Ignite Creation Date:
2024-10-26 @ 3:38 PM
Last Modification Date:
2024-10-26 @ 3:38 PM
Study NCT ID:
NCT06570759
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-08-22
Brief Title:
Time for a Diagnostic Paradigm Shift From STEMINSTEMI to OMINOMI
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Time for a DIagnostic Paradigm Shift From ST-elevationNon-ST-elevation to OCClUsionNon-occLusion Myocardial infarcTion
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
DIFOCCULT-3
Brief Summary:
The investigators hypothesize that occlusion myocardial infarctionMInon-occlusion MI approach to MI treatment will better predict acute coronary occlusion on coronary angiography better limit infarct size better preserve left ventricular function and result in lower long-term adverse cardiac events all cause mortality all cause rehospitalization compared to standard ST-elevationnon-ST-elevation MI paradigm
Detailed Description:
I BACKGROUND AND SIGNIFICANCE
The patients with acute coronary occlusion ACO or potentially imminent occlusion with insufficient collateral circulation have myocardium that is at risk of infarction unless they undergo immediate reperfusion via thrombolytics or percutaneous coronary intervention PCI One of the most important tasks in emergency cardiology is to immediately identify acute coronary occlusion ACO myocardial infarction OMI among all patients who present with symptoms compatible with acute myocardial infarction MI and distinguish them from those without MI and from those with MI that does not have ongoing myocyte loss Non-OMI or NOMI who can be managed with medical therapy and for whom potentially harmful invasive interventions can be deferred The electrocardiogram ECG plays a central role in this process
The presence or absence of ST-segment elevation STE is principally used to define patients who need emergent coronary revascularization since subgroup analyses of the Fibrinolytic Therapy Trialists FTT meta-analysis indicated that patients with STE on ECG gain a slightly better survival benefit from emergent reperfusion After fine-tuning of STE cutoffs used in this analysis universally agreed STEMI criteria became the current guideline-supported ECG paradigm
However the evidence accumulated in the past 20 years indicate that there is still room for substantial improvement Although patients with ACO are the group that is believed to benefit from emergent reperfusion therapy fibrinolytic studies did not investigate the presence or absence of ACO among enrolled patients Moreover they did not specifically focus on ECG findings including STE four of the nine trials even did not use ECG for enrollment and the remaining five defined their version of STE with varying cutoffs and without specified measurement methods To reconcile different STE criteria used in various studies several investigators compared STE in normal subjects and patients with MI However none of the studies cited in the current universal definition of MI used ACO on angiography as an endpoint so these criteria were actually not designed to differentiate STEMI from non-STEMI
In the past 20 years several investigators including our group have demonstrated that factors other than STE including STE of magnitude less than those recommended by the guidelines but in combination with other features can help in diagnosing ACO or excluding it Proportionality which is unfortunately completely absent in the STEMI criteria is a common factor in most of these studies proportionality is the idea that any amount of STE or STD or T-wave size must be assessed relative to the QRS amplitude Many other clues should also be taken into account when differentiating STE due to ACO from other causes of STE which has been described in detail in recent reviews published by our group
Studies show current STEMI criteria miss nearly one-third of ACO with the result that this unfortunate group of patients labeled as non-STEMI are deprived of emergent reperfusion therapy Many studies showed that approximately one third to one-fifth of the patients with ACO had equal to or less than 1 mm of STE hyperacute T-waves non-contiguous STE patterns etc These patients are unfortunately deprived of emergent reperfusion therapy and ACO is only found after rising troponin level identifies them as having MI and they undergo a next-day angiogram Furthermore this proportion may be underestimated since a large percentage of total thrombotic occlusions are spontaneously reperfused by this time unfortunately only after a substantial loss of myocardium These findings are highly relevant and important as those with unrecognized ACO had higher short and long-term risk of mortality
It is not clear why a disease of a known pathophysiology ACO was named with an inaccurate surrogate ECG sign Q-wave MInon-Q-wave MI or STEMInon-STEMI instead of the pathologic substrate itself ACO-MInon-ACO-MI or OMI for short but this fundamental mistake created important implications for our current practice As briefly outlined above ACO can be reliably recognized with the help of many other ECG findings such as minor STE not fulfilling STEMI criteria STE disproportionate to preceding QRS unusual patterns with contiguous leads showing opposite ST deviations and some patterns not showing STE at all
Recently the DIagnostic accuracy oF electrocardiogram for acute coronary OCClUsion resuLTing in myocardial infarction DIFOCCULT study compared OMInon-OMI approach with STEMInon-STEMI paradigm This is the largest study specifically designed to question the STEMInon-STEMI paradigm in which a set of predefined ECG findings in addition to STEMI criteria were used and the final outcome was a composite ACO endpoint In accordance with the previous observations over one-fourth of the patients initially classified as having non-STEMI were re-classified by the ECG reviewers blinded to all outcome data as having OMI This subgroup had a higher frequency of ACO myocardial damage and both in-hospital and long-term mortality compared to the non-OMI group The OMInon-OMI approach to the ECG had a superior diagnostic accuracy compared to the STEnon-STEMI approach in the prediction of both ACO and long-term mortality
II THE HYPOTHESIS
Our hypothesis is that the new OMINOMI approach will be superior to the established STEMINSTEMI paradigm in early detection of ACO limiting infarct size reducing rehospitalizations and most important of all reducing mortality
III METHODS
1 Application for Institutional Review Board IRBEthics board approval IRBEthics board approval is obtained from Marmara University Ethical Board Later modifications will be reviewed by Başakşehir Pine and Sakura City Hospital Ethical Board Each principal investigator at each individual study site will be required to obtain IRBEthics board approval from hisher own institution
2 Study population The adult patients age 18 years who are admitted to the emergency department with a clinical picture compatible with acute coronary syndrome will be screened for enrollment into the study patients with an ECG or clinical see below diagnosis of acute myocardial infarction will be enrolled into the study
An ECG will be acquired as soon as possible in all screened patients and serial ECGs will be taken if the first one is not diagnostic The ECGs will be scanned and digitized via an artificial intelligence AI-powered mobile phone application If the patient gets a STEMI or OMI diagnosis by the ECG or clinical gestalt refractory pain hemodynamic instability arrhythmia cardiac arrest they will be included in the study even if the later troponin results turn negative If the ECG is not diagnostic for OMI or STEMI a myocardial infarction diagnosis with a positive troponin will be necessary for the inclusion in the study According to 4th universal definition of MI the term acute MI will be used when there is acute myocardial injury detection of a rise andor fall of cTn values with at least one value above the 99th percentile upper range limit with at least one of the following clinical indicators of acute myocardial ischemia
Symptoms of myocardial ischemia
New ischemic ECG changes
Development of pathological Q waves
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology
Identification of a coronary thrombus by angiography or autopsy
Post-mortem demonstration of acute atherothrombosis in the artery supplying the infarcted myocardium
All non-procedure related excluding type 4a and 5 MIs including type 1 MI caused by atherothrombotic coronary artery disease which is usually precipitated by atherosclerotic plaque disruption rupture or erosion type 2 evidence of an imbalance between myocardial oxygen supply and demand unrelated to acute atherothrombosis type 3 cardiac death in patients with symptoms suggestive of myocardial ischemia and presumed new ischemic ECG changes before cTn values become available or abnormal and type 4b and c stentscaffold thrombosis ore restenosis associated with percutaneous coronary intervention will be included in the study Patients with myocardial injury either acute as in acute heart failure or myocarditis or chronic as in chronic kidney disease or stable increased troponin levels with structural heart disease without ischemia abovementioned following clinical indicators of acute myocardial ischemia will be excluded from the study
The inclusion and exclusion criteria are summarized below Inclusion criteria Age 18 years ECG andor clinical diagnosis of acute myocardial infarction
Exclusion criteria Active pregnancy or a suspicion of pregnancy Rejection or withdrawal of consent Failure to acquire any of the pre-participation ECGs Non-ischemic myocardial injury Application of thrombolytic therapy instead of primary PCI Re-occlusion of the culprit lesion after intervention New vessel occlusion during hospital stay
Exclusion from final analyses
Randomization The patients will be randomized to the current STEMINSTEMI versus OMINOMI approaches using a cluster randomized trial design Although the STEMINSTEMI approach is the current norm a diagnosis of STEMI requires emergent catheterization whereas the patients with NSTEMI are stabilized first and then electively undergo catheterization unless there are high-risk features it would be unethical for a ECG reviewer who is trained in recognizing the signs of ACO not fulfilling the current STEMI criteria to suspend emergent reperfusion therapy after an OMI diagnosis has been made Therefore the ECG interpreters who are trained in OMI diagnosis cannot be randomized to STEMINSTEMI versus OMINOMI approaches Hence the groups will be randomized in the following fashion In each center a STEMINSTEMI and an OMINOMI intervention group will be formed After these two groups are formed the patients will be block-randomized into STEMINSTEMI and OMINOMI cohorts according to the team on-duty ie the approach that center will follow on a certain day will be defined by the team on duty The interventional cardiologists in both groups will be ensured to have a similar experience level in terms of years of training and angiography and primary PCI counts in the past year
All possible first responders in the network of a study center who contact the patient first according to the center this can be either a referring physician an emergency physician or a cardiologist will be provided with an AI-powered application for ECG diagnosis These responders will receive diagnostic prompts from the application according to the centers on-duty team If an OMI team member is on duty the ECG interpretation will be OMI or not-OMI If a STEMI team member is on-duty the ECG interpretation will be disabled and will read follow standard care The first responder will thus elect to go for catheterization based on this approach and whether that is by OMI or STEMI paradigm the patient will be enrolled accordingly and the reason for proceeding to the catheterization laboratory will be written on the study form or electronic sheet on the dedicated website
In the STEMINSTEMI arm the contributors will blindly continue their usual practice the ECG interpretation and decision to activate the catheterization laboratory will be done as usual The STEMINSTEMI group will use the following criteria for the diagnosis of STEMI 1 New ST-segment elevation at the J-point in two contiguous leads with the cut-point 1 mm in all leads other than leads V2-V3 where the following cut-points apply 2 mm in men 40 years 25 mm in men 40 years or 15 mm in women regardless of age and 2 a peak troponin level above 99th percentile with a characteristic rapid rise and fall retrospectively and 3 a clinical picture compatible with acute coronary syndrome If the decision to proceed to the cath lab was done only with the first criterion the participant will remain in the study even if the second criterion is not met The patients meeting only criteria 2 and 3 will be classified as NSTEMI
In the OMINOMI group the algorithm defined in the DIFOCCULT trial Aslanger et al In J Cardiol Heart Vasc 2020 Aslanger et al J Electrocardiol 2021 Aslanger et al Arch Turk Soc Cardiol 2021 or the AI-powered application diagnosis will be used for ECG diagnosis Therefore an OMI-ECG diagnosis will not be limited to AI-powered app but also can be done by human ECG interpreter due to a single ECG or serial ECG changes 1 Additionally 2 a peak troponin level above 99th percentile rapid rise and fall retrospectively and 3 a clinical picture compatible with acute coronary syndrome will be required If the decision to proceed emergently to the cath lab was done only with the first criterion the participant will remain in the study even if the second criterion is not met The patients who do not meet ECG-OMI criteria will be classified as NOMI if 1 a peak troponin level above 99th percentile rapid rise and fall retrospectively and 2 a clinical picture compatible with acute coronary syndrome is present
STEMI and OMI patients will be taken as STEMI equivalents for therapeutic purposes will be managed according to the current STEMI guidelines whereas NSTEMI and NOMI patients are managed according to the current NSTEMI guidelines A separate diagnostic group with probable OMI and high-risk STEMI is also allowed for patients who do not fulfil STEMIOMI criteria but need urgent catheterization for other high-risk features or high clinical suspicion for having an ACO These patients will also be managed according to the current guidelines However patients will be excluded from analysis if their early catheterization is based solely on social or logistical considerations and not based on the medical need For example a patient would be excluded if heshe is brought to the cath lab early based on the immediate availability of cath lab or because the patient is already scheduled for elective coronary angiography The patients who have alternative diagnoses myocarditis pericarditis pulmonary embolism etc but were not included due to a clinical or ECG diagnosis of STEMINSTEMI or OMINOMI will be excluded from the study Similarly the patients without a characteristic troponin kinetics who were not included due to a clinical or ECG diagnosis of STEMINSTEMI or OMINOMI will be excluded from the study
Endpoints The primary composite endpoint is all-cause mortality and all-cause re-hospitalization during follow-up The co-primary endpoint is all-cause mortality and all-cause re-hospitalization in OMI STEMI - patient subgroups The secondary comparisons will be done for the presence of ACO on angiogram false positive catheterization laboratory activation rate the infarct size as defined by 24-72 hour peak troponin wall motion score index WMSI left ventricular ejection fraction LVEF in-hospital CPR intubation and mortality These will be analyzed both with intention to treat and per protocol approaches
Estimated number of subjects to be submitted
It was estimated that the enrollment of 3472 participants would provide the study with a statistical power of 95 to detect a 4 absolute decrease in combined primary endpoint in OMINOMI approach compared to STEMINSTEMI approach from 25 to 21 with the use of a two-sided test at the 005 level with a prediction of an additional 25 OMI in NSTEMI cohort Similarly 2351 participants would be necessary to detect a 5 difference in area under curve AUC from 0750 to 0700 for the comparison of the predictive accuracy of two approaches for primary outcomes For the co-primary outcome a total of 698 OMI STEMI - participants would provide the study with a statistical power of 95 to detect a 6 absolute decrease in combined primary endpoint in OMINOMI approach compared to STEMINSTEMI approach from 15 to 8 with the use of a two-sided test at the 005 level This corresponds to an approximate total sample size of 4000 patients with a prediction of 115 STEMINSTEMI ratio and a frequency of 25 OMI in NSTEMI cohort However a one-year enrollment duration is planned which is expected to enroll over 5000 patients with a 115-2 STEMINSTEMI ratio into the study This total number is also expected to provide the study with a statistical power of 95 to detect at least a 10 relative decrease in infarct size 10 better left ventricular ejection fraction and 10 better wall-motion score index STEMI - OMI patients who underwent early revascularization in OMI arm compared to those who underwent revascularization with standard timing in STEMINSTEMI approach with a prediction of an additional 25 OMI in NSTEMI cohort
3 Participating centers Listed elsewhere
4 Data Collection From September 1 2024 AI-powered ECG App will be distributed to the referring hospitals by the participating centers The study will start at all participating centers on October 1 2024 A dedicated website difoccultorg will be used for data entry and storage Study data is collected and managed using REDCap Research Electronic Data Capture tool hosted at a dedicated server REDCap is a secure web-based software platform designed to support data capture for research studies providing 1 an intuitive interface for validated data capture 2 audit trails for tracking data manipulation and export procedures 3 automated export procedures for seamless data downloads to common statistical packages and 4 procedures for data integration and interoperability with external sources
Baseline variables Collected baseline variables and their definitions are listed in the REDCap printout in the supplemental file In brief the following baseline variables will be entered to the study spreadsheet Center specific enrollment no protocol no cohort age gender prior history of MI prior history of PCI or CABG presence or absence of diabetes medication use or HbA1c65 dyslipidemia LDL 160 mgdL or anti-lipid medication use hypertension medication use or average blood pressure over 14090 mmHg during hospital stay smoking current smoker or past smoker with in 1 year chronic kidney disease baseline creatinine level greater than the upper limit of normal admission systolic blood pressure admission heart rate admission creatinine level admission hemoglobin level Killip class on admission admission troponin T level from a blood sample collected before during or just after coronary angiography or at admission to the emergency department 24 48 and 72h troponin level the maximum troponin level during hospital stay ejection fraction wall motion score index time from constant pain to ECG time from ECG to PCI will be calculated from system recordings infarct related artery number of diseased vessels the number of additional lesions treated in-hospital mortality in-hospital resuscitation in-hospital intubation long term mortality From these parameters baseline GRACE risk score the change within troponin value in the first 24 hours will be calculated
Electrocardiogram
ECGs will be acquired using standard conventions If the first ECG is non-diagnostic serial ECGs will be acquired every 15 minutes for an hour and the first diagnostic ECG will be used in the analyses If all of them are non-diagnostic the physician may still use additional tools such as the clinical picture bedside echocardiogram troponin results to diagnose high-risk NSTEMI or possible OMI All pre-intervention ECGs and at least one pre-discharge ECG will be uploaded to a central cloud database to be retrospectively reviewed by core lab investigators The absence of a technically adequate pre-cath ECG will be a reason for the exclusion of the participant If ECG diagnosis is not compatible with the inclusion criteria for the assigned group this will be noted and the patient will be excluded from the per-protocol analyses Following coding will be used for ECGs
Type 1 EGGs New ST-segment elevation at the J-point in two contiguous leads with the cut-point 1 mm in all leads other than leads V2-V3 where the following cut-points apply 2mm in men 40 years 25 mm in men 40 years or 15 mm in women regardless of age
Type 1a The amplitude morphology extent of STE and the presence of additional findings hyperacute T waves Q-waves terminal QRS distortion make ECG highly obvious for MI presumably due to acute thrombotic occlusion These ECGs will be included in both STEMI and OMI definitions
Type 1b There is ST-segment elevation that meets criteria for STEMI but it is uncertain whether it is due to MI or to another condition such as benign variant STE left ventricular hypertrophy left bundle branch block prior MI pericarditis etc These ECGs will be included in the STEMI definition but not in the OMI definition unless there are additional findings suspicious for acute coronary occlusion as follows Differential diagnosis for benign variant STE Type 1b if fulfills STEMI criteria But re-classified as Type 2b if the AslangerSmith formula is positive Aslangers formula R-wave amplitude in lead V4 QRS amplitude in V2 - QT interval in millimeters STE60 in V3 12 Aslanger E Am J Cardiol 2018 Differential diagnosis for left ventricular hypertrophy Type 1b unless ST segment to R-S-wave magnitude is equal or greater than 15 then indicates OMI Type 2b Armstrong EJ et al Am J Cardiol 2012 Aslanger et al Arch Turk Soc Cardiol 2021 Differential diagnosis for isolated left bundle branch block Will be coded as Type 1b unless one of the modified Sgarbossa criteria is positive then indicates OMI Type 2b 1 lead with 1 mm of concordant ST elevation 1 lead of V1-V3 with 1 mm of concordant ST depression 1 lead anywhere with 1 mm STE and proportionally excessive discordant STE as defined by 25 of the depth of the preceding S-wave Smith SW et al Ann Emerg Med 2012 Differential diagnosis for prior MI Type 1b unless Smiths rule is positive then indicates OMI Type 2b Smiths rule If any 1 lead between V1-V4 has a T-wave amplitude to QRS amplitude ratio greater than or equal to 036 Klein LR et al Am J Emerg Med 2015 Differential diagnosis for pericarditis Type 1b unless there is ST-depression in aVL then indicates OMI Type 2b Bischof JE et al Am J Emerg Med 2016
Type 1c There is ST-segment elevation that meets criteria for STEMI but there is also T-wave inversion and pathologic Q waves indicative of subacute MI These ECGs will be excluded from per-protocol analyses since these patients have ACO on angiogram and higher long-term mortality but gain little if not any benefit from reperfusion with both approaches Patients with preserved QRS complexes Wellens pattern will be included in type 2c ECGs
Type 2 EGGs ECG that meets acute myocardial ischemia criteria recommended by fourth universal definition of MI
Type 2a The ECG has primary ie cannot be completely explained as secondary to a depolarization disorder ST-segment depression or T-wave inversion that is nondiagnostic of STEMI but is diagnostic of myocardial ischemia
Type 2b Does not meet recommended criteria for STEMI but highly suggestive for ACO despite being subtle and difficult Possible findings are minor STE with or without minor reciprocal ST-depression not fulfilling STEMI criteria hyperacute T-waves or DeWinters pattern subtle anterior STE hard to differentiate from benign variant STE and nonconsecutive STE These ECGs will be included in the OMI definition but not in the STEMI definition The detailed algorithm defined in the DIFOCCULT trial Aslanger et al In J Cardiol Heart Vasc 2020 Aslanger et al J Electrocardiol 2021 Aslanger et al Arch Turk Soc Cardiol 2021 will be used for recognizing these ECGs
Type 2c Patients with preserved QRS complexes Wellens pattern with or without some STE but with significant T wave negativity will be included in type 2c ECGs These ECGs will be excluded from per-protocol analyses since these patients may not gain benefit from emergent reperfusion in both approaches
Type 3 ECGs Nonspecific ECG that is abnormal but nondiagnostic of any kind of acute coronary syndrome Minor abnormalities including left ventricular hypertrophy without ST-T changes arrhythmias impulse generation and conduction diseases etc
Type 4 ECGs Completely normal ECG
AI-Powered ECG Application In OMINOMI arm ECGs can be digitized and interpreted by AI-powered ECG application prospectively In STEMINSTEMI arm interpretation will be done retrospectively
After the study completion ECGs in both study arms will be reviewed and coded as defined above for intention-to-treat and per-protocol analyses This will be done by two separate ECG interpreter Should there be any discrepancy between these interpreters a third interpreter from data monitoring board will be consulted
Type 1a 1b and 1c ECGs will be deemed as compatible with STEMI Type 1a 2b and 2c ECGs will be deemed compatible with OMI diagnosis
Troponins The troponin levels will be measured at admission hourly if needed for the diagnosis every 6 hours until it peaks after an MI diagnosis is made and then daily The 24-72 hour peak troponin level usually 48h will be used as a surrogate for infarct size
Angiograms Coronary angiography will be undertaken according to the standard conventions Each angiogram will be reviewed by two interventionalist Should there be any discrepancy between these interpreters a third interpreter from data monitoring board will be consulted
Following points will be noted for the presence of an ACO 1 the Thrombolysis in Myocardial Infarction Study TIMI flow level in the infarct-related vessel The presence of well-developed collaterals to the distal vessel appearance of the total occlusion easiness of guidewire crossing will also be assessed to determine if the total occlusion is acute in nature If necessary the primary operator will also be contacted 2 The presence of an acute lesion with definitive culprit features which was defined based on several angiographic properties including critical stenosis irregular lesion borders presence of angiographic thrombus or staining
ACO Adjudication
Because the infarct-related artery may spontaneously open by the time of the angiogram or total occlusion may be chronic in nature a composite ACO using following criteria is defined
1 An acute culprit lesion with TIMI 0-2 flow PLUS a peak troponin level equal to or greater 5 than five times the ULN PLUS at least 20 rise within the first 24 hours
2 A highly elevated peak for troponin T1000 ngmL and for troponin I 200 times of the average of ULN known to be highly correlated with ACO without an obvious alternative diagnosis or with supporting evidence ECG evolution culprit-looking lesion on angiogram in a coronary territory compatible with ECGechocardiographic area at concern
3 cardiac arrest before any troponin rise has been documented with supporting clinical evidence of possible ACO
Follow-up The last participant in the study will be followed up to one year The survival status and re-hospitalization will be checked from the national database and a phone call if required
Statistical Analysis Baseline characteristics will be summarized using standard descriptive statistics Comparisons of relevant parameters between groups will be performed by chi-square Fishers exact test Mann-Whitney U and student t-test as appropriate Patients with missing values will be excluded pairwise from analyses A Cohens κ test will be used for determination of the intra- and inter-observer agreement for ECG classifications and ACO adjudication
Kaplan-Meier analysis will be performed to determine the cumulative long-term mortality rates in different ECG subgroups The mortality across groups will be compared using a log-rank test A Cox-regression model will be used to perform a survival analysis according to basal GRACE risk score intervention timing and revascularization status Baseline characteristics with a P value of 005 or less in the univariate analysis will be included and a step-down procedure will be applied for selection of final covariates
The sensitivity specificity and diagnostic accuracy of STEMINSTEMI or OMINOMI ECG approaches will be calculated using receiver operating characteristics analysis As these parameters are highly dependent on the pre-test probability of the disease and pre-test probability of ACO and long-term mortality are closely associated with the presentation type the investigators will also repeat these analyses after weighing cases for the total number of hospital admissions in the study period
Statistical analyses will be performed with SPSS version 240 SPSS Inc Chicago IL and MedCalc Software version 1821 Evaluation version MedCalc Software Ostend Belgium
5 Safety monitoring and reporting Study REDCap forms necessitate in-hospital adverse events to be actively collected to monitor and report any in-hospital adverse events An independent Data Safety Monitoring Board DSMB has been established to oversee the safety and progress of the trial The DSMB convened via teleconference during the pretrial period upon enrollment of 20 of the participant sample size and will continue to meet after each subsequent 20 enrollment milestone The primary objective of the DSMB is to monitor enrollment milestones and the safety of the interventions A four-point combined safety endpoint will be closely monitored 1 myocardial infarction size by 48hour troponin ejection fraction and wall motion score index 2 integrity of coronary intervention by in-hospital stent thrombosis 3 integrity of in-hospital care by in-hospital intubation in-hospital cardiopulmonary resuscitation and in-hospital mortality and 4 long-term therapy by discharge treatment If a statistically significant increase in this four-point combined safety endpoint is observed in either of the study arms after the enrollment of any 20 of the participant sample size the DSMB will make a recommendation regarding the revision rearrangement or potential exclusion of the study participants or the study center
6 Study integrity The study is an investigator-initiated trial conducted under the auspices of the Turkish Society of Cardiology The Turkish Society of Cardiology supports the investigator team in developing the trial design and organizing the participating centers The steering committee oversees the processes of recruitment consent and assent follow-up and ensures the validity and integrity of data acquisition The trial has been approved by the Ethical Board of Marmara University 092021523 any change in protocol or centers will be addressed by this board The study will be conducted in accordance with Good Clinical Practice guidelines
The patients with acute coronary occlusion ACO or potentially imminent occlusion with insufficient collateral circulation have myocardium that is at risk of infarction unless they undergo immediate reperfusion via thrombolytics or percutaneous coronary intervention PCI One of the most important tasks in emergency cardiology is to immediately identify acute coronary occlusion ACO myocardial infarction OMI among all patients who present with symptoms compatible with acute myocardial infarction MI and distinguish them from those without MI and from those with MI that does not have ongoing myocyte loss Non-OMI or NOMI who can be managed with medical therapy and for whom potentially harmful invasive interventions can be deferred The electrocardiogram ECG plays a central role in this process
The presence or absence of ST-segment elevation STE is principally used to define patients who need emergent coronary revascularization since subgroup analyses of the Fibrinolytic Therapy Trialists FTT meta-analysis indicated that patients with STE on ECG gain a slightly better survival benefit from emergent reperfusion After fine-tuning of STE cutoffs used in this analysis universally agreed STEMI criteria became the current guideline-supported ECG paradigm
However the evidence accumulated in the past 20 years indicate that there is still room for substantial improvement Although patients with ACO are the group that is believed to benefit from emergent reperfusion therapy fibrinolytic studies did not investigate the presence or absence of ACO among enrolled patients Moreover they did not specifically focus on ECG findings including STE four of the nine trials even did not use ECG for enrollment and the remaining five defined their version of STE with varying cutoffs and without specified measurement methods To reconcile different STE criteria used in various studies several investigators compared STE in normal subjects and patients with MI However none of the studies cited in the current universal definition of MI used ACO on angiography as an endpoint so these criteria were actually not designed to differentiate STEMI from non-STEMI
In the past 20 years several investigators including our group have demonstrated that factors other than STE including STE of magnitude less than those recommended by the guidelines but in combination with other features can help in diagnosing ACO or excluding it Proportionality which is unfortunately completely absent in the STEMI criteria is a common factor in most of these studies proportionality is the idea that any amount of STE or STD or T-wave size must be assessed relative to the QRS amplitude Many other clues should also be taken into account when differentiating STE due to ACO from other causes of STE which has been described in detail in recent reviews published by our group
Studies show current STEMI criteria miss nearly one-third of ACO with the result that this unfortunate group of patients labeled as non-STEMI are deprived of emergent reperfusion therapy Many studies showed that approximately one third to one-fifth of the patients with ACO had equal to or less than 1 mm of STE hyperacute T-waves non-contiguous STE patterns etc These patients are unfortunately deprived of emergent reperfusion therapy and ACO is only found after rising troponin level identifies them as having MI and they undergo a next-day angiogram Furthermore this proportion may be underestimated since a large percentage of total thrombotic occlusions are spontaneously reperfused by this time unfortunately only after a substantial loss of myocardium These findings are highly relevant and important as those with unrecognized ACO had higher short and long-term risk of mortality
It is not clear why a disease of a known pathophysiology ACO was named with an inaccurate surrogate ECG sign Q-wave MInon-Q-wave MI or STEMInon-STEMI instead of the pathologic substrate itself ACO-MInon-ACO-MI or OMI for short but this fundamental mistake created important implications for our current practice As briefly outlined above ACO can be reliably recognized with the help of many other ECG findings such as minor STE not fulfilling STEMI criteria STE disproportionate to preceding QRS unusual patterns with contiguous leads showing opposite ST deviations and some patterns not showing STE at all
Recently the DIagnostic accuracy oF electrocardiogram for acute coronary OCClUsion resuLTing in myocardial infarction DIFOCCULT study compared OMInon-OMI approach with STEMInon-STEMI paradigm This is the largest study specifically designed to question the STEMInon-STEMI paradigm in which a set of predefined ECG findings in addition to STEMI criteria were used and the final outcome was a composite ACO endpoint In accordance with the previous observations over one-fourth of the patients initially classified as having non-STEMI were re-classified by the ECG reviewers blinded to all outcome data as having OMI This subgroup had a higher frequency of ACO myocardial damage and both in-hospital and long-term mortality compared to the non-OMI group The OMInon-OMI approach to the ECG had a superior diagnostic accuracy compared to the STEnon-STEMI approach in the prediction of both ACO and long-term mortality
II THE HYPOTHESIS
Our hypothesis is that the new OMINOMI approach will be superior to the established STEMINSTEMI paradigm in early detection of ACO limiting infarct size reducing rehospitalizations and most important of all reducing mortality
III METHODS
1 Application for Institutional Review Board IRBEthics board approval IRBEthics board approval is obtained from Marmara University Ethical Board Later modifications will be reviewed by Başakşehir Pine and Sakura City Hospital Ethical Board Each principal investigator at each individual study site will be required to obtain IRBEthics board approval from hisher own institution
2 Study population The adult patients age 18 years who are admitted to the emergency department with a clinical picture compatible with acute coronary syndrome will be screened for enrollment into the study patients with an ECG or clinical see below diagnosis of acute myocardial infarction will be enrolled into the study
An ECG will be acquired as soon as possible in all screened patients and serial ECGs will be taken if the first one is not diagnostic The ECGs will be scanned and digitized via an artificial intelligence AI-powered mobile phone application If the patient gets a STEMI or OMI diagnosis by the ECG or clinical gestalt refractory pain hemodynamic instability arrhythmia cardiac arrest they will be included in the study even if the later troponin results turn negative If the ECG is not diagnostic for OMI or STEMI a myocardial infarction diagnosis with a positive troponin will be necessary for the inclusion in the study According to 4th universal definition of MI the term acute MI will be used when there is acute myocardial injury detection of a rise andor fall of cTn values with at least one value above the 99th percentile upper range limit with at least one of the following clinical indicators of acute myocardial ischemia
Symptoms of myocardial ischemia
New ischemic ECG changes
Development of pathological Q waves
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology
Identification of a coronary thrombus by angiography or autopsy
Post-mortem demonstration of acute atherothrombosis in the artery supplying the infarcted myocardium
All non-procedure related excluding type 4a and 5 MIs including type 1 MI caused by atherothrombotic coronary artery disease which is usually precipitated by atherosclerotic plaque disruption rupture or erosion type 2 evidence of an imbalance between myocardial oxygen supply and demand unrelated to acute atherothrombosis type 3 cardiac death in patients with symptoms suggestive of myocardial ischemia and presumed new ischemic ECG changes before cTn values become available or abnormal and type 4b and c stentscaffold thrombosis ore restenosis associated with percutaneous coronary intervention will be included in the study Patients with myocardial injury either acute as in acute heart failure or myocarditis or chronic as in chronic kidney disease or stable increased troponin levels with structural heart disease without ischemia abovementioned following clinical indicators of acute myocardial ischemia will be excluded from the study
The inclusion and exclusion criteria are summarized below Inclusion criteria Age 18 years ECG andor clinical diagnosis of acute myocardial infarction
Exclusion criteria Active pregnancy or a suspicion of pregnancy Rejection or withdrawal of consent Failure to acquire any of the pre-participation ECGs Non-ischemic myocardial injury Application of thrombolytic therapy instead of primary PCI Re-occlusion of the culprit lesion after intervention New vessel occlusion during hospital stay
Exclusion from final analyses
Randomization The patients will be randomized to the current STEMINSTEMI versus OMINOMI approaches using a cluster randomized trial design Although the STEMINSTEMI approach is the current norm a diagnosis of STEMI requires emergent catheterization whereas the patients with NSTEMI are stabilized first and then electively undergo catheterization unless there are high-risk features it would be unethical for a ECG reviewer who is trained in recognizing the signs of ACO not fulfilling the current STEMI criteria to suspend emergent reperfusion therapy after an OMI diagnosis has been made Therefore the ECG interpreters who are trained in OMI diagnosis cannot be randomized to STEMINSTEMI versus OMINOMI approaches Hence the groups will be randomized in the following fashion In each center a STEMINSTEMI and an OMINOMI intervention group will be formed After these two groups are formed the patients will be block-randomized into STEMINSTEMI and OMINOMI cohorts according to the team on-duty ie the approach that center will follow on a certain day will be defined by the team on duty The interventional cardiologists in both groups will be ensured to have a similar experience level in terms of years of training and angiography and primary PCI counts in the past year
All possible first responders in the network of a study center who contact the patient first according to the center this can be either a referring physician an emergency physician or a cardiologist will be provided with an AI-powered application for ECG diagnosis These responders will receive diagnostic prompts from the application according to the centers on-duty team If an OMI team member is on duty the ECG interpretation will be OMI or not-OMI If a STEMI team member is on-duty the ECG interpretation will be disabled and will read follow standard care The first responder will thus elect to go for catheterization based on this approach and whether that is by OMI or STEMI paradigm the patient will be enrolled accordingly and the reason for proceeding to the catheterization laboratory will be written on the study form or electronic sheet on the dedicated website
In the STEMINSTEMI arm the contributors will blindly continue their usual practice the ECG interpretation and decision to activate the catheterization laboratory will be done as usual The STEMINSTEMI group will use the following criteria for the diagnosis of STEMI 1 New ST-segment elevation at the J-point in two contiguous leads with the cut-point 1 mm in all leads other than leads V2-V3 where the following cut-points apply 2 mm in men 40 years 25 mm in men 40 years or 15 mm in women regardless of age and 2 a peak troponin level above 99th percentile with a characteristic rapid rise and fall retrospectively and 3 a clinical picture compatible with acute coronary syndrome If the decision to proceed to the cath lab was done only with the first criterion the participant will remain in the study even if the second criterion is not met The patients meeting only criteria 2 and 3 will be classified as NSTEMI
In the OMINOMI group the algorithm defined in the DIFOCCULT trial Aslanger et al In J Cardiol Heart Vasc 2020 Aslanger et al J Electrocardiol 2021 Aslanger et al Arch Turk Soc Cardiol 2021 or the AI-powered application diagnosis will be used for ECG diagnosis Therefore an OMI-ECG diagnosis will not be limited to AI-powered app but also can be done by human ECG interpreter due to a single ECG or serial ECG changes 1 Additionally 2 a peak troponin level above 99th percentile rapid rise and fall retrospectively and 3 a clinical picture compatible with acute coronary syndrome will be required If the decision to proceed emergently to the cath lab was done only with the first criterion the participant will remain in the study even if the second criterion is not met The patients who do not meet ECG-OMI criteria will be classified as NOMI if 1 a peak troponin level above 99th percentile rapid rise and fall retrospectively and 2 a clinical picture compatible with acute coronary syndrome is present
STEMI and OMI patients will be taken as STEMI equivalents for therapeutic purposes will be managed according to the current STEMI guidelines whereas NSTEMI and NOMI patients are managed according to the current NSTEMI guidelines A separate diagnostic group with probable OMI and high-risk STEMI is also allowed for patients who do not fulfil STEMIOMI criteria but need urgent catheterization for other high-risk features or high clinical suspicion for having an ACO These patients will also be managed according to the current guidelines However patients will be excluded from analysis if their early catheterization is based solely on social or logistical considerations and not based on the medical need For example a patient would be excluded if heshe is brought to the cath lab early based on the immediate availability of cath lab or because the patient is already scheduled for elective coronary angiography The patients who have alternative diagnoses myocarditis pericarditis pulmonary embolism etc but were not included due to a clinical or ECG diagnosis of STEMINSTEMI or OMINOMI will be excluded from the study Similarly the patients without a characteristic troponin kinetics who were not included due to a clinical or ECG diagnosis of STEMINSTEMI or OMINOMI will be excluded from the study
Endpoints The primary composite endpoint is all-cause mortality and all-cause re-hospitalization during follow-up The co-primary endpoint is all-cause mortality and all-cause re-hospitalization in OMI STEMI - patient subgroups The secondary comparisons will be done for the presence of ACO on angiogram false positive catheterization laboratory activation rate the infarct size as defined by 24-72 hour peak troponin wall motion score index WMSI left ventricular ejection fraction LVEF in-hospital CPR intubation and mortality These will be analyzed both with intention to treat and per protocol approaches
Estimated number of subjects to be submitted
It was estimated that the enrollment of 3472 participants would provide the study with a statistical power of 95 to detect a 4 absolute decrease in combined primary endpoint in OMINOMI approach compared to STEMINSTEMI approach from 25 to 21 with the use of a two-sided test at the 005 level with a prediction of an additional 25 OMI in NSTEMI cohort Similarly 2351 participants would be necessary to detect a 5 difference in area under curve AUC from 0750 to 0700 for the comparison of the predictive accuracy of two approaches for primary outcomes For the co-primary outcome a total of 698 OMI STEMI - participants would provide the study with a statistical power of 95 to detect a 6 absolute decrease in combined primary endpoint in OMINOMI approach compared to STEMINSTEMI approach from 15 to 8 with the use of a two-sided test at the 005 level This corresponds to an approximate total sample size of 4000 patients with a prediction of 115 STEMINSTEMI ratio and a frequency of 25 OMI in NSTEMI cohort However a one-year enrollment duration is planned which is expected to enroll over 5000 patients with a 115-2 STEMINSTEMI ratio into the study This total number is also expected to provide the study with a statistical power of 95 to detect at least a 10 relative decrease in infarct size 10 better left ventricular ejection fraction and 10 better wall-motion score index STEMI - OMI patients who underwent early revascularization in OMI arm compared to those who underwent revascularization with standard timing in STEMINSTEMI approach with a prediction of an additional 25 OMI in NSTEMI cohort
3 Participating centers Listed elsewhere
4 Data Collection From September 1 2024 AI-powered ECG App will be distributed to the referring hospitals by the participating centers The study will start at all participating centers on October 1 2024 A dedicated website difoccultorg will be used for data entry and storage Study data is collected and managed using REDCap Research Electronic Data Capture tool hosted at a dedicated server REDCap is a secure web-based software platform designed to support data capture for research studies providing 1 an intuitive interface for validated data capture 2 audit trails for tracking data manipulation and export procedures 3 automated export procedures for seamless data downloads to common statistical packages and 4 procedures for data integration and interoperability with external sources
Baseline variables Collected baseline variables and their definitions are listed in the REDCap printout in the supplemental file In brief the following baseline variables will be entered to the study spreadsheet Center specific enrollment no protocol no cohort age gender prior history of MI prior history of PCI or CABG presence or absence of diabetes medication use or HbA1c65 dyslipidemia LDL 160 mgdL or anti-lipid medication use hypertension medication use or average blood pressure over 14090 mmHg during hospital stay smoking current smoker or past smoker with in 1 year chronic kidney disease baseline creatinine level greater than the upper limit of normal admission systolic blood pressure admission heart rate admission creatinine level admission hemoglobin level Killip class on admission admission troponin T level from a blood sample collected before during or just after coronary angiography or at admission to the emergency department 24 48 and 72h troponin level the maximum troponin level during hospital stay ejection fraction wall motion score index time from constant pain to ECG time from ECG to PCI will be calculated from system recordings infarct related artery number of diseased vessels the number of additional lesions treated in-hospital mortality in-hospital resuscitation in-hospital intubation long term mortality From these parameters baseline GRACE risk score the change within troponin value in the first 24 hours will be calculated
Electrocardiogram
ECGs will be acquired using standard conventions If the first ECG is non-diagnostic serial ECGs will be acquired every 15 minutes for an hour and the first diagnostic ECG will be used in the analyses If all of them are non-diagnostic the physician may still use additional tools such as the clinical picture bedside echocardiogram troponin results to diagnose high-risk NSTEMI or possible OMI All pre-intervention ECGs and at least one pre-discharge ECG will be uploaded to a central cloud database to be retrospectively reviewed by core lab investigators The absence of a technically adequate pre-cath ECG will be a reason for the exclusion of the participant If ECG diagnosis is not compatible with the inclusion criteria for the assigned group this will be noted and the patient will be excluded from the per-protocol analyses Following coding will be used for ECGs
Type 1 EGGs New ST-segment elevation at the J-point in two contiguous leads with the cut-point 1 mm in all leads other than leads V2-V3 where the following cut-points apply 2mm in men 40 years 25 mm in men 40 years or 15 mm in women regardless of age
Type 1a The amplitude morphology extent of STE and the presence of additional findings hyperacute T waves Q-waves terminal QRS distortion make ECG highly obvious for MI presumably due to acute thrombotic occlusion These ECGs will be included in both STEMI and OMI definitions
Type 1b There is ST-segment elevation that meets criteria for STEMI but it is uncertain whether it is due to MI or to another condition such as benign variant STE left ventricular hypertrophy left bundle branch block prior MI pericarditis etc These ECGs will be included in the STEMI definition but not in the OMI definition unless there are additional findings suspicious for acute coronary occlusion as follows Differential diagnosis for benign variant STE Type 1b if fulfills STEMI criteria But re-classified as Type 2b if the AslangerSmith formula is positive Aslangers formula R-wave amplitude in lead V4 QRS amplitude in V2 - QT interval in millimeters STE60 in V3 12 Aslanger E Am J Cardiol 2018 Differential diagnosis for left ventricular hypertrophy Type 1b unless ST segment to R-S-wave magnitude is equal or greater than 15 then indicates OMI Type 2b Armstrong EJ et al Am J Cardiol 2012 Aslanger et al Arch Turk Soc Cardiol 2021 Differential diagnosis for isolated left bundle branch block Will be coded as Type 1b unless one of the modified Sgarbossa criteria is positive then indicates OMI Type 2b 1 lead with 1 mm of concordant ST elevation 1 lead of V1-V3 with 1 mm of concordant ST depression 1 lead anywhere with 1 mm STE and proportionally excessive discordant STE as defined by 25 of the depth of the preceding S-wave Smith SW et al Ann Emerg Med 2012 Differential diagnosis for prior MI Type 1b unless Smiths rule is positive then indicates OMI Type 2b Smiths rule If any 1 lead between V1-V4 has a T-wave amplitude to QRS amplitude ratio greater than or equal to 036 Klein LR et al Am J Emerg Med 2015 Differential diagnosis for pericarditis Type 1b unless there is ST-depression in aVL then indicates OMI Type 2b Bischof JE et al Am J Emerg Med 2016
Type 1c There is ST-segment elevation that meets criteria for STEMI but there is also T-wave inversion and pathologic Q waves indicative of subacute MI These ECGs will be excluded from per-protocol analyses since these patients have ACO on angiogram and higher long-term mortality but gain little if not any benefit from reperfusion with both approaches Patients with preserved QRS complexes Wellens pattern will be included in type 2c ECGs
Type 2 EGGs ECG that meets acute myocardial ischemia criteria recommended by fourth universal definition of MI
Type 2a The ECG has primary ie cannot be completely explained as secondary to a depolarization disorder ST-segment depression or T-wave inversion that is nondiagnostic of STEMI but is diagnostic of myocardial ischemia
Type 2b Does not meet recommended criteria for STEMI but highly suggestive for ACO despite being subtle and difficult Possible findings are minor STE with or without minor reciprocal ST-depression not fulfilling STEMI criteria hyperacute T-waves or DeWinters pattern subtle anterior STE hard to differentiate from benign variant STE and nonconsecutive STE These ECGs will be included in the OMI definition but not in the STEMI definition The detailed algorithm defined in the DIFOCCULT trial Aslanger et al In J Cardiol Heart Vasc 2020 Aslanger et al J Electrocardiol 2021 Aslanger et al Arch Turk Soc Cardiol 2021 will be used for recognizing these ECGs
Type 2c Patients with preserved QRS complexes Wellens pattern with or without some STE but with significant T wave negativity will be included in type 2c ECGs These ECGs will be excluded from per-protocol analyses since these patients may not gain benefit from emergent reperfusion in both approaches
Type 3 ECGs Nonspecific ECG that is abnormal but nondiagnostic of any kind of acute coronary syndrome Minor abnormalities including left ventricular hypertrophy without ST-T changes arrhythmias impulse generation and conduction diseases etc
Type 4 ECGs Completely normal ECG
AI-Powered ECG Application In OMINOMI arm ECGs can be digitized and interpreted by AI-powered ECG application prospectively In STEMINSTEMI arm interpretation will be done retrospectively
After the study completion ECGs in both study arms will be reviewed and coded as defined above for intention-to-treat and per-protocol analyses This will be done by two separate ECG interpreter Should there be any discrepancy between these interpreters a third interpreter from data monitoring board will be consulted
Type 1a 1b and 1c ECGs will be deemed as compatible with STEMI Type 1a 2b and 2c ECGs will be deemed compatible with OMI diagnosis
Troponins The troponin levels will be measured at admission hourly if needed for the diagnosis every 6 hours until it peaks after an MI diagnosis is made and then daily The 24-72 hour peak troponin level usually 48h will be used as a surrogate for infarct size
Angiograms Coronary angiography will be undertaken according to the standard conventions Each angiogram will be reviewed by two interventionalist Should there be any discrepancy between these interpreters a third interpreter from data monitoring board will be consulted
Following points will be noted for the presence of an ACO 1 the Thrombolysis in Myocardial Infarction Study TIMI flow level in the infarct-related vessel The presence of well-developed collaterals to the distal vessel appearance of the total occlusion easiness of guidewire crossing will also be assessed to determine if the total occlusion is acute in nature If necessary the primary operator will also be contacted 2 The presence of an acute lesion with definitive culprit features which was defined based on several angiographic properties including critical stenosis irregular lesion borders presence of angiographic thrombus or staining
ACO Adjudication
Because the infarct-related artery may spontaneously open by the time of the angiogram or total occlusion may be chronic in nature a composite ACO using following criteria is defined
1 An acute culprit lesion with TIMI 0-2 flow PLUS a peak troponin level equal to or greater 5 than five times the ULN PLUS at least 20 rise within the first 24 hours
2 A highly elevated peak for troponin T1000 ngmL and for troponin I 200 times of the average of ULN known to be highly correlated with ACO without an obvious alternative diagnosis or with supporting evidence ECG evolution culprit-looking lesion on angiogram in a coronary territory compatible with ECGechocardiographic area at concern
3 cardiac arrest before any troponin rise has been documented with supporting clinical evidence of possible ACO
Follow-up The last participant in the study will be followed up to one year The survival status and re-hospitalization will be checked from the national database and a phone call if required
Statistical Analysis Baseline characteristics will be summarized using standard descriptive statistics Comparisons of relevant parameters between groups will be performed by chi-square Fishers exact test Mann-Whitney U and student t-test as appropriate Patients with missing values will be excluded pairwise from analyses A Cohens κ test will be used for determination of the intra- and inter-observer agreement for ECG classifications and ACO adjudication
Kaplan-Meier analysis will be performed to determine the cumulative long-term mortality rates in different ECG subgroups The mortality across groups will be compared using a log-rank test A Cox-regression model will be used to perform a survival analysis according to basal GRACE risk score intervention timing and revascularization status Baseline characteristics with a P value of 005 or less in the univariate analysis will be included and a step-down procedure will be applied for selection of final covariates
The sensitivity specificity and diagnostic accuracy of STEMINSTEMI or OMINOMI ECG approaches will be calculated using receiver operating characteristics analysis As these parameters are highly dependent on the pre-test probability of the disease and pre-test probability of ACO and long-term mortality are closely associated with the presentation type the investigators will also repeat these analyses after weighing cases for the total number of hospital admissions in the study period
Statistical analyses will be performed with SPSS version 240 SPSS Inc Chicago IL and MedCalc Software version 1821 Evaluation version MedCalc Software Ostend Belgium
5 Safety monitoring and reporting Study REDCap forms necessitate in-hospital adverse events to be actively collected to monitor and report any in-hospital adverse events An independent Data Safety Monitoring Board DSMB has been established to oversee the safety and progress of the trial The DSMB convened via teleconference during the pretrial period upon enrollment of 20 of the participant sample size and will continue to meet after each subsequent 20 enrollment milestone The primary objective of the DSMB is to monitor enrollment milestones and the safety of the interventions A four-point combined safety endpoint will be closely monitored 1 myocardial infarction size by 48hour troponin ejection fraction and wall motion score index 2 integrity of coronary intervention by in-hospital stent thrombosis 3 integrity of in-hospital care by in-hospital intubation in-hospital cardiopulmonary resuscitation and in-hospital mortality and 4 long-term therapy by discharge treatment If a statistically significant increase in this four-point combined safety endpoint is observed in either of the study arms after the enrollment of any 20 of the participant sample size the DSMB will make a recommendation regarding the revision rearrangement or potential exclusion of the study participants or the study center
6 Study integrity The study is an investigator-initiated trial conducted under the auspices of the Turkish Society of Cardiology The Turkish Society of Cardiology supports the investigator team in developing the trial design and organizing the participating centers The steering committee oversees the processes of recruitment consent and assent follow-up and ensures the validity and integrity of data acquisition The trial has been approved by the Ethical Board of Marmara University 092021523 any change in protocol or centers will be addressed by this board The study will be conducted in accordance with Good Clinical Practice guidelines
Study Oversight
Has Oversight DMC:
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Is a FDA Regulated Drug?:
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Is a FDA Regulated Device?:
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Is an Unapproved Device?:
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Is a PPSD?:
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Is a US Export?:
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Is an FDA AA801 Violation?:
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