Clinical trial NCT01985360: ISCHEMIA-Chronic Kidney Disease Trial
Official title: International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Cardiovascular Diseases
Coronary Artery Disease
Heart Diseases
Myocardial Ischemia
Kidney Disease
End Stage Renal Failure on Dialysis
Lead sponsor: NYU Langone Health
Sponsor class: OTHER
Collaborators: name: New York University
name: National Heart, Lung, and Blood Institute (NHLBI)
name: Duke University
name: Stanford University
name: Columbia University
First posted: 2013-11-15
Enrollment: 777
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the ISCHEMIA-CKD trial is to determine the best management strategy for patients with stable ischemic heart disease (SIHD), at least moderate inducible ischemia and advanced chronic kidney disease (CKD; estimated glomerular filtration rate \[eGFR\] \<30 ml/min/1.73 m² or on dialysis). This is a multicenter randomized controlled trial of 777 randomized participants with advanced CKD. Participants were assigned at random to a routine invasive strategy (INV) with cardiac catheterization (cath) followed by revascularization (if suitable) plus optimal medical therapy (OMT) or to a conservative strategy (CON) of OMT, with cath and revascularization reserved for those who fail OMT. The trial is designed to run seamlessly in parallel to the main ISCHEMIA trial as a companion trial.

SPECIFIC AIMS

A. Primary Aim. The primary aim of the ISCHEMIA-CKD trial is to determine whether an invasive strategy of cardiac cath followed by optimal revascularization, in addition to OMT, will reduce the primary composite endpoint of death or nonfatal myocardial infarction in participants with SIHD and advanced CKD over an average follow-up of approximately 2.8 years compared with an initial conservative strategy of OMT alone with catheterization reserved for those who fail OMT. The primary endpoint is time to centrally adjudicated death or nonfatal myocardial infarction (MI).

B. Secondary Aims. Major: To compare the incident of the composite of death, nonfatal MI, resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure, and angina symptoms and quality of life, as assessed by the Seattle Angina Questionnaire, between the INV and CON strategies. Other secondary aims include: comparing the incidence of the composite of death, nonfatal MI, hospitalization for unstable angina, hospitalization for heart failure, resuscitated cardiac arrest, or stroke; composite of death, nonfatal MI, or stroke; composite endpoints incorporating cardiovascular death; composite endpoints incorporating other definitions of MI as defined in the clinical event charter; individual components of the primary and major secondary endpoints; stroke and health resource utilization, costs, and cost effectiveness.

A major secondary aim of ISCHEMIA-CKD trial is to compare the quality of life (QOL) 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 secondary endpoint will be analyzed and interpreted, with the individual SAQ scores being used in a secondary, explanatory and descriptive role. A key subgroup analysis will be to stratify the results among those with daily/weekly angina (baseline SAQ Angina Frequency score ≤60), monthly angina (SAQ Angina Frequency score 61-99) and no angina (SAQ Angina Frequency score = 100).

Condition: Coronary Disease 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:

Among patients with advanced CKD, cardiovascular disease is the leading cause of death,15-30 times higher than the age-adjusted cardiovascular mortality rate in the general population. The projected 4-year mortality is \>50% in patients with advanced CKD and is worse than that for patients in the general population who have cancers, heart failure, stroke or MI. Participants with advanced CKD are 5-10 times more likely to die than to reach end stage renal disease (ESRD). Despite this, \~80% of contemporary coronary artery disease (CAD) trials exclude participants with advanced CKD. Most of the treatments aimed at reducing cardiovascular events in advanced CKD are therefore extrapolated from cohorts without advanced CKD. Participants with advanced CKD and cardiovascular disease are undertreated with less frequent use of statins and revascularization therapies, and the optimal management approach to these patients is unknown. Participants with advanced CKD are notably underrepresented in contemporary trials comparing revascularization with medical therapy in SIHD patients, such as the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial or the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial,making any assessment about the efficacy of revascularization plus medical therapy vs. initial medical therapy alone in this cohort problematic.

Participants with advanced CKD are at increased risk for complications of the assigned invasive procedure, specifically contrast-induced acute kidney injury (AKI), dialysis, major bleeding and short-term risk of death. However, there is controversy in the medical literature regarding the incidence (\<1% to \>30%), effective treatment (saline hydration, N-acetyl cysteine, or sodium bicarbonate), and prognosis of contrast induced AKI (\<0.5% to \>5% requiring dialysis). In addition, although contrast induced AKI have been associated with increase in short-term mortality, residual confounding in these studies makes interpretation difficulty. Moreover, it is unknown if these short-term increased risks are offset by long-term benefits. Limited observational studies in the CKD cohort suggest a long-term survival benefit of revascularization when compared with medical therapy alone, despite an increase in short-term risks. However, the medical therapy in these trials was not optimized, drug eluting stents were rarely used and there is undoubtedly inherent selection and ascertainment bias with observational studies. The above has resulted in clinical equipoise in the management of these patients, with the rates of revascularization only around 10-45%. The results of ISCHEMIA-CKD will have profound implications for guidelines, health policy, and clinical practice.

Eligibility criteria: Inclusion Criteria:

* At least moderate ischemia on an exercise or pharmacologic stress test
* End-stage renal disease on dialysis or estimated glomerular filtration rate (eGFR) \<30mL/min/1.73m²
* Willingness to comply with all aspects of the protocol, including adherence to the assigned strategy, medical therapy and follow-up visits
* Willingness to give written informed consent
* Age ≥ 21 years

Exclusion Criteria:

* Left Ventricular Ejection Fraction \< 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 coronary artery disease" (\<50% stenosis in all major epicardial vessels) on prior CCTA or prior catheterization, performed within 12 months
* Coronary anatomy unsuitable for either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (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
* 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
* High likelihood of significant unprotected left main stenosis, in the judgment of the patient's physician
* Enrollment in a competing trial that involves a non-approved cardiac drug or device
* Inability to comply with the protocol
* Body weight or size exceeding the limit for 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

Primary outcomes:
measure: Incidence of Death From Any Cause or Myocardial Infarction
timeFrame: 2.2 years
measure: Cumulative Event Rate of Death From Any Cause or Myocardial Infarction
timeFrame: 3 years
Secondary outcomes:
Other outcomes:
Locations:
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
Study officials:
affiliation: NYU Langone Health
name: Harmony Reynolds, MD, MHA
role: PRINCIPAL_INVESTIGATOR
affiliation: ISCHEMIA trial Chair, New York University School of Medicine
name: Judith Hochman, MD
role: STUDY_CHAIR
affiliation: ISCHEMIA trial Co-chair, Stanford University
name: David Maron, MD
role: STUDY_CHAIR
References:
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