclavian venous punctures should be avoided to 
minimize bleeding from the noncompressible sites.  In the event of serious bleeding, heparin 
and antiplatelet agents should be discontinued immediately and treated appropriately.  
Heparin effects can be reversed by protamine. 
Bleeding 
The most common complication encountered during tenecteplase therapy is bleeding. This may 
be either superficial from punctures or damaged blood vessels or internal bleeding at any site 
or body cavity.  Bleeding may result in life-threatening situations, permanent disability, or 
death.  
● The incidence of intracranial hemorrhage, especially symptomatic intracranial hemorrhage 
(sICH), in patients with AIS is higher in alteplase-treated patients than placebo-treated 
patients in published studies (for detailed information, see the alteplase United States 
Package Insert [USPI]) 
 
The type of bleeding associated with thrombolytic therapy can be divided into two broad 
categories: 
● Internal bleeding, involving intracranial and retroperitoneal sites, or the gastrointestinal, 
genitourinary, or respiratory tracts 
● Superficial or surface bleeding, observed mainly at vascular puncture and access sites (e.g., 
venous cutdowns, arterial punctures) or sites of recent surgical intervention 

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Management of Bleeding 
Patients will be excluded for the presence of conditions related to risks of bleeding. 
Should an arterial puncture be necessary during the first few hours following tenecteplase 
therapy, use an upper extremity vessel that is accessible to manual compression is preferable.  
Pressure should be applied for at least 30 minutes, a pressure dressing applied, and the 
puncture site checked frequently for evidence of bleeding. 
Each patient being considered for therapy with tenecteplase should be carefully evaluated and 
anticipated benefits weighed against potential risks associated with therapy. 
Guidelines for management of patients who develop bleeding are provided in Table 1.  
In addition, any intracranial hemorrhage events (symptomatic and/or asymptomatic), if not 
already reported as an SAE by the investigator, are considered non-serious adverse events of 
special interest for this study and should be reported and submitted to the Sponsor. 
Arrhythmias 
Coronary thrombolysis may result in arrhythmias associated with reperfusion.  These 
arrhythmias (such as sinus bradycardia, accelerated idioventricular rhythm, ventricular 
premature depolarizations, ventricular tachycardia, etc.) are not different from those often 
seen in the ordinary course of AMI and may be managed with standard antiarrhythmic 
measures.  It is recommended that anti-arrhythmic therapy for bradycardia and ventricular 
irritability be available when tenecteplase is administered. 
Thromboembolism 
The use of thrombolytics can increase the risk of thromboembolic events in patients with high 
likelihood of left heart thrombus, such as patients with mitral stenosis or atrial fibrillation. 
Cholesterol Embolization 
Cholesterol embolism has been reported rarely in patients treated with all types of 
thrombolytic agents; the true incidence is unknown.  This serious condition, which can be 
lethal, is also associated with invasive vascular procedures (e.g., cardiac catheterization, 
angiography, vascular surgery) and/or anticoagulant therapy.  Clinical features of cholesterol 
embolism may include livedo reticularis, “purple toe” syndrome, acute renal failure, 
gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal 
cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis. 
Use with Percutaneous Coronary Intervention 
In patients with ST segment elevation myocardial infarction, physicians should choose either 
thrombolysis or percutaneous coronary intervention (PCI) as the primary treatment strategy for 
reperfusion.  Rescue PCI if medically appropriate or subsequent elective PCI may be performed 
after administration of thrombolytic therapies; however, the optimal use of adjunctive 
antithrombotic and antiplatelet therapies in this setting is unknown. 

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Precautions 
Standard management of acute ischemic stroke should be implemented concomitantly with 
tenecteplase treatment.  Arterial and venous punctures should be minimized. Noncompressible 
arterial puncture must be avoided and internal jugular and subclavian venous punctures should 
be avoided to minimize bleeding from the noncompressible sites. In the event of serious 
bleeding, heparin and antiplatelet agents should be discontinued immediately.  Heparin effects 
can be reversed by protamine. 
Re-administration 
Readministration of plasminogen activators, including tenecteplase, to patients who have 
received prior plasminogen activator therapy has not been systematically studied.  Three of 487 
patients tested for antibody formation to tenecteplase had a positive antibody titer at 30 days.  
The data reflect the percentage of patients whose test results were considered positive for 
antibodies to tenecteplase in a radioimmunoprecipitation assay, and are highly dependent on 
the sensitivity and specificity of the assay.  Additionally, the observed incidence of antibody 
positivity in an assay may be influenced by several factors including sample handling, 
concomitant medications, and underlying disease.  For these reasons, comparison of the 
incidence of antibodies to tenecteplase with the incidence of antibodies to other products may 
be misleading.  Although sustained antibody formation in patients receiving one dose of 
tenecteplase has not been documented, readministration should be undertaken with caution. 
 
Hypersensitivity 
Hypersensitivity, including urticarial/anaphylactic reactions, have rarely (< 1%) been reported 
after administration of tenecteplase (e.g., anaphylaxis, angioedema, laryngeal edema, rash, and 
urticaria).  Monitor patients treated with tenecteplase during and for several hours after 
infusion.  If symptoms of hypersensitivity occur, appropriate therapy should be initiated. 
Drug Interactions 
Formal interaction studies of tenecteplase with other drugs have not been performed.  Patients 
studied in clinical trials of tenecteplase were routinely treated with heparin and aspirin.  
Anticoagulants (such as direct oral anticoagulants, heparin and vitamin K antagonists) and drugs 
that alter platelet function (such as acetylsalicylic acid, dipyridamole, and GP IIb/IIIa inhibitors) 
may increase the risk of bleeding if administered prior to, during, or after tenecteplase therapy. 
Drug/Laboratory Test Interactions 
During tenecteplase therapy, results of coagulation tests and/or measures of fibrinolytic activity 
may be unreliable unless specific precautions are taken to prevent in vitro artifacts.  
Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, 
remains active under in vitro conditions.  This can lead to degradation of fibrinogen in blood 
samples removed for analysis. 
Management of Patients Who Experience Adverse Events 

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Management Guidelines 
Guidelines for management of specific adverse events are outlined in Table 1. 
Table 1 
Guidelines for Management of Patients Who Experience Bleeding 
Event 
Action to Be Taken 
Bleeding 
● In the event of serious bleeding, heparin and antiplatelet 
agents should be discontinued immediately and treated 
appropriately.  Heparin effects can be reversed by 
protamine.  
● Intramuscular injections and nonessential handling of the 
patient should be avoided for the first few hours 
following treatment with tenecteplase.  
● Venipunctures should be performed and monitored 
carefully. 
● Should an arterial puncture be necessary during the first 
few hours following tenecteplase therapy, it is preferable 
to use an upper extremity vessel that is accessible to 
manual compression.  Pressure should be applied for at 
least 30 minutes, a pressure dressing applied, and the 
puncture site checked frequently for evidence of 
bleeding. 
 
Refer to Sections 5.2−5.4 for details on safety reporting (e.g., adverse events) for this study. 
SAFETY PARAMETERS AND DEFINITIONS 
Specification of Safety Variables 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) per protocol.  This includes all events of death and any study-specific 
issue of concern. 
Adverse Events 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational medicinal product 
(IMP) or other protocolimposed intervention, regardless of attribution. 
This includes the following: 
● 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with STEMI Care that were not 
present prior to the AE reporting period 

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● 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations) 
● 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention 
● 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period 
 
Serious Adverse Events 
An AE should be classified as an SAE if any of the following criteria are met: 
● 
It results in death (i.e., the AE actually causes or leads to death) 
● 
It is life-threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death.  It does not include an AE that, had it occurred in a more severe 
form, might have caused death.) 
● 
It requires or prolongs inpatient hospitalization 
● 
It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions) 
● 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP 
● 
It is considered a significant medical event by the investigator based on medical judgment 
(e.g., may jeopardize the subject or may require medical/surgical intervention to prevent 
one of the outcomes listed above) 
 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, are collected and reported to the FDA, appropriate IRB(s), and Genentech, Inc. 
in accordance with CFR 312.32 (IND Safety Reports).  
Reporting of Unanticipated Problems, Adverse Events or Deviations 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol 
changes will be promptly reported by the principal investigator or designated member of the 
research team to the IRB and sponsor or appropriate government agency if appropriate. 
Expected adverse events in this project are limited to a potential loss of confidentiality.  If a 
breach in confidentiality occurs, the event will be promptly reported to the IRB and other 
applicable regulatory agencies. The medical record will not be reviewed with the intent of 
detecting adverse events. In the event that an adverse event is identified during the chart 
review, the event will be recorded in the project records and IRB, sponsor, and other 
government agency event reporting criteria and guidelines will be followed. 

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Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has completed or 
discontinued study participation if attributed to prior tenecteplase exposure.  If the investigator 
should become aware of the development of cancer or a congenital anomaly in a subsequently 
conceived offspring of a female subject [add if applicable, including pregnancy occurring in the 
partner of a male study subject] who participated in the study, this should be reported as an 
SAE adequately to Genentech Patient Safety during the followup period. 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means, will be 
reported appropriately.  Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the 
tenecteplase (see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and administration of 
the tenecteplase, and the AE cannot be readily explained by the subject’s clinical state, 
intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of 
response to the tenecteplase or with similar treatments; and/or the AE abates or resolves upon 
discontinuation of the tenecteplase or dose reduction and, if applicable, reappears upon re-
challenge. 
No 
Evidence exists that the AE has an etiology other than the tenecteplase (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or 
the AE has no plausible temporal relationship to tenecteplase administration (e.g., cancer 
diagnosed 2 days after first dose of teneceteplase). 
Expected adverse events are those adverse events that are listed or characterized in the 
package insert (PI) or current Investigator’s Brochure (IB). 
Unexpected adverse events are those not listed in the PI or current IB or not identified.  This 
includes adverse events for which the specificity or severity is not consistent with the 
description in the PI or IB.  For example, under this definition, hepatic necrosis would be 
unexpected if the PI or IB only referred to elevated hepatic enzymes or hepatitis. 
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy. 

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PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE EVENTS 
ELICITING ADVERSE EVENT INFORMATION 
A consistent methodology for eliciting AEs at all subject evaluation time points should be 
adopted.  Examples of non-directive questions include: 
● 
"How have you felt since your last clinical visit?" 
● 
"Have you had any new or changed health problems since you were last here?" 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs.  
Avoid colloquialisms and abbreviations. 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, it is 
acceptable to report the information that is currently available.  If a diagnosis is subsequently 
established, it should be reported as follow-up information. 
 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 5.3.1), 
regardless of attribution, will be reported to the appropriate parties.  When recording a death, 
the event or condition that caused or contributed to the fatal outcome should be reported as 
the single medical concept.  If the cause of death is unknown and cannot be ascertained at the 
time of reporting, report “Unexplained Death.” 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study.  Such conditions 
should be reported as medical and surgical history.  A preexisting medical condition should be 
re-assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study.  When reporting such events, it is 
important to convey the concept that the preexisting condition has changed by including 
applicable descriptors (e.g., “more frequent headaches”). 
 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE.  If a subject is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE.  For example, if a subject is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE. 
Hospitalizations for the following reasons do not require reporting: 
● 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for preexisting conditions 

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● 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study, or 
● 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of 
the study 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0 ) will be used for assessing 
adverse event severity.  Below Table should be used for assessing severity for adverse events 
that are not specifically listed in the NCI CTCAE. 
Table 2 Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTCAE 
Grade Severity 
 
Pregnancy 
 
If a female subject becomes pregnant while receiving the study drug or within 90 days after the 
last dose of study drug, or if the female partner of a male study subject becomes pregnant 
while the study subject is receiving the study drug or within90 days, a report should be 
completed and expeditiously submitted to Genentech, Inc. Pregnancies will be followed-up 

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until the outcome of the pregnancy is known, whenever possible, based upon due diligence 
taken to obtain the follow-up information. Abortion, whether accidental, therapeutic, or 
spontaneous, should always be classified as serious, and expeditiously reported as an SAE. 
Similarly, any congenital anomaly/birth defect in a child born to a female subject exposed to 
the study drug should be reported as an SAE. 
 
AEs of Special Interest (AESIs) 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the 
product, for which ongoing monitoring and rapid communication by the Investigator to the 
Sponsor is required. Such an event might require further investigation in order to characterize 
and understand it. Depending on the nature of the event, rapid communication by the trial 
Sponsor to other parties (e.g., Regulatory Authorities) may also be warranted. 
Adverse events of special interest for this study include the following: 
• Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law: 
o Treatment-emergent ALT or AST > 3 x ULN in combination with total bilirubin > 2 
x ULN 
o Treatment-emergent ALT or AST > 3 x ULN in combination with clinical jaundice 
• Data related to a suspected transmission of an infectious agent by the study drug 
(STIAMP), as defined below: 
o Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected 
Other Special Situation Reports 
 
The following other Special Situations Reports (referred hereinafter to as “Special Situation 
Reports) should be collected even in the absence of an Adverse Event and transmitted to 
Genentech: 
 
● 
Data related to the Product usage during breastfeeding 
● 
Data related to overdose, abuse, misuse or medication error (including 
potentially exposed or intercepted medication errors), off-label use, occupational health, lack of 
efficacy, unexpected beneficial effects and drug interaction 

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● 
Data related to a suspected transmission of an infectious agent via a studied 
product 
● 
Cases of potential medicine-induced liver injury, as defined by Hy’s Law 
● 
In addition, reasonable attempts should be made to obtain and submit the age 
or age group of the patient, in order to be able to identify potential safety signals specific to a 
particular population’’ 
 
Product Complaints 
A product complaint is defined as any written or oral information received from a complainant 
that alleges deficiencies related to identity, quality, safety, strength, purity, reliability, 
durability, effectiveness, or performance of a product after it has been released and distributed 
to the commercial market or clinical trial. 
Exchange of Single Case Report with Genentech 
 
Dr. Simon Mahler will be responsible for collecting all protocol-defined Adverse Events 
(AEs)/Serious Adverse Events (SAEs) (related and not related to the product), pregnancy reports 
(including pregnancy occurring in the partner of a male study subject), other Special Situation 
reports, Non-Serious AESIs, Product Complaints (with or without an AE) where the patient has 
been exposed to the Product 
It is understood and agreed that Dr. Simon Mahler will perform adequate due diligence with 
regard to obtaining follow-up information on these events, if they are incomplete.  
In addition, reasonable attempts must be made to obtain and submit the age or age group of 
the patient in order to be able to identify potential safety signals specific to a particular 
population. 
The Dr. Simon Mahler agrees to allow requests for follow-up information from Genentech, for 
instance, in order to fulfill regulatory obligations, or where the requested information is not 
already routinely covered by standard follow-up activities (e.g. clarification of data 
discrepancies, or to request typical confirmatory laboratory data or batch numbers for biologics 
and other advanced therapies). Genentech will not contact the reporter directly for such data, 
but will route all such requests for follow-up to the provided Dr. Simon Mahler contact. It is 
understood and agreed that Dr. Simon Mahler will be responsible for the evaluation of all the 
case safety reports originating from the study. 
Transmission of these reports (initial and follow-up) will be either electronically via email or by 
fax to the following email address/fax number: 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
All Product Complaints without an AE should be reported via: 

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PC Hotline Number: (800) 334-0290 (M-F: 5 am to 5 pm PST) 
The MedWatch form should be sent to the Genentech contact specified above to report 
applicable events. 
 
Reporting Timeline for Applicable Events 
Transmission of the applicable event reports (initial and follow-up) will be sent within the 
timelines specified below: 
Type of Report  
Timelines  
Serious Adverse Events (related and not 
related to the Product) 
 
 
30 calendar days from awareness date 
 
Special Situation Reports (With or without AE 
and pregnancy) 
Product Complaints (With or without AE) 
AESI 
 
Dr. Simon Mahler will send to will forward quarterly listings of non-serious AEs originating from 
the Study to Genentech.  
Case Transmission Verification (CTV) of Single Case Reports 
The Parties will verify that all Single Case Reports have been adequately received by 
Genentech/Roche, via Dr. Simon Mahler emailing Genentech/Roche a quarterly Line Listing 
that includes all fields detailed in Appendix 2: Content Required in the CTV Line Listing , 
documenting Single Case Report(s) sent by Dr. Simon Mahler to Genentech/Roche in the 
preceding quarter. The quarterly Line Listing will be exchanged within seven (7) Calendar Days 
of the end of the quarter. Following CTV, any Single Case Report which has not been received 
by Genentech/Roche must be forwarded by Dr. Simon Mahler to Genentech/Roche within five 
(5) Calendar Days from the request by Genentech/Roche. 
 
At the end of the study a final cumulative case transmission verification report consisting of all 
the single case reports for the study will be sent to Genentech. 
Quarterly line listings and cumulative/final CTV should be sent to ctvistsa@gene.com. 
 
 
MedWatch 3500a Reporting Guidelines 

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In addition to completing appropriate patient demographic (Section A) and suspect medication 
information (Section C & D), the report should include the following information within the 
Event Description (Section B.5) of the MedWatch 3500A form: 
• Protocol number and title description  
• Description of event, severity, treatment, and outcome if known 
• Supportive laboratory results and diagnostics (Section B.6) 
• Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
Follow-Up Information 
• Additional information may be added to a previously submitted report by any of the 
following methods: 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form 
• Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B. initial, patient number), protocol description and number, if 
assigned, brief adverse event description, and notation that additional or follow-up 
information is being submitted (The patient identifiers are important so that the 
new information is added to the correct initial report) 
MedWatch 3500A (Mandatory Reporting) form is available at 
https://www.fda.gov/media/69876/download 
 
REPORTING TO REGULATORY AUTHORITIES 
Genentech/Roche as the Marketing Authorisation Holder (MAH) will be responsible for the 
reporting of Individual Case Safety Reports (ICSRs) from the Study to the Regulatory Authority 
in compliance with applicable regulations. 
Dr. Simon Mahler will be responsible for the distribution of safety information to its own 
investigators, where relevant, in accordance with local regulations. 
Dr. Simon Mahler will be responsible for the expedited reporting of safety reports originating 
from the Study to the Independent Ethics Committees/ Institutional Review Boards (IEC/IRB), 
where applicable. 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS ORIGINATING FROM PATIENT REPORTED 
OUTCOMES 
Although sites are not expected to review the PRO data, if physician/study personnel become 
aware of a potential adverse event during site review of the PRO questionnaire data, he/she 

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will determine whether the criteria for an adverse event have been met and, if so, these must 
be reported per the reporting format agreed as above. 
AGGREGATE REPORTS  
Dr. Simon Mahler will be responsible for the distribution of safety information to Site IRB:  
WFU Health Sciences IRB Office 
Phone: (336)716-4542 
Fax: (336)716-4480 
For questions related to safety reporting, please contact Genentech Patient Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
All summary reports submitted by the Sponsor-investigator to any health authority should also 
be sent to Genentech. Copies of such reports, as described below, should be emailed to 
Genentech at: ctvistsa@gene.com 
Dr. Simon Mahler will forward a copy of the Interim safety analysis 
 
AND 
 
Dr. Simon Mahler will forward a copy of the Publication to Genentech/Roche upon completion 
of the Study. 
 
Study Close-Out 
 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final study 
report). Additionally, any literature articles that are a result of the study should be sent to 
Genentech. Copies of such reports should be mailed to the assigned Clinical Operations contact 
for the study: 
 
Clinical Operations Contact Information Here: lytics-gsur@gene.com 
 
 
And to Genentech Patient Safety CTV oversight mail box at: ctvistsa@gene.com. 
 
Queries 
 

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Queries related to the Study will be answered by Dr. Simon Mahler. However, responses to all 
safety queries from regulatory authorities, Ethics Committees and Institutional Review Board or 
for publications will be discussed and coordinated between the Parties. The Parties agree that 
Genentech shall have the final say and control over safety queries relating to the Product. Dr. 
Simon Mahler agrees that it shall not answer such queries from regulatory authorities and 
other sources relating to the Product independently but shall redirect such queries to 
Genentech. 
 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent 
requests from Regulatory Authorities and/or IRB/IEC for information or review of data are met. 
The Parties will clearly indicate on the request the reason for urgency and the date by which a 
response is required. 
 
Signal Management and Risk Management  
 
Genentech is responsible for safety signal management (signal detection and/or evaluation) for 
their own Product. However, it is agreed that Dr. Simon Mahler as Sponsor of the Study, will be 
primarily responsible for assessment of the benefit-risk balance of the Study. 
 
If Dr. Simon Mahler issues a safety communication relevant for Genentech (i.e., a safety issue 
that notably impacts the benefit-risk balance of the Study and / or triggers any changes to the 
Study) this will be sent to Genentech within five (5) business days of its internal approval. 
 
As needed, Genentech will reasonably assist Dr. Simon Mahler  with signal and risk 
management activities related to the Product within the Study. 
 
Genentech will also provide Dr. Simon Mahler with any new relevant information that may 
modify or supplement known data regarding the Product (e.g., relevant Dear Investigator 
Letter).  
 
Compliance With Pharmacovigilance Agreement / Audit 
 
The Parties shall follow their own procedures for adherence to single case reporting timelines. 
Each Party shall monitor and, as applicable, request feedback from the other Party regarding 
single case report timeliness in accordance with its own procedures. The Parties agree to 
provide written responses in a timely manner to inquiries from the other Party regarding single 
case reports received outside the agreed upon Agreement timelines. If there is any detection of 
trends of increasing or persistent non-compliance to transmission timelines stipulated in this 
Agreement, both Parties agree to conduct ad hoc or institute a regular joint meeting to address 
the issue. In case of concerns related to non-compliance of processes, other than exchange 
timelines, with this Agreement, the Parties will jointly discuss and collaborate on clarifying and 
resolving the issues causing non-compliance. Every effort will be made by the non-compliant 
Party to solve the non-compliance issues and inform the other Party of the corrective and 
preventative actions taken. 

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Upon justified request, given sufficient notice of no less than sixty (60) calendar days, an audit 
under the provisions of this Agreement can be requested by either Party. The Parties will then 
discuss and agree in good faith upon the audit scope, agenda and execution of the audit. The 
requesting Party will bear the cost of the audit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 1. 
 
 
 
 
 
SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
 
AE / SAE FAX No: 650-238-6067 
 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[ ] - [ ] - [ ] 
 
 
SAE or Safety Reporting questions, contact Genentech Patient Safety: (888) 835-2555 
 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET 
 
 
 

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APPENDIX 2: Content Required in the CTV Line Listing 
 
The following fields must be populated by Dr. Simon Mahler in the CTV Line-Listing and sent 
to Genentech in an agreed format (e.g., Excel): 
 
● CTV Period 
● Product name 
● Protocol/Program number (if applicable) 
● Patient number/other identifier 
● Sponsor reference number of case 
● Submission date to Genentech 
● Patient initials, as applicable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 3 
 

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1. 
Cenko E, Yoon J, Kedev S, et al. Sex Differences in Outcomes After STEMI: Effect 
Modification by Treatment Strategy and Age. JAMA Intern Med. 05 2018;178(5):632-639. 
doi:10.1001/jamainternmed.2018.0514 
2. 
O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the 
management of ST-elevation myocardial infarction: a report of the American College of 
Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 
Circulation. Jan 29 2013;127(4):e362-425. doi:10.1161/CIR.0b013e3182742cf6 
3. 
De Luca G, Suryapranata H, Ottervanger JP, Antman EM. Time delay to treatment and 
mortality in primary angioplasty for acute myocardial infarction: every minute of delay counts. 
Circulation. Mar 16 2004;109(10):1223-5. doi:10.1161/01.CIR.0000121424.76486.20 
4. 
Mell HK, Mumma SN, Hiestand B, Carr BG, Holland T, Stopyra J. Emergency Medical 
Services Response Times in Rural, Suburban, and Urban Areas. JAMA Surg. Oct 1 
2017;152(10):983-984. doi:10.1001/jamasurg.2017.2230 
5. 
Hsia RY, Shen YC. Percutaneous Coronary Intervention in the United States: Risk Factors 
for Untimely Access. Health Serv Res. Apr 2016;51(2):592-609. doi:10.1111/1475-6773.12335 
6. 
Solhpour A, Chang KW, Arain SA, et al. Ischemic time is a better predictor than door-to-
balloon time for mortality and infarct size in ST-elevation myocardial infarction. Catheter 
Cardiovasc Interv. Jun 2016;87(7):1194-200. doi:10.1002/ccd.26230 
7. 
Smalling RW. Ischemic time: the new gold standard for ST-segment elevation myocardial 
infarction care. J Am Coll Cardiol. Dec 01 2009;54(23):2154-6. doi:10.1016/j.jacc.2009.08.023 
8. 
Stopyra JP, Crowe RP, Snavely AC, et al. Prehospital Time Disparities for Rural Patients 
with Suspected STEMI. Prehosp Emerg Care. Apr 27 2022:1-8. 
doi:10.1080/10903127.2022.2061660 
9. 
Ibánez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute 
myocardial infarction in patients presenting with ST-segment elevation. Rev Esp Cardiol (Engl 
Ed). 12 2017;70(12):1082. doi:10.1016/j.rec.2017.11.010 
10. 
De Bonis S, Salerno N, Bisignani A, et al. The Telecardiology Revolution: From Emergency 
Management to Daily Clinical Practice. J Clin Med. Mar 30 2022;11(7)doi:10.3390/jcm11071920 
11. 
Brunetti ND, Dellegrottaglie G, Lopriore C, et al. Prehospital telemedicine 
electrocardiogram triage for a regional public emergency medical service: is it worth it? A 
preliminary cost analysis. Clin Cardiol. Mar 2014;37(3):140-5. doi:10.1002/clc.22234