Study Protocol: Outcomes in Dialysis Patients with Aortic Stenosis

Worldwide, the number of patients receiving maintenance dialysis is increasing. Diabetic nephropathy and hypertensive kidney disease account for many of these patients. In addition, chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease, which leads to difficulty with dialysis therapy. While coronary heart disease is typical among patients with cardiovascular disease, patients on dialysis are increasingly being diagnosed with aortic stenosis.

Results of previous studies have indicated a relationship between aging, hypertension, diabetes, or lipid disorders with onset and progression of aortic stenosis. Due to factors that include hyperphosphatemia and anemia, patients on dialysis are more likely to develop aortic stenosis compared with the general population; however, there are few data available on morbidity rate and risk factors of aortic stenosis among dialysis patients. Data are also lacking on the association between aortic stenosis in dialysis patients and mortality or onset of cardiovascular events.

Daijo Inaguma, MD, PhD, and colleagues recently described study protocol for a multicenter, prospective cohort analysis in the Tokai region of Japan (Tokai Aortic Stenosis Cohort in Patients on Dialysis). The researchers are seeking to determine whether there is an association between morbidity of aortic stenosis in dialysis patients and mortality. The study protocol was reported online in BMC Nephrology [doi.org/10.1186/s12882-018-0877-6].

The study is designed to test the hypothesis that: (1) the prevalence of aortic stenosis is higher in patients on dialysis than in the general population; (2) there is an association between new onset and development of aortic stenosis and traditional risk factors, including aging and comorbidity of diabetes; (3) there is an association between new onset and development of aortic stenosis and dialysis-specific factors, including hyperphosphatemia, hypercalcemia, and hyperparathyroidism; (4) patients with aortic stenosis have poorer outcomes compared with patients without aortic stenosis at baseline; and (5) outcomes are poorer depending on stage of aortic stenosis.

Seventy-five centers in the Tokai region of Japan will enroll approximately 2400 patients with and without aortic stenosis during a 12-month enrollment period. Inclusion criteria are receiving outpatient maintenance dialysis for at least 12 months, age >20 years, echocardiography annually, and participation agreement. Outcomes of interest will be all-cause mortality rates, incidence of cardiovascular events, cardiovascular-related mortality rates, infection-related mortality rates, and new onset or development of aortic stenosis. Follow-up will continue until June 2023.

Baseline is defined as the first echocardiography from July 2017 to June 2018. The researchers will review (1) age, sex, dialysis vintage, and original kidney disease, blood pressure, and resting heart rate; (2) comorbidities, including diabetes mellitus and malignancy; (3) medical history including hospitalization due to heart failure within 1 year, coronary heart disease, aortic disease, stroke, peripheral artery disease, malignancy, and history of parathyroidectomy; (4) medications, including renin-angiotensin blockers, calcium channel blockers, beta blockers, vitamin D receptor activators, calcimimetics, phosphate binders, and warfarin; (5) laboratory data including hemoglobin, platelet count, and serum albumin, alkaline phosphatase, uric acid, urea nitrogen, creatinine, adjusted calcium, phosphorus, magnesium, intact parathyroid hormone, ferritin, and C-reactive protein levels.

Aortic stenosis will be diagnosed using criteria based on the 2014 American Heart Association/American College of Cardiology Guideline (AHA/ACC) for the Management of Patients with Valvular Heart Disease: (1) mean pressure gradient (mPG) >20 mmHg or (2) aortic valve area (AVA) <1.0 cm2 or (3) aortic maximum aortic jet velocity (Vmax) >2.0 m/s. Stages A to D of aortic stenosis will be evaluated according to the AHA/ACC Guideline.

Transthoracic echocardiography will be performed using commercially available ultrasound systems owned by each facility during enrollment and at 12, 24, 36, 48, and 60 months. Findings will be confirmed by a cardiologist. Doppler echocardiographic measurements will include the peal and trans-aortic mPG using the Bernoullis equation, and the AVA using the standard continuity equation or planimetry method in most facilities.

Survival prognosis and cardiovascular events will be assessed at the end of June 2019, 2020, 2012, 2022, and 2023. Development of aortic stenosis will be evaluated as new onset or annual change in aortic stenosis parameters (mPG, AVA, and aortic Vmax).

Patients will be classified based on the presence or absence of aortic stenosis, and on stage of aortic stenosis. Outcomes will be compared between the two groups.

Either the Thoracic Surgeons predicted risk of mortality score or the EuroScore is generally used in evaluations of risk in decision-making regarding selection of surgical treatment for patients with aortic stenosis with high risk, such as patients on dialysis. “However,” the current study’s researchers said, “the incidence of complications and morality associated with treatment have been higher in dialysis patients.

“Optimal treatment selection by stages of aortic stenosis in dialysis patients remains unknown. Therefore, we expect that the results of our study will lead to a treatment strategy for dialysis patients with aortic stenosis.”

Trial registration: UMIN000026756

Takeaway Points

  1. Precise rates of morbidity and risk factors for aortic stenosis in patients on maintenance dialysis are unknown. Researchers in Japan are conducting a prospective cohort analysis to determine whether there is an association between morbidity of aortic stenosis in dialysis patients and mortality.
  2. The study will include 75 centers and will enroll approximately 2400 patients with and without aortic stenosis. Enrollment began in June 2017, and follow-up will continue until June 2023.
  3. The researchers predict that the results of the study may provide aid in decision-making regarding a treatment strategy for dialysis patients with aortic stenosis.