Trimetazidine as an adjunct to standard hydration reduces the incidence of contrast-induced acute kidney injury in patients with renal insufficiency undergoing coronary angiography or percutaneous cardiac intervention: a systematic review and meta-analysis.

Abstract

Background

Contrast-induced acute kidney injury (CI-AKI) is a known complication after coronary angiography (CAG) or percutaneous coronary intervention (PCI). Clinical evidence suggests that trimetazidine (TMZ), an anti-ischemic drug, may prevent CI-AKI. We aimed to evaluate the role of trimetazidine in preventing CI-AKI in patients with pre-existing renal dysfunction undergoing CAG or PCI.

Methods

We searched PubMed, Cochrane Library, EBSCOhost, Web of Science, and Google Scholar databases from January 2004 to January 2024. We reviewed RCTs involving participants aged ≥ 18 years with pre-existing renal insufficiency who underwent CAG or PCI. Outcomes should include the incidence of CI-AKI, adverse events, and changes in serum creatinine (Scr) levels at different time intervals. Two reviewers independently extracted the data, evaluated the quality and relevance of the studies, and graded the strength of evidence for each study through consensus.

Results

Nine RCTs met the inclusion criteria and assessed the role of TMZ in patients with renal dysfunction who underwent CAG or PCI. All RCTs showed a significant decrease in the incidence of CI-AKI in the TMZ group compared to the control group (RR 0.36, 95% CI, [0.25, 0.52] P < 0.001). Changes in Scr at 24 h (SMD -0.33, 95% CI, [-0.56, -0.10], P = 0.01), at 48 h (SMD -0.27, 95% CI, [-0.46, -0.09], P = 0.01), and 72 h (SMD -0.32, 95% CI, [-0.56, -0.07], P = 0.01) were statistically significant in the TMZ group compared to the control group. However, the changes in Scr beyond 72 h following CAG or PCI were statistically insignificant in the TMZ group when compared to the control group (SMD -0.22, 95% CI, [-0.52, 0.09], P = 0.16). The incidence of adverse effects was lower in the TMZ group than in the control group, and the difference was statistically significant (RR 0.51, 95% CI, [0.29, 0.90]; P = 0.02).

Conclusion

The addition of TMZ to standard hydration protocols may offer a promising strategy for lowering the incidence of CI-AKI, adverse events, and postoperative SCr levels in patients with renal insufficiency within 72 h after CAG or PCI. However, large-scale RCTs are necessary to definitively establish the efficacy and safety of TMZ in patients with renal insufficiency after CAG or PCI.

Introduction

Contrast-induced acute kidney injury (CI-AKI) is the third most common cause of hospital-acquired acute kidney injury [1]. It is defined as a relative (≥ 25%) or absolute (≥ 0.5 mg/dl; 44 μmol/L) increase in serum creatinine from baseline value 48–72 h following intravascular administration of contrast media (CM) when alternative explanations or etiology for renal impairment have been excluded [2, 3].

Among all procedures using contrast agents for diagnostic or therapeutic purposes, CAG and PCI are associated with the highest rates of CI-AKI [1]; this is mainly related to intra-arterial injection and high doses of contrast media used. Furthermore, in most cases, the patients are typically of advanced age and have one or more comorbid conditions, including advanced vascular disease, longstanding hypertension, diabetes, renal insufficiency, congestive heart failure, and concurrent use of nephrotoxic medications. However, pre-existing renal insufficiency is considered the most significant risk factor for CI-AKI [4, 5].

Although CI-AKI after CAG or PCI is usually self-limiting, it is associated with prolonged hospitalization, more adverse cardiovascular events, increased costs, and increased morbidity and mortality [5].

Currently, the pathophysiology of CI-AKI is complex, poorly understood and multifactorial. Available evidence shows that possible mechanisms may involve (1) renal vasocontraction or slowing renal medullary blood flow, resulting in medullary hypoxemia (mediated by alterations in nitric oxide (NO), endothelin, or adenosine), and (2) the direct cytotoxic effects of CM [6].

Renal vasoconstriction is mediated by the contrast-induced release of endothelin, adenosine, and reduced NO levels. This imbalance between vasoconstrictors (endothelin and adenosine) and vasodilators (nitric oxide) leads to renal medullary ischemia, hypoxia, and eventual endothelial dysfunction [7]. Additionally, the high viscosity and high permeability of contrast media result in slowing renal medullary blood flow, leading to renal medullary ischemia [8].

Patients with pre-existing renal insufficiency are particularly susceptible to CI-AKI. Impaired renal function leads to ineffective elimination of the contrast agent, leading to its accumulation in the renal tubules and subsequently causing damage to the renal tissue [9, 10].

Moreover, patients with renal insufficiency often have an imbalance between reactive oxygen species (ROS) production and antioxidant defense mechanisms, which can be exacerbated by CM. This can result in increased oxidative stress in the kidneys, leading to cellular damage and inflammation and subsequently contributing to CI-AKI development [11].

Furthermore, patients with renal insufficiency often have decreased renal blood flow, which can be worsened by vasoconstriction induced by the contrast media. This can lead to increased hypoxic and ischemic insults to the kidneys and increase the risk of CI-AKI [10, 12].

Currently, the treatment for CI-AKI is primarily supportive, and the key focus of management is prevention, particularly in high-risk patients. Several preventive options are available, including reducing the contrast dose, using iso-osmolar contrast, avoiding volume depletion, cessation of nephrotoxic medications, and administration of intravenous (IV) isotonic saline or sodium bicarbonate. To date, only hydration with isotonic saline is generally accepted in the clinical setting for the prevention of CI-AKI [13]. Despite the adherence to these hydration strategies, the occurrence of CI-AKI remains a significant concern. Therefore, there is a need to explore adjunctive therapies to mitigate the risk of CI-AKI in this high-risk population.

Previous studies have explored several adjunctive pharmacological prophylactic regimens for preventing CI-AKI. N-acetylcysteine (NAC), an antioxidant agent, and intravenous sodium bicarbonate have been extensively studied as potential pharmacological agents for CI-AKI prevention by reducing oxidative stress and mitigating the decline in renal function. Early studies showed promising results [14,15,16]; however, a larger randomized controlled trial, the PRESERVE trial, demonstrated insignificant benefits of NAC and intravenous sodium bicarbonate over standard hydration [17]. Furthermore, Khaledifar et al. observed insignificant benefits of ascorbic acid and NAC in the prevention of CI-AKI in patients with renal insufficiency [18].

Zhou et al. [19] revealed that pre-treatment with statins reduced the incidence of CI-AKI in CKD patients with DM. However, statin pre-treatment was ineffective for CKD patients without DM. Additionally, in a prospective, randomized, double-blind, controlled study (PROMISS trial) evaluating the use of statins for CI-AKI prevention, short-term simvastatin pre-treatment at a high dose did not prevent renal function deterioration after CM administration in patients with renal insufficiency undergoing [20].

Trimetazidine (TMZ) is a cellular anti-ischemic agent that inhibits the production of oxygen-free radicals, reduces apoptosis, prevents mitochondrial swelling, enhances mitochondrial activity, and prevents cell lysis, thereby protecting cell functions. TMZ also improves the concentration of intracellular superoxide dismutase (SOD), which is essential for removing oxygen free radicals. Moreover, TMZ can reduce intracellular H + , Ca2 + , and Na + overload, while simultaneously increasing the utilization rate of lactic acid, decreasing cell ketogenesis, and improving lipid metabolism. TMZ reduces oxidative stress and cytolysis and improves renal function in renal ischemia or reperfusion injury [21,22,23].

The effectiveness of TMZ as a preventive agent against CI-AKI has been a subject of debate due to contradictory findings and limited evidence. A meta-analysis conducted by Sharp et al. [24] on pharmacological interventions for CI-AKI prevention in high-risk adult patients undergoing coronary angiography revealed a decrease in the incidence of CI-AKI. However, it only included two studies with respect to TMZ. Additionally, Nadkarni et al. [25] performed a meta-analysis to assess the role of TMZ in reducing the risk of CI-AKI in patients with chronic kidney disease (CKD). Despite the observed decrease in the incidence of CI-AKI, only three studies were included.

Furthermore, a study conducted by Savaj et al. [26]. including 100 CKD patients with mean estimated glomerular filtration rate (eGFR) of 50.6 ± 7, receiving TMZ, 35 mg twice daily from 4 h before to 2 h after CAG showed a decrease in the incidence of CI-AKI, but the findings were statistically insignificant.

Despite contradictory results and scarcity of data, there is growing evidence that the addition of TMZ to standard hydration is beneficial in preventing CI-AKI after CAG or PCI in patients with renal insufficiency. This meta-analysis intends to synthesize the available data, focusing on the role of TMZ in preventing CI-AKI after CAG or PCI in patients with renal insufficiency.

Methods

Our meta-analysis was conducted in accordance with the guidelines outlined in the Cochrane Handbook for Systematic Reviews of Interventions [27], and we reported our findings following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines [28]. Furthermore, the current study was registered with PROSPERO (International Prospective Register of Systematic Reviews) under the registration number CRD42024506179.

Data sources and literature searches

We searched RCTs that assessed TMZ as an adjunct to standard hydration in patients with renal insufficiency through electronic databases (Cochrane Library, PubMed, Cochrane Library, EBSCOhost, Web of Science, and Google Scholar) from January 2004 to January 2024 without restricting language, country, or race. Our search strategy included the following keywords: randomized controlled trials, contrast-induced acute kidney injury, contrast-associated acute kidney injury, contrast-induced nephropathy, kidney dysfunction, chronic kidney disease, trimetazidine, renal insufficiency, coronary angiography, and percutaneous cardiac intervention. We used Boolean operators (AND, OR), together with the following keywords: "trimetazidine" AND "contrast-induced nephropathy" OR "contrast-induced acute kidney injury" OR "contrast-associated acute kidney injury" AND "renal insufficiency" OR "kidney dysfunction" OR "chronic kidney disease" AND "coronary angiography" OR "percutaneous coronary interventions."

We searched all fields in PubMed, EBSCOhost, Web of Science, and Google Scholar but were restricted to the areas of abstracts and titles in the Cochrane Library. The literature search strategy is presented in Table S1.

We defined PICOS as follows: P (population), patients with renal insufficiency undergoing PCI/CAG; I(intervention), Trimetazidine; C(comparison), standard hydration; O (outcome), incidence of CI-AKI; and S (study design), randomized controlled trial.

Study selection

Studies were selected based on the following inclusion criteria: (1) RCTs comparing trimetazidine as an adjunct to the standard hydration method versus the standard hydration method as a control group regardless of the TMZ dosage, types and volume of contrast used; (2) Patients with mild to moderate renal dysfunction (eGFR of 30–90 mL/min/1.73 m² or CrCl of 30–90 mL/min) aged more than 18 years undergoing CAG or PCI.

The exclusion criteria were case reports, review articles, non-randomized controlled trials, patients without renal insufficiency or those not undergoing CAG or PCI, and patients aged < 18 years. All analyses were performed using previously published studies; therefore, no patient consent or ethical approval was required.

Data extraction

First, randomized controlled trials were identified by screening titles or abstracts based on predefined inclusion and exclusion criteria. Subsequently, eligible studies were selected by reviewing abstracts or full-text articles. Two reviewers (A.L and Y.L) independently performed this process.

The following information was extracted from each study: lead author, publication year, participant characteristics, TMZ dosage, hydration method, cardiac procedures performed, types of contrast agent and volume, mean baseline Scr, mean age, comorbidities, significant adverse effects, CI-AKI definitions, CKD definitions, and key findings.

If the trials had more than two groups or factorial study designs, and permitted several comparisons, we extracted only the data and information of interest reported in the original trials.

The main objective of this review was to evaluate the incidence of CI-AKI as the primary outcome. Additionally, we evaluated secondary outcomes, such as changes in Scr levels at different time intervals and assessed the frequency of adverse events in the TMZ group compared to the control group.

Risk of bias and quality of evidence assessment

Two reviewers (A. F. L. and J. C.) assessed the risk of bias at both the study and outcome levels using the Cochrane risk of bias tool (RoB-2) of randomized trials and judged each study as low, high, or some concern risk of bias. The domains used to evaluate the risk of bias in each study included the randomization process, missing outcome data, selection of the reported result, measurement of the outcome, and deviations from the intended interventions [29].

For a trial with a low overall risk of bias, all the domains should have a low risk of bias. For a trial with overall some concerns risk of bias, at least one domain should be of some concern risk of bias but no component of the high risk of bias, whereas, for the overall high risk of bias, trials should have at least one domain of high risk of bias or to have some concerns risk of bias in multiple domains. Disagreements were resolved through discussion and consensus or adjudication by a third reviewer.

To assess the quality of evidence for the studies included in the meta-analyses and their relevance to predetermined outcomes, we employed the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. The GRADE approach incorporates five key domains: (1) risk of bias, (2) inconsistency, (3) indirectness, (4) imprecision of evidence, and (5) reporting bias. Two reviewers (A. F. L. and Y. L.) assessed each domain for each selected outcome and resolved the differences by consensus discussion.

We provided justifications for any decisions made to downgrade or upgrade the quality of the studies by using footnotes. Additionally, we have included comments throughout the review to enhance readers’ comprehension and interpretation of the findings.

We ranked the overall quality of evidence as 'high,' 'moderate,' 'low,' or 'very low' based on the likelihood of further research changing our confidence in the estimate of effect [30]. We used GRADEpro (https://gradepro.org) to develop a summary of findings tables for outcomes, such as the incidence of CI-AKI, adverse events, and changes in Scr at different time points.

Statistical analyses

All statistical analyses were performed using STATA 18.0 (Stata Corp, College Station, TX, USA). For binary outcomes, the combined results were reported as relative risks (RRs), while for continuous outcomes, the pooled results were presented as standardized mean differences (SMD).

All pooled results are presented with 95% confidence intervals (CIs) and two-sided P values. A random-effects model was employed to accommodate both within-study and between-study variance components. The within-study variance captures variability in effect estimates attributable to sampling error, while the between-study variance accounts for variability arising from differences in study design, patient demographics, and intervention protocols, and other contextual factors [31]. Results were considered statistically significant at P -value < 0.05.

To ensure uniformity in measurement scale, serum creatinine values were standardized by converting from SI units (μmol/L) to conventional units (mg/dL), applying a conversion factor of 88.4 where applicable [32].

Heterogeneity was assessed using the I² statistic, which measures the percentage of variation in point estimates among the studies. We interpreted the I² statistic as follows: 0–40% heterogeneity may not be significant, 30–60% may indicate moderate heterogeneity, 50–90% may indicate substantial heterogeneity, and 75–100% may indicate considerable heterogeneity [27]. When the I² statistic exceeded 50%, subgroup analysis was conducted to explore the sources of potential heterogeneity.

Sensitivity analysis was performed by eliminating studies one by one and recalculating the pooled effect (leave-one-out approach).

Publication bias was assessed through visual analysis of funnel plots, with roughly symmetrical funnel plots indicating no evidence of publication bias, and asymmetrical funnel plots indicating evidence of publication bias. Additionally, publication bias was analyzed using Egger’s test, with a value of P < 0.05 being indicative of publication bias. To further assess publication bias, we utilized the nonparametric trim-and-fill methods developed by Duval and Tweedie [33].

Results

Literature search

A total of 643 RCTs were retrieved from PubMed, Cochrane Library, EBSCOhost, Web of Science, and Google Scholar databases. The titles and abstracts of the retrieved RCTs were screened according to the inclusion criteria, and the full texts of 28 studies were reviewed. Ultimately, nine RCTs met the inclusion criteria (Fig. 1). These studies specifically assessed the role of TMZ in reducing the incidence of CI-AKI in patients with renal dysfunction who underwent CAG or PCI.

Fig. 1

Flow diagram of literature search and screening process

Study characteristics

Table 1 provides a comprehensive overview of the characteristics of the nine included RCTs [34,35,36,37,38,39,40,41,42]. All the included RCTs focused on interventions involving TMZ in patients with renal insufficiency undergoing CAG or PCI. These trials specifically included participants who were ≥ 18 years old and had mild to moderate renal dysfunction defined as eGFR ranging from 30–90 mL/min/1.73 m², CrCl ranging from 30–90 mL/min, or Scr level ranging from 1.2- 2.5 mg/dL.

Table 1 Characteristics of included studies

The outcomes evaluated in relation to TMZ included the incidence of CI-AKI, adverse events, and changes in Scr levels at different time intervals. The overall analysis included 1480 patients, with 736 in the TMZ group and 744 in the control group. All the included studies involved patients who underwent PCI, CAG, or both.

All studies included patients with renal insufficiency who were hypertensive, diabetic, or both. However, one study focused exclusively on hypertensive patients and excluded those with diabetes [42].

Of the nine included RCTs, only five provided the estimated mean values of the left ventricular ejection fraction (LVEF), which ranged from 48 to 56% for both the TMZ and control groups.

In five of the included RCTs, TMZ was administered at a dosage of 20 mg three times per day, whereas in the remaining RCTs, the TMZ dosage was 35 mg twice daily.

In all included RCTs, every patient received an intravenous infusion of 0.9% normal saline (NS) at a rate ranging from 0.5–1.5 ml/kg/hour. However, the patients with impaired LVEF received a lower infusion rate of 0.5 ml/kg/hour.

Four studies used Iopramide, three studies used Iodixanol, and two studies used both Iopramide and Iodixanol as the type of contrast media. The mean CM volume ranged from 95.34 to 270 mL in the TMZ group and 97.45 to 280Ml in the control group.

Assessment of risk of bias

Table 2 shows the risk of bias assessment of the included studies, as assessed using the Cochrane Collaboration risk of bias tool (RoB-2).

Table 2 Risk of bias assessment by Cochrane Collaboration Risk of Bias tool (RoB-2)

All nine studies included in our analysis were prospective RCTs. Among these, five studies provided a detailed description of the randomization process, whereas the remaining four studies did not describe a detailed randomization procedure.

In all the included RCTs, the domains assessing the deviations from intended interventions, measurement of the outcome, and selection of the reported result had a low risk of bias.

The domain assessing missing outcome data in all included studies was also rated as having a low risk of bias, with either no or minimal number of participants with missing outcome data. Additionally, studies with minimal missing data conducted sensitivity analyses, which confirmed that including or excluding these data points did not significantly affect the effect estimates or alter the overall conclusions of the analyses.

Among the included studies, five were classified as having a low overall risk of bias, while the remaining four studies were deemed to have an overall rating of some concerns risk of bias.

Incidence of CI-AKI

All the studies concluded that the TMZ group had a lower incidence of CI-AKI than the control group. In the TMZ group, 41 (6%) of the 736 patients developed CI-AKI compared to 117(16%) of the 744 patients in the control group. Upon pooling the RR, the TMZ group was associated with a statistically significant reduction in the incidence of CI-AKI (RR 0.36, 95% CI, [0.25, 0.52] P < 0.001). The heterogeneity between the pooled studies was insignificant (I² = 9.95%, P = 0.97). (Fig. 2). The number needed to treat (NNT) to prevent one occurrence of CI-AKI was ten patients.

Fig. 2

Forest plot comparing the incidence of CI-AKI between the TMZ group and control group

Changes in serum creatinine levels at different time points

Three studies assessed the changes in Scr levels 24 h after CAG or PCI, involving 162 and 170 patients in the TMZ and control groups, respectively.

The findings revealed that patients in the TMZ group had lower Scr levels than those in the control group at 24 h after CAG or PCI. The difference in Scr levels between the TMZ and control groups was statistically significant (SMD -0.33, 95% CI, [-0.56, -0.10], P = 0.01). Additionally, no heterogeneity was observed among the included studies (I² = 10.52%, P = 0.74; (Fig. 3).

Fig. 3

Forest plot comparing changes in serum creatinine between the TMZ group and the control group 24 h after CAG or PCI

Four studies reported Scr levels 48 h after CAG or PCI, including 332 patients in the TMZ group and 342 patients in the control group. The results showed that the Scr level in the TMZ group was significantly lower than that in the control group 48 h after CAG or PCI. The difference was statistically significant (SMD -0.27, 95% CI, [-0.46, -0.09], P = 0.01), and there was insignificant heterogeneity between studies (I² = 30.71%, P = 0.61). (Fig. 4).

Fig. 4

Forest plot comparing changes in serum creatinine between the TMZ group and control group 48 h after CAG or PCI

Five studies reported Scr 72 h after CAG or PCI, including 392 patients in the TMZ group and 400 patients in the control group. The results revealed that compared with the control group, the Scr levels were lower in the TMZ group 72 h after CAG or PCI, and the results were statistically significant (SMD -0.32, 95% CI, [-0.56, -0.07], P = 0.01). (Fig. 5), and heterogeneity was observed among the included studies (I² = 62.48%, P = 0.01).

Fig. 5

Forrest plot comparing changes in serum creatinine levels between the TMZ and control groups 72 h after CAG or PCI

Given the significant heterogeneity in Scr levels at 72 h following CAG/PCI, we conducted subgroup analysis stratified by TMZ dosage to elucidate its impact on the observed outcomes. Subgroup analyses stratified by TMZ dosage demonstrated a reduction in heterogeneity within both subgroups compared to the overall analysis. Specifically, the subgroup receiving a 20 mg TMZ dose exhibited a moderate level of heterogeneity (I² = 39.61%, P = 0.08), while the subgroup receiving a 35 mg TMZ dose displayed a somewhat higher degree of heterogeneity (I² = 47.46%, P = 0.05), albeit still lower than the overall analysis. (Figure S12). Subgroup analyses suggest that variations in TMZ dosage may contribute to the observed heterogeneity in the overall effect size.

Two studies reported Scr levels of more than 72 h after CAG or PCI, including 90 patients in the TMZ group and 92 patients in the control group. The results showed that the changes in Scr levels in the TMZ group compared to the control group were statistically insignificant (SMD -0.22, 95% CI, [-0.52, 0.09], P = 0.16), and there was insignificant heterogeneity between studies (I² = 8.26%, P = 0.64). (Fig. 6).

Fig. 6

Forrest plot comparing changes in serum creatinine levels between the TMZ group and control group more than 72 h after CAG or PCI

Incidence of adverse events

In this study, an adverse event was defined as any undesirable clinical outcome or complication occurring during or after the administration of TMZ, documented either during hospitalization or at follow-up assessment in outpatient settings. It is important to note that the occurrence of these events was not necessarily linked to the pharmacological action of TMZ.

In our meta-analyses, five studies assessed the incidence of adverse events in the TMZ group versus the control group. Fourteen (4%) out of 396 patients in the TMZ group and 28 (7%) out of 402 in the control group experienced adverse events (RR 0.51, 95% CI, [0.29, 0.90]; P = 0.02). The heterogeneity between the studies was insignificant (I² = 8.9%, P = 0.82). (Fig. 7). These findings indicated that the incidence of adverse effects was statistically significantly lower in the TMZ group than in the control group.

Fig. 7

Forrest plot comparing the incidence of adverse effects between the TMZ group and the control group

In both the TMZ and control groups, the most common adverse events were cardiovascular-related adverse events (such as cardiac death, nonfatal myocardial infarction, ischemic stroke, congestive heart failure, and pulmonary edema), followed by kidney-related adverse events (including end-stage kidney disease and renal failure requiring dialysis in two patients in the control group), and one instance of upper gastrointestinal bleeding. None of the included studies reported any adverse events explicitly associated with TMZ administration. The duration of follow-up across all included studies exploring adverse events ranged from 48 h to 12 months. (Table. S4).

Sensitivity analysis

Sensitivity analyses were conducted to evaluate the robustness of our results by sequentially excluding one study at a time from the pooled results. The analysis demonstrated that the pooled RR for the incidence of CI-AKI did not exhibit significant variations, indicating the stability of our findings (Figure S1).

Additionally, leave-one-out sensitivity analysis of changes in Scr at different time intervals showed no significant variation from the original results, indicating the stability of our findings (Figure S2-S4).

Furthermore, leave-one-out sensitivity analyses demonstrated that the overall estimates of adverse event occurrence were significantly affected by the exclusion of the study conducted by Liu et al. Specifically, omitting this study resulted in the overall effect size becoming statistically non-significant (RR 0.57, 95% CI [0.28–1.15], P = 0.113) (Figure S5).

The potential impact of Liu et al. on the overall pooled results could be explained by the higher number of reported adverse events in this study, which might be influenced by a more extended follow-up period compared with the other studies included in the analysis. Consequently, conclusions drawn from the overall analysis should be approached with caution.

Publication bias

Publication bias was evaluated by visual analysis of funnel plots and Egger's test. In this study, the examination of funnel plots and Egger's test for the incidence of CI-AKI, adverse events, and change in Scr at 24 h and 48 h indicated no significant evidence of publication bias (Figure S6-S9). However, asymmetrical funnel plots were observed for the change in Scr at 72 h and beyond 72 h postoperative, indicating evidence of publication bias (Figure S10-S11); nevertheless, the results of Egger's test and the trim and fill method, revealed no evidence of publication bias (Table S2).

Assessment of quality of evidence

Table S3 summarizes the quality of the evidence, as assessed using GRADEpro. We found the quality of evidence for outcomes to be high or moderate, and we downgraded the evidence primarily due to imprecision and inconsistency.

The overall quality of evidence relating to the decrease in the incidence of CI-AKI, adverse events, and changes in Scr at 24 h and 48 h after CAG or PCI was high, as neither domain posed a serious threat to warrant a downgrade. However, the quality of evidence regarding changes in Scr 72 h after CAG or PCI was downgraded one level to 'moderate' for inconsistency due to the presence of heterogeneity among the included studies and the quality of evidence for changes in Scr more than 72 h after CAG or PCI was downgraded one level to 'moderate' for imprecision due to a wide confidence interval of the relevant SMD (-0.52 to 0.09).

Discussion

Based on the currently available data, our meta-analysis revealed a notable reduction in the incidence of CI-AKI when TMZ was administered alongside 0.9% normal saline compared to the use of 0.9% normal saline alone in patients with renal dysfunction undergoing CAG or PCI. This finding implies that TMZ may have a beneficial effect in preventing or reducing the incidence of CI-AKI in patients with renal dysfunction, thereby improving patient outcomes and reducing the burden of renal complications.

CI-AKI is an iatrogenic renal injury that arises within 48–72 h after exposure to contrast media. Despite several prevention strategies, CI-AKI remains responsible for approximately 10% of all hospital-acquired acute kidney injuries. Additionally, patients developing CI-AKI are at a high risk of further decline in renal function and increase in adverse clinical outcomes following CAG or PCI [43].

Gruberg et al. [44] conducted a study to assess the prognostic significance of worsening renal function within 48 h following interventional coronary procedures in patients with pre-existing chronic renal insufficiency. Deterioration of renal function following coronary intervention is identified as a significant marker of poor outcomes in patients with pre-existing renal insufficiency. This association is particularly notable in the patients who required dialysis. However, it is noteworthy that in the present meta-analysis, only Chen et al. [36] observed two patients who required dialysis.

Consistent with our findings, previous studies have shown that TMZ, in addition to standard hydration, decreases the occurrence of CI-AKI in patients with renal insufficiency undergoing CAG or PCI. Elserafy et al. [45] conducted a study and observed that oral administration of TMZ at a dose of 35 mg twice daily, along with early normal saline hydration, proved to be a practical approach to prevent or reduce the incidence of CI-AKI during CAG in patients with mild to moderate pre-existing renal insufficiency.

Although the mechanisms underlying the pathogenesis of CI-AKI remain uncertain, it has been suggested that renal vasoconstriction and renal hemodynamic disturbances, increased endothelin, impaired nitric oxide production, endothelial dysfunction, direct cellular toxicity due to relatively high tissue osmolality, reperfusion injury due to free radical formation, and oxidative stress play a significant role in the development of CI-AKI [46].

In the context of pre-existing renal insufficiency, the pathophysiology of CKD includes a gradual decline in kidney function, often accompanied by impaired cellular energy metabolism, activation of renal fibroblasts, inflammation, oxidative stress, and renal hypoperfusion [47]. The administration of CM can exacerbate the underlying pathophysiology of CKD or worsen renal insufficiency, thereby increasing the risk of developing CI-AKI. A comprehensive understanding of the underlying pathophysiology of CKD and its relationship with CM is crucial for developing effective interventions and treatments to prevent CI-AKI and to preserve renal function.

Identification of renal protective agents that can prevent CI-AKI has been proven to be complicated. Currently, preventive measures for CI-AKI, including adequate hydration, discontinuation of nephrotoxic agents, use of lower volumes of contrast media, and opting for low osmolar, nonionic contrast agents, and possibly statins, among other therapeutic agents, have been implemented with varying degrees of success [48]. Despite the implementation of the aforementioned protective measures in clinical practice for patients with renal insufficiency, the occurrence of CI-AKI remains elevated, with an incidence ranging from approximately 20% to 30%. This can be attributed to the intricate mechanisms involved in the development of CI-AKI [49].

Previous experimental studies have provided evidence that the renoprotective effects of TMZ can be attributed to multiple factors, including its anti-ischemic and antioxidant properties, ability to regulate cellular energy metabolism, and capacity to mitigate renal fibrosis. Yang et al. [50] revealed that TMZ can prevent tubulointerstitial fibrosis by inhibiting the epithelial-to-mesenchymal transition (EMT) through transforming growth factor-beta (TGF-β) and deacetylation forkhead box O1 (FoxO1) pathways. TMZ may help preserve kidney structure and function by reducing renal fibrosis. Furthermore, an experimental study conducted by Mahfoudh-Boussaid et al. [51] found that TMZ treatment resulted in upregulation of glycogen synthase kinase 3-beta (GSK3-β) phosphorylation and downregulation of voltage-dependent anion channel (VDAC) phosphorylation in renal cells. This leads to improved renal mitochondrial function, resulting in enhanced energy production and ultimately improved renal function.

Furthermore, Akgüllü et al. [21] conducted an experimental study on the histopathological evidence of TMZ for the prevention of CI-AKI and observed that TMZ increased antioxidant defense mechanisms and reduced renal tubule dilatation, necrosis, interstitial infiltration, and vascular congestion. These findings suggest that TMZ may play a significant role in preventing CI-AKI by mitigating renal damage and preserving renal tissue integrity.

Additionally, Mahfoudh-Boussaid et al. [52]. performed an experimental study and observed TMZ improved renal functions by reducing oxidative stress and apoptosis in renal cells through activation of Akt/endothelial nitric oxide synthase (eNOS)/heme oxygenase-1 (HO-1) pathways and stabilization of hypoxia-inducible factor-1α (HIF-1α).

Considering the interrelationship between the pathogenesis of CIN, the pathophysiology of CKD, and pharmacological characteristics of TMZ, such as its antioxidant properties, ability to regulate cellular energy metabolism, mitigate renal fibrosis, exhibit anti-inflammatory properties, along with protective effects against ischemia–reperfusion injury in the kidneys, we anticipate that TMZ could serve as a valuable prophylactic option for preventing CI-AKI and preserving kidney function.

Our meta-analysis included RCTs that evaluated the use of TMZ as an adjunct to standard hydration methods. The main finding of our study was a significant reduction in the incidence of CI-AKI when TMZ was administered alongside normal saline, compared to normal saline alone, in patients with renal dysfunction undergoing coronary procedures. While these mechanisms suggest the potential benefits of TMZ in reducing the incidence of CI-AKI, it is essential to acknowledge that clinical evidence is still evolving, and further research is needed to establish its long-term effects and safety, specifically in CKD patients.

In our meta-analysis, we observed that TMZ administration resulted in reduced Scr levels within 72 h following CAG or PCI. This decline in Scr levels suggests that TMZ plays a significant role in the prevention of CI-AKI in patients with renal insufficiency. However, the changes in Scr levels in the TMZ group beyond 72 h after CAG or PCI were not statistically significant compared to the control group. Additionally, the moderate quality of evidence concerning Scr changes beyond 72 h, particularly due to imprecision reflected in wide confidence intervals, underscores the necessity for careful interpretation of these findings.

The results from our meta-analysis are consistent with the results of a separate meta-analysis conducted by Ye et al. [53], which included 377 patients in the TMZ group and 387 patients in the control group. This meta-analysis also revealed a significant decrease in Scr levels postoperatively; however, it should be noted that the decrease in Scr levels at 72-h postoperative was statistically insignificant.

Overall, our findings indicate that TMZ has the potential to reduce Scr levels in the early postoperative period after CAG or PCI, suggesting a beneficial effect in preventing CI-AKI in clinical settings.

Unlike other conventional anti-ischemic agents, TMZ has a different side-effect profile. Generally, treatment-related side effects are mild and well tolerated, mainly comprising gastrointestinal disturbances (such as nausea and vomiting) muscular cramps, dizziness, depression, sedation, drowsiness, palpitations, visual disturbances, anorexia, and hyperoxia [54]. Much more concerning is an association with Parkinson's syndrome and other motor disorders such as muscle rigidity, tremor, and restless legs syndrome [55]. However, none of these side effects were reported in the studies included in our meta-analysis.

In our meta-analysis, we observed statistically significant lower incidences of adverse events in the TMZ group than in the control group. The most common adverse events were cardiovascular- related adverse events. In the TMZ group, none of the patients required dialysis, whereas in the control group, Chen et al. reported two patients who required dialysis. These adverse events might have been precipitated by overhydration or hemodynamic instability in the involved patients.

Our study holds clinical significance and notable strengths in the following aspects. First, this meta-analysis included more studies, thus providing a more comprehensive assessment of the effectiveness of TMZ in reducing the incidence of CI-AKI.

Second, our findings demonstrate that the addition of TMZ to standard hydration significantly decreased the occurrence of CI-AKI in patients with renal insufficiency. This study highlights the potential significance of TMZ as a practical intervention in the clinical setting to mitigate the risk of CI-AKI in patients with pre-existing renal insufficiency.

Third, TMZ significantly reduced Scr levels within 72 h postoperatively. The ability of TMZ to lower Scr levels suggests a potential protective effect on renal function and highlights its clinical relevance in the prevention of CI-AKI in patients with renal insufficiency.

Finally, a lower incidence of adverse events was observed in the TMZ group than in the control group. The lower incidence of adverse events further supports the potential benefits and safety profile of TMZ in preventing CI-AKI following CM administration.

Our study has the following limitations. First, there was significant variability in the dosage of trimetazidine (TMZ) administered and the timing of post-procedural serum creatinine (Scr) measurements across the included studies. This lack of standardization may introduce variability in treatment responses and outcomes, complicating the comparability of results. The differing protocols for TMZ administration and Scr assessment could lead to inconsistencies in data interpretation.

Second, all RCTs included in our meta-analysis were single-center studies, and most had relatively small sample sizes. This limited setting and participant pool may restrict the external validity of our findings. Results obtained from single-center trials might not be fully representative of the broader patient population, thereby limiting the generalizability of our conclusions across diverse clinical settings.

Third, the current definition of contrast-induced acute kidney injury (CI-AKI) is predominantly based on changes in Scr levels. Relying solely on Scr as a diagnostic criterion may overlook more subtle yet clinically significant changes in renal function that can occur after the administration of CM. Therefore, incorporating additional, more sensitive, and specific biomarkers of renal function—such as cystatin C or novel urinary markers—could provide a more comprehensive understanding of the nephrotoxic effects of CM and enhance the early detection of CI-AKI.

In future studies, we recommend that researchers prioritize the following aspects: (1) Optimal TMZ dosage and postprocedural starting time for the evaluation of Scr levels should be established. This is crucial for standardizing the administration of TMZ and ensuring a consistent and accurate assessment of renal function. (2) Large and multicentric RCTs need to be conducted to confirm the clinical value of TMZ in preventing CI-AKI in patients with varying severities of renal dysfunction. This would provide more robust evidence, increase the generalizability of the findings (including a diverse range of patients with varying degrees of renal dysfunction), and strengthen the reliability of conclusions regarding the effectiveness of TMZ. (3) Exploring more diagnostic indices: Currently, the diagnosis of CI-AKI relies predominantly on changes in Scr levels. Future studies should consider incorporating more reliable biomarkers to enable earlier and more accurate detection of CI-AKI. Biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL), cystatin-C, interleukin-18, liver-type fatty acid-binding protein (L-FABP), and kidney injury marker 1 (KIM-1) could offer valuable insights and improve the effectiveness of TMZ evaluation [56].

Conclusions

Our meta-analysis suggests that trimetazidine (TMZ) may be a promising prophylactic option for preventing CI-AKI in patients with renal insufficiency undergoing CAG or PCI. Additionally, our findings point out that TMZ may be effective in reducing serum creatinine (Scr) levels within 72 h after CAG or PCI. However, the changes in Scr levels beyond 72 h were insignificant, and the quality of evidence supporting these findings was moderate. Therefore, caution should be exercised when interpreting these results.

Nevertheless, large-scale, well-designed clinical trials are essential to evaluate the effectiveness of TMZ in preventing contrast-induced acute kidney injury (CI-AKI). These trials should include participants with varying underlying risk factors for developing CI-AKI and comprehensively assess relevant clinical outcomes. Additionally, the trials should focus on determining the optimal regimen for TMZ, including appropriate dosing and duration of treatment. Conducting these studies will yield clearer insights into the effectiveness of TMZ, enhance its clinical application, and evaluate its overall impact on patient outcomes in CI-AKI prevention.