ISCHEMIA-Chronic Kidney Disease Trial

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 study in the CKD cohort suggests a survival benefit
of revascularization when compared with medical therapy alone long-term, despite 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 substantial clinical equipoise in
the management of these patients with the rates of revascularization of only around 10-45%.
The results of ISCHEMIA-CKD will have profound implications for guidelines, health policy,
and clinical practice.

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