Ignite Creation Date:
2024-05-05 @ 9:27 PM
Last Modification Date:
2024-10-26 @ 10:04 AM
Study NCT ID:
NCT00880802
Status:
UNKNOWN
Last Update Posted:
2010-01-12
First Post:
2009-04-11
Brief Title:
Finding Acute Coronary Syndromes ACS With Serial Troponin Testing for Rapid Assessment of Cardiac Ischemic Symptoms
Sponsor:
Nanosphere Inc
Organization:
Nanosphere Inc
Study Overview
Official Title:
Finding ACS With Serial Troponin Testing for Rapid Assessment of Cardiac Ischemic Symptoms
Status:
UNKNOWN
Status Verified Date:
2010-01
Last Known Status:
ACTIVE_NOT_RECRUITING
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:
FAST-TRAC
Brief Summary:
Study Objectives
The following items will be prospectively assessed
Primary Endpoints
1 For patients presenting with clinical suspicion of Acute Coronary Syndromes ACS high sensitivity-cardiac Troponin I hs-cTnI provides improved diagnostic accuracy for ACS including Acute Myocardial Infarction AMI andor Unstable Angina UA within the first two 2 hours after emergency department presentation when compared to currently available troponin assays
2 For patients presenting with clinical suspicion of ACS hs-cTnI provides improved prognostic information with regard to 180 day event rates of Major Adverse Cardiac Event outcomes including cardiac deaths which are defined as all deaths except those that are clearly non-cardiac in nature eg trauma when compared to a currently available troponin assay
Secondary Endpoints
1 For patients presenting with clinical suspicion of ACS using the rate of rise of hs-cTnI over time between presentation and 2 hours delta hs-cTnI allows for the differentiation between ACS and other disease states
2 For patients presenting with clinical suspicion of ACS hs-cTnI provides improved sensitivity for detecting AMI within the first two 2 hours after presentation when compared to a currently available troponin assay
3 For patients presenting with clinical suspicion of ACS hs-cTnI provides improved negative predictive value for ruling out ACS AMI or UA within the first 2 hours after presentation when compared to a currently available troponin assay
4 For alternative endpoints of cardiac mortality and for alternative censor time points of 30 days 90 days and 1 year hs-cTnI provides improved prognostic information when compared to the currently available troponin assay
5 In cases where the emergency physician has limited diagnostic confidence hs-cTnI AMI diagnostic accuracy will be superior to local hospital standards for AMI determination
6 In cases where the emergency physician has limited diagnostic confidence the slope for the hs-cTnI between presentation and 2 hours will add diagnostic accuracy for ACS diagnosis over and above local hospital standards for ACS determination
7 For patients presenting with clinical suspicion of ACS the difference in diagnostic accuracy for ACS including AMI andor UA using hs-cTnI measurement from time of onset of symptoms to emergency department presentation eg 3 hours instead of 6 hours will be evaluated to assess any variation
The following items will be prospectively assessed
Primary Endpoints
1 For patients presenting with clinical suspicion of Acute Coronary Syndromes ACS high sensitivity-cardiac Troponin I hs-cTnI provides improved diagnostic accuracy for ACS including Acute Myocardial Infarction AMI andor Unstable Angina UA within the first two 2 hours after emergency department presentation when compared to currently available troponin assays
2 For patients presenting with clinical suspicion of ACS hs-cTnI provides improved prognostic information with regard to 180 day event rates of Major Adverse Cardiac Event outcomes including cardiac deaths which are defined as all deaths except those that are clearly non-cardiac in nature eg trauma when compared to a currently available troponin assay
Secondary Endpoints
1 For patients presenting with clinical suspicion of ACS using the rate of rise of hs-cTnI over time between presentation and 2 hours delta hs-cTnI allows for the differentiation between ACS and other disease states
2 For patients presenting with clinical suspicion of ACS hs-cTnI provides improved sensitivity for detecting AMI within the first two 2 hours after presentation when compared to a currently available troponin assay
3 For patients presenting with clinical suspicion of ACS hs-cTnI provides improved negative predictive value for ruling out ACS AMI or UA within the first 2 hours after presentation when compared to a currently available troponin assay
4 For alternative endpoints of cardiac mortality and for alternative censor time points of 30 days 90 days and 1 year hs-cTnI provides improved prognostic information when compared to the currently available troponin assay
5 In cases where the emergency physician has limited diagnostic confidence hs-cTnI AMI diagnostic accuracy will be superior to local hospital standards for AMI determination
6 In cases where the emergency physician has limited diagnostic confidence the slope for the hs-cTnI between presentation and 2 hours will add diagnostic accuracy for ACS diagnosis over and above local hospital standards for ACS determination
7 For patients presenting with clinical suspicion of ACS the difference in diagnostic accuracy for ACS including AMI andor UA using hs-cTnI measurement from time of onset of symptoms to emergency department presentation eg 3 hours instead of 6 hours will be evaluated to assess any variation
Detailed Description:
This study will evaluate the ability of a high sensitivity cardiac troponin I hs-cTnI assay to detect and to rule-out high-risk ischemic cardiac injury in emergency room patients experiencing signs and symptoms consistent with acute coronary syndromes ACS Cardiovascular disease is still the most frequent cause of morbidity and mortality among industrialized nations In the US there are nearly 100 million adults who suffer from cardiovascular disease Over 5 million patients present to emergency departments EDs annually with a chief complaint consistent with ACS A majority of these patients are found to be experiencing non-cardiac chest pain about 70-82 of patients Myocardial infarction MI including non-ST-segment elevation MI NSTEMIs about 6-10 of patients and ST-segment elevation MI STEMIs about 2-5 of patients occurs in about 8-15 of these patients Unstable angina UA which is often a precursor condition to MI accounts for 10-15 of patients Together MI plus UA combine to define ACS about 18-30 patients
MI is caused by rupture of an atherosclerotic plaque in a coronary artery leading to platelet aggregation and thrombus formation to an extent that oxygenation of the myocardial tissue is completely interrupted ie total occlusion with the occurrence of some degree of myocardial necrosis High concentrations of cardiac enzymes and proteins eg cardiac troponin I or T cTnI or cTnT CK-MB myoglobin are observed in blood as the result of significant irreversible injury to cardiac tissue distal to the site of rupture and secondary to arterial occlusion Current assays can detect STEMIs and NSTEMIs but by definition of the 2007 AHAACC updated guidelines for NSTEMI and UA the NSTEMI threshold is defined as the 99th percentile upper reference limit URL of a cardiac troponin cTn assays reference range in a healthy subject population and they cannot detect what is currently labeled unstable angina UA or ischemia without necrosis In addition it typically takes 4-6 hours after ischemic symptoms begin for the cardiac troponin to rise above the current commercial assay NSTEMI threshold ie the upper reference limit URL the 99th percentile upper reference limit These issues expose a sensitivity problem with current generation cTn assays including the most sensitive tests available
UA is also associated with plaque rupture but only partial coronary artery occlusion occurs resulting in ischemic pain but no or unmeasureable necrosis No rise is observable in cardiac marker levels on currently available assays best limit of detection LOD of 001 ngmL 10 pgmL and best URL of 003 ngmL 30 pgmL Since there is no test currently available that accurately diagnoses UA many UA patients are discharged home in the midst of a high-risk ischemic event Note Ischemia modified albumin IMA is on the market but is not widely used due to its poor specificity The negative predictive value of the diagnostic test is important in this regard as increases in sensitivity may be offset if there are also increases in false positive results
As many as 2 30000 patients to 4 60000 pts of patients with MI or UA 750000 MI patients 750000 UA patients 15 million total patients at risk are inadvertently discharged from the ED with an associated short-term mortality of 10 to 26 Duseja and Feldman 2004 Missed acute cardiac ischemia is one of the major causes of malpractice litigation against emergency physicians Duseja and Feldman 2004 Even though chest pain and other symptoms consistent with ACS patients represent only 6 of the ED patient volume it has been estimated that 20 of ED-related malpractice dollars are expended for ischemic heart disease complications Rusnak et al 1989 Therefore the misdiagnosis of ischemic cardiac injury is of great importance from a human-life and economic perspective
In the typical hospital ED today cardiac biomarkers are drawn and the results are back to the ED physician within about 15 hours ie therapeutic turnaround time TTAT vein to brain time Some hospitals have moved to point-of-care devices with relatively low sensitivity URL 0080 ngmL that can give results within 10-15 minutes and on the other extreme some EDs that are still dependent on the central laboratory have a therapeutic turnaround time of 2-4 hours Most chest pain patients that continue to have discomfort and other cardiac symptoms are held in the ED or chest pain observation unit for 6 to 23 hours before discharge allowing serial cardiac markers to be drawn Therefore keeping these time points in mind a highly sensitive eg URL 0003 ngmL and precise cTn assay eg 20-30CV that takes 1 hour to give a result may be very useful for any hospital ED
Time is important but in the case of ischemic heart disease accurate information is more important and is potentially life-saving The information that the assay would give to the ED physician would allow for accurate diagnosis of what is currently labeled UA and not discharge a patient who actually requires close monitoring treatment or follow-up at a cardiologists office Also the diagnosis of an MI could be made much earlier with high sensitivity and specificity than the 4-6 hours after ED presentation that it takes for cTn to be detected by current assays
With no cardiac marker assay available that can diagnose UA with appropriate accuracy and precision development of a cost-effective timely 1 hr assay time cardiac troponin assay that allows accurate measurement of cTn at concentrations that are 10-100 fold below the best of the current assays detection limits has the potential to improve ACS patient care It will allow diagnosis of ischemic injury in UA patients in the ED so they can be admitted appropriately to the hospital instead of being sent home to experience a possible cardiac event or death With current therapeutic capabilities eg LMWHs beta-blockers glycoprotein IIbIIIa inhibitors other anti-platelet agents that are known to lower the risk of future cardiac events and mortality it can be expected that the earlier detection of MI and diagnosis of UA may lead to reductions in morbidity and mortality in ACS patients
The need for a highly sensitive assay for cardiac troponin is predicated on the observation that the URL of the true reference range in nominally healthy subjects is significantly below the concentrations that current assays can measure A new nanoparticle-based highly sensitive cTnI assay ie nano-assay appears to offer a significant technological advantage over the current macroparticle-based sensitive assays The new highly sensitive assays LOD is 800 fgmL 800 fgmL 08 pgmL 00008 ngmL for cardiac troponin I as compared to 10 pgmL 0010 ngmL for the most sensitive cTnI assay currently on the market The new assay has an imprecision CV at the LOD of 20-30 as compared to 30 at the LOD for the most sensitive cTnI assay currently on the market The URL of the reference range in healthy subjects for the new assay is about 28 pgmL 00028 ngmL compared to 30 pgmL 0030 ngmL for the most sensitive cTnI assay currently on the market Under these differences in analytical performance it is likely that the majority of patients with what is currently labeled UA will reveal detectable troponin concentrations that exceed the nano-assays threshold limit ie 28 pgmL 00028 ngmL on the nanoparticle-based highly sensitive cTnI assay but non-detectable levels of troponin on the current macroparticle-based sensitive cTnI assays
In a pilot study banked serial serum samples of ten NSTEMI patients from the Hospital of the University of Pennsylvania ED were evaluated on a research version of the nano-assay These serial samples were troponin-negative on an older laboratory assay laboratory assay URL 06 ngmL 600pgmL for the first 1-3 blood draws Samples from these patients at presentation 90min and 180min were measured by a current sensitive assay Siemens Dade Behring Stratus CS sensitive assay URL 0070ngmL 70pgmL and by the experimental highly sensitive assay highly sensitive assay URL00028 ngmL 28 pgmL None 0 two 20 and ten 100 of the ten NSTEMI patients were found to be cTnI positive at presentation on the laboratory sensitive and highly sensitive assays respectively All 10 patients measured at 35pgmL on the highly sensitive assay at presentation Three of the patients remained cTnI negative for 180 min on the current sensitive assay
In another research study samples from 100 chest pain patients with known ACS ie 50 NSTEMI and 50 UA patients were evaluated Comparison was made between the laboratory device and the highly sensitive nano-assay with a URL of 00028 ngmL 28 pgmL Using the current laboratory assay Siemens Dade Behring Dimension URL 0100 ngmL 100 pgmL the 50 NSTEMI patients were cTnI negative on the first draw and the 50 UA patients were cTnI negative throughout their stay in the ED andor hospital At presentation t 0 hrs 7 hrs and 24 hrs none 0 of the UA patients were found to be positive for cTnI on the laboratory instrument Using the nano-assay with the same UA patients serum samples 48 64 and 82 were positive for cTnI at presentation 2 hrs and 7 hrs respectively For the NSTEMI patients at presentation t 0 hrs 7 hrs and 24 hrs none 0 56 and 98 respectively of the patients were found to be positive for cTnI on the laboratory instrument Using the nano-assay with the same NSTEMI patients serum 76 98 and 100 were positive for cTnI at presentation 2 hrs and 7 hrs respectively
These preliminary results demonstrate the potential strength of this highly sensitive cTnI assay to reveal an abnormal cTnI at ED presentation that may progress to MI ie NSTEMI or STEMI and to detect acute ischemic insult that may not progress to MI ie UA This high sensitivity protein assay may enhance the clinical utility of testing for ACS in the ED and other cardiac care settings eg earlier detection leading to directed therapies improve risk stratification earlier rule-out of non-cardiac-related chest pain NCCP detection of re-infarction
The definition of myocardial infarction used in this study will be the meaning that was recently updated and published in the November 27 2007 issue of Circulation Thygesen et al 2007 Page 18 of this study protocol contains this definition The definition is based on cardiac troponin as the biomarker of choice with any value above the 99th percentile of an assays reference range population considered abnormal Therefore if the nano-assays URL is much lower than the current assays URL all values that are above the nano-assays URL but below the current assays URL that were considered UA on the current assay should now be considered myocardial infarction when measured on the nano-assay This may result in the UA category being removed as an ACS categorization
There are also recent studies Zethelius et al 2006 Waxman et al 2006 that show very low cTnI values 30-40 pgmL can predict future cardiac events and mortality in the asymptomatic elderly male population 70 years and in symptomatic ED patients with cTnI levels that remain in the reference normal ranges of current assays A highly sensitive assay that could detect silent cardiac damage in these cTnI ranges in the cardiologists office and ED settings could be a predictor of future risk that could direct appropriate therapeutics and preventative care
MI is caused by rupture of an atherosclerotic plaque in a coronary artery leading to platelet aggregation and thrombus formation to an extent that oxygenation of the myocardial tissue is completely interrupted ie total occlusion with the occurrence of some degree of myocardial necrosis High concentrations of cardiac enzymes and proteins eg cardiac troponin I or T cTnI or cTnT CK-MB myoglobin are observed in blood as the result of significant irreversible injury to cardiac tissue distal to the site of rupture and secondary to arterial occlusion Current assays can detect STEMIs and NSTEMIs but by definition of the 2007 AHAACC updated guidelines for NSTEMI and UA the NSTEMI threshold is defined as the 99th percentile upper reference limit URL of a cardiac troponin cTn assays reference range in a healthy subject population and they cannot detect what is currently labeled unstable angina UA or ischemia without necrosis In addition it typically takes 4-6 hours after ischemic symptoms begin for the cardiac troponin to rise above the current commercial assay NSTEMI threshold ie the upper reference limit URL the 99th percentile upper reference limit These issues expose a sensitivity problem with current generation cTn assays including the most sensitive tests available
UA is also associated with plaque rupture but only partial coronary artery occlusion occurs resulting in ischemic pain but no or unmeasureable necrosis No rise is observable in cardiac marker levels on currently available assays best limit of detection LOD of 001 ngmL 10 pgmL and best URL of 003 ngmL 30 pgmL Since there is no test currently available that accurately diagnoses UA many UA patients are discharged home in the midst of a high-risk ischemic event Note Ischemia modified albumin IMA is on the market but is not widely used due to its poor specificity The negative predictive value of the diagnostic test is important in this regard as increases in sensitivity may be offset if there are also increases in false positive results
As many as 2 30000 patients to 4 60000 pts of patients with MI or UA 750000 MI patients 750000 UA patients 15 million total patients at risk are inadvertently discharged from the ED with an associated short-term mortality of 10 to 26 Duseja and Feldman 2004 Missed acute cardiac ischemia is one of the major causes of malpractice litigation against emergency physicians Duseja and Feldman 2004 Even though chest pain and other symptoms consistent with ACS patients represent only 6 of the ED patient volume it has been estimated that 20 of ED-related malpractice dollars are expended for ischemic heart disease complications Rusnak et al 1989 Therefore the misdiagnosis of ischemic cardiac injury is of great importance from a human-life and economic perspective
In the typical hospital ED today cardiac biomarkers are drawn and the results are back to the ED physician within about 15 hours ie therapeutic turnaround time TTAT vein to brain time Some hospitals have moved to point-of-care devices with relatively low sensitivity URL 0080 ngmL that can give results within 10-15 minutes and on the other extreme some EDs that are still dependent on the central laboratory have a therapeutic turnaround time of 2-4 hours Most chest pain patients that continue to have discomfort and other cardiac symptoms are held in the ED or chest pain observation unit for 6 to 23 hours before discharge allowing serial cardiac markers to be drawn Therefore keeping these time points in mind a highly sensitive eg URL 0003 ngmL and precise cTn assay eg 20-30CV that takes 1 hour to give a result may be very useful for any hospital ED
Time is important but in the case of ischemic heart disease accurate information is more important and is potentially life-saving The information that the assay would give to the ED physician would allow for accurate diagnosis of what is currently labeled UA and not discharge a patient who actually requires close monitoring treatment or follow-up at a cardiologists office Also the diagnosis of an MI could be made much earlier with high sensitivity and specificity than the 4-6 hours after ED presentation that it takes for cTn to be detected by current assays
With no cardiac marker assay available that can diagnose UA with appropriate accuracy and precision development of a cost-effective timely 1 hr assay time cardiac troponin assay that allows accurate measurement of cTn at concentrations that are 10-100 fold below the best of the current assays detection limits has the potential to improve ACS patient care It will allow diagnosis of ischemic injury in UA patients in the ED so they can be admitted appropriately to the hospital instead of being sent home to experience a possible cardiac event or death With current therapeutic capabilities eg LMWHs beta-blockers glycoprotein IIbIIIa inhibitors other anti-platelet agents that are known to lower the risk of future cardiac events and mortality it can be expected that the earlier detection of MI and diagnosis of UA may lead to reductions in morbidity and mortality in ACS patients
The need for a highly sensitive assay for cardiac troponin is predicated on the observation that the URL of the true reference range in nominally healthy subjects is significantly below the concentrations that current assays can measure A new nanoparticle-based highly sensitive cTnI assay ie nano-assay appears to offer a significant technological advantage over the current macroparticle-based sensitive assays The new highly sensitive assays LOD is 800 fgmL 800 fgmL 08 pgmL 00008 ngmL for cardiac troponin I as compared to 10 pgmL 0010 ngmL for the most sensitive cTnI assay currently on the market The new assay has an imprecision CV at the LOD of 20-30 as compared to 30 at the LOD for the most sensitive cTnI assay currently on the market The URL of the reference range in healthy subjects for the new assay is about 28 pgmL 00028 ngmL compared to 30 pgmL 0030 ngmL for the most sensitive cTnI assay currently on the market Under these differences in analytical performance it is likely that the majority of patients with what is currently labeled UA will reveal detectable troponin concentrations that exceed the nano-assays threshold limit ie 28 pgmL 00028 ngmL on the nanoparticle-based highly sensitive cTnI assay but non-detectable levels of troponin on the current macroparticle-based sensitive cTnI assays
In a pilot study banked serial serum samples of ten NSTEMI patients from the Hospital of the University of Pennsylvania ED were evaluated on a research version of the nano-assay These serial samples were troponin-negative on an older laboratory assay laboratory assay URL 06 ngmL 600pgmL for the first 1-3 blood draws Samples from these patients at presentation 90min and 180min were measured by a current sensitive assay Siemens Dade Behring Stratus CS sensitive assay URL 0070ngmL 70pgmL and by the experimental highly sensitive assay highly sensitive assay URL00028 ngmL 28 pgmL None 0 two 20 and ten 100 of the ten NSTEMI patients were found to be cTnI positive at presentation on the laboratory sensitive and highly sensitive assays respectively All 10 patients measured at 35pgmL on the highly sensitive assay at presentation Three of the patients remained cTnI negative for 180 min on the current sensitive assay
In another research study samples from 100 chest pain patients with known ACS ie 50 NSTEMI and 50 UA patients were evaluated Comparison was made between the laboratory device and the highly sensitive nano-assay with a URL of 00028 ngmL 28 pgmL Using the current laboratory assay Siemens Dade Behring Dimension URL 0100 ngmL 100 pgmL the 50 NSTEMI patients were cTnI negative on the first draw and the 50 UA patients were cTnI negative throughout their stay in the ED andor hospital At presentation t 0 hrs 7 hrs and 24 hrs none 0 of the UA patients were found to be positive for cTnI on the laboratory instrument Using the nano-assay with the same UA patients serum samples 48 64 and 82 were positive for cTnI at presentation 2 hrs and 7 hrs respectively For the NSTEMI patients at presentation t 0 hrs 7 hrs and 24 hrs none 0 56 and 98 respectively of the patients were found to be positive for cTnI on the laboratory instrument Using the nano-assay with the same NSTEMI patients serum 76 98 and 100 were positive for cTnI at presentation 2 hrs and 7 hrs respectively
These preliminary results demonstrate the potential strength of this highly sensitive cTnI assay to reveal an abnormal cTnI at ED presentation that may progress to MI ie NSTEMI or STEMI and to detect acute ischemic insult that may not progress to MI ie UA This high sensitivity protein assay may enhance the clinical utility of testing for ACS in the ED and other cardiac care settings eg earlier detection leading to directed therapies improve risk stratification earlier rule-out of non-cardiac-related chest pain NCCP detection of re-infarction
The definition of myocardial infarction used in this study will be the meaning that was recently updated and published in the November 27 2007 issue of Circulation Thygesen et al 2007 Page 18 of this study protocol contains this definition The definition is based on cardiac troponin as the biomarker of choice with any value above the 99th percentile of an assays reference range population considered abnormal Therefore if the nano-assays URL is much lower than the current assays URL all values that are above the nano-assays URL but below the current assays URL that were considered UA on the current assay should now be considered myocardial infarction when measured on the nano-assay This may result in the UA category being removed as an ACS categorization
There are also recent studies Zethelius et al 2006 Waxman et al 2006 that show very low cTnI values 30-40 pgmL can predict future cardiac events and mortality in the asymptomatic elderly male population 70 years and in symptomatic ED patients with cTnI levels that remain in the reference normal ranges of current assays A highly sensitive assay that could detect silent cardiac damage in these cTnI ranges in the cardiologists office and ED settings could be a predictor of future risk that could direct appropriate therapeutics and preventative care
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None