Study Population
This study (trial registration: ClinicalTrials.gov NCT03329443) will be an investigator-initiated, single-center, double-blind placebo-controlled, randomized clinical trial. Trial design was approved by two independent institutional review boards (Basra Health directorate review board, and University of Baghdad/College of Pharmacy review board) before patients’ enrollment in the study. Patients admitted for coronary angio in the cardiology department in Al-Sader teaching hospital-Basra will be selected for randomization by a computer-based algorithm into two groups. The study population will consist of 400+ patients 18 years or older, admitted for coronary angiography or PCI and provide informed consent for participation in the study. Patients will be excluded if they received contrast medium administration within the previous 7 days, had end-stage renal failure or kidney transplantation, acute kidney injury defined as 0.3 mg/dl elevation in serum creatinine (S.Cr.) in the previous 4 weeks, lactation, pregnancy or documented current tumor, periprocedural administration of nephrotoxic drugs, (nonsteroidal anti-inflammatory drugs, cyclosporine, aminoglycosides or cisplatin in the previous 48 days or in the follow-up period).
Study Protocol
We are using an Excel spreadsheet with random number generator to allocate eligible patients in a 1:1 ratio for either active or placebo groups. Simple randomization is selected without any stratification, which was felt to be adequate.
The active arm allocated group will receive 200 mg of spironolactone prior to angiography/plasty at admission along with their premedication and chronic treatments. The placebo group will receive only their usual premedication and chronic treatment.
Blood samples will be collected for assessment of serum creatinine, NGAL (neutrophil gelatinase-associated lipocalin), potassium, and hematocrit at baseline. Serum NGAL and potassium is further collected after 6 h of the procedure. Finally, patients are advised to report serum creatinine after 48–72 h post procedure. Patients who fail to report will receive a reminder text message within 48–72 h to enhance feedback (Fig. 1).
Patients’ demographic data, including phone number, weight, age, gender, type, and volume of contrast agent received in the procedure, type of procedure (PCI/angio), lesion location, hypertension, DM, chronic kidney disease stage by Cockcroft–Gault equation, Mehran score, type and fluid given in the peri-procedure, current medication including spironolactone and any nephrotoxic drugs like metformin and diuretics will be carefully collected by the research personnel.
Compliance with Ethics Guidelines
All procedures performed in this study involving human participants will be in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent will be obtained from all individual participants included in the study.
Study Status
We are ongoing now with an estimated enrollment rate of more than 20 patients per week from five consultant cardiologists out of seven in our center.
Study End Points
Primary Endpoint
The primary outcome will be a documentation of CIN defined as 0.25% or 0.3 mg absolute increase in Sr. Cr. after 48–72 h after the procedure as adopted by the K-DIGO guidelines [11, 12].
Key Secondary Endpoints
Key secondary endpoints will be an evaluation of CIN by the novel surrogate marker serum NGAL after only 6 h post procedure [13].
As a safety end point and because of inherent risks of hyperkalemia, patients will be followed up for hyperkalemia for 6 h after procedure and contacted in 2–3 days to look for any signs and symptoms of hyperkalemia and they will be specifically advised to immediately measure serum potassium level if any signs hyperkalemia would develop or a documented gastrointestinal tract (GIT) upset in the same period [14, 15].
Data and Safety Monitoring Board
Data will be sent periodically to the principal administrators of the study to look for efficacy, safety, and the will to continue or terminate the study.
Statistical Analysis
Sample size calculation for our study was based on our pilot observation (unpublished yet) and other studies reported in similar Iraqi patients from nearby centers with a CIN incidence in the control group of around 20% and an assumable effect of 10% reduction with spironolactone [16, 17]. Using GPower 3.1 with two-sided Chi-square test and an alpha error of 0.05, a total of 428 patients are required to give at least an 80% power for our analysis to detect a difference at the specified effect.
Primary and secondary analysis of categorical variables will be conducted using Chi-square test or a proper exact test if necessary. A multivariate logistic regression model will be developed to adjust for a priori specified clinical variables with known influence of CIN as were defined by previous studies [2, 18, 19].
For normally distributed continuous variables, we will adopt a mean + standard deviation (SD) and comparisons will be done with two-sample t tests. Non-normally distributed variables will be presented as median and interquartile range, and analysis will be used according to a suitable non-parametric test if necessary.
All analyses will be done on an intention-to-treat principle. All tests will be two-tailed and a p value of < 0.05 will be considered statistically significant. Data analysis will be performed using SPSS 23 software.