N Engl J Med April 23, 2020

Management of Coronary Disease in Patients with Advanced Kidney Disease

Sripal Bangalore, David J. Maron, Sean M. O'Brien et al.

Bottom Line

In patients with stable coronary artery disease, advanced chronic kidney disease, and moderate or severe ischemia, an initial invasive strategy did not reduce the risk of death or nonfatal myocardial infarction compared to an initial conservative strategy, but was associated with an increased risk of stroke and initiation of dialysis.

Key Findings

1. At a median follow-up of 2.2 years, the primary outcome of death or nonfatal MI occurred in 36.4% of the invasive-strategy group versus 36.7% of the conservative-strategy group (HR 1.01; 95% CI, 0.79 to 1.29; P=0.95) [3.2.5].

2. The key secondary composite outcome (death, nonfatal MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest) showed no significant difference between the groups (38.5% vs. 39.7%; HR 1.01; 95% CI, 0.79 to 1.29).

3. The invasive strategy was associated with a significantly higher risk of stroke (HR 3.76; 95% CI, 1.52 to 9.32; P=0.004).

4. The invasive strategy also resulted in a higher incidence of the composite of death or initiation of dialysis (HR 1.48; 95% CI, 1.04 to 2.11; P=0.03).

Study Design

Design

RCT

Open-Label

Sample

777

Patients

Duration

2.2 yr

Median

Setting

International, multicenter

Population Patients with advanced chronic kidney disease (eGFR <30 ml/min/1.73m2 or on dialysis) and stable coronary disease with moderate or severe ischemia on stress testing.

Intervention Initial invasive strategy consisting of routine coronary angiography and revascularization (PCI or CABG if appropriate) added to guideline-directed medical therapy.

Comparator Initial conservative strategy consisting of optimal medical therapy alone, with angiography reserved for medical therapy failure.

Outcome Composite of death from any cause or nonfatal myocardial infarction.

Study Limitations

• The trial was terminated prematurely due to slow enrollment, resulting in a lower than anticipated sample size, though the lack of any trend toward benefit makes a missed treatment effect unlikely.

• There was a substantial rate of crossover, with approximately 20% of patients in the conservative arm undergoing angiography or revascularization by 4 years.

• Patients with highly symptomatic angina or unacceptable symptoms at baseline were generally not randomized, limiting the generalizability of the findings to that specific subgroup.

• The open-label design inherently risks bias in the management and reporting of soft outcomes, although the primary hard outcome components were blindly adjudicated.

Clinical Significance

ISCHEMIA-CKD demonstrated that for patients with stable CAD, advanced CKD, and moderate-to-severe ischemia, an initial routine invasive strategy offers no prognostic benefit over optimal medical therapy and may cause harm (e.g., increased risk of stroke and need for dialysis). This paradigm-shifting result strongly supports an initial conservative strategy centered on guideline-directed medical therapy for this population, reserving angiography and revascularization for patients with refractory symptoms or acute coronary syndromes.

Historical Context

Historically, patients with advanced chronic kidney disease (CKD) have been systematically excluded from major cardiovascular trials (such as COURAGE, BARI 2D, and the main ISCHEMIA trial). This exclusion led to widespread uncertainty and 'renalism'—whereby patients either received aggressive but unproven revascularization risking contrast nephropathy, or were undertreated due to fear of complications. ISCHEMIA-CKD was run in parallel with the main ISCHEMIA trial to definitively test whether routine invasive management improved outcomes over modern optimal medical therapy in this specific, high-risk population.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Why are patients with advanced chronic kidney disease at an inherently higher risk for cardiovascular events, and how does the pathophysiology of their coronary artery disease differ from patients with normal renal function?

Key Response

CKD patients have accelerated atherosclerosis and medial vascular calcification due to uremia, oxidative stress, and secondary hyperparathyroidism. Their CAD is often more diffuse and heavily calcified, making percutaneous interventions technically challenging and less likely to yield the same symptomatic or prognostic benefits as seen in non-CKD populations.

Resident

Based on the ISCHEMIA-CKD findings, how should you approach a patient with advanced CKD presenting with stable angina and an abnormal stress test, and what are the primary risks to discuss if considering an angiogram?

Key Response

The initial strategy should be optimal medical therapy. Residents must recognize that routine invasive management does not improve mortality or MI outcomes in stable disease but significantly increases the risk of procedure-related stroke and the need for new dialysis due to contrast-induced nephropathy or atheroembolism. Angiography should be reserved for refractory symptoms or acute coronary syndromes.

Fellow

The ISCHEMIA-CKD trial demonstrated an increased risk of stroke in the invasive arm. What procedural and anatomical factors specific to the advanced CKD population contribute to this finding, and how does it influence your choice of revascularization modality?

Key Response

CKD patients typically have extensive aortic and cerebrovascular atherosclerosis and calcification. Catheter manipulation during angiography or PCI, as well as aortic cross-clamping during CABG, highly increases atheroembolic stroke risk. Furthermore, bleeding complications from periprocedural antithrombotics are higher in uremic patients, necessitating careful multidisciplinary heart team discussions when intervention is unavoidable.

Attending

Given that nephrologists and cardiologists have historically favored aggressive risk stratification in transplant candidates, how does ISCHEMIA-CKD challenge the routine practice of screening and revascularizing asymptomatic advanced CKD patients awaiting kidney transplantation?

Key Response

Historically, transplant protocols mandated rigorous CAD screening and prophylactic revascularization to clear patients for surgery. ISCHEMIA-CKD suggests that in stable patients with moderate-to-severe ischemia, prophylactic revascularization does not mitigate cardiovascular risk but exposes them to contrast and procedural harm. Attendings must lead the paradigm shift toward prioritizing optimal medical therapy over routine anatomical fixes in pre-transplant workups.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

ISCHEMIA-CKD utilized a composite primary endpoint in a population with high baseline mortality. How does the competing risk of non-cardiovascular death in an advanced CKD population affect the statistical power and interpretation of time-to-event analyses in cardiovascular trials?

Key Response

Advanced CKD patients have high mortality rates from non-cardiovascular causes like infections or sudden uremic complications. In standard time-to-event analyses, competing risks can lead to an overestimation of the cumulative incidence of the primary CV endpoint if censored, or dilute the observable benefit of the intervention. A rigorous methodological approach must utilize competing risk analyses, such as Fine-Gray models, to validate the null findings and ensure the study is adequately powered.

Journal Editor

The trial was unblinded, and the conservative arm had a non-negligible rate of crossover to invasive management. As a reviewer, how would you evaluate the impact of this crossover on the internal validity of the trial's safety outcomes, specifically the increased stroke and dialysis rates?

Key Response

A reviewer would note that crossover dilutes the intention-to-treat effect, potentially masking a true benefit of the invasive strategy. However, since the invasive arm still showed significantly worse safety outcomes, the intention-to-treat analysis might actually underestimate the true procedural harm. Scrutinizing the per-protocol and as-treated sensitivity analyses would be critical to confirm the magnitude of iatrogenic harm from the invasive strategy.

Guideline Committee

Current ACC/AHA guidelines emphasize symptom relief and risk reduction for stable ischemic heart disease. Based on ISCHEMIA-CKD, how should guidelines update the Class of Recommendation for routine invasive evaluation in stable CAD patients with an eGFR below 30?

Key Response

Guidelines should update routine invasive evaluation in asymptomatic or medically manageable stable CAD with advanced CKD to a Class III (Harm) recommendation. Given the lack of mortality or MI benefit and the demonstrated increase in stroke and new-onset dialysis, the evidence level is strong (Level B-R) to pivot toward maximal guideline-directed medical therapy as the definitive initial strategy, reserving angiography for those failing medical therapy.

Clinical Landscape

Noteworthy Related Trials

2007

COURAGE Trial

n = 2,287 · NEJM

Tested

Percutaneous coronary intervention (PCI) plus optimal medical therapy

Population

Patients with stable coronary artery disease

Comparator

Optimal medical therapy alone

Endpoint

Death from any cause and nonfatal myocardial infarction

Key result: As an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to optimal medical therapy.

2009

BARI 2D Trial

n = 2,368 · NEJM

Tested

Prompt revascularization (CABG or PCI) plus intensive medical therapy

Population

Patients with type 2 diabetes and stable coronary artery disease

Comparator

Intensive medical therapy alone

Endpoint

Death from any cause

Key result: No significant difference in overall survival or the rate of major cardiovascular events between prompt revascularization and medical therapy.

2020

ISCHEMIA Trial

n = 5,179 · NEJM

Tested

Routine invasive strategy (angiography and revascularization) plus medical therapy

Population

Patients with stable, moderate-to-severe ischemia and preserved kidney function

Comparator

Conservative strategy (optimal medical therapy alone)

Endpoint

Composite of CV death, MI, resuscitated cardiac arrest, or hospitalization for unstable angina or HF

Key result: No significant evidence that an initial invasive strategy reduced the risk of ischemic cardiovascular events or death compared to conservative therapy.

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