Ferumoxytol for Magnetic Resonance Imaging in Patients With Severe Kidney Disease

This is a case control study which will assess the resolution by which the coronary arteries
can be visualized using ferumoxytol-enhanced cardiac magnetic resonance angiography (fcMRA)
in patients with prior regional cardiac ischemia localized by stress-induced
echocardiography. Resolution will be compared to invasive coronary arteriography completed in
all patients that will be analyzed at the end of the study.

Masked experts will interpret fcMRA images to determine if coronary stenosis is present or
absent. By strict definitions, this is a single-arm study. However comparison will be made
between fcMRA and invasive coronary arteriography performed in each patient. With a
prevalence of disease of approximately 0.35 in the study population, it is anticipated that
both sensitivity and specificity of fcMRA to identify the absence of coronary artery stenosis
can be calculated.

We anticipate a population size of 70 will be needed to adequately study the primary outcome
due to potential confounders, including racial and sex differences which may exist (see
below), which are known to exist in a population with significant renal and possible cardiac
disease to determine if fcMRA is differs in its ability to exclude greater than or equal to
50 percent stenosis in a single coronary artery compared to dobutamine stress
echocardiography (DSE). This is based on prevalence of disease of 0.35. Non-invasive cardiac
stress testing in those with eGFR <30ml/min/1.73m2 is estimated to have a sensitivity of 0.81
(CI 0.57-0.94) and specificity of 0.83 (CI 0.62-0.95) to identify coronary epicardial lesion
of greater than 70 percent. The sensitivity of non-invasive non-intraluminal testing is
anticipated to be 0.60 when patients with myocardial scar are enrolled. We anticipate that 50
percent of patients with a positive DSE will have evidence of myocardial scar. Predicted
sensitivity of fcMRA will likely be increased compared to referenced estimates because true
positives will be defined by stenosis greater than or equal to 50 percent. Based on a
prevalence of 0.35, we anticipate DSE will yield 24 true positives, 25 true negatives, 7
false positives, and 14 false negatives resulting in sensitivity of 0.63 and specificity of
0.78. To achieve study power that will allow for the null hypothesis to be ignored, in as
study size of 70, fcMRA must yield at least 28 true positives and 27 true negatives allowing
for 5 false positives and 10 false negatives resulting in sensitivity of 0.737 and
specificity of 0.843. To account for drop-out and incomplete data collection in 50 percent of
patients approached, recruitment of 140 patients will be needed. The drop-out rate from
recruitment to enrollment approximates the fcMRA study experience at the Brigham and Women's
Hosptial in 2017.

Racial/sex subgroup analysis will involve testing in whites vs. non-whites and males vs.
females. Prevalence of 0.35 will again be assumed. Previously, 45 percent of patients
enrolled were of non-white racial origin. An additional 85 patients would be necessary to
demonstrate a difference between fcMRA and DSE when comparing sensitivity and specificity as
above, therefore this will be considered an exploratory analysis.

Using the Partners Healthcare System Research Patient Data Registry (RPDR) all patients in
calendar year 2017 were identified with a diagnosis of chronic kidney disease stage 4-5D and
who underwent a left heart cardiac catheterization at either Brigham and Women's Hospital or
Massachusetts General Hospital (MGH). "chronic kidney disease stage 4", "chronic kidney
disease stage 5", and "left heart catheterization", and "abnormal echocardiogram" were used
as mesh terms resulting in 68 patients. 108 patients utilizing hemodialysis or peritoneal
dialysis completed ICA. 35 patients not yet requiring renal replacement therapy completed ICA
in the same time period. Separately, clinical practices at the Brigham and Women's Hospital
kidney transplant center in calendar year 2017 were reviewed. 207 patients underwent
non-invasive cardiac stress testing and 16 patients underwent ICA. All patients that
underwent arteriography had prior non--invasive cardiac stress testing. Surveying both the
inpatient and outpatient settings a total of 159 patients were identified in the Partners
Healthcare System that would have qualified for the proposed study.

Both female and male participants are being studied aged 18-85 years old with an estimated
glomerular filtration rate (eGFR) of less than 30ml/min/1.73 meters squared. Patients will
have undergone cardiac screening tests that warrant further evaluation. Patients will be
excluded with an eGFR >30ml/min/1.73 meters squared.