Abstract
Background/Aim: There is limited evidence about the nephrotoxicity of calcium channel blockers (CCBs) and renin-angiotensin system (RAS) inhibitors with concomitant cisplatin (CDDP). We investigated whether combinations of antihypertensive drugs are associated with CDDP-related acute kidney injury (AKI) using the Japanese Adverse Drug Event Report database. Patients and Methods: We analysed 544,864 reports in the database from 2004 to 2020. A reporting odds ratio (ROR) and confidence interval (CI) with adjustment for potential confounding factors was calculated for AKI for each drug and the combined use of the drugs and CDDP. Results: CDDP, CCBs, and RAS inhibitors were all detected signals for AKI. The ROR in cases with concomitant use of CCBs, RAS inhibitors, and CDDP (adjusted ROR 7.28; 95% CI=5.56-9.54) was higher than that in cases with use of each drug. Conclusion: AKI may require more attention when patients receiving CDDP take CCBs and RAS inhibitors together.
Cisplatin (CDDP) is a platinum-based anticancer drug with many indications, and is positioned as a key drug for a wide range of cancer types including head and neck (1), lung (2, 3), oesophageal (4), and gastric (5) cancers. However, CDDP-based therapies can cause severe and life-threatening adverse events, typically mucosal injury in the gastrointestinal tract and myelosuppression. Acute kidney injury (AKI) is another adverse event of CDDP administration, with a reported incidence of 30-40% (6). Because CDDP-induced AKI is dose-dependent, large fluid volumes, diuretics, and magnesium are often administered to prevent its development. Despite these measures, it is difficult to completely prevent AKI in patients receiving CDDP, and it often becomes a problem with advancing treatment. Identified risk factors for CDDP-induced AKI include older age, total CDDP dose, hypoalbuminaemia, hypokalaemia, diabetes, and cardiovascular disease (7-9). Hypertension (HT) was also identified as a risk factor for CDDP-induced AKI (10, 11), but studies have evaluated the presence or absence of a diagnosis of HT and did not clarify whether there were differences in AKI development depending on the antihypertensive drugs taken.
Antihypertensive drugs are classified into several types, including calcium channel blockers (CCBs), renin-angiotensin system (RAS) inhibitors, and beta blockers. The prescription ratios of CCBs and RAS inhibitors were reported to be high among antihypertensive drugs in Japan (12). In animal studies, combined use of CCBs and CDDP was shown to increase the risk of nephrotoxicity development in rats (13, 14). Use of RAS inhibitors was further identified as an independent risk factor for CDDP-induced AKI in elderly patients (15). However, the relationship between these combinations and the expression of AKI have not been clarified.
Adverse event reports compiled during the post-marketing stages of drugs are provided by the Japanese regulatory authorities in a database and act as valuable tools for post-marketing surveillance to reflect the realities of clinical practice. The purpose of the present study was to use the Japanese Adverse Drug Event Reporting (JADER) database to investigate whether reports of CDDP-related AKI were modified by the existence or nonexistence of CCBs and RAS inhibitors, even after adjustment for other risk factors.
Patients and methods
Study population. The Pharmaceutical and Medical Device Agency (PMDA) in Japan has been managing adverse event reports of drugs from medical users, and these adverse event reports are utilized by various studies as the JADER database (16). The details of the JADER database have been described elsewhere (17). As shown in Figure 1, the extracted data were 654,795 reports and 544,864 reports were analysed in the current study.
Flowchart for creating the analysis data.
Detection of signals for acute kidney injury. In the JADER database, adverse events are coded according to the terminology preferred by the Japanese version of the Medical Dictionary for Regulatory Activities (MedDRA/J) version 14.0. AKI events were identified using Preferred Terms related to AKI in the Standardized MedDRA Query (SMQ) for acute renal failure (20000003), as described in previous studies (18, 19). The drugs selected for this investigation were CCBs (amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, diltiazem, efonidipine, felodipine, manidipine, nicardipine, nifedipine, nilvadipine, and nitrendipine) and RAS inhibitors (alacepril, aliskiren, azilsartan, benazepril, candesartan, captopril, cilazapril, delapril, enalapril, imidapril, irbesartan, lisinopril, losartan, olmesartan, perindopril, quinapril, telmisartan, temocapril, trandolapril, and valsartan). Comorbidities that are risk factors for AKI, such as chronic kidney disease (CKD) (20), HT (21), diabetes mellitus (DM) (22), and heart failure (HF) (23) were also defined by the SMQs in the MedDRA/J. These comorbidities were defined in the table of primary diseases. The SMQs of comorbidities included chronic kidney disease (20000213), hypertension (20000147), hyperglycaemia/new-onset diabetes mellitus (20000041), and cardiac failure (20000004). In the JADER database, the contributions of drugs to adverse events are classified into three categories: “suspected medication,” “concomitant medication,” and “interaction.” CDDP, CCBs, and RAS inhibitors were extracted from all categories.
Statistical analysis. The analyses were performed using previously described methods (24). Briefly, the reports were divided into four groups as follows: (a) cases identified as AKI with the target medication; (b) cases identified as AKI without the target medication; (c) cases not identified as AKI with the target medication; and (d) cases not identified as AKI without the target medication. Using these groups, the reporting odds ratio (ROR) and 95% confidence interval (CI) were calculated using the following equations:
The calculated RORs (crude RORs) of AKI derived for CDDP, CCBs, and RAS inhibitors alone and in combination were adjusted for age (two categories: <70 and ≥70 years), sex, reporting year (continuous), and history of CKD, DM, or HF as explanatory variables in the logistic regression analysis. Because older age is a risk factor for CDDP-induced AKI (7), age as an adjustment factor was divided into two groups (<70 and ≥70 years). Signals for drug–drug interactions were examined in two steps. First, AKI signals were evaluated as positive when the lower limit of the 95% CI of the ROR exceeded 1. Second, if the adjusted RORs and 95% CIs for cases with drugs or concomitantly used drugs had significance differences, the signals for drug–drug interactions in the reported AKI were defined as positive (25, 26). All statistical analyses were performed using JMP®14 software (SAS Institute Inc., Cary, NC, USA).
Results
Of the 544,864 reports analysed, 18,317 described AKI and 526,547 included other adverse events. There were 11,000 reports on CDDP as the suspected drug for all adverse events. Of these, 729 were reported as AKI. There were 70,511 and 69,233 reports on CCBs and RAS inhibitors as the suspected drugs for all adverse events, respectively. Of these, 3,825 and 4,080 included CCBs and RAS inhibitors as the suspected drugs responsible for AKI, respectively. CDDP (crude ROR 2.08; 95% CI=1.93-2.25), CCBs (crude ROR 1.82; 95% CI=1.75-1.89), and RAS inhibitors (crude ROR 2.03; 95% CI=1.96-2.10) were all detected signals for AKI (Table I). Patients with existing risk factors, including age ≥70 years and history of CKD, DM, HT, or HF, had a significantly higher crude ROR for AKI.
Comparison of AKI and other adverse events.
We evaluated the signals for CDDP-related AKI with concomitant use of CCBs and/or RAS inhibitors. A multivariate analysis was performed to adjust for covariates including age ≥70 years, sex, and history of CKD, DM, or HF. The adjusted RORs in each group are shown in Figure 2. Cases with concomitant use of CCBs or RAS inhibitors and CDDP had a higher ROR than cases with monotherapy of either drug type. However, 95% CIs were not mutually exclusive between concomitant use of CDDP and RAS inhibitors and CDDP alone. Furthermore, the ROR in cases with concomitant use of CCBs, RAS inhibitors, and CDDP (adjusted ROR 7.28; 95% CI=5.56-9.54) was higher than that in any other group, and the 95% CIs were mutually exclusive.
Discussion
We performed a large-sample study that considered potential confounding factors by analysing data from the JADER database. We found that combined use of CCBs, RAS inhibitors, and CDDP resulted in a significantly increased ROR for AKI. To the best of our knowledge, the present study is the first to evaluate the risk of AKI for combined use of these drugs using large-sample data.
Regarding the combination of CDDP and CCBs, it was reported that rats treated with verapamil or nicardipine at the same time as CDDP had significantly higher renal accumulation of CDDP than rats treated with CDDP alone (13). Although the underlying mechanism for these findings is unclear, it is possible that combined use with a CCB may cause renal accumulation of the platinum preparation. In the present analysis, concomitant use of CDDP and CCBs showed an increase in which the 95% CIs were mutually exclusive for AKI signals compared to CDDP alone. Meanwhile, there is a report showing that the initial decrease in effective renal plasma flow during and after the first CDDP infusion was completely prevented by verapamil in testicular cancer patients (27). However, the sample size was small, and the results may differ when other AKI risk factors are taken into consideration.
RORs for CDDP-related AKI with concomitant use of CCBs and RAS inhibitors. Boxes represent the ROR and vertical lines represent the 95% CI. The RORs were adjusted for age, sex, reporting year, and history of chronic kidney disease, diabetes mellitus, or heart failure. ROR, Reporting odds ratio; CI, confidence interval; AKI, acute kidney injury; CCBs, calcium channel blockers; RAS, renin-angiotensin system; CDDP, cisplatin.
The concomitant use of CDDP and RAS inhibitors showed an increase in AKI signals compared to CDDP alone, but the 95% CIs were not mutually exclusive. Meanwhile, the concomitant use of CDDP, CCBs, and RAS inhibitors showed an increase in which the 95% CIs were mutually exclusive for AKI signals compared to concomitant use of CDDP and CCBs. In a previous report, the use rate of RAS inhibitors in elderly patients with CDDP-induced AKI was significantly higher than that in patients without CDDP-induced AKI (21.2% vs. 8.1%; p=0.014) (15). In another study, it was shown that lower blood pressure and use of RAS inhibitors were associated with the incidence of CDDP nephrotoxicity (28). Patients taking RAS inhibitors are at high risk of developing AKI during volume depletion, because the contraction of efferent arterioles is inhibited by the inhibitors (29). In addition, it was reported that the plasma renin activity and plasma aldosterone concentration were elevated after CDDP administration, which also caused a decrease in the glomerular filtration rate (30). Another clinical study found that angiotensin-converting enzyme inhibitor use was associated with renal toxicity during platinum-based chemoradiation (31). However, our study could not examine the effect of radiation therapy on AKI.
The ROR in cases with concomitant use of CCBs, RAS inhibitors, and CDDP was significantly higher than that in any other group. It is speculated that the combined use of CDDP and CCBs increases the renal accumulation of the platinum preparation, while the decreases in renal blood flow and glomerular filtration rate caused by RAS inhibitors delay the excretion of CDDP, resulting in an increase in the AKI expression rate. However, further studies are needed to clarify the underlying mechanisms.
The strength our study includes the large sample size and the careful adjustment for potential confounders using the JADER database which is more informative (e.g., concomitant drug and comorbidities). As a clinical implication, our study suggests that AKI caused by drug–drug interactions such as combination therapy with CDDP and CCBs or RAS inhibitors may confer the need for greater attention. Meanwhile, several limitations should be mentioned. First, the results were obtained from a spontaneous reporting system and should be interpreted with caution. For example, it may be subject to some biases caused by over-under reporting, missing data, exclusion of healthy individuals, and lack of a denominator for incidence estimation (24, 32). Especially, it should be noted that the “true” risk of AKI cannot be evaluated without information concerning the total number of patients administered CCBs or RAS inhibitors and CDDP. Second, residual confounding may have occurred as a result of unadjusted factors, such as cancer type, treatment regimen, total dose of CDDP, hypoalbuminaemia, and hypokalaemia. Moreover, the United States Food and Drug Administration’s Adverse Event Reporting System refers to an increase in adverse event reporting over the initial 2 years after a drug is approved, followed by a rapid decline in reporting rates (33). Therefore, we adjusted age, disease history, and the reporting year which can be used to minimize these confounding factors. Third, the accuracy of the diagnosis of AKI is limited because the diagnosis could not be validated by a chart review in the JADER database. Finally, a signal for an increased risk of developing AKI with CDDP upon combined use with CCBs and RAS inhibitors was detected, but it remained unclear whether the combined CCBs and RAS inhibitors themselves or the severity of the HT contributed to the risk.
In conclusion, it is suggested that AKI may require more attention when patients receiving CDDP are taking CCBs and RAS inhibitors together, based on this study and using the JADER database. Clinical studies are needed to further evaluate the modifying effect of CDDP on the association of AKI with CCBs and RAS inhibitors.
Acknowledgements
We thank Alison Sherwin, Ph.D., from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript. This study was supported by JSPS KAKENHI Grants (18K10049 and 21K06645) from the Japanese Ministry of Education, Culture, Sports, Science and Technology.
Footnotes
Authors’ Contributions
K.T., R.S., S.T., and C.S. designed this study. K.T., C.M., and S.T. analyzed the data. K.T., R.S., S.K., and C.S. drafted the manuscript. All authors have read and approved the final manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to declare.
- Received January 14, 2022.
- Revision received February 8, 2022.
- Accepted February 21, 2022.
- Copyright © 2022 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
