Cardiol Ther (2018) 7:101–106 https://doi.org/10.1007/s40119-018-0112-3 STUDY PROTOCOL The Effect of Spironolactone on the Incidence of Contrast-Induced Nephropathy in Patients Undergoing Cardiac Catheterization: Study Design and Rationale . . . Alhasan Mujtaba Mohammed A. Taher Mazin A. Hazza . . . Hassan M. Al-Rubaye Asaad H. Kata Hamid AbdulWahab AbdulAmeer AbdulBari Hayder K. AlRubay Received: April 11, 2018 / Published online: May 21, 2018 The Author(s) 2018 center will be allocated in a 1:1 ratio to receive ABSTRACT either spironolactone 200 mg single dose or placebo in addition to their usual Introduction: Patients undergoing coronary premedication. catheterization are at high risk of developing Planned Outcomes: Primary end point will be contrast-induced nephropathy (CIN) acute kid- CIN deﬁned as more than 25% or 0.3 mg/dl ney injury (AKI). Several approaches have been elevation in serum creatinine (S.Cr.) from supposed to limit such an effect but with mixed baseline during the ﬁrst 2–3 days after the pro- results or non-practical methods. Spironolac- cedure. We hope to identify or answer an tone is supposed to be effective as a nephro- important question regarding CIN in such high- protective agent in animal studies. This study risk patients. will try to measure the effect of spironolactone Trial Registration: ClinicalTrials.gov Identiﬁer, on the incidence of CIN-AKI in patients NCT03329443. undergoing coronary catheterization (angiog- raphy angioplasty). Keywords: Acute kidney injury (AKI); Methods: This study is a single-center, investi- Aldactone; Angiography; Angioplasty; gator-driven, double-blinded randomized con- Contrast-induced nephropathy (CIN); Ischemic trolled study in Iraq-Basra. More than 400 heart disease (IHD); Percutaneous coronary patients admitted for coronary angio unit in our angiography (PCI); Spironolactone Enhanced digital features To view enhanced digital features for this article go to https://doi.org/10.6084/ m9.ﬁgshare.6244637. INTRODUCTION A. Mujtaba (&) M. A. Taher Patients who opt for percutaneous coronary Department of Clinical Pharmacy, College of intervention (PCI) to help them with their Pharmacy, University of Baghdad, Basra, Iraq ischemic heart disease (IHD) problems are at e-mail: firstname.lastname@example.org high risk of developing contrast-induced M. A. Hazza A. AbdulBari nephropathy (CIN) . The CIN could ulti- College of Medicine, University of Basra, Basra, Iraq mately have a detrimental effect on such patients including a negative effect on mortality H. M. Al-Rubaye A. H. Kata H. AbdulWahab Basra Cardiac Catheterization Center, Basra, Iraq and morbidity as well [2, 3]. Several interventions have been done to H. K. AlRubay limit this negative effect on such patients, but AlSader Teaching Hospital, Basra, Iraq 102 Cardiol Ther (2018) 7:101–106 the evidence is still lacking on the best method, injury deﬁned as 0.3 mg/dl elevation in serum and the maximum beneﬁt that can be achieved creatinine (S.Cr.) in the previous 4 weeks, lac- to prevent CIN. Several approaches may include tation, pregnancy or documented current aggressive hydration prior to the procedure, but tumor, periprocedural administration of results are still pending [4–6]. Furthermore, it nephrotoxic drugs, (nonsteroidal anti-inﬂam- has been reported that another innovative matory drugs, cyclosporine, aminoglycosides or approach was based on blocking the neuro- cisplatin in the previous 48 days or in the fol- hormonal activation known to cause or aggra- low-up period). vate acute kidney injury (AKI). One such approach is the use of spironolactone, where Study Protocol animal studies highlighted the damaging effect of aldosterone on causing and aggravating AKI We are using an Excel spreadsheet with random and speciﬁcally CIN. On the other hand, number generator to allocate eligible patients in human studies are conﬂicting and importantly a 1:1 ratio for either active or placebo groups. no study yet have been done on patients with Simple randomization is selected without any CIN or PCI [7–10]. stratiﬁcation, which was felt to be adequate. Given all the previous information, we The active arm allocated group will receive designed this study to measure the effect of 200 mg of spironolactone prior to angiogra- aldosterone blockage promoted by the utiliza- phy/plasty at admission along with their tion of spironolactone prior to coronary premedication and chronic treatments. The angiography on CIN incidence measured by placebo group will receive only their usual different biochemical approaches and deﬁni- premedication and chronic treatment. tions that were reported in the literature and Blood samples will be collected for assess- adopted by global societies. ment of serum creatinine, NGAL (neutrophil gelatinase-associated lipocalin), potassium, and hematocrit at baseline. Serum NGAL and METHODS potassium is further collected after 6 h of the procedure. Finally, patients are advised to report Study Population serum creatinine after 48–72 h post procedure. Patients who fail to report will receive a This study (trial registration: ClinicalTrials.gov reminder text message within 48–72 h to NCT03329443) will be an investigator-initiated, enhance feedback (Fig. 1). single-center, double-blind placebo-controlled, Patients’ demographic data, including phone randomized clinical trial. Trial design was number, weight, age, gender, type, and volume approved by two independent institutional of contrast agent received in the procedure, type review boards (Basra Health directorate review of procedure (PCI/angio), lesion location, board, and University of Baghdad/College of hypertension, DM, chronic kidney disease stage Pharmacy review board) before patients’ by Cockcroft–Gault equation, Mehran score, enrollment in the study. Patients admitted for type and ﬂuid given in the peri-procedure, cur- coronary angio in the cardiology department in rent medication including spironolactone and Al-Sader teaching hospital-Basra will be selected any nephrotoxic drugs like metformin and for randomization by a computer-based algo- diuretics will be carefully collected by the rithm into two groups. The study population research personnel. will consist of 400? patients 18 years or older, admitted for coronary angiography or PCI and Compliance with Ethics Guidelines provide informed consent for participation in the study. Patients will be excluded if they All procedures performed in this study involv- received contrast medium administration ing human participants will be in accordance within the previous 7 days, had end-stage renal with the ethical standards of the institutional failure or kidney transplantation, acute kidney Cardiol Ther (2018) 7:101–106 103 As a safety end point and because of inherent Paents admied for risks of hyperkalemia, patients will be followed coronary angio/plasty up for hyperkalemia for 6 h after procedure and contacted in 2–3 days to look for any signs and Exclusion criteria symptoms of hyperkalemia and they will be speciﬁcally advised to immediately measure Randomizaon serum potassium level if any signs hyperkalemia would develop or a documented gastrointesti- nal tract (GIT) upset in the same period [14, 15]. Placebo Acve group Premedicaon only Spironolactone 200 before procedure mg single dose Data and Safety Monitoring Board Data will be sent periodically to the principal 6hrs administrators of the study to look for efﬁcacy, NGAL, S.K safety, and the will to continue or terminate the study. 2-3 days S.Cr. Statistical Analysis Fig. 1 Study ﬂow diagram. NGAL neutrophil gelatinase- associated lipocalin, S.K serum potassium, S.Cr. serum Sample size calculation for our study was based creatinine on our pilot observation (unpublished yet) and other studies reported in similar Iraqi patients and/or national research committee and with from nearby centers with a CIN incidence in the the 1964 Helsinki Declaration and its later control group of around 20% and an assumable amendments or comparable ethical standards. effect of 10% reduction with spironolactone Informed consent will be obtained from all [16, 17]. Using GPower 3.1 with two-sided Chi- individual participants included in the study. square test and an alpha error of 0.05, a total of 428 patients are required to give at least an 80% Study Status power for our analysis to detect a difference at the speciﬁed effect. Primary and secondary analysis of categori- We are ongoing now with an estimated enroll- cal variables will be conducted using Chi-square ment rate of more than 20 patients per week test or a proper exact test if necessary. A multi- from ﬁve consultant cardiologists out of seven variate logistic regression model will be devel- in our center. oped to adjust for a priori speciﬁed clinical variables with known inﬂuence of CIN as were Study End Points deﬁned by previous studies [2, 18, 19]. For normally distributed continuous vari- Primary Endpoint ables, we will adopt a mean ? standard devia- The primary outcome will be a documentation tion (SD) and comparisons will be done with of CIN deﬁned as 0.25% or 0.3 mg absolute two-sample t tests. Non-normally distributed increase in Sr. Cr. after 48–72 h after the pro- variables will be presented as median and cedure as adopted by the K-DIGO guidelines interquartile range, and analysis will be used [11, 12]. according to a suitable non-parametric test if necessary. Key Secondary Endpoints All analyses will be done on an intention-to- Key secondary endpoints will be an evaluation treat principle. All tests will be two-tailed and a of CIN by the novel surrogate marker serum p value of \ 0.05 will be considered statistically NGAL after only 6 h post procedure . 104 Cardiol Ther (2018) 7:101–106 signiﬁcant. Data analysis will be performed within the safe range, especially to note that it using SPSS 23 software. will be a single dose only. Nevertheless, we will measure the effect of this moderate dose on serum potassium (S.K?) SUMMARY after 6 h in all patients and possibly after 3 days in randomly selected patients. Many studies This study will try to measure the effect of reported the safety of moderate acute (single or spironolactone as an add-on pre-PCI treatment few days) dose on serum potassium levels and to limit the effect of CIN in stable IHD patients chronic follow-up of such levels were unneces- opting for angiography for diagnosis and sary [22–24]. If hyperkalemia were to be found, treatment. it will be reported to the treating physician immediately for follow-up and treatment according local guidelines. DISCUSSION As mentioned earlier, there are numerous ACKNOWLEDGEMENTS efforts to limit the damaging effects of coronary intervention and speciﬁcally the contrast agents on the kidneys [4–6]. Several of such approaches Funding. No funding or sponsorship was/ have failed, proved to be non-practical, or gave will be received for this study or publication of mixed results at best [20, 21]. Spironolactone is this article. The article processing charges were poorly studied in this regard given its proven funded by the authors. beneﬁt in animal studies [7–9]; two studies in cardiac surgery units reported its effect on Authorship. All named authors meet the ischemic kidney injury. One study was not pri- International Committee of Medical Journal marily powered to detect that effect, and the Editors (ICMJE) criteria for authorship for this other was underpowered and groups were not article, take responsibility for the integrity of homogenous for important covariates relevant the work as a whole, and have given their to the effect [7, 10]. There is no study yet so far, approval for this version to be published. registered or published, that studied this drug in coronary angio patients. We aim to measure Disclosures. Alhasan Mujtaba, Mohammed such an effect in our planned study in a broad A. Taher, Mazin A. Hazza, Hassan M. Al-Rubaye, category of patients who are admitted for elec- Asaad H. Kata, Hamid AbdulWahab, Abdu- tive coronary angio. lAmeer AbdulBari and Hayder K. AlRubay have Physicians were given the freedom of treat- nothing to disclose. Alhasan Mujtaba, Moham- ment regarding prevention of CIN with ﬂuids or med A. Taher, Mazin A. Hazza, Hassan M. Al- any other means but all of these variables will Rubaye, Asaad H. Kata, Hamid AbdulWahab, be collected as well. A promising method for AbdulAmeer AbdulBari and Hayder K. AlRubay CIN prevention might be based on the POSEI- alone, are responsible for the writing and pro- DON protocol, but it is difﬁcult to come up with duction of the present article. in practical terms and will not be done in our trial due to procedure limitation. Nevertheless, Compliance with Ethics Guidelines. All any ﬂuid given will be collected and any other procedures performed in this study involving method of CIN prevention will be monitored human participants will be in accordance with and collected too . the ethical standards of the institutional and/or The studies that aimed to measure the effect national research committee and with the 1964 of spironolactone did so with minimal doses (7, Helsinki Declaration and its later amendments r10). Given the max chronic dose of 400 mg, we or comparable ethical standards. Informed thought that a higher dose (200-mg single dose) consent will be obtained from all individual might give a more noticeable effect and still be participants included in the study. Cardiol Ther (2018) 7:101–106 105 randomized, placebo-controlled trial. Am J Kidney Data Availability. Data sharing is not Dis. 2016. https://doi.org/10.1053/j.ajkd.2016.06. applicable to this article as no datasets were generated or analyzed during the current study. 8. Mejia-Vilet JM, et al. Renal ischemia-reperfusion Open Access. This article is distributed injury is prevented by the mineralocorticoid receptor blocker spironolactone. Am J Physiol Renal under the terms of the Creative Commons Physiol. 2007;293:F78–86. Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/ 9. Sanchez-Pozos K, et al. 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Published: May 21, 2018
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