International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA)
Description
Brief Summary
The purpose of the ISCHEMIA trial is to determine the best management strategy for
higher-risk patients with stable ischemic heart disease. This is a multicenter randomized
controlled trial with a target enrollment of ~5000 patients with at least moderate ischemia
on stress imaging. Patients will be assigned at random to a routine invasive strategy (INV)
with cardiac catheterization (cath) followed by revascularization plus optimal medical
therapy (OMT) or to a conservative strategy (CON) of OMT, with cath 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 or nonfatal myocardial infarction in participants with SIHD and at least moderate
ischemia over an average follow-up of approximately 4 years compared with an initial
conservative strategy of OMT alone with catheterization reserved for failure of OMT. The
primary endpoint is time to centrally adjudicated cardiovascular death or nonfatal
myocardial infarction.
B. Secondary Aims Major: To compare angina-related quality of life between groups. Other
secondary aims include: a) comparing the incidence of all-cause death; the components of the
primary endpoint; the composite endpoint of cardiovascular death, myocardial infarction, or
hospitalization for unstable angina, resuscitated cardiac arrest, or heart failure; stroke;
and stroke combined with cardiovascular death, myocardial infarction, or hospitalization for
unstable angina, resuscitated cardiac arrest, or heart failure between randomized groups;
and b) comparing health resource utilization, costs, and cost-effectiveness between groups.
Condition: Coronary Disease Procedure: Coronary CT Angiogram Procedure: Cardiac
catheterization Phase: Phase III
Condition: Cardiovascular Diseases Procedure: Angioplasty, Transluminal, Percutaneous
Coronary, other catheter-based interventions Phase: Phase III
Condition: Heart Diseases Procedure: Coronary Artery Bypass Surgery Phase: Phase III
Detailed Description
BACKGROUND:
Evidence supporting a routine invasive practice paradigm for patients with stable ischemic
heart disease (SIHD) is outdated.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 cath, 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
cath--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 level documented at baseline had only mild or moderate ischemia, leaving open the
question of the appropriate role of cath 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 cath, 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 cath, introducing undefined
selection biases (e.g., highest risk patients not enrolled) and making translation of study
results problematic for clinicians managing patients who have not yet had cath.
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:
The study protocol is final, and was distributed to sites February 2012. Study protocol v2.0
was approved in January 2014.
PARTICIPATING COUNTRIES:
North America
- Canada
- Mexico
- USA (~150 sites)
South America
- Argentina
- Brazil
- Chile
- Peru
Asia
- China
- India
- Japan
- Singapore
- Taiwan
- Thailand
- Russian Federation
Pacifica
- Australia
- New Zealand
Europe
- Austria
- Belgium
- Denmark
- France
- Germany
- Hungary
- Italy
- Lithuania
- Macedonia
- Netherlands
- Poland
- Portugal
- Romania
- Serbia
- Spain
- Sweden
- UK
Middle East
- Israel
- Saudi Arabia
- Turkey
Phase
N/AInclusion and Exclusion Criteria
- At least moderate ischemia on an ischemia test
- Participant is willing to comply with all aspects of the protocol, including adherence to the assigned strategy, medical therapy and follow-up visits
- Participant is willing to give written informed consent
- Age ≥ 21 years
- LVEF < 35%
- History of unprotected left main stenosis >50% on prior coronary computed tomography angiography (CCTA) or prior cardiac catheterization (if available)
- Finding of "no obstructive CAD" (<50% stenosis in all major epicardial vessels) on prior CCTA or prior catheterization, performed within 12 months
- Coronary anatomy unsuitable for either PCI or CABG
- Unacceptable level of angina despite maximal medical therapy
- Very dissatisfied with medical management of angina
- History of noncompliance with medical therapy
- Acute coronary syndrome within the previous 2 months
- PCI within the previous 12 months
- Stroke within the previous 6 months or spontaneous intracranial hemorrhage at any time
- History of ventricular tachycardia requiring therapy for termination, or symptomatic sustained ventricular tachycardia not due to a transient reversible cause
- NYHA class III-IV heart failure at entry or hospitalization for exacerbation of chronic heart failure within the previous 6 months
- Non-ischemic dilated or hypertrophic cardiomyopathy
- End stage renal disease on dialysis or estimated glomerular filtration rate (eGFR) <30mL/min (not an exclusion criterion for CKD ancillary trial, see CKD ancillary trial, Section 18)
- Severe valvular disease or valvular disease likely to require surgery or percutaneous valve replacement during the trial
- Allergy to radiographic contrast that cannot be adequately pre-medicated, or any prior anaphylaxis to radiographic contrast
- Planned major surgery necessitating interruption of dual antiplatelet therapy (note that patients may be eligible after planned surgery)
- Life expectancy less than the duration of the trial due to non-cardiovascular comorbidity
- Pregnancy (known to be pregnant; to be confirmed before CCTA and/or randomization, if applicable)
- Patient who, in the judgment of the patient's physician, is likely to have significant unprotected left main stenosis (Those who are able to undergo CCTA will have visual assessment of the left main coronary artery by the CCTA core lab)
- Enrolled in a competing trial that involves a non-approved cardiac drug or device
- Inability to comply with the protocol
- Exceeds the weight or size limit for CCTA or cardiac catheterization at the site
- Canadian Cardiovascular Society Class III angina of recent onset, OR angina of any class with a rapidly progressive or accelerating pattern
- Canadian Cardiovascular Society Class IV angina, including unprovoked rest angina
- High risk of bleeding which would contraindicate the use of dual antiplatelet therapy
- Cardiac transplant recipient
- Prior CABG, unless CABG was performed more than 12 months ago, and coronary anatomy has been demonstrated to be suitable for PCI or repeat CABG to accomplish complete revascularization of ischemic areas (CCC approval required)
Sites
Please contact Bhushan Desai to learn more about where you can participate in this trial. Please use the contact form on the right side.
Presentado por
SC CTSI