Ignite Creation Date:
2024-07-17 @ 11:27 AM
Last Modification Date:
2024-10-26 @ 3:33 PM
Study NCT ID:
NCT06475456
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-06-26
First Post:
2024-05-21
Brief Title:
Pilot Italian Cardiogenic Shock Initiative
Sponsor:
Fondazione GISE Onlus
Organization:
Fondazione GISE Onlus
Study Overview
Official Title:
SPOKE-HUB SHOCK PROTOCOL MANAGEMENT ACCORDING TO SCAI CLASS IN TURIN AND MILAN AREA
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ICSI
Brief Summary:
Study Objective To evaluate the impact on 30-day mortality of the adoption of a dedicated cardiogenic shock protocol designed to improve communication and collaboration among centres to timely refer Cardiogenic Shock CS patients from spoke to hub centres in Turin and Milan metropolitan Area Study Design A multicentre observational study consisting of
retrospective cohort including anonymous data from electronic health records of patients admitted with acute myocardial infarction complicated by cardiogenic shock AMICS SCAI class B-D from Jan 2016 until Dec 2019
prospective cohort including all consecutive patients admitted for AMICS SCAI class B-D in the study centres Study Population and Centres 768 patients admitted in spoke hospitals for AMICS 384 in each study cohort Four centres - two in Milan metropolitan Area and two in Turin - will serve as hub centres each one receiving CS patients from three referring spoke centres In total 16 centres will be involved in the study Follow-up period Up to 30 days from hospital admission Primary Endpoint The primary endpoint will be the short-term mortality defined as inhospital or 30-day mortality Secondary Endpoints
In-hospital or 30-day incidence of
1 stroke fatal or non-fatal or TIA
2 bleedings BARC classification 3
3 renal replacement therapy CVVH new onset of dialysis
4 vascular complications all complication needing intervention
5 non-fatal myocardial infarction
Door-to-support time
Onset of symptoms to support time Inclusion criteria Prospective cohort
For conscious patients signed and dated informed consent and consent to the processing of personal data
For unconscious patients informed consent signed and dated by the legal representative or a proxy or a relative The consent will be presented to the patient as soon the health conditions will improve
Aging more than 18 years
Patients admitted within 24h from the diagnosis of AMICS and SCAI SHOCK classification B to D
CS will be defined as
1 Systolic blood pressure SBP 90 mmHg or mean arterial pressure MAP 60 mmHg after an appropriate fluid challenge if there is no sign of overt fluid overload OR need of vasoactive agents to maintain SBP 90 mmHg or MAP 60 mmHg OR need of mechanical cardiac support MCS
2 At least one of the following criteriasigns of overt hypoperfusion mixed venous oxygen saturation 60 arterial lactates 2 mmolL oliguria 05 mlKgh for at least 6 hours
3 CS SCAI B-C-D following an acute myocardial infarction AMICS or acute decompensation of heart failure ADHFCS Exclusion criteria
1 Cardiac arrest with no quantifiable or longer than 10 minutes no-flow time or with refractory cardiac arrest defined as CPR lasting more than 20 2 Absolute contraindication to mechanical circulatory support devices 3 CS due to other aetiology apart from the ones in inclusion criteria as well as SCAI A and E before device positioning 4 Age less than 18 years 5 Life expectancy 1 year due to other reason than cardiogenic shock Study Timetable Retrospective data collection Jan 2016 until Dec 2019 Date of first enrolment planned September 2024 Duration of recruitment 24 months Follow-up period 30 days Statistical methods A sample size of 768 patients 384 in each arm is required to provide the study an 80 power to detect superiority in the primary endpoint with an alpha error set at 005 and assuming 30-day mortality estimates of 48 in the pre-protocol group and 38 in group post protocol
retrospective cohort including anonymous data from electronic health records of patients admitted with acute myocardial infarction complicated by cardiogenic shock AMICS SCAI class B-D from Jan 2016 until Dec 2019
prospective cohort including all consecutive patients admitted for AMICS SCAI class B-D in the study centres Study Population and Centres 768 patients admitted in spoke hospitals for AMICS 384 in each study cohort Four centres - two in Milan metropolitan Area and two in Turin - will serve as hub centres each one receiving CS patients from three referring spoke centres In total 16 centres will be involved in the study Follow-up period Up to 30 days from hospital admission Primary Endpoint The primary endpoint will be the short-term mortality defined as inhospital or 30-day mortality Secondary Endpoints
In-hospital or 30-day incidence of
1 stroke fatal or non-fatal or TIA
2 bleedings BARC classification 3
3 renal replacement therapy CVVH new onset of dialysis
4 vascular complications all complication needing intervention
5 non-fatal myocardial infarction
Door-to-support time
Onset of symptoms to support time Inclusion criteria Prospective cohort
For conscious patients signed and dated informed consent and consent to the processing of personal data
For unconscious patients informed consent signed and dated by the legal representative or a proxy or a relative The consent will be presented to the patient as soon the health conditions will improve
Aging more than 18 years
Patients admitted within 24h from the diagnosis of AMICS and SCAI SHOCK classification B to D
CS will be defined as
1 Systolic blood pressure SBP 90 mmHg or mean arterial pressure MAP 60 mmHg after an appropriate fluid challenge if there is no sign of overt fluid overload OR need of vasoactive agents to maintain SBP 90 mmHg or MAP 60 mmHg OR need of mechanical cardiac support MCS
2 At least one of the following criteriasigns of overt hypoperfusion mixed venous oxygen saturation 60 arterial lactates 2 mmolL oliguria 05 mlKgh for at least 6 hours
3 CS SCAI B-C-D following an acute myocardial infarction AMICS or acute decompensation of heart failure ADHFCS Exclusion criteria
1 Cardiac arrest with no quantifiable or longer than 10 minutes no-flow time or with refractory cardiac arrest defined as CPR lasting more than 20 2 Absolute contraindication to mechanical circulatory support devices 3 CS due to other aetiology apart from the ones in inclusion criteria as well as SCAI A and E before device positioning 4 Age less than 18 years 5 Life expectancy 1 year due to other reason than cardiogenic shock Study Timetable Retrospective data collection Jan 2016 until Dec 2019 Date of first enrolment planned September 2024 Duration of recruitment 24 months Follow-up period 30 days Statistical methods A sample size of 768 patients 384 in each arm is required to provide the study an 80 power to detect superiority in the primary endpoint with an alpha error set at 005 and assuming 30-day mortality estimates of 48 in the pre-protocol group and 38 in group post protocol
Detailed Description:
Background and rationale Acute myocardial infarction complicated by cardiogenic shock AMICS is the leading cause of inhospital mortality in acute myocardial infarctions AMI occurs in up to 10 of cases and is increasingly frequent 23 Primary percutaneous coronary intervention pPCI is the cornerstone of treatment for AMI complicated by CS AMICS and its routine use is associated with a long-term survival benefit4 However despite innovations in pharmacologic and device-based therapies and systems of care in-hospital and 30-day mortality in AMICS remain high 50 to 70 5 To address this survival plateau percutaneous mechanical circulatory support devices pMCS have been introduced in this clinical setting 6-8 Unfortunately these technologies are restricted to tertiary hub centres with specific expertise selection and management As a result shock centres have developed internal protocols to timely manage cardiogenic shock patients Nevertheless spoke centres frequently lack dedicated shock protocols for correct and timely management and refer AMICS patients to hub centres especially in the early phase of the acute presentation On the other side a standardized approach to cardiogenic shock performed by a shock team has been demonstrated to have a significant impact on in-hospital and 1-month mortality The Hub-and-Spoke model is based on the current model for STEMI trauma and stroke referral systems9 Studies including patients receiving ECMO and LVADs 1011 have all demonstrated better outcomes in higher volume facilities This model can potentially contribute to concentrating resources in each region The key to the success of the hub and spoke model is the close collaboration between the hub and the spoke centres to develop common protocols and provide training for their effective implementation 12 Recent experiences in the US demonstrated how correct management among Hub and Spoke centres may improve the outcomes of the AMICS patients admitted at Emergency Departments of the spoke centres
The Spoke and Hub network is a consolidated reality in the Italian sanitary system since the primary PCI networkintroduction for STEMI patients at the end of the 1990s This approach has been proposed in the last few years also for more complex clinical scenarios such as cardiogenic shock
The implementation of a hub and spoke network for the management of cardiogenic shock offers significant advantages as the opportunity to benefit from a specialized shock team and the maximize the implementation of mechanical circulatory support Having a dedicated multidisciplinary cardiogenic shock team within a referral centre hub is crucial Clinical studies have demonstrated that the timely activation of a multidisciplinary team including interventional cardiologists cardiothoracic surgeons and intensivists can dramatically reduce mortality associated with this critical condition13 The speed of intervention and the team and expertise in performing life-saving procedures such as pPCI or the implantation and management of ventricular assist devices are determining factors to improve patient survival
The hub and spoke network also offer the possibility to use more advanced medical therapy andor mechanical circulatory support and to serve as bridge to recovery or bridge to permanent ventricular assist device or heart transplantation In fact patients with cardiogenic shock might benefit from temporary and or permanent ventricular assist devices VAD The availability of these devices in hub centres allows for more effective management and continuous monitoring of critically ill patients14
Timely access to these technologies can significantly increase the chances of hemodynamic stabilization and recovery
In conclusion a hub and spoke network for cardiogenic shock offers an integrated and specialized approach that can significantly improve the clinical outcome of patients both through the presence of an expert team and through the optimization of mechanical circulatory support
However although an informal agreement already exists among hub and spoke centres a consolidated network it is not standardized in term of patient stratification and communication between physicians of different hospitals
Therefore the aim of the spoke-hub cardiogenic shock protocol is to test whether in a real-world setting the use of a prespecified shock management protocol improving communication and collaboration among centres to timely refer AMICS patients from spoke to hub centres can reduce the incidence of in hospital and 30-day mortality A correct transfer protocol of selected patients will extend the implementation of dedicated and complex cardiogenic shock treatments to patients initially admitted to spoke centres this protocol must be adapted according to the local health care organization and economic availability in each area or country This will help to provide an equal access to care for CS patients in the metropolitan area and is expected to improve their outcomes This study will evaluate the impact on in-hospital or 30-day mortality of the use of a prespecified shock management protocol improving communication and collaboration among centres in the same area to timely refer CS patients from spoke to hub centres in hospital networks in Turin and Milan metropolitan Area
21 Hub and spoke network literature review The creation of hub and spoke networks has demonstrated a significant benefit on mortality in various cardiovascular acute care settings greatly improving the management of complex patients In both STEMI and stroke the presence of hub and spoke networks has enabled easier communication between referral centres and the periphery to improve clinical management of the patient Preliminary data regarding the impact of the hub and spoke-integrated protocols regarding CS have been published by several groups
Daniel Lu et al 13 compared the outcomes of CS patients among three cohorts A direct admissions to spokes B direct admissions to hubs and C interhospital transfer to hubs The authors stratified all consecutive patients enrolled in their CS registry Nationwide Readmissions Database 2010 - 2014 A total of 130 656 317 patients with CS were directly admitted to spokes 253 234 614 were directly admitted to hubs and 28 777 70 were transferred to hubs Similarly to the Italian health care organization most of the included centres were spoke centres in sub-urban regions with limited access to mechanical support devices and low volume for PCI while hub centres were about 30 and mainly in metropolitan areas CS mortality was 478 at spoke hospitals and was lower at hub hospitals both for direct admissions 393 and transferred 334 patients On multivariable analysis direct admission to CS hubs odds ratio OR 086 95 confidence interval CI 084-089 and transfer to hubs OR 072 95 CI 069-076 were both associated with lower mortality The authors conclude that treatment of CS at transfer hubs was associated with significantly lower mortality within this large real-world sample Another experience has been reported by WellStar Medical Center15 and consists of the implementation of the hub-and-spoke model with a cardiogenic shock algorithm Well-Star Kennestone Regional Medical Centre served as the hub it is a highvolume centre for of cardiogenic shock with 250 STEMIs per year and 24-hour cardiology critical care expertise cardiac surgery and advanced heart failure therapies for patients in need of more advanced care When WellStar implemented its hub-and-spoke model the survival rate for AMI-CS was at about 50 percent consistent with national averages Within a few months survival rates raised to 60 and up to 70
A further example of the effectiveness of optimal protocols applications in the care of patients presenting with CS comes from the experience described in the Japanese registry by Dr Ako et al who analysed 593 consecutive AMICS patients from the J-PVAD registry and their cumulative 30-day survival and safety profiles The overall 30-day survival was 809 when microaxial flow pumps were used These results were obtained with a strict application of the enrolment protocol16 Tehrani et al 14 compared the outcomes of CS patients initially admitted to spoke versus hub hospitals within a regional care network The Inova Health System Regionalized Care Network for Cardiogenic Shock The authors stratified all consecutive patients enrolled in their CS registry January 2017 to December 2019 by first admission to a spoke versus hub hospitals Of 520 CS patients more than half initially presented to spoke hospitals In their analysis patients first admitted to hub centres were more often supported with pVAD 44 vs 11 P amplt 001 and veno-arterial extracorporeal membrane oxygenation 13 vs 0 P amplt 001 Initial presentation to a spoke was not associated with increased risk-adjusted 30-day mortality bleeding or stroke The authors conclude that spoke and hub patients experienced similar short-term outcomes within a regionalized CS network
In all these experiences the applied protocol was promoting a prompt stratification and diagnosis of SCAI shock class recognition of right ventricular failure use of pVADs when indicated - as soon as possible down titration of inotropic agents prompt upscale of mechanical cardiac support if needed bridge to recovery and or permanent VAD and or heart transplantation Recently it was published by Lombardy region a local guideline DGR N XII 1117 meeting date 16102023 about acute heart failurecardiogenic shock network identifying in Milano area two hub centres IRCCS San Raffaele ASST Grande Ospedale Metropolitano Niguarda whom the spoke centre should refer to Nevertheless this network system is not nowadays applied in our country and the Italian healthcare system is still lacking a CS Network The optimal strategy to promote standardized care and improved outcomes across regional CS networks deserve further investigation 22 Creation of hub and spoke network A hub and spoke network in cardiogenic shock facilitates the rapid transfer of patients to specialized tertiary care centres When a patient presents with cardiogenic shock at a spoke hospital immediate hemodynamic stabilization is the priority The network communication channels enable rapid consultation with the hub where specialised cardiac teams evaluate the patient condition remotely and provide expert recommendations If advanced interventions such as pPCI or mechanical circulatory support are required the patient is promptly transferred to the hub This expedited transfer process ensures that patients receive timely access to specialized care reducing treatment delays and improving the chances of a favourable outcome
A hub and spoke network establishes regional centres of excellence in the management of cardiogenic shock The hub acts as the central facility equipped with advanced cardiac interventions highly skilled healthcare professionals and state-of-the-art infrastructure This concentration of expertise allows for specialised care that may not be available at smaller spoke hospitals By designating specific hubs patients have improved access to specialized resources including cardiac catheterization laboratories advanced imaging technologies and multidisciplinary CS teams trained in managing complex cases of cardiogenic shock These regional centres of excellence ensure that patients are directed to facilities with the highest level of expertise increasing the likelihood of successful treatment and improved patient outcomes
Cardiogenic shock patients often face geographic disparities when accessing specialized care especially in rural or remote areas A hub and spoke network addresses this challenge by bringing specialized services closer to patients locations The spoke hospitals act as local access points providing initial stabilization and interventions Through efficient transfer protocols patients can be quickly transported to the hub bypassing the need for long-distance travel This reduces the burden on patients and their families while minimizing delays in receiving critical care By bridging the geographical gap the hub and spoke network ensures that patients with cardiogenic shock regardless of their location can access specialised care promptly leading to improved outcomes and potentially saving lives
The hub and spoke model promotes effective coordination and communication between healthcare providers involved in the care of cardiogenic shock patients Communication channels are established to facilitate real-time consultation and collaboration between spoke hospitals and the hub This seamless exchange of information allows for accurate assessment of patient conditions and prompt decision-making regarding transfer and specialized interventions Moreover the network encourages regular meetings case discussions and knowledge sharing fostering continuous education and professional development among healthcare teams By streamlining communication the hub and spoke network enhances the overall quality of care and ensures that patients with cardiogenic shock benefit from the collective expertise of the network healthcare professionals
3 Objectives and hypotheses of the study The main objective of this study is to compare in hospital-30 days clinical outcome of patients with AMICS who were admitted in spoke centres in a historical retrospective vs prospective cohort The main hypothesis of the study is that the time factor as well as the presence of a multidisciplinary CS team is crucial in the management and treatment of cardiogenic shock Patients who can benefit from circulatory support through medication andor mechanical support the earlier they receiv treatment the better their outcome Thus a constant communication between hub and spoke centres would allow early identification of patients at risk of unfavourable evolution and enable faster treatment of them
31 Justification of the study design The study includes a prospective and a retrospective cohort This study design will allow us to compare the impact on 30 days mortality of patients admitted with AMICS in study centres following the adoption of a dedicated protocol designed to improve communication and collaboration among centres to timely refer such patients from spoke to hub centres prospective cohort as compared to prior practise in the same centres not adopting such a protocol retrospective cohort These data will be extremely useful to assess whether there is a clinical benefit for CS patients following the creation of the Hub and Spoke network for AMICS
32 Endpoints Primary and clinical secondary endpoints will be adjudicated by an independent Clinical Event Adjudication Committee 321 Primary Endpoint The primary endpoint is all-cause mortality in-hospital or up to30-days Overall all-cause mortality is indisputable and cannot be subject to subjective interpretation and is considered the gold standard for demonstrating clinical benefit The relatively short follow-up will minimize the competing risk that death is caused conditions other than CS 322 Secondary Endpoints
The secondary endpoints are so defined
In-hospital or 30-days incidence of adjudicated stroke fatal or non-fatal or TIA
In-hospital or 30-days incidence of bleedings to classify bleeding we use BARC classification in the endpoints we include only bleedings with a BARC score greater than or equal to 3
In-hospital or 30-days incidence of renal replacement therapy need for at least one cycle of CVVH or the initiation of dialysis therapy
In-hospital or 30-days incidence of vascular complications as vascular complications we refer to all those complications requiring medical intervention referring to vascular diagnostic andor therapeutic accesses
In-hospital or 30-days incidence of non-fatal myocardial infarction excluding any presenting event Non-fatal was defined according to the definition of NSTE-ACS or STE-ACS respectively 17
Door-to-support time indicates the time from patient presentation at a hub or spoke center to the start of hemodynamic support with MCS
The onset of symptoms-to-support time indicates the time from the onset of clinical symptoms reported by the patient to the start of hemodynamic support with MCS 4 Study Design This will be an observational multicentre study including consecutive patients admitted in the spoke centres with CS SCAI classification B-D in the retrospective cohort from 2016 to 2019 and in the prospective cohort from 2024 to 2026 Four centres - two in Milan metropolitan Area and two in Turin - will serve as hub centres each one receiving CS patients from three referring spoke centres In total 16 centres will be involved in the study In the retrospective cohort the information will be derived from Diagnosis Related Groups DRGs see appendix only anonymous data will be collected In the prospective cohort a prespecified protocol following the current ESC guidelines on Acute and Chronic Heart Failure17 improving communication and collaboration among centres in the same area to timely refer CS patients from spoke to hub centres will be adopted allocating patients referred for advanced shock treatment from a spoke to a hub centre The patients who will fulfil the following inclusion criteria will be enrolled retrospectively and prospectively 41 Study Population Patients presenting with cardiogenic shock SCAI B to D as defined in inclusion criteria as shown below 42 Subject Selection 421 Inclusion Criteria
All subjects participating in this clinical trial must meet the following criteria
Prospective cohort
For conscious patients signed and dated informed consent and consent to the processing of personal data
For unconscious patients informed consent signed and dated by the legal representative or a proxy or a relative The consent will be presented to the patient as soon the health conditions will improve Aging 18
CS will be defined as
1 Systolic blood pressure SBP 90 mmHg or mean arterial pressure MAP 60 mmHg after an appropriate fluid challenge if there is no sign of overt fluid overload OR need of vasoactive agents to maintain SBP 90 mmHg or MAP 60 mmHg OR need of MCS
2 At least one of the following criteriasigns of overt hypoperfusion mixed venous oxygen saturation 60 arterial lactates 2 mmolL oliguria 05 mlKgh for at least 6 hours
3 CS following an acute myocardial infarction AMICS or acute decompensation of heart failure ADHF-CS 422 Exclusion Criteria
Patients will be excluded if any of the following conditions apply
1 Cardiac arrest with no quantifiable or longer than 10 minutes no-flow time or with refractory cardiac arrest as defined by CPR prolonging for more than 20
2 Absolute contraindication to support devices
3 CS due to other aetiology apart from the ones in inclusion criteria as well as SCAI A and E before device positioning
4 Age greater than 75-year-old
5 Life expectancy 1 year due to other reason than cardiogenic shock 5 Study procedures 51 Hub and spoke centre definitions
The Hub centre is frequently a 3rd level Hospital where there is the availability of
CS team 247
PCI service 247
Dedicated CCU
pVAD availability and extensive expertise in management 247 as well as mobile ECMO team
Cardiac surgery backup LVAD capabilityheart transplant
Cardiac Shock team The shock team is a multidisciplinary team dedicated to optimizing the care of Cardiogenic shock patients via
1 Rapid identification
2 Coordinated consultation
3 Early transferadmission to cardiac
4 ICU Cath Lab or Operating room It is composed by Interventional Cardiologist Cardiac Surgeon Advanced Heart failure specialist Intensivists and Anesthesiologists
The Spoke centre is frequently
1st level Hospital with dedicated CCU
2nd level Hospital with dedicated CCU and with some pVAD expertise
The spoke centres in each area that will be included in the study have to fulfil the following criteria
24h cath lab for primary PCI
already an informal patient transferal protocol with the hub center
less than 30 km of distance 52 Communication Protocol The following communication protocol is based on guidelines and cardiogenic shock consensus 1 its aim is to improve physicians communication and guidelines adherence and in any situation can overcome the physicians judgment
521 Communication protocol 1 Stepwise checklist application for the on-call cardiologist at the spoke centre according to SCAI class 5211 CS Diagnosis classification and exclusion criteria 5213 WHO activates the Shock Team
1 Emergency department
2 Other units in the hospital eg Cath lab or ICUs
3 Spoke centre cardiology department The efferent unit will call the shock team on a dedicated phone number 522 Protocol 2 stepwise checklist for the on-call cardiologist at the hub centre Communication between the spoke and hub centres should be performed at the time of diagnosis or in case of worsening after two consecutive worsening evaluation at 30 min time difference
After reaching consensus on transfer to hub centre activation of CS team
CS management according to the local hub protocol 523 Patient transfer between spoke and hub centres After the case discussion and bilateral agreement the patient will be transferred from the spoke to the hub centre according to the local protocol by a dedicated ambulance system with a cardiologist andor anesthesiologist onboard In case of life threatening hemodynamic instability of the patients a dedicated team of the hub centre may place a pVAD at the spoke centre for a protected transfer In this perspective all the data regarding the transportation duration also considering the time of day day or night will be collected to evaluate the impact of time and distance between the spoke and the hub centres 524 Hub centres management protocol The hub centres will have a shared management protocol according to current ST segment elevation non-ST segment elevation myocardial infarction guidelines18 Acute heart failure and pVAD implantation recommendation19 CS phenotypisation will be performed according to invasive or not invasive hemodynamic evaluation
6 Settings and locations for data collection For prospective data collection baseline clinical characteristics clinical examinations and in-hospital procedures of the patients are collected during their hospitalization by dedicated physicians The data regarding the patients that will be transferred from spoke to hub centers will be collected from the spoke andor the hub according to the role in the clinical management of the patient
Need for MCS timing of device insertion size of device extent of support as well as optimal duration of therapy will also be recorded Special attention will be given to the documentation of the patients clinical status regarding morbidity and mortality major adverse cardiac cerebrovascular events MACCE such as stroke or TIA bleedings cardiac ischemic events and vascular complications as well as renal replacement therapy
The information will be derived from the hospital clinical charts up to 30 days from admission and recorded in the electronic CRF of the study No intervention nor changes in therapeutic strategies and decisions will be implemented for the purpose of the study For the retrospective data collection DRG code will be used in order to select cases affected by CS and data collected in anonymous fashion Only data related to the clinical outcome associated to the DRG will be retrieved from hospital registries without any personal data DRG codes of interest for the study are reported in Appendix 1 7 Statistical considerations Outcomes will be compared between the retrospective cohort and the prospective cohort
Targets for analysis will focus on improving outcomes and quality of care Specifically assessing morbidity and mortality need for MCS timing of device insertion size of device extent of support as well as optimal duration of therapy are all opportunities to expand the appropriate use and understanding of the role of hemodynamic support 71 Determination of Sample Size A sample size of 768 patients 384 in each cohort is required to provide the study an 80 power to detect superiority in the primary endpoint with an alpha error set at 005 and assuming 30-day mortality estimates of 48 in the historical cohort and 38 in the prospective cohort
A 48 30-day death rate was calculated based on the mean mortality of SCAI SHOCK patients Class C-D as reported by previous metanalysis19 while 38 for the prospective cohort is based on the recently published papers 20-21 that evaluated similar outcomes in USA area after the improvement of the hub-spoke network Considering a 10 of patient loss due to consent unavailabilitywithdrawal the total number of screened patients will be 845 72 General Statistical Approach Descriptive statistics mean with standard deviation minimum and maximum median with the first and third quartile and 95 confidence interval will be calculated for quantitative variables For qualitative variables counts and percentages will be provided together with the 95 confidence interval In calculation of percentages patients with missing data will not be considered unless otherwise specified All baseline characteristics will be summarized The baseline value for each patient is defined as the last available value prior to spoke hospital admission A detailed Statistical Analysis Plan will be developed 721 Main Analysis Comparisons will be made via Students t-test Wilcoxon rank sum test 1-way analysis of variance chi-square or Fishers exact tests where appropriate To determine the potential relationship between site of initial triage and the primary and secondary outcomes we will fit multivariable logistic regression models which adjusted for clinical and hemodynamic variables historically associated with outcomes in CS SCAI CS stage C vs D-E age per 5 years duration of vasopressors minutes female sex diabetes baseline log lactate and log cardiac power output CPO measurements MCS use haemolysis and dialysis We will compare the risk of primary and secondary outcomes in spoke vs hub patients and calculate adjusted ORs with corresponding 95 Cis for the primary and secondary outcomes Statistical significance is defined as a P value amplt005 for 2- sided tests All analyses are performed using R version 402 software R Foundation for Statistical Computing 7211 Prespecified sub-analysis Prespecified sub-analysis according to the time between symptoms onsetpPCI to pVAD placement will be performed
Pre-specified supplementary analysis
1 The analysis will be performed with artificial intelligence methods to create a risk stratification model to increase the protocol efficiency and patients selection to be transferred
2 Protocol adherence in both spoke and hub center will be evaluated
3 Spoke center misdiagnosis for CS 722 Safety Analysis Adverse Events AE occurred to the patients and collected in the e-CRF will be coded to a Preferred Term PT and associated System-Organ Class according to the most recent version of the MedDRA dictionary before analysis Patients will be counted only once in each system organ class category and only once in each preferred term category All adverse events will be summarized by presenting the number and percentage of patients having any adverse event and having at least one serious adverse event For quantitative safety parameters descriptive statistics will be used to summarise results and change from baseline values Concomitant medications will be collected in the CRF and summarised by number and percentages n 8 Data management Data collection will be carried out by means of Electronic Data Capture EDC systems whereby data recorded in an electronic CRF e-CRF are directly registered in the study database The e-CRF for the study will be provided by the CRO Mediolanum Cardio Research Italy Main characteristics of the EDC system are
compliance with FDA 21 CFR part 11 requirements and guidelines concerning security and data protection
multi-user and simultaneous data entry
intuitive friendly web forms
browsers Edge Google Chrome - preferred one - Safari and Opera
access control and advanced user management
advanced user profiling management and customization
Audit Trail tracking all user operations eg visited pages user data audit patients and centres audit CRF data audit
CRF source verified data locking at visit page single variable levels
off-line and on-line control of data plausibility and consistency
automatic and manual query generation
supervision and validation of solved queries optional
e-monitoring tools
documentation area protocols manuals etc
production of blank and annotated CRF
use of ad hoc medical dictionaries MedDRA WHO etc
exporting data to SAS and Excel format
graphic reports and descriptive statistics
production of SAEMACCE listings
alert email new patient new SAE etc
SAS clinical data base
dedicated section for upload of study documents Security
Hosting server in a secure Web farm in Italy under 7x24 monitoring
Server protected by firewall to prevent unauthorized access
Secure data transmission adopted using 256-bit SSL HTTPS the module and the relative Certificate acquired from Thawte Certification Authority
User authentication through complex personal password
Session timeout after 15 minutes inactivity
Redundant hardware
Redundant daily backups Only the study Investigators will have access rights to enter and to modify the data It is the responsibility of the Investigator to maintain adequate and accurate e-CRFs to record all observations and other data pertinent to the clinical investigation Appropriate edit checks will be developed to identify the discrepancies in the entered data embedded in the database to ensure data validity Discrepancies may be due to inconsistent data missing data range checks and deviations from the protocol The data validation process will be run every night and queries released in the e-CRF for identifying discrepancies These discrepancies queries will be resolved by investigators after logging into the system It is the Investigators responsibility to respond by confirming or modifying the data questioned Data management will be in accordance with the SOPs of the CRO Ongoing quality control of data processing is undertaken at regular intervals during the course of the study A study-specific data management plan will be produced describing the data entry and data tracking guidelines quality control measures discrepancy management data transferextraction and database locking guidelines
Coding of medical terms and medications will be performed using MedDRA and the WHO Drug Dictionary respectively
The Spoke and Hub network is a consolidated reality in the Italian sanitary system since the primary PCI networkintroduction for STEMI patients at the end of the 1990s This approach has been proposed in the last few years also for more complex clinical scenarios such as cardiogenic shock
The implementation of a hub and spoke network for the management of cardiogenic shock offers significant advantages as the opportunity to benefit from a specialized shock team and the maximize the implementation of mechanical circulatory support Having a dedicated multidisciplinary cardiogenic shock team within a referral centre hub is crucial Clinical studies have demonstrated that the timely activation of a multidisciplinary team including interventional cardiologists cardiothoracic surgeons and intensivists can dramatically reduce mortality associated with this critical condition13 The speed of intervention and the team and expertise in performing life-saving procedures such as pPCI or the implantation and management of ventricular assist devices are determining factors to improve patient survival
The hub and spoke network also offer the possibility to use more advanced medical therapy andor mechanical circulatory support and to serve as bridge to recovery or bridge to permanent ventricular assist device or heart transplantation In fact patients with cardiogenic shock might benefit from temporary and or permanent ventricular assist devices VAD The availability of these devices in hub centres allows for more effective management and continuous monitoring of critically ill patients14
Timely access to these technologies can significantly increase the chances of hemodynamic stabilization and recovery
In conclusion a hub and spoke network for cardiogenic shock offers an integrated and specialized approach that can significantly improve the clinical outcome of patients both through the presence of an expert team and through the optimization of mechanical circulatory support
However although an informal agreement already exists among hub and spoke centres a consolidated network it is not standardized in term of patient stratification and communication between physicians of different hospitals
Therefore the aim of the spoke-hub cardiogenic shock protocol is to test whether in a real-world setting the use of a prespecified shock management protocol improving communication and collaboration among centres to timely refer AMICS patients from spoke to hub centres can reduce the incidence of in hospital and 30-day mortality A correct transfer protocol of selected patients will extend the implementation of dedicated and complex cardiogenic shock treatments to patients initially admitted to spoke centres this protocol must be adapted according to the local health care organization and economic availability in each area or country This will help to provide an equal access to care for CS patients in the metropolitan area and is expected to improve their outcomes This study will evaluate the impact on in-hospital or 30-day mortality of the use of a prespecified shock management protocol improving communication and collaboration among centres in the same area to timely refer CS patients from spoke to hub centres in hospital networks in Turin and Milan metropolitan Area
21 Hub and spoke network literature review The creation of hub and spoke networks has demonstrated a significant benefit on mortality in various cardiovascular acute care settings greatly improving the management of complex patients In both STEMI and stroke the presence of hub and spoke networks has enabled easier communication between referral centres and the periphery to improve clinical management of the patient Preliminary data regarding the impact of the hub and spoke-integrated protocols regarding CS have been published by several groups
Daniel Lu et al 13 compared the outcomes of CS patients among three cohorts A direct admissions to spokes B direct admissions to hubs and C interhospital transfer to hubs The authors stratified all consecutive patients enrolled in their CS registry Nationwide Readmissions Database 2010 - 2014 A total of 130 656 317 patients with CS were directly admitted to spokes 253 234 614 were directly admitted to hubs and 28 777 70 were transferred to hubs Similarly to the Italian health care organization most of the included centres were spoke centres in sub-urban regions with limited access to mechanical support devices and low volume for PCI while hub centres were about 30 and mainly in metropolitan areas CS mortality was 478 at spoke hospitals and was lower at hub hospitals both for direct admissions 393 and transferred 334 patients On multivariable analysis direct admission to CS hubs odds ratio OR 086 95 confidence interval CI 084-089 and transfer to hubs OR 072 95 CI 069-076 were both associated with lower mortality The authors conclude that treatment of CS at transfer hubs was associated with significantly lower mortality within this large real-world sample Another experience has been reported by WellStar Medical Center15 and consists of the implementation of the hub-and-spoke model with a cardiogenic shock algorithm Well-Star Kennestone Regional Medical Centre served as the hub it is a highvolume centre for of cardiogenic shock with 250 STEMIs per year and 24-hour cardiology critical care expertise cardiac surgery and advanced heart failure therapies for patients in need of more advanced care When WellStar implemented its hub-and-spoke model the survival rate for AMI-CS was at about 50 percent consistent with national averages Within a few months survival rates raised to 60 and up to 70
A further example of the effectiveness of optimal protocols applications in the care of patients presenting with CS comes from the experience described in the Japanese registry by Dr Ako et al who analysed 593 consecutive AMICS patients from the J-PVAD registry and their cumulative 30-day survival and safety profiles The overall 30-day survival was 809 when microaxial flow pumps were used These results were obtained with a strict application of the enrolment protocol16 Tehrani et al 14 compared the outcomes of CS patients initially admitted to spoke versus hub hospitals within a regional care network The Inova Health System Regionalized Care Network for Cardiogenic Shock The authors stratified all consecutive patients enrolled in their CS registry January 2017 to December 2019 by first admission to a spoke versus hub hospitals Of 520 CS patients more than half initially presented to spoke hospitals In their analysis patients first admitted to hub centres were more often supported with pVAD 44 vs 11 P amplt 001 and veno-arterial extracorporeal membrane oxygenation 13 vs 0 P amplt 001 Initial presentation to a spoke was not associated with increased risk-adjusted 30-day mortality bleeding or stroke The authors conclude that spoke and hub patients experienced similar short-term outcomes within a regionalized CS network
In all these experiences the applied protocol was promoting a prompt stratification and diagnosis of SCAI shock class recognition of right ventricular failure use of pVADs when indicated - as soon as possible down titration of inotropic agents prompt upscale of mechanical cardiac support if needed bridge to recovery and or permanent VAD and or heart transplantation Recently it was published by Lombardy region a local guideline DGR N XII 1117 meeting date 16102023 about acute heart failurecardiogenic shock network identifying in Milano area two hub centres IRCCS San Raffaele ASST Grande Ospedale Metropolitano Niguarda whom the spoke centre should refer to Nevertheless this network system is not nowadays applied in our country and the Italian healthcare system is still lacking a CS Network The optimal strategy to promote standardized care and improved outcomes across regional CS networks deserve further investigation 22 Creation of hub and spoke network A hub and spoke network in cardiogenic shock facilitates the rapid transfer of patients to specialized tertiary care centres When a patient presents with cardiogenic shock at a spoke hospital immediate hemodynamic stabilization is the priority The network communication channels enable rapid consultation with the hub where specialised cardiac teams evaluate the patient condition remotely and provide expert recommendations If advanced interventions such as pPCI or mechanical circulatory support are required the patient is promptly transferred to the hub This expedited transfer process ensures that patients receive timely access to specialized care reducing treatment delays and improving the chances of a favourable outcome
A hub and spoke network establishes regional centres of excellence in the management of cardiogenic shock The hub acts as the central facility equipped with advanced cardiac interventions highly skilled healthcare professionals and state-of-the-art infrastructure This concentration of expertise allows for specialised care that may not be available at smaller spoke hospitals By designating specific hubs patients have improved access to specialized resources including cardiac catheterization laboratories advanced imaging technologies and multidisciplinary CS teams trained in managing complex cases of cardiogenic shock These regional centres of excellence ensure that patients are directed to facilities with the highest level of expertise increasing the likelihood of successful treatment and improved patient outcomes
Cardiogenic shock patients often face geographic disparities when accessing specialized care especially in rural or remote areas A hub and spoke network addresses this challenge by bringing specialized services closer to patients locations The spoke hospitals act as local access points providing initial stabilization and interventions Through efficient transfer protocols patients can be quickly transported to the hub bypassing the need for long-distance travel This reduces the burden on patients and their families while minimizing delays in receiving critical care By bridging the geographical gap the hub and spoke network ensures that patients with cardiogenic shock regardless of their location can access specialised care promptly leading to improved outcomes and potentially saving lives
The hub and spoke model promotes effective coordination and communication between healthcare providers involved in the care of cardiogenic shock patients Communication channels are established to facilitate real-time consultation and collaboration between spoke hospitals and the hub This seamless exchange of information allows for accurate assessment of patient conditions and prompt decision-making regarding transfer and specialized interventions Moreover the network encourages regular meetings case discussions and knowledge sharing fostering continuous education and professional development among healthcare teams By streamlining communication the hub and spoke network enhances the overall quality of care and ensures that patients with cardiogenic shock benefit from the collective expertise of the network healthcare professionals
3 Objectives and hypotheses of the study The main objective of this study is to compare in hospital-30 days clinical outcome of patients with AMICS who were admitted in spoke centres in a historical retrospective vs prospective cohort The main hypothesis of the study is that the time factor as well as the presence of a multidisciplinary CS team is crucial in the management and treatment of cardiogenic shock Patients who can benefit from circulatory support through medication andor mechanical support the earlier they receiv treatment the better their outcome Thus a constant communication between hub and spoke centres would allow early identification of patients at risk of unfavourable evolution and enable faster treatment of them
31 Justification of the study design The study includes a prospective and a retrospective cohort This study design will allow us to compare the impact on 30 days mortality of patients admitted with AMICS in study centres following the adoption of a dedicated protocol designed to improve communication and collaboration among centres to timely refer such patients from spoke to hub centres prospective cohort as compared to prior practise in the same centres not adopting such a protocol retrospective cohort These data will be extremely useful to assess whether there is a clinical benefit for CS patients following the creation of the Hub and Spoke network for AMICS
32 Endpoints Primary and clinical secondary endpoints will be adjudicated by an independent Clinical Event Adjudication Committee 321 Primary Endpoint The primary endpoint is all-cause mortality in-hospital or up to30-days Overall all-cause mortality is indisputable and cannot be subject to subjective interpretation and is considered the gold standard for demonstrating clinical benefit The relatively short follow-up will minimize the competing risk that death is caused conditions other than CS 322 Secondary Endpoints
The secondary endpoints are so defined
In-hospital or 30-days incidence of adjudicated stroke fatal or non-fatal or TIA
In-hospital or 30-days incidence of bleedings to classify bleeding we use BARC classification in the endpoints we include only bleedings with a BARC score greater than or equal to 3
In-hospital or 30-days incidence of renal replacement therapy need for at least one cycle of CVVH or the initiation of dialysis therapy
In-hospital or 30-days incidence of vascular complications as vascular complications we refer to all those complications requiring medical intervention referring to vascular diagnostic andor therapeutic accesses
In-hospital or 30-days incidence of non-fatal myocardial infarction excluding any presenting event Non-fatal was defined according to the definition of NSTE-ACS or STE-ACS respectively 17
Door-to-support time indicates the time from patient presentation at a hub or spoke center to the start of hemodynamic support with MCS
The onset of symptoms-to-support time indicates the time from the onset of clinical symptoms reported by the patient to the start of hemodynamic support with MCS 4 Study Design This will be an observational multicentre study including consecutive patients admitted in the spoke centres with CS SCAI classification B-D in the retrospective cohort from 2016 to 2019 and in the prospective cohort from 2024 to 2026 Four centres - two in Milan metropolitan Area and two in Turin - will serve as hub centres each one receiving CS patients from three referring spoke centres In total 16 centres will be involved in the study In the retrospective cohort the information will be derived from Diagnosis Related Groups DRGs see appendix only anonymous data will be collected In the prospective cohort a prespecified protocol following the current ESC guidelines on Acute and Chronic Heart Failure17 improving communication and collaboration among centres in the same area to timely refer CS patients from spoke to hub centres will be adopted allocating patients referred for advanced shock treatment from a spoke to a hub centre The patients who will fulfil the following inclusion criteria will be enrolled retrospectively and prospectively 41 Study Population Patients presenting with cardiogenic shock SCAI B to D as defined in inclusion criteria as shown below 42 Subject Selection 421 Inclusion Criteria
All subjects participating in this clinical trial must meet the following criteria
Prospective cohort
For conscious patients signed and dated informed consent and consent to the processing of personal data
For unconscious patients informed consent signed and dated by the legal representative or a proxy or a relative The consent will be presented to the patient as soon the health conditions will improve Aging 18
CS will be defined as
1 Systolic blood pressure SBP 90 mmHg or mean arterial pressure MAP 60 mmHg after an appropriate fluid challenge if there is no sign of overt fluid overload OR need of vasoactive agents to maintain SBP 90 mmHg or MAP 60 mmHg OR need of MCS
2 At least one of the following criteriasigns of overt hypoperfusion mixed venous oxygen saturation 60 arterial lactates 2 mmolL oliguria 05 mlKgh for at least 6 hours
3 CS following an acute myocardial infarction AMICS or acute decompensation of heart failure ADHF-CS 422 Exclusion Criteria
Patients will be excluded if any of the following conditions apply
1 Cardiac arrest with no quantifiable or longer than 10 minutes no-flow time or with refractory cardiac arrest as defined by CPR prolonging for more than 20
2 Absolute contraindication to support devices
3 CS due to other aetiology apart from the ones in inclusion criteria as well as SCAI A and E before device positioning
4 Age greater than 75-year-old
5 Life expectancy 1 year due to other reason than cardiogenic shock 5 Study procedures 51 Hub and spoke centre definitions
The Hub centre is frequently a 3rd level Hospital where there is the availability of
CS team 247
PCI service 247
Dedicated CCU
pVAD availability and extensive expertise in management 247 as well as mobile ECMO team
Cardiac surgery backup LVAD capabilityheart transplant
Cardiac Shock team The shock team is a multidisciplinary team dedicated to optimizing the care of Cardiogenic shock patients via
1 Rapid identification
2 Coordinated consultation
3 Early transferadmission to cardiac
4 ICU Cath Lab or Operating room It is composed by Interventional Cardiologist Cardiac Surgeon Advanced Heart failure specialist Intensivists and Anesthesiologists
The Spoke centre is frequently
1st level Hospital with dedicated CCU
2nd level Hospital with dedicated CCU and with some pVAD expertise
The spoke centres in each area that will be included in the study have to fulfil the following criteria
24h cath lab for primary PCI
already an informal patient transferal protocol with the hub center
less than 30 km of distance 52 Communication Protocol The following communication protocol is based on guidelines and cardiogenic shock consensus 1 its aim is to improve physicians communication and guidelines adherence and in any situation can overcome the physicians judgment
521 Communication protocol 1 Stepwise checklist application for the on-call cardiologist at the spoke centre according to SCAI class 5211 CS Diagnosis classification and exclusion criteria 5213 WHO activates the Shock Team
1 Emergency department
2 Other units in the hospital eg Cath lab or ICUs
3 Spoke centre cardiology department The efferent unit will call the shock team on a dedicated phone number 522 Protocol 2 stepwise checklist for the on-call cardiologist at the hub centre Communication between the spoke and hub centres should be performed at the time of diagnosis or in case of worsening after two consecutive worsening evaluation at 30 min time difference
After reaching consensus on transfer to hub centre activation of CS team
CS management according to the local hub protocol 523 Patient transfer between spoke and hub centres After the case discussion and bilateral agreement the patient will be transferred from the spoke to the hub centre according to the local protocol by a dedicated ambulance system with a cardiologist andor anesthesiologist onboard In case of life threatening hemodynamic instability of the patients a dedicated team of the hub centre may place a pVAD at the spoke centre for a protected transfer In this perspective all the data regarding the transportation duration also considering the time of day day or night will be collected to evaluate the impact of time and distance between the spoke and the hub centres 524 Hub centres management protocol The hub centres will have a shared management protocol according to current ST segment elevation non-ST segment elevation myocardial infarction guidelines18 Acute heart failure and pVAD implantation recommendation19 CS phenotypisation will be performed according to invasive or not invasive hemodynamic evaluation
6 Settings and locations for data collection For prospective data collection baseline clinical characteristics clinical examinations and in-hospital procedures of the patients are collected during their hospitalization by dedicated physicians The data regarding the patients that will be transferred from spoke to hub centers will be collected from the spoke andor the hub according to the role in the clinical management of the patient
Need for MCS timing of device insertion size of device extent of support as well as optimal duration of therapy will also be recorded Special attention will be given to the documentation of the patients clinical status regarding morbidity and mortality major adverse cardiac cerebrovascular events MACCE such as stroke or TIA bleedings cardiac ischemic events and vascular complications as well as renal replacement therapy
The information will be derived from the hospital clinical charts up to 30 days from admission and recorded in the electronic CRF of the study No intervention nor changes in therapeutic strategies and decisions will be implemented for the purpose of the study For the retrospective data collection DRG code will be used in order to select cases affected by CS and data collected in anonymous fashion Only data related to the clinical outcome associated to the DRG will be retrieved from hospital registries without any personal data DRG codes of interest for the study are reported in Appendix 1 7 Statistical considerations Outcomes will be compared between the retrospective cohort and the prospective cohort
Targets for analysis will focus on improving outcomes and quality of care Specifically assessing morbidity and mortality need for MCS timing of device insertion size of device extent of support as well as optimal duration of therapy are all opportunities to expand the appropriate use and understanding of the role of hemodynamic support 71 Determination of Sample Size A sample size of 768 patients 384 in each cohort is required to provide the study an 80 power to detect superiority in the primary endpoint with an alpha error set at 005 and assuming 30-day mortality estimates of 48 in the historical cohort and 38 in the prospective cohort
A 48 30-day death rate was calculated based on the mean mortality of SCAI SHOCK patients Class C-D as reported by previous metanalysis19 while 38 for the prospective cohort is based on the recently published papers 20-21 that evaluated similar outcomes in USA area after the improvement of the hub-spoke network Considering a 10 of patient loss due to consent unavailabilitywithdrawal the total number of screened patients will be 845 72 General Statistical Approach Descriptive statistics mean with standard deviation minimum and maximum median with the first and third quartile and 95 confidence interval will be calculated for quantitative variables For qualitative variables counts and percentages will be provided together with the 95 confidence interval In calculation of percentages patients with missing data will not be considered unless otherwise specified All baseline characteristics will be summarized The baseline value for each patient is defined as the last available value prior to spoke hospital admission A detailed Statistical Analysis Plan will be developed 721 Main Analysis Comparisons will be made via Students t-test Wilcoxon rank sum test 1-way analysis of variance chi-square or Fishers exact tests where appropriate To determine the potential relationship between site of initial triage and the primary and secondary outcomes we will fit multivariable logistic regression models which adjusted for clinical and hemodynamic variables historically associated with outcomes in CS SCAI CS stage C vs D-E age per 5 years duration of vasopressors minutes female sex diabetes baseline log lactate and log cardiac power output CPO measurements MCS use haemolysis and dialysis We will compare the risk of primary and secondary outcomes in spoke vs hub patients and calculate adjusted ORs with corresponding 95 Cis for the primary and secondary outcomes Statistical significance is defined as a P value amplt005 for 2- sided tests All analyses are performed using R version 402 software R Foundation for Statistical Computing 7211 Prespecified sub-analysis Prespecified sub-analysis according to the time between symptoms onsetpPCI to pVAD placement will be performed
Pre-specified supplementary analysis
1 The analysis will be performed with artificial intelligence methods to create a risk stratification model to increase the protocol efficiency and patients selection to be transferred
2 Protocol adherence in both spoke and hub center will be evaluated
3 Spoke center misdiagnosis for CS 722 Safety Analysis Adverse Events AE occurred to the patients and collected in the e-CRF will be coded to a Preferred Term PT and associated System-Organ Class according to the most recent version of the MedDRA dictionary before analysis Patients will be counted only once in each system organ class category and only once in each preferred term category All adverse events will be summarized by presenting the number and percentage of patients having any adverse event and having at least one serious adverse event For quantitative safety parameters descriptive statistics will be used to summarise results and change from baseline values Concomitant medications will be collected in the CRF and summarised by number and percentages n 8 Data management Data collection will be carried out by means of Electronic Data Capture EDC systems whereby data recorded in an electronic CRF e-CRF are directly registered in the study database The e-CRF for the study will be provided by the CRO Mediolanum Cardio Research Italy Main characteristics of the EDC system are
compliance with FDA 21 CFR part 11 requirements and guidelines concerning security and data protection
multi-user and simultaneous data entry
intuitive friendly web forms
browsers Edge Google Chrome - preferred one - Safari and Opera
access control and advanced user management
advanced user profiling management and customization
Audit Trail tracking all user operations eg visited pages user data audit patients and centres audit CRF data audit
CRF source verified data locking at visit page single variable levels
off-line and on-line control of data plausibility and consistency
automatic and manual query generation
supervision and validation of solved queries optional
e-monitoring tools
documentation area protocols manuals etc
production of blank and annotated CRF
use of ad hoc medical dictionaries MedDRA WHO etc
exporting data to SAS and Excel format
graphic reports and descriptive statistics
production of SAEMACCE listings
alert email new patient new SAE etc
SAS clinical data base
dedicated section for upload of study documents Security
Hosting server in a secure Web farm in Italy under 7x24 monitoring
Server protected by firewall to prevent unauthorized access
Secure data transmission adopted using 256-bit SSL HTTPS the module and the relative Certificate acquired from Thawte Certification Authority
User authentication through complex personal password
Session timeout after 15 minutes inactivity
Redundant hardware
Redundant daily backups Only the study Investigators will have access rights to enter and to modify the data It is the responsibility of the Investigator to maintain adequate and accurate e-CRFs to record all observations and other data pertinent to the clinical investigation Appropriate edit checks will be developed to identify the discrepancies in the entered data embedded in the database to ensure data validity Discrepancies may be due to inconsistent data missing data range checks and deviations from the protocol The data validation process will be run every night and queries released in the e-CRF for identifying discrepancies These discrepancies queries will be resolved by investigators after logging into the system It is the Investigators responsibility to respond by confirming or modifying the data questioned Data management will be in accordance with the SOPs of the CRO Ongoing quality control of data processing is undertaken at regular intervals during the course of the study A study-specific data management plan will be produced describing the data entry and data tracking guidelines quality control measures discrepancy management data transferextraction and database locking guidelines
Coding of medical terms and medications will be performed using MedDRA and the WHO Drug Dictionary respectively
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None