Effects of Renin-Angiotensin System Inhibitors in Peritoneal Dialysis Patients

Effects of Renin-Angiotensin System Inhibitors on Mortality and Cardiovascular Outcomes in Peritoneal Dialysis Patients: A Retrospective Cohort Study in Thailand

Among antihypertensive medications, RAS inhibitor classes, namely angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) have the most prospective data on mortality and cardiovascular outcomes in specific high-risk populations with mild to moderate chronic kidney disease (CKD). Whereas, long-term data on the risks and benefits of ACEI/ARB usage in end-stage kidney disease (ESKD) patients undergoing peritoneal dialysis (PD) are limited. Recently, increasing clinical studies suggested that ACEI/ARB had a beneficial effect on intermediate outcomes, including short-term blood pressure variability, left ventricular hypertrophy, and may have an important role in the peritoneum and the kidney protection. Subsequently, treatment with ACEI/ARB has been recommended by the International Society for Peritoneal Dialysis for PD patients with significant residual kidney function (RKF).

Although existing reviews demonstrated that ACEI/ARB significantly has benefit in preserving RKF in PD patients, evidence regarding the relative efficacy on mortality, cardiovascular outcomes, and adverse events is lacking. Given that there exist few controlled trials of the effectiveness of ACEI/ARB in PD patients, we intend to perform a retrospective cohort study to assess the association between the use of ACEI/ARB and the risk of long-term mortality, cardiovascular outcomes, and adverse events in terms of hyperkalemia.

A retrospective cohort of Thai PD patients will be constructed by using the local joint registry data of adult PD patients from five centers in Thailand between 2006 to 2017 and followed to December 2018. We will link the following health datasets: (i) the electronic health records, contains outpatient and inpatient data; (ii) the Support System Pharmacy Dispensing extract, an administrative database which covers pharmacy dispensing; (iii) the PD Patient Care Database, which provides patient-level detail on sociodemographic and clinical characteristics as well as long-term PD care data; and (iv) the Laboratory Support System extract, which includes claims and routine laboratory results.

The exposure of interest in this cohort will be the use of ACEI/ARB within a 90-day after the date of PD initiation. Outcomes of interest will include all-cause mortality, cardiovascular mortality, a composite endpoint of cardiovascular events, and adverse events in terms of hyperkalemia.

Study Overview

• Status: Unknown
• Conditions: Peritoneal Dialysis
• Intervention / Treatment: Drug: angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB)

• Study Type: Observational
• Enrollment (Anticipated): 1468

Contacts and Locations

Study Locations

• Thailand
  • Chiang Mai, Thailand, 50200
    • Pharmacoepidemiology and Statistics Research Center, Faculty of Pharmacy, Chiang Mai University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Adult ESKD patients undergoing PD from January 1, 2006, to December 31, 2017, and followed to December 2018.

Description

Inclusion Criteria:

• Adult patients aged 18 years or over at the date of PD initiation
• Patients with ESKD who were undergoing PD either continuous ambulatory peritoneal dialysis or automated peritoneal dialysis between January 1, 2006, to December 31, 2017
• Received PD treatment more than 90 days in an outpatient nephrology clinic visit after the date of PD initiation
• Received of any outpatient prescriptions within 90 days after the date of PD initiation

Exclusion Criteria:

• Previously been treated by maintenance hemodialysis (for more than 90 days) or initiated PD for acute kidney injury or after a failed kidney transplantation
• Died within 90 days after the date of PD initiation
• Received a combination of ACEIs and ARBs therapy
• Received ACEIs/ARBs within 180 days before PD initiation
• Had no information regarding ACEI/ARB dosage regimen during the follow-up period
• Inadequate follow-up clinical information on blood pressure monitoring

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
ACEI/ARB users	Drug: angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB); The use of ACEI/ARB within a 90-day after the date of PD initiation (exposure ascertainment window period).
ACEI/ARB non-users

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
All-cause mortality	12 years
Cardiovascular mortality	12 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite endpoint of atherosclerotic cardiovascular disease (ASCVD) events	ASCVD events of interest will include hospitalization for acute fatal and nonfatal myocardial infarction, coronary or other arterial revascularization, fatal and nonfatal stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin.	12 years
Hyperkalemia	Incident hyperkalemia will define as a serum potassium concentration of more than 5.0 mEq/L. The severity of hyperkalemia will be categorized as mild (>5.0 to <5.5 mEq/L), moderate (5.5 to 6.0 mEq/L), and severe (>6.0 mEq/L).	12 years

Collaborators and Investigators

• Sponsor: Chiang Mai University

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 31, 2019
• Primary Completion (ANTICIPATED): January 1, 2020
• Study Completion (ANTICIPATED): March 1, 2020

Study Registration Dates

• First Submitted: August 30, 2019
• First Submitted That Met QC Criteria: August 30, 2019
• First Posted (ACTUAL): September 4, 2019

Study Record Updates

• Last Update Posted (ACTUAL): November 5, 2019
• Last Update Submitted That Met QC Criteria: November 1, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: Cardiovascular; Mortality; Peritoneal dialysis; Hyperkalemia; Renin-angiotensin system; Retrospective cohort
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Protease Inhibitors; Enzyme Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists
• Other Study ID Numbers: THOR-PD: RAS Inhibitors

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Data from the retrospective cohort study part will be made available at the end of the study, on request. Requests will subject to approval by the chief investigator, the advisory Committee and the relevant ethical bodies.

Drug and device information, study documents

• 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