Ignite Creation Date:
2024-05-06 @ 12:01 AM
Last Modification Date:
2024-10-26 @ 10:43 AM
Study NCT ID:
NCT01471522
Status:
COMPLETED
Last Update Posted:
2023-06-01
First Post:
2011-11-10
Brief Title:
International Study of Comparative Health Effectiveness With Medical and Invasive Approaches ISCHEMIA
Sponsor:
NYU Langone Health
Organization:
NYU Langone Health
Study Overview
Official Title:
International Study of Comparative Health Effectiveness With Medical and Invasive Approaches ISCHEMIA
Status:
COMPLETED
Status Verified Date:
2023-05
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:
ISCHEMIA
Brief Summary:
The purpose of the ISCHEMIA trial is to determine the best management strategy for higher-risk patients with stable ischemic heart disease SIHD This is a multicenter randomized controlled trial with 5179 randomized participants with moderate or severe ischemia on stress testing A blinded coronary computed tomography angiogram CCTA was performed in most participants with eGFR 60 mLmin173m2 to identify and exclude participants with either significant unprotected left main disease 50 stenosis or those without obstructive CAD 50 stenosis in all major coronary arteries Of 8518 participants enrolled those that had insufficient ischemia ineligible anatomy demonstrated on CCTA or another exclusion criterion did not go on to randomization Eligible participants were then assigned at random to a routine invasive strategy INV with cardiac catheterization followed by revascularization if feasible plus optimal medical therapy OMT or to a conservative strategy CON of OMT with cardiac catheterization and revascularization reserved for those who fail OMT
SPECIFIC AIMS
A Primary Aim The primary aim of the ISCHEMIA trial is to determine whether an initial invasive strategy of cardiac catheterization followed by optimal revascularization if feasible in addition to OMT will reduce the primary composite endpoint of cardiovascular death nonfatal myocardial infarction resuscitated cardiac arrest or hospitalization for unstable angina or heart failure in participants with SIHD and moderate or severe ischemia over an average follow-up of approximately 35 years compared with an initial conservative strategy of OMT alone with catheterization reserved for failure of OMT
B Secondary Aims Secondary aims are to determine whether an initial invasive strategy compared to a conservative strategy will improve 1 the composite of CV death or MI 2 angina symptoms and quality of life as assessed by the Seattle Angina Questionnaire 3 all-cause mortality 4 net clinical benefit assessed by including stroke in the primary and secondary composite endpoints and 5 individual components of the composite endpoints
Condition Coronary Disease Procedure Coronary CT Angiogram Procedure Cardiac catheterization Phase Phase III per NIH
Condition Cardiovascular Diseases Procedure Angioplasty Transluminal Percutaneous Coronary other catheter-based interventions Phase Phase III per NIH
Condition Heart Diseases Procedure Coronary Artery Bypass Surgery Phase Phase III per NIH
SPECIFIC AIMS
A Primary Aim The primary aim of the ISCHEMIA trial is to determine whether an initial invasive strategy of cardiac catheterization followed by optimal revascularization if feasible in addition to OMT will reduce the primary composite endpoint of cardiovascular death nonfatal myocardial infarction resuscitated cardiac arrest or hospitalization for unstable angina or heart failure in participants with SIHD and moderate or severe ischemia over an average follow-up of approximately 35 years compared with an initial conservative strategy of OMT alone with catheterization reserved for failure of OMT
B Secondary Aims Secondary aims are to determine whether an initial invasive strategy compared to a conservative strategy will improve 1 the composite of CV death or MI 2 angina symptoms and quality of life as assessed by the Seattle Angina Questionnaire 3 all-cause mortality 4 net clinical benefit assessed by including stroke in the primary and secondary composite endpoints and 5 individual components of the composite endpoints
Condition Coronary Disease Procedure Coronary CT Angiogram Procedure Cardiac catheterization Phase Phase III per NIH
Condition Cardiovascular Diseases Procedure Angioplasty Transluminal Percutaneous Coronary other catheter-based interventions Phase Phase III per NIH
Condition Heart Diseases Procedure Coronary Artery Bypass Surgery Phase Phase III per NIH
Detailed Description:
BACKGROUND
Evidence supporting a routine invasive practice paradigm for patients with SIHD is outdated In strategy trials conducted in the 1970s coronary artery bypass grafting CABG improved survival as compared with no CABG in SIHD patients with high-risk anatomic features The relevance of these studies today is speculative because contemporary secondary prevention-aspirin beta-blockers statins ACE inhibitors and lifestyle interventions-were used minimally if at all Subsequent trials have compared percutaneous coronary intervention PCI with medical therapy as PCI has replaced CABG as the dominant method of revascularization for SIHD To date PCI has not been shown to reduce death or myocardial infarction MI compared with medical therapy in SIHD patients
COURAGE and BARI 2D the two largest trials comparing coronary revascularization vs medical therapy in SIHD patients found that among patients selected on the basis of coronary anatomy after cardiac catheterization an initial management strategy of coronary revascularization PCI PCI or CABG respectively did not reduce the primary endpoints of death or MI COURAGE or death BARI 2D compared with OMT alone These data suggest but do not prove that routine cardiac catheterization--which often leads to ad hoc PCI through the diagnostic-therapeutic cascade--may not be required in SIHD patients However most patients enrolled in COURAGE and BARI 2D who had ischemia severity documented at baseline had only mild or moderate ischemia leaving open the question of the appropriate role of cardiac catheterization and revascularization among higher-risk patients with more severe ischemia Observational data suggest that revascularization of patients with moderate-to-severe ischemia is associated with a lower mortality than medical therapy alone but such data cannot establish a cause and effect relationship In clinical practice only about half such patients are referred for cardiac catheterization indicating equipoise Furthermore analysis of outcomes for 468 COURAGE patients with moderate-to-severe ischemia at baseline did not reveal a benefit from PCI This issue cannot be resolved using available data because all prior SIHD strategy trials enrolled patients after cardiac catheterization introducing undefined selection biases eg highest risk patients not enrolled and making translation of study results problematic for clinicians managing patients who have not yet had cardiac catheterization
A clinical trial in SIHD patients uniformly at higher risk which could not have been performed before COURAGE and BARI 2D results were available is needed to inform optimal management for such patients
DESIGN NARRATIVE INCLUDING MODIFICATIONS DURING THE TRIAL
Primary Endpoint
A composite of CV death MI resuscitated cardiac arrest or hospitalization for unstable angina or heart failure was proposed as the primary endpoint in the application that was funded by NLHBI with a secondary endpoint of CV death or MI Study protocol version 10 was finalized on January 18 2012 after review and approval by the protocol review committee DSMB with the primary endpoint specified as the composite of CV death or MI Regarding the final status of the primary endpoint the protocol stated
To ensure that the primary analysis is well-powered and useful a prospective plan to allow extending follow-up andor changing the primary endpoint based on aggregate event rate data will be established prior to the first review of unblinded trial data At a designated time during the trial an analysis will be conducted to estimate the overall aggregate primary endpoint event rate and project the final number of observed events If the estimated unconditional power ie based on aggregate event rate data not by treatment group is less than the originally targeted 90 then one or more of the following options will be considered
1 Extend follow-up to allow more events to accrue
2 Change the primary endpoint to one that occurs more frequently The current primary endpoint would become a secondary endpoint The proposed new primary endpoint would be the composite of CV death MI resuscitated cardiac arrest or hospitalization for unstable angina or heart failure
3 Follow the recommendation of an independent advisory panel An independent advisory panel separate from the DSMB will be convened for the purpose of reviewing unconditional power estimates and making a recommendation to the NHLBI Director Members of this panel will not have access to unblinded data by treatment group or other data that may bias their recommendation All 5 event types were adjudicated throughout the trial Study protocol v20 January 2014 allowed ischemia eligibility by non-imaging exercise stress test if more stringent 70 stenosis CCTA criteria were met The 2016 protocol addendum describes the NHLBI-approved reduction in sample size and extension of recruitment and follow-up due to slower than projected recruitment
The pre-specified first analysis for monitoring and projecting the final aggregate number of primary endpoint events was conducted in 2015 In 2016 the projected need to increase the power by extending follow-up and elevating the 5-component secondary endpoint to become primary was discussed at Steering Committee and Investigator meetings and communicated by email
An Independent Advisory Panel convened by NHLBI met in May 2017 and in June 2017 NHLBI approved the Independent Advisory Panels recommendation to elevate the 5-component secondary endpoint to become primary and retain the 2-component composite as a key secondary endpoint The panel also recommended extension of follow-up This was communicated to the Steering Committee and Investigators at August and November 2017 meetings and by email The last visit date was June 30 2019
A statistical plan developed for the Independent Advisory Panel process in 2012 specified that a decision about changing the primary endpoint would be targeted to occur before 75 of the final number of primary endpoint events had accrued Although the final number of primary endpoint events was unknown during the course of the trial estimates performed at the time of the Advisory Panel meeting suggested that the ratio of accrued endpoint events to final endpoint events was below 50 See Maron DJ et al Am Heart J 2018 201124-135 PMC6005768 for additional details about modifications to the trial while it was being conducted
Analysis of Patients Health Status as a Key Secondary Endpoint
A key secondary objective of the ISCHEMIA trial is to compare the quality of life outcomes-patients symptoms functioning and well-being-between those assigned to an invasive strategy as compared with a conservative strategy In the protocol angina frequency and disease-specific quality of life measured by the Seattle Angina Questionnaire SAQ Angina Frequency and Quality of Life scales respectively are described as the tools that will be used to make this comparative assessment Recent work has indicated that it is possible to combine the information from the individual domain scores in the SAQ into a new Summary Score that captures the information from the SAQ Angina Frequency Physical Limitation and Quality of Life scales into a single overall score The advantages of using a summary score as the primary measure of QOL effects of a therapy are a single primary endpoint comparison rather than two or three eliminating concerns some may have about multiple comparisons and a more intuitive holistic patient-centric interpretation of the effectiveness results With these advantages in mind the ISCHEMIA leadership has agreed that the SAQ Summary Score will be designated as the primary way this outcome for this key secondary endpoint of the ISCHEMIA trial will be analyzed and interpreted with the individual SAQ scores being used in a secondary explanatory and descriptive role
PARTICIPATING COUNTRIES
North America
Canada Mexico USA
South America
Argentina Brazil Peru
Asia
China India Japan Malaysia Singapore Taiwan Thailand Russian Federation
Pacifica
Australia New Zealand
Europe
Austria Belgium France Germany Hungary Italy Lithuania Macedonia Netherlands Poland Portugal Romania Serbia Spain Sweden Switzerland UK
Middle East
Egypt Israel Saudi Arabia
Africa
South Africa
Evidence supporting a routine invasive practice paradigm for patients with SIHD is outdated In strategy trials conducted in the 1970s coronary artery bypass grafting CABG improved survival as compared with no CABG in SIHD patients with high-risk anatomic features The relevance of these studies today is speculative because contemporary secondary prevention-aspirin beta-blockers statins ACE inhibitors and lifestyle interventions-were used minimally if at all Subsequent trials have compared percutaneous coronary intervention PCI with medical therapy as PCI has replaced CABG as the dominant method of revascularization for SIHD To date PCI has not been shown to reduce death or myocardial infarction MI compared with medical therapy in SIHD patients
COURAGE and BARI 2D the two largest trials comparing coronary revascularization vs medical therapy in SIHD patients found that among patients selected on the basis of coronary anatomy after cardiac catheterization an initial management strategy of coronary revascularization PCI PCI or CABG respectively did not reduce the primary endpoints of death or MI COURAGE or death BARI 2D compared with OMT alone These data suggest but do not prove that routine cardiac catheterization--which often leads to ad hoc PCI through the diagnostic-therapeutic cascade--may not be required in SIHD patients However most patients enrolled in COURAGE and BARI 2D who had ischemia severity documented at baseline had only mild or moderate ischemia leaving open the question of the appropriate role of cardiac catheterization and revascularization among higher-risk patients with more severe ischemia Observational data suggest that revascularization of patients with moderate-to-severe ischemia is associated with a lower mortality than medical therapy alone but such data cannot establish a cause and effect relationship In clinical practice only about half such patients are referred for cardiac catheterization indicating equipoise Furthermore analysis of outcomes for 468 COURAGE patients with moderate-to-severe ischemia at baseline did not reveal a benefit from PCI This issue cannot be resolved using available data because all prior SIHD strategy trials enrolled patients after cardiac catheterization introducing undefined selection biases eg highest risk patients not enrolled and making translation of study results problematic for clinicians managing patients who have not yet had cardiac catheterization
A clinical trial in SIHD patients uniformly at higher risk which could not have been performed before COURAGE and BARI 2D results were available is needed to inform optimal management for such patients
DESIGN NARRATIVE INCLUDING MODIFICATIONS DURING THE TRIAL
Primary Endpoint
A composite of CV death MI resuscitated cardiac arrest or hospitalization for unstable angina or heart failure was proposed as the primary endpoint in the application that was funded by NLHBI with a secondary endpoint of CV death or MI Study protocol version 10 was finalized on January 18 2012 after review and approval by the protocol review committee DSMB with the primary endpoint specified as the composite of CV death or MI Regarding the final status of the primary endpoint the protocol stated
To ensure that the primary analysis is well-powered and useful a prospective plan to allow extending follow-up andor changing the primary endpoint based on aggregate event rate data will be established prior to the first review of unblinded trial data At a designated time during the trial an analysis will be conducted to estimate the overall aggregate primary endpoint event rate and project the final number of observed events If the estimated unconditional power ie based on aggregate event rate data not by treatment group is less than the originally targeted 90 then one or more of the following options will be considered
1 Extend follow-up to allow more events to accrue
2 Change the primary endpoint to one that occurs more frequently The current primary endpoint would become a secondary endpoint The proposed new primary endpoint would be the composite of CV death MI resuscitated cardiac arrest or hospitalization for unstable angina or heart failure
3 Follow the recommendation of an independent advisory panel An independent advisory panel separate from the DSMB will be convened for the purpose of reviewing unconditional power estimates and making a recommendation to the NHLBI Director Members of this panel will not have access to unblinded data by treatment group or other data that may bias their recommendation All 5 event types were adjudicated throughout the trial Study protocol v20 January 2014 allowed ischemia eligibility by non-imaging exercise stress test if more stringent 70 stenosis CCTA criteria were met The 2016 protocol addendum describes the NHLBI-approved reduction in sample size and extension of recruitment and follow-up due to slower than projected recruitment
The pre-specified first analysis for monitoring and projecting the final aggregate number of primary endpoint events was conducted in 2015 In 2016 the projected need to increase the power by extending follow-up and elevating the 5-component secondary endpoint to become primary was discussed at Steering Committee and Investigator meetings and communicated by email
An Independent Advisory Panel convened by NHLBI met in May 2017 and in June 2017 NHLBI approved the Independent Advisory Panels recommendation to elevate the 5-component secondary endpoint to become primary and retain the 2-component composite as a key secondary endpoint The panel also recommended extension of follow-up This was communicated to the Steering Committee and Investigators at August and November 2017 meetings and by email The last visit date was June 30 2019
A statistical plan developed for the Independent Advisory Panel process in 2012 specified that a decision about changing the primary endpoint would be targeted to occur before 75 of the final number of primary endpoint events had accrued Although the final number of primary endpoint events was unknown during the course of the trial estimates performed at the time of the Advisory Panel meeting suggested that the ratio of accrued endpoint events to final endpoint events was below 50 See Maron DJ et al Am Heart J 2018 201124-135 PMC6005768 for additional details about modifications to the trial while it was being conducted
Analysis of Patients Health Status as a Key Secondary Endpoint
A key secondary objective of the ISCHEMIA trial is to compare the quality of life outcomes-patients symptoms functioning and well-being-between those assigned to an invasive strategy as compared with a conservative strategy In the protocol angina frequency and disease-specific quality of life measured by the Seattle Angina Questionnaire SAQ Angina Frequency and Quality of Life scales respectively are described as the tools that will be used to make this comparative assessment Recent work has indicated that it is possible to combine the information from the individual domain scores in the SAQ into a new Summary Score that captures the information from the SAQ Angina Frequency Physical Limitation and Quality of Life scales into a single overall score The advantages of using a summary score as the primary measure of QOL effects of a therapy are a single primary endpoint comparison rather than two or three eliminating concerns some may have about multiple comparisons and a more intuitive holistic patient-centric interpretation of the effectiveness results With these advantages in mind the ISCHEMIA leadership has agreed that the SAQ Summary Score will be designated as the primary way this outcome for this key secondary endpoint of the ISCHEMIA trial will be analyzed and interpreted with the individual SAQ scores being used in a secondary explanatory and descriptive role
PARTICIPATING COUNTRIES
North America
Canada Mexico USA
South America
Argentina Brazil Peru
Asia
China India Japan Malaysia Singapore Taiwan Thailand Russian Federation
Pacifica
Australia New Zealand
Europe
Austria Belgium France Germany Hungary Italy Lithuania Macedonia Netherlands Poland Portugal Romania Serbia Spain Sweden Switzerland UK
Middle East
Egypt Israel Saudi Arabia
Africa
South Africa
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
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 1U01HL105907 | NIH | None | httpsreporternihgovquickSearch1U01HL105907 |