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ISCHEMIA-CKD: ISCHEMIA-Chronic Kidney Disease Trial

Sponsor
NYU Langone Health (Other)
Overall Status
Completed
CT.gov ID
NCT01985360
Collaborator
New York University (Other), National Heart, Lung, and Blood Institute (NHLBI) (NIH), Duke University (Other), Stanford University (Other), Columbia University (Other)
777
Enrollment
1
Location
2
Arms
78
Duration (Months)
10
Patients Per Site Per Month

Study Details

Study Description

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

  1. 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).

  2. 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

Condition or Disease Intervention/Treatment Phase
  • Procedure: Cardiac Catheterization
  • Procedure: Coronary Artery Bypass Graft Surgery
  • Procedure: Percutaneous Coronary Intervention
  • Behavioral: Lifestyle
  • Drug: Medication
 Phase 4

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
777 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease Trial
Study Start Date :
Jan 1, 2014
Actual Primary Completion Date :
Jun 1, 2019
Actual Study Completion Date :
Jul 1, 2020

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Invasive Strategy (INV)

Routine invasive strategy with cardiac catheterization followed by revascularization (Percutaneous Coronary Intervention or Coronary Artery Bypass Graft Surgery) plus optimal medical therapy.

Procedure: Cardiac Catheterization
Narrowed blood vessels can be opened without surgery using stents or can be bypassed with surgery. To determine which is the best approach for you the doctor needs to look at your blood vessels to see where the narrowings are and how much narrowing there is. This is done by a procedure known as a cardiac catheterization.
Other Names:
  • cath

    • Procedure: Coronary Artery Bypass Graft Surgery
    Artery narrowing is bypassed during surgery with a healthy artery or vein from another part of the body. This is known as coronary artery bypass grafting, or CABG (said "cabbage"). The surgery creates new routes around narrowed and blocked heart arteries. This allows more blood flow to the heart.
    Other Names:
  • CABG

    • Procedure: Percutaneous Coronary Intervention
    Percutaneous coronary intervention may be done as part of the cardiac catheterization procedure. With this procedure a small, hollow, mesh tube (stent) is inserted into the narrowed part of the artery. The stent pushes the plaque against the artery wall, and opens the vessel to allow better blood flow.
    Other Names:
  • PCI

    • Behavioral: Lifestyle
    Diet, physical activity, smoking cessation
    Other Names:
  • Behavior change

    • Drug: Medication
    antiplatelet, statin, other lipid lowering, antihypertensive, and anti-ischemic medical therapies
    Other Names:
  • Pharmacologic Therapy

    		•
    Active Comparator: Conservative Strategy (CON)

    Optimal medical therapy with cardiac catheterization and revascularization reserved for patients with OMT failure.

    Behavioral: Lifestyle
    Diet, physical activity, smoking cessation
    Other Names:
  • Behavior change

    • Drug: Medication
    antiplatelet, statin, other lipid lowering, antihypertensive, and anti-ischemic medical therapies
    Other Names:
  • Pharmacologic Therapy

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Incidence of Death From Any Cause or Myocardial Infarction [2.2 years]

    2. Cumulative Event Rate of Death From Any Cause or Myocardial Infarction [3 years]

      This measure represents the estimated cumulative probability of experiencing Death from any cause or Myocardial Infarction within the indicated timeframe in each treatment group. The interpretation of the measure is similar to Kaplan-Meier event rates. Estimates are expressed as percentages ranging from 0% (endpoint is certain not to occur) to 100% (endpoint is certain to occur).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    21 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 NYU Langone Medical Center New York New York United States 10016

    Sponsors and Collaborators

    • NYU Langone Health
    • New York University
    • National Heart, Lung, and Blood Institute (NHLBI)
    • Duke University
    • Stanford University
    • Columbia University

    Investigators

    • Principal Investigator: Harmony Reynolds, MD, MHA, NYU Langone Health
    • Study Chair: Judith Hochman, MD, ISCHEMIA trial Chair, New York University School of Medicine
    • Study Chair: David Maron, MD, ISCHEMIA trial Co-chair, Stanford University

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    Responsible Party:
    NYU Langone Health
    ClinicalTrials.gov Identifier:
    NCT01985360
    Other Study ID Numbers:
    • 12-01059
    • U01HL117905
    First Posted:
    Nov 15, 2013
    Last Update Posted:
    Oct 18, 2021
    Last Verified:
    Sep 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Additional relevant MeSH terms:
    Kidney Diseases
    Renal Insufficiency, Chronic
    Kidney Failure, Chronic
    Cardiovascular Diseases
    Coronary Artery Disease
    Myocardial Ischemia
    Heart Diseases
    Ischemia

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Invasive Strategy (INV) Conservative Strategy (CON)
    Arm/Group Description Routine invasive strategy with cardiac catheterization followed by revascularization + optimal medical therapy. Cardiac Catheterization: Narrowed blood vessels can be opened without surgery using stents or bypassed with surgery. The doctor will examine blood vessels to determine the location and extent of narrowings. Coronary Artery Bypass Graft Surgery (CABG): Artery narrowing is bypassed during surgery with a healthy artery or vein from another part of the body. This creates new routes around narrowed/blocked heart arteries. Percutaneous Coronary Intervention: A small, hollow, mesh tube (stent) is inserted into the narrowed part of the artery. The stent pushes the plaque against the artery wall, and opens the vessel to allow better blood flow. Lifestyle: Diet, physical activity, smoking cessation Medication: antiplatelet, statin, other lipid lowering, antihypertensive, and anti-ischemic medical therapies Optimal medical therapy with cardiac catheterization and revascularization reserved for patients with OMT failure. Lifestyle: Diet, physical activity, smoking cessation Medication: antiplatelet, statin, other lipid lowering, antihypertensive, and anti-ischemic medical therapies
    Period Title: Overall Study
    STARTED 388 389
    COMPLETED 379 386
    NOT COMPLETED 9 3

    Baseline Characteristics

    Arm/Group Title Invasive Strategy (INV) Conservative Strategy (CON) Total
    Arm/Group Description Routine invasive strategy with cardiac catheterization followed by revascularization + optimal medical therapy. Cardiac Catheterization: Narrowed blood vessels can be opened without surgery using stents or bypassed with surgery. The doctor will examine blood vessels to determine the location and extent of narrowings. Coronary Artery Bypass Graft Surgery (CABG): Artery narrowing is bypassed during surgery with a healthy artery or vein from another part of the body. This creates new routes around narrowed/blocked heart arteries. Percutaneous Coronary Intervention: A small, hollow, mesh tube (stent) is inserted into the narrowed part of the artery. The stent pushes the plaque against the artery wall, and opens the vessel to allow better blood flow. Lifestyle: Diet, physical activity, smoking cessation Medication: antiplatelet, statin, other lipid lowering, antihypertensive, and anti-ischemic medical therapies Optimal medical therapy with cardiac catheterization and revascularization reserved for patients with OMT failure. Lifestyle: Diet, physical activity, smoking cessation Medication: antiplatelet, statin, other lipid lowering, antihypertensive, and anti-ischemic medical therapies Total of all reporting groups
    Overall Participants 388 389 777
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    62
    64
    63
    Sex: Female, Male (Count of Participants)
    Female
    120
    30.9%
    122
    31.4%
    242
    31.1%
    Male
    268
    69.1%
    267
    68.6%
    535
    68.9%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    54
    13.9%
    44
    11.3%
    98
    12.6%
    Not Hispanic or Latino
    318
    82%
    319
    82%
    637
    82%
    Unknown or Not Reported
    16
    4.1%
    26
    6.7%
    42
    5.4%
    Region of Enrollment (participants) [Number]
    North America
    95
    24.5%
    88
    22.6%
    183
    23.6%
    Europe
    120
    30.9%
    119
    30.6%
    239
    30.8%
    Africa
    1
    0.3%
    2
    0.5%
    3
    0.4%
    Pacifica
    3
    0.8%
    7
    1.8%
    10
    1.3%
    Middle East
    3
    0.8%
    3
    0.8%
    6
    0.8%
    South America
    27
    7%
    22
    5.7%
    49
    6.3%

    Outcome Measures

    1. Primary Outcome
    Title Incidence of Death From Any Cause or Myocardial Infarction
    Description
    Time Frame 2.2 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Invasive Strategy Conservative Strategy
    Arm/Group Description Invasive Strategy Conservative Strategy
    Measure Participants 388 389
    Count of Participants [Participants]
    123
    31.7%
    129
    33.2%
    2. Primary Outcome
    Title Cumulative Event Rate of Death From Any Cause or Myocardial Infarction
    Description This measure represents the estimated cumulative probability of experiencing Death from any cause or Myocardial Infarction within the indicated timeframe in each treatment group. The interpretation of the measure is similar to Kaplan-Meier event rates. Estimates are expressed as percentages ranging from 0% (endpoint is certain not to occur) to 100% (endpoint is certain to occur).
    Time Frame 3 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Invasive Strategy Conservative Strategy
    Arm/Group Description Invasive Strategy Conservative Strategy
    Measure Participants 388 389
    Number (95% Confidence Interval) [cumulative event rate - %]
    36.4
    36.7
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Invasive Strategy, Conservative Strategy
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.01
    Confidence Interval (2-Sided) 95%
    0.79 to 1.29
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame 3 years
    Adverse Event Reporting Description
    Arm/Group Title Invasive Strategy Conservative Strategy
    Arm/Group Description Invasive Strategy Conservative Strategy
    All Cause Mortality
    Invasive Strategy Conservative Strategy
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 94/388 (24.2%) 98/389 (25.2%)
    Serious Adverse Events
    Invasive Strategy Conservative Strategy
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 75/388 (19.3%) 61/389 (15.7%)
    Renal and urinary disorders
    Death from any cause or Initiation of dialysis 75/388 (19.3%) 75 61/389 (15.7%) 61
    Other (Not Including Serious) Adverse Events
    Invasive Strategy Conservative Strategy
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/388 (0%) 0/389 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Sripal Bangalore
    Organization NYU Langone Health
    Phone (212) 263 3540
    Email Sripal.Bangalore@nyulangone.org
    Responsible Party:
    NYU Langone Health
    ClinicalTrials.gov Identifier:
    NCT01985360
    Other Study ID Numbers:
    • 12-01059
    • U01HL117905
    First Posted:
    Nov 15, 2013
    Last Update Posted:
    Oct 18, 2021
    Last Verified:
    Sep 1, 2021