Trials evaluating nicorandil renoprotection against contrast-induced nephropathy after coronary angiography or percutaneous coronary intervention: a systematic review and meta-analysis.

Introduction

Ischaemic heart disease (IHD), also known as coronary artery disease (CAD), is the most prevalent cardiovascular disease and the leading cause of disability and mortality globally 9 [ 1 – 3 ]. It accounted for more than 180 million Disability-Adjusted Life Years (DALYs) in 2019 [ 4 ], approximately 720,000 cases, and over 9 million deaths globally every year [ 5 ]. Despite advances in medical care, the burden of IHD is increasing globally, thus making it a significant threat to global public health and attracting a large percentage of annual global healthcare expenditure [ 4 , 5 ].

Prompt treatment of IHD with coronary angioplasty reduce the risk of patient’s mortality and comorbidity resulting in improved quality of life [ 6 , 7 ]. Nevertheless, coronary angioplasty also has complications and some of these complications are related to the contrast media such as iodine and gadolinium used during coronary angioplasty. These media are also used in diagnostic tests such as computed tomography myocardial perfusion imaging (CT-MPI), coronary CT angiography (CCTA), coronary angiography (CAG), or percutaneous coronary intervention (PCI) [ 5 , 8 – 11 ].

Contrast media induced nephropathy, allergic reaction, anaphylaxis, renal replacement therapy, major adverse cardiovascular and renal outcomes are some of the serious side effects observed in patients [ 8 , 9 ]. Certain patients’ characteristics such as anemia, chronic kidney disease, diabetes mellitus, dehydration, volume of contrast used, advanced age, heart failure, multiple myeloma, hypoalbuminemia, liver cirrhosis, concomitant use of nephrotoxic drugs is more likely to predispose patients to CIN [ 5 , 12 , 13 ].

CIN can be defined as an increase in serum creatinine by ≥ 0.5 mg/dL (44 µmol/L) or by >25% from baseline within 48 h after the administration of radiocontrast media (RCM), without any other attributable causes [ 12 , 14 , 15 ]. CIN is the third most common cause of hospital-acquired ARI, responsible for approximately 12% of ARI cases, although the incidence may be as high as 24%, depending on the risk factors [ 15 ]. Various proposed mechanisms responsible for CIN included enhanced cellular damager due to reactive oxygen species, reduced intramedullary renal blood flow due to renal vasoconstriction caused by imbalance of local vasoactive mediators such as adenosine, nitrous oxide, endothelin, prostaglandin and reactive oxygen species that are released by the vascular endothelium in response to the contrast media induced cytotoxicity. The vasoconstriction effect seems to be more common in patients with chronic kidney disease [ 14 – 16 ].

Some of the recommended measures to reduce the risk of CIN include pre-hydration mainly in patients with chronic kidney disease (CKD), low-osmolar iodinated contrast media (ICM), and the use of prophylactic statins, low volume of contrast, stopping nephrotoxic drugs such as metformin before coronary angioplasty and reassessing renal function tests in one week post procedure [ 14 ]. Certain agents such as Nicorandil, nitrates and nitrates, ascorbic acid, theophylline, N-acetyl cysteine, high dose statins, and Prostaglandin E1 have been used to minimize the risk of CIN [ 17 – 20 ]. Nicorandil is an anti-anginal medicine owing to its ability to dilate blood vessels through potassium channel activation and its nitrate moiety [ 21 ]. This meta-analysis aimed at determining whether nicorandil can prevent CIN.

Objectives

The primary endpoint was to evaluate whether nicorandil exerted nephroprotection against CIN in patients undergoing CAG or PCI. The secondary endpoint was to identify major adverse events (MAE) and major adverse kidney events (MAKE) associated with CAG or PCI.

Methodology and material

This systematic review and meta-analysis were conducted using the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the PICO framework (Table 1 ). The study is registered with PROSPERO under registration number CRD42024567009.

Data source and search strategy

The search was performed across the PubMed, Scopus, Embase, Google Scholar, and ScienceDirect databases. Some of the searched items included Nicorandil, Contrast-Induced Nephropathy, Acute Renal Injury, chronic kidney disease, impaired renal function, renal insufficiency, renoprotection, ischaemic heart disease, cardiac catheterisation, computed tomography, myocardial perfusion imaging (CT-MPI), coronary CT angiography (CCTA), coronary angiography (CAG), and percutaneous coronary intervention (PCI). The search was performed in September 2024 by two independent reviewers, identifying two hundred eighty-two (282) related articles. The articles were reduced to 49 after duplicate analyses were performed using the Rayyan App. After applying the inclusion and exclusion criteria, 17 articles were included in the study, as shown in the PRISMA chart (Fig. 1 ). All included articles were published between 2011 and 2023. All discrepancies were resolved through consensus.

Inclusion criteria

The inclusion criteria were as follows: randomised controlled trials (RCTs), observational studies, case-control studies, cohort studies, systematic reviews, and meta-analyses; full articles; articles written in the English language; and articles on adult human populations regarding the effect of nicorandil, compared to placebo, on preventing CIN nephropathy after CAG/PCI.

Exclusion criteria

The exclusion criteria were as follows: guidelines, case reports, qualitative research, and letters to the editor, commentaries, conference proceedings, gray literature, opinions, policy papers, and case series.

Data collection process and data items

The literature search was performed by two reviewers and extracted data was recorded in a standardised data abstraction form (Microsoft Excel ® ). Duplicates were removed using the Rayyan software. The data collected included title, authors, year of publication, study population, intervention group, control group, follow-up period after the procedure, results in terms of CIN events comparing nicorandil and placebo, as well as nicorandil double dose (DD) and nicorandil standard dose (SD), and the analysis of nicorandil regarding MAE, which were considered as follows: nonfatal MI, revascularization, stroke, coronary artery bypass graft surgery, congestive heart failure, worsening of heart failure, pulmonary oedema, ventricular fibrillation, cardiac death, and gastrointestinal bleeding. End-stage kidney disease and temporary renal replacement therapy were the circumstances encompassed by MAKE.

Statistical analysis

Due to low heterogeneity among studies, statistical analysis was performed using the Cochrane Review Manager (RevMan) 5.3 (The Cochrane Collaboration, Copenhagen) with dichotomous data and the fixed-effect model. Having said that, this analysis mitigated the risk of assigning greater weight to the results of small-sample research. The Risk of Bias evaluation was conducted using the Cochrane Risk of Bias 2 (RoB) tool (Figs. 2 and 3 ), and publication bias was assessed using funnel plots. The AMSTAR-2 tool was used to determine the quality of the systematic reviews and meta-analyses in this study, categorising them as low, moderate, or high quality (Table 2 ).

Table 2 presents the AMSTAR-2 tool for assessing risk of bias in systematic reviews and meta-analyses.

Results

Selected studies are shown in Table 3 and their respective forest and funnel plots in the following sequence, as per the assessed primary and secondary endpoints. Overall, the analysis showed no significant heterogeneity among the studies included. Concerning the prevention of CIN, nicorandil showed a significant protective effect in comparison with the control in terms of the overall effect ( P < 0.00001) (Fig. 4 ) in a dose-dependent manner ( P = 0.02) (Fig. 5 ). There was also a dose-dependent pattern in the occurrence of Major Adverse Events (MAE) ( P = 0.02), as indicated by the Chi-Square test (Fig. 6 ). However, concerning the prevention of Major Adverse Kidney Events (MAKE), no robust findings contradicted the null hypothesis ( P = 0.72) (Fig. 7 ). Thus, there was no significant association between MAKE and the use of nicorandil in this study.

Effect of nicorandil on CIN

For this assessment, a total of 7,204 patients out of 16 papers with low heterogeneity (< 30%) ( P < 0.00001; I2 = 0%) evaluating the effect of nicorandil on CIN showed a meaningful statistical difference in favor of the intervention group, as the occurrence of CIN was 5,14% in the nicorandil group, in contrast with 13.15% in the control group. Thus, the respective forest plot also confirmed the superior results of the intervention drug regarding CIN (Fig. 4 ).

Nicorandil dose-dependent effect on CIN

The forest plot also confirmed the dose-dependent effect of nicorandil on CIN. Among 662 patients enrolled in three research types, 3,9% in the DD group presented with CIN, compared with 8,4% in the SD group. Despite the small sample size, the CI and low heterogeneity variables showed statistical reliability ( P = 0.02; I2 = 0%) (Fig. 5 ).

Nicorandil effect on MACE

This meta-analysis showed that CIN was less in patients receiving nicorandil compared to placebo group and the incidence of MACE was 5.7% and 8.2% in the Nicorandil group and the control group respectively. This difference was however statistically non-significant ( P = 0.02; I2 = 0%). Furthermore, three studies by Ko et al. 2013, Zhang et al. 202, Zhang et al. 2019, did not show any evidence of nicorandil providing higher protection versus placebo against MACE [ 25 , 36 , 37 ]. The odds ratio for the use of nicorandil versus placebo using fixed effect model was 0.70 (CI 0.52–0.94).

It is also noteworthy to mention that, although authors from study [ 33 ] assessed a dose-dependent effect of nicorandil on MACE, and there was no difference between the groups. The number of MACE in the nicorandil versus SD group was 2 out of 111 and 2 out of 107 respectively.

Nicorandil consequences in terms of MAKE

The cross-sectional presentation of the diamond in Fig. 8 indicates that nicorandil administration could not contradict the null hypothesis. In other words, this study could not state that episodes of MAKE would be reduced by nicorandil use (Fig. 7 ).

No apparent heterogeneity was observed in these studies, and the funnel plots (Figs. 8 and 9 ) did not indicate publication bias. Additionally, we performed sensitivity analysis by excluding one study at a time and this did not show any significant difference in the results confirming the robustness of data and analysis.

Discussion

This systematic review and meta-analysis, whose primary endpoint was to evaluate the efficacy of nicorandil as a nephroprotective agent against CIN in patients undergoing CAG or PCI, and the secondary endpoint was to identify the major adverse events (MAE) and major adverse kidney events (MAKE) associated with CAG or PCI after the use of nicorandil, revealed many interesting results.

In renal blood flow, only 10% of the arterial blood reaches the renal medulla, making the area more susceptible to ischaemic injury than the renal cortex upon exposure to contrast media [ 15 ]. Although the exact pathophysiological mechanism of CIN has not been fully elucidated, likely causes include contrast media-induced reduction in medullary blood flow, renal tubular cell apoptosis, and the generation of oxygen-free radicals [ 14 , 15 ].

Considering that endothelial nitric oxide synthase inhibition, inflammation, and oxidative stress have all been shown to alter nitric oxide (NO) bioavailability by over 82%, it is reasonable to assume that any situation that causes an imbalance between NO and free radicals, as seen after the use of some contrast media (CM), may worsen renal cell damage [ 40 ]. Thus, antioxidants that scavenge reactive oxygen species (ROS) induced by exposure to contrast media and increase NO levels in the renal microcirculation play a critical role in preventing medullary hypoxaemia and volume depletion, and in lowering interstitial pressure [ 40 ]. Kidneys are particularly vulnerable to ischemic injury due to high metabolic and osmotic stress that can affect the intricate microvascular circulation susceptible to local and systemic hypoperfusion. This hypoperfusion or ischemia is most evident in the outer medullary region of the kidneys where the oxygen requirement is quite high. This renal ischemia risk is even higher in patients with CKD due to increased metabolic demands placed on the reduced nephron bed that also faced reduced microvascular and macrovascular circulation. It is believed that the likely pathogenesis for CIN included ischemia in the outer medullary region of kidneys exacerbated by a prolonged period of renal vasoconstriction that occurs due to imbalance of local vasoactive mediators such as adenosine, nitrous oxide, prostaglandin and reactive oxygen species, released by the vascular endothelium in response to contrast media toxicity. The resulting ischemia in tissues releasees further noxious mediators that leads to prolonged duration of vasoconstriction. Additionally, the increased viscosity of the admixture of CM and bloods plasma along with the hyperosmolality of the CM in the plasma results in further reduced blood flow, red cell distortion and aggregation contributing to significant hypoperfusion due to capillary obstruction. The combination of vasoconstriction, cytotoxicity and increased viscosity together causes significant medullary ischemic injury.

Nicorandil exerts its anti-anginal effect via two primary mechanisms: the NO pathway and the potassium channel-opening pathway [ 21 ]. However, in the context of CIN, the formal mechanism appears to be a more rational justification for its use as a CIN prophylaxis/treatment agent, as the drug itself contains a nitrate moiety that, upon reaction with the sulfhydryl group, facilitates NO release [ 21 ].

Effect of nicorandil on contrast-induced nephropathy (CIN)

All included studies in this systematic review and meta-analysis demonstrated a significant nephroprotective effect of Nicorandil against CIN compared with controls, and the meta-analysis showed an overall nephroprotective impact of Nicorandil against CIN. The pooled OR on the effect of nicorandil in preventing CIN showed a strong statistically significant effect (Z = 11.17, p < 0.00001), where the odds of CIN were reduced by 64% with nicorandil use, implying it as a protective factor against CIN (OR – 0.36[0.30, 0.43]). Thus, oral nicorandil may be a promising adjunct to the standard hydration regimen for the at-risk population to prevent CIN. Results from similar studies supported this finding.

According to a recent study, the rate of arterial renal perfusion can independently predict the Congestive heart failure (CHF) outcomes in patients; thus, to balance the axis between the ‘total vascular organs’ (heart and kidney), the administration of intravenous infusion of Nicorandil was able to reduce the incidence of CIN [ 29 ]. However, the study noted that achieving a positive effect requires maintaining a stable nicorandil concentration in the blood during contrast exposure, as the latter has a longer half-life [ 29 ]. However, the study was limited to patients with early-stage kidney disease [ 29 ].

Route of administration and dosage of nicorandil in renoprotection

Most of the included studies in this systematic review and meta-analysis administered nicorandil orally at 10 mg TID. However, the best route of administration (IV vs. oral) for nicorandil has yet to be determined, and more studies are needed to reach a definitive conclusion [ 30 ]. A meta-analysis showed a favourable effect of oral Nicorandil on CIN prevention in Asian patients; however, the study included only 4 RCTs (2 per arm), had wider CIs for the IV Nicorandil, and was only of moderate design quality, limiting its impact [ 27 ]. One likely explanation for this higher renal protection offered by oral nicorandil is due to its prolonged effect or bioavailability resulting in longer vasodilatation and nephroprotection. The ‘PRINCIPLE study’ by Ko et al. inferred that intravenous administration of nicorandil did not significantly decrease the incidence of CIN [ 25 ].

Furthermore, this meta-analysis demonstrated that the nephroprotective effect of Nicorandil against CIN was dose-dependent ( P = 0.02). The forest plot comparing single-dose (SD) vs. double-dose (DD) nicorandil in our study showed a statistically significant benefit for the latter, with a 55% reduction in the odds of CIN. This finding is supported by the results of a recent study, which observed that the periprocedural use of double dose (DD) nicorandil (30 mg) significantly reduced the incidence of CIN, rather than a single dose (SD), where only a slight improvement in Renal Function Test (RFT) was seen with SD [ 33 ]. In a subgroup analysis of the use of DD IV nicorandil in the referenced study, patients who received ≥ 140 ml of contrast dye showed a significant decrease in CIN incidence compared with the standard contrast dose [ 33 ]. Thus, until more studies are available, DD Nicorandil may be beneficial for renoprotection against CIN.

Major adverse events (MAE) and major adverse kidney events (MAKE) and the use of nicorandil

This study found that, in most studies, the occurrence of Major Adverse Events (MAE) after nicorandil use was dose-dependent and the overall result was statistically significant. Some of the MAEs that were observed with the use of nicorandil in the included studies, especially at high doses, were nonfatal MI, revascularisation, stroke, coronary artery bypass graft surgery, congestive heart failure, worsening of heart failure, pulmonary oedema, ventricular fibrillation, cardiac death, and gastrointestinal bleeding. However, this meta-analysis did not demonstrate a significant increase in Major Adverse Kidney Events (MAKE) with nicorandil use across the included studies. However, this result may be due to most of the included studies not including MAKE as an outcome. In addition, there is generally little data available on the effects of Nicorandil on MAKE. A few other studies have associated MAE, such as oral and gastrointestinal bleeding [ 41 ] and stroke [ 42 ], with the use of nicorandil. Thus, a cautious use and monitoring protocols for nicorandil should be initiated at any time for renoprotection against CIN or any other purpose.

Limitations

None of the included studies reported the stages of chronic kidney disease (CKD) of the included patients, as this would have provided further insight into which patient category benefited most from the intervention. However, they included patients with e-GFR ˂60 ml/min. The volume and type of contrast dye used significantly affect the incidence of CIN, but most included studies failed to account for this by not providing this information. Also, the possible long-term MAE and MAKE in patients were not investigated in terms of hospital stay length, and the cost implications of using Nicorandil were not mentioned. All this information could affect the study’s outcomes.

Conclusion

A healthy kidney is much less susceptible to potential iatrogenic complications associated with contrast media use. However, the degree of contrast media-induced acute kidney injury (AKI) and the risk of CIN vary drastically based on the presence of different harmful factors, such as advanced age, heart failure, dehydration, hypoalbuminaemia, diabetes mellitus, and anaemia. This study demonstrated that the risk of CIN in patients undergoing CAG or PCI can be reduced if nicorandil is used as a prophylaxis in addition to the standard CIN prevention protocol. Nicorandil is an effective oral medication, and its renoprotective effects are enhanced if used as a double dose. In addition, the renoprotective effect of nicorandil in this study was dose-dependent, with higher doses associated with greater MAE. Thus, while available studies have demonstrated the renoprotective effects of nicorandil in patients undergoing CAG or PCI, necessary measures and protocols should be implemented to prevent potential MAE.

Only a few studies are available on the effects of nicorandil on CIN prevention. To further generalise the potential renoprotective effects of nicorandil in patients undergoing CAG or PCI, additional studies, particularly RCTs and systematic reviews/meta-analyses, are needed. There is also insufficient information on the optimal dosage and route of administration of nicorandil in the prevention and treatment of CIN. In addition, there are limited studies on the potential renoprotective effects of nicorandil in other control conditions, such as type 2 diabetes. In fact, during the literature search, only one study reported the beneficial effect of oral Nicorandil in patients with Type 2 diabetes mellitus. Therefore, further studies are required to determine the optimal dosage, the most effective route of administration, and the effects of Nicorandil in individuals with other comorbidities.

Acknowledgements

Not applicable.

Abbreviations

Contrast-induced nephropathy

Coronary artery disease

Coronary artery pass graft

Myocardial infarction

ST-elevation myocardial infarction

Gastrointestinal

Chronic kidney disease

Percutaneous coronary intervention

Ischemic heart disease

Disability-Adjusted Life Years

Computed tomography myocardial perfusion imaging

Coronary CT angiography

Acute renal injury

Radiocontrast media

Contrast media

Major adverse events

Major adverse kidney events

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Population, intervention, comparison, and outcome (PICO) framework, coronary angiography

Randomised controlled trials

Double dose

Standard dose

Risk of Bias 2

A Measurement Tool to Assess systematic Reviews, version 2

Major adverse cardiovascular event

Nitric oxide

Congestive heart failure

Renal Function Test

Acute kidney injury

Author contributions

NLF contributed to the literature search, data synthesis, draft and final review.DRA contributed to the literature search, data synthesis, draft and final review.SGN contributed to the literature search, data synthesis, draft and final review. MAS contributed to the literature search, data synthesis, draft and final review.ABA contributed to the literature search, data synthesis, draft and final review.MRD contributed to the literature search, data synthesis, draft and final review.DJ contributed to the data review, result review, draft review and final review.KR contributed to the data review, results review, draft review and final review.ZK contributed to the literature search, data synthesis, draft and final review. ZK also supervised this project. All authors reviewed the final draft for submission.

Funding

The authors did not receive any funding for this project.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.