Preventing contrast-induced acute kidney injury with probucol and hydration in patients with coronary heart disease: A systematic review and meta-analysis of randomized controlled trials

Abstract

Background: 

Preventing contrast-induced acute kidney injury (CI-AKI) is critical because of its association with poor clinical outcomes, including extended hospital stays and increased mortality. The effects of probucol on preventing CI-AKI have been controversial. Therefore, this systematic review and meta-analysis evaluated the influence of probucol combined with hydration on the CI-AKI risk in patients with coronary heart disease undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI).

Methods: 

We retrieved data from the following databases from their inception to May 29, 2022: PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Chinese Biomedical Literature Database (Sinomed), Wanfang Database, and Chinese Scientific Journal Database. The methodological quality of the trials was assessed following the Cochrane Handbook guidelines, and Review Manager 5.3 and Stata 14.0 software were used for the data analysis.

Results: 

We included 14 trials comprising 3306 patients in the analysis. All included trials reported the CI-AKI incidence rate (the primary outcome). Probucol with hydration significantly reduced the CI-AKI incidence compared to hydration alone (odds ratio [OR]: 0.33, 95% confidence interval [CI]: 0.25–0.44, P < .001). Subgroup analyses were performed based on the contrast medium type (iso-osmolality vs low-osmolality contrast medium [LOCM]) and volume (less than or more than 200 mL); the effects of probucol with hydration versus hydration-only on CI-AKI were comparable within each subgroup. Additionally, the serum creatinine (Scr) concentration 24 hours, 48 hours, and 72 hours and the estimated glomerular filtration rate (eGFR) 72 hours after contrast exposure were better in the probucol with hydration group than the hydration-only group. Finally, major clinical adverse events and adverse drug reactions were comparable between the probucol with hydration and hydration-only groups.

Conclusion: 

Probucol with hydration decreases the CI-AKI incidence compared to hydration only in patients with coronary heart disease undergoing CAG or PCI. However, more high-quality, large-sample, multicenter randomized trials are needed to confirm this conclusion.

1. Introduction

Iodinated contrast mediums are essential for diagnostic imaging or invasive catheter-based procedures, such as coronary angiography (CAG) and percutaneous coronary intervention (PCI). However, their widespread use may cause acute kidney injury, given that the third leading hospital-acquired health problem is contrast-induced acute kidney injury (CI-AKI).^[1] CI-AKI has various definitions. One of the most common is from the European Society of Urogenital Radiology, defining CI-AKI as a serum creatinine (Scr) concentration increase of ≥0.5 mg/dL (44.2 mmol/L) or an increase >25% from the baseline value 48 to 72 hours after contrast medium administration.^[2]

The CI-AKI incidence rate has varied among previous studies, ranging from 2% to 30% owing to variations in the participants’ baseline characteristics, contrast medium types and volumes, and CI-AKI definitions.^[3,4] Nonetheless, CI-AKI prevention is critical because it has been associated with adverse clinical outcomes, such as a longer hospital stay, increased risk of cardiovascular events and renal failure, and increased all-cause mortality.^[5,6]

The exact pathophysiological mechanisms of CI-AKI have not been fully elucidated. However, oxidative stress, renal vasoconstriction, and tubular cell damage are hypothesized to mediate CI-AKI.^[7] Probucol is a potent antioxidant drug with significant antioxidative stress and antiinflammatory properties. Furthermore, it reduces urinary protein in patients with type 2 diabetes^[8] and suppresses the progression of diabetic nephropathy and renal dysfunction events.^[9] Moreover, a meta-analysis by Xin et al of 5 randomized controlled trials (RCTs) with 1367 participants demonstrated that probucol reduced the incidence of CI-AKI in patients undergoing CAG or PCI.^[10] However, a meta-analysis by Pranata et al with 4 RCTs and 1270 participants reported opposite results.^[11] Considering these contradictory conclusions, an updated meta-analysis with a larger sample size is needed to reevaluate the probucol renal protection effects after contrast medium administration. Therefore, this study synthesized the latest evidence and performed a systematic review and meta-analysis to evaluate the influence of probucol combined with hydration on the CI-AKI risk in patients with coronary heart disease undergoing CAG or PCI.

2. Methods

2.1. Study registration and reporting guidelines

The study protocol is registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (i.e., INPLASY) with registration number INPLASY202250157. This study followed the PRISMA Extension Statement guidelines.

This study did not require ethical approval or informed consent since all original trials were approved by their local institutional review boards and ethics committees, and all participants provided written informed consent.

2.2. Inclusion and exclusion criteria

1.2.2. Study types.

RCTs investigating probucol combined with hydration for preventing CI-AKI were included.

2.2.2. Participants.

Participants aged 18 years or older with coronary heart disease who underwent CAG or PCI in the hospital were included. There were no sex, race, or nationality restrictions.

3.2.2. Interventions.

Both groups received standard coronary heart disease treatment. The control group received only hydration therapy during the perioperative period, and the probucol group received probucol and hydration therapy.

4.2.2. Outcomes.

The primary outcome was the incidence of CI-AKI. The secondary outcomes were the Scr concentration 24 hours, 48 hours, and 72 hours after CAG or PCI, the estimated glomerular filtration rate (eGFR) 72 hours after CAG or PCI, the incidence of dialysis, major clinical adverse events, and adverse drug reaction (ADR).

5.2.2. Exclusion criteria.

Studies without explanations of the contrast medium type or volume, duplicate studies, studies without data on the required outcomes, and studies published in languages other than English or Chinese were excluded.

2.3. Search strategy

Two trained researchers (CX and XB) independently searched English-language (PubMed, Embase, Web of Science, and Cochrane Library) and Chinese-language (China National Knowledge Infrastructure, Chinese Biomedical Literature Database, Wanfang Database, and Chinese Scientific Journal Database) electronic databases from their inception through May 29, 2022 for RCTs. We also hand-scanned the references of the retrieved reports and pertinent reviews for relevant studies. All search results were downloaded and imported into EndNote X7 software (see Table S1, https://links.lww.com/MD/I668, which reported the search strategy for this systematic review and meta-analysis).

2.4. Study selection and data extraction

Two researchers (CXJ and XB) independently screened all original trials based on the inclusion and exclusion criteria. After checking for duplicates, reviews and irrelevant trials were excluded based on the titles and abstracts. Furthermore, trials that did not meet the prespecified inclusion criteria were excluded after reading the full text. Disagreements were resolved by consensus or a third opinion (WH).

Data from the original trials, including the first author name, publication year, sex and age of the participants, study samples, CI-AKI definitions, contrast medium types and volume, interventions, outcomes, and adverse reactions, amongst others, were independently extracted and entered into a predefined database by 2 other researchers (WH and LF).

2.5. Quality assessment

Two researchers (QF and YX) independently assessed the risk of bias in the included trials using the Cochrane Collaboration tool, including the following items: random sequence generation, allocation concealment, participant and personnel blinding, outcome assessment blinding, incomplete outcome data, selective reporting, and other biases. For each item, the risk of bias was rated as low, high, or unclear. Inconsistent evaluation results were resolved by rechecking the source papers and discussing the results with a third researcher (ZJ).

2.6. Quality of evidence ratings

The Grading of Recommendations Assessment, Development, and Evaluation system was used to evaluate the level of evidence, rated as high, moderate, low, or very low.

2.7. Statistical analyses

The data were analyzed using Review Manager version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and Stata 14.0 (StataCorp LP, College Station, TX) software. For binary outcomes, the combined results were calculated as odds ratios (ORs) with 95% confidence intervals (CIs). Mean differences (MD) with 95% CIs were used as the effective index for continuous outcomes. The heterogeneity of the trials was assessed using Cochran Q and I² statistics. We pooled the study-specific estimate using a fixed effect model for instances of low statistical inconsistency (I² ≤ 50%) and a random effect model for instances of moderate or high statistical inconsistency (I² > 50%). The source of heterogeneity was explored by sensitivity analysis for analyses with moderate or high inconsistency. Publication bias was evaluated using a funnel plot analysis and Egger test if enough trials (≥10) were identified.

3. Results

3.1. Literature selection and study characteristics

We initially retrieved 200 records; 106 duplicate articles were removed, as were 54 articles based on the title and abstract and 26 based on the full text. Finally, our systematic review and meta-analysis included 14 RCTs^[12–25] comprising 3306 patients. Figure 1 presents the literature screening flow chart.

Figure 1: . Flow chart for literature screening.

Of the 14 included trials, 1 was a multicenter study. All trials were performed in China and published between 2009 and 2020. Furthermore, all trials reported the baseline Scr level, contrast medium type and volume, CI-AKI definition, and probucol use details (Table 1).

Table 1 - Characteristics of the included trials.

First author (yr)	No. of center	Sample size	Age (P/C)	Sex (M/F)		Scr (T/C)	Types of CM (medicine)	Volume of CM	Definition of CI-AKI	Intervention		Outcome	Adverse effects
	(	(P/C)		P	C					P	C
Li G 2009[12]	SC	102/103	62 ± 11/63 ± 11	50/52	66/37	87.52 ± 35.36/95.47 ± 62.76	LOCM (Iohexol)	116 ± 65/121 ± 56	A relative increase in the Scr from the baseline value of 25% or an absolute increase of 0.5 mg/dL (44.2 mol/l) within 3 d after interventional rocedure	Probucol 500 mg bid for 3 d before and after the procedure (PCI or CAG) +HD	HD	①②③④	NR
Pan H 2011[13]	SC	97/81	63.58 ± 9.7/62.94 ± 9.98	51/46	46/35	86.35 ± 34.68/96.47 ± 60.97	LOCM (Iohexol)	138.47 ± 12.96/137.87 ± 13.65	Increase in Scr by 0.5 mg/dL (44.2 mmol/L) or a relative 25% increase from baseline within 48–72 h after CM administration	Probucol 375 mg before CAG or PCI and 375 mg bid 3 d after the operation + HD	HD	①②③④	NR
Wu Y 2012[14]	SC	143/137	57.9 ± 10.4/58.2 ± 10.2	92/51	89/48	80.6 ± 18.1/78.8 ± 17.4	LOCM (NR)	146 ± 86/152 ± 97	Increase in Scr by 0.5 mg/dL (44.2 mmol/L) or a relative 25% increase from baseline within 48 h after CM administration	Probucol 250 mg bid at 3 d before the selective PCI + HD	HD	①⑥	NR
Yin L 2013[15]	SC	96/108	65.1 ± 10.5/65.4 ± 12.5	67/29	74/34	70.72 ± 20.33/77.80 ± 33.59	LOCM (Iopromide)	168.89 ± 79.77/157.9 ± 69.9	Increase in the Scr concentration at least 25% or an absolute increase of ≥0.5 mg/dL (≥44.2 µmol/l) within 72 h period after coronary intervention	Probucol 1000 mg before primary or urgent angioplasty, and 500 mg bid for 3 d after intervention +HD	HD	①	NR
Zhao K 2013[16]	SC	82/81	75.58 ± 3.74/76.94 ± 4.28	42/40	43/38	86.76 ± 16.74/86.24 ± 17.34	LOCM (Iopamidol)	236.85 ± 39.74/238.87 ± 38.69	Increase in Scr by 0.5 mg/dL (44.2 mmol/L) or a relative 25% increase from baseline within 72 h after CM administration	Probucol 250 mg tid at 3 d before and 3 d after the selective PCI + HD	HD	①②③④	NR
Li J 2014[17]	SC	52/51	62.58 ± 3.71/63.94 ± 4.26	27/25	28/23	85.78 ± 16.84/85.26 ± 16.54	LOCM (Iopamidol)	246.85 ± 49.74/ 248.87 ± 48.69	Increase in Scr by 0.5 mg/dL (44.2 mmol/L) or a relative 25% increase from baseline within 72 h after CM administration	Probucol 250 mg bid at 3 d before and 3 d after selective PCI + HD	HD	①②③④	NR
Li X 2015[18]	SC	125/125	69.09 ± 7.61/69.21 ± 6.91	90/35	87/38	87.85 ± 15.33/87.65 ± 11.74	IOCM (Iodixanol)	128.42 ± 8.66/ 126.59 ± 7.52	Increase in Scr by 0.5 mg/dL (44.2 mmol/L) or a relative 25% increase from baseline within 72 h after CM administration	Probucol 500 mg bid at 1 d before and 3 d after selective PCI + HD	HD	①④⑤⑥	NR
Zhang P 2015[19]	SC	125/125	63.0 ± 10.61/63.2 ± 10.91	90/35	87/38	87.85 ± 15.33/87.65 ± 11.74	IOCM (Iodixanol)	146 ± 86/152 ± 97	Increase in Scr by 0.5 mg/dL (44.2 mmol/L) or a relative 25% increase from baseline within 72 h after CM exposure	Probucol 500 mg bid at 3 d before and 3 d after the selective PCI + HD	HD	①④⑤⑥	NR
Ma Z 2016[20]	SC	120/120	62.7 ± 11.51/62.9 ± 11.96	85/35	82/38	88.87 ± 14.37/87.54 ± 13.74	IOCM (Iodixanol)	127.14 ± 10.78/129.22 ± 10.52	Increase in Scr by 0.5 mg/dL (44.2 mmol/L) or a relative 25% increase from baseline within 72 h after CM administration	Probucol 500 mg before PCI and 500 mg bid 3 d after the operation + HD	HD	①④⑥	NR
Fu N 2017[21]	MC	321/320	60 ± 12/62 ± 12	184/137	191/129	75 ± 17/74 ± 14	LOCM (ioversol)	147.45 ± 10.68/149.50 ± 10.56	Increase in Scr by ≥ 44.2 µmol/L or ≥ 25% within 72 h after CM administration	Probucol 500 mg bid at 1 d before and 3 d after the operation + HD	HD	①③④⑤⑥	Y
Zhang P 2017[22]	SC	110/110	66.7 ± 5.4/65.3 ± 7.1	72/38	68/42	79.85 ± 16.37/80.91 ± 16.73	IOCM (Iodixanol)	176.74 ± 45.47/182.09 ± 54.57	Increase in Scr by 0.5 mg/dL (44.2 mmol/L) or a relative 25% increase from baseline within 48–72 h after CM administration	Probucol 250 mg tid, 1 d before and 3 d after the selective PCI + HD	HD	①④	Y
Zhao Z 2018[23]	SC	46/46	62.9 ± 12.8/63.5 ± 11.3	31/15	33/13	78.61 ± 16.08/79.83 ± 15.96	IOCM (Iodixanol)	170.2 ± 20.9/169.7 ± 19.8	Increase in Scr by 0.5 mg/dL (44.2 mmol/L) or a relative 25% increase from baseline within 72 h after CM administration	Probucol 500 mg bid at 3 d before and 3 d after the operation + HD	HD	①④⑥	Y
Wang Y 2019[24]	SC	110/110	63.4 ± 10.69/60.7 ± 11.01	68/42	64/46	82.09 ± 18.68/84.27 ± 19.68	IOCM (Iodixanol)	175.63 ± 56.83/173.81 ± 58.48	Increase in Scr by 0.5 mg/dL (44.2 mmol/L) or a relative 25% increase from baseline within 48–72 h after CM administration	Probucol 500 mg bid at 1 d before and 3 d after the selective PCI + HD	HD	①③④⑥	Y
Zhao Z 2020[25]	SC	130/130	62.3 ± 10.8/63.7 ± 9.4	90/40	94/36	78.95 ± 14.98/79.63 ± 15.46	IOCM (Iodixanol)	170.2 ± 20.9/165.7 ± 19.8	Increase in Scr by 0.5 mg/dL (44.2 mmol/L) or a relative 25% increase from baseline within 48–72 h after CM administration	Probucol 500 mg bid at 1 d before and 3 d after the selective PCI + HD	HD	①④	NR

C = control group, CAG = coronary angiography, CM = contrast medium, HD = hydration, IOCM = iso-osmolality contrast medium, LOCM = low-osmolality contrast medium, M/F = male/female, MC = multicenter, NR = not reported, P = probucol group, PCI = percutaneous coronary intervention, SC = single center, Y = yes.

①incidence of CI-AKI ②level of serum creatinine at 24 h after contrast medium administration ③level of serum creatinine at 48 h after contrast medium administration ④level of serum creatinine at 72 h after contrast medium administration ⑤eGFR at 72 h after contrast medium exposure ⑥incidence of dialysis.

3.2. Quality assessment

Seven trials randomly assigned participants based on a random number table or a computer-generated random sequence. However, 1 trial improperly assigned their participants using the admission dates. The remaining 6 trials only reported randomly dividing their participants into 2 groups without explaining the specific randomization methods. Ten trials did not report their allocation and concealment details. Furthermore, 3 trials were double-blinded, 2 trials were single-blinded, and 9 trials did not report their blinding information, but these investigators were less affected by the blinding method owing to the objective test results, except for major clinical adverse events and ADRs. Finally, none of the included trials reported selective or incomplete outcome data (Fig. 2).

Figure 2.: (A) Risk of bias graph. (B) Risk of bias summary.

3.3. Primary outcome

The CI-AKI incidence was reported in all included trials.^[12–25] Additionally, all trials evaluated the participants within 72 hours after contrast medium exposure, except 1,^[14] which evaluated the participants within 48 hours. Probucol with hydration significantly reduced the CI-AKI incidence compared to hydration alone (OR: 0.33, 95% CI: 0.25–0.44, P < .001; I² = 17%, P = .27, fixed-effect model; Fig. 3 and Table 2). Sensitivity analyses omitting 1 trial at a time did not significantly alter the direction of the overall estimates. Furthermore, subgroup analyses were performed successively based on the contrast medium volume (less than or more than 200 mL) and type (iso-osmolality contrast medium or low-osmolality contrast medium [LOCM]); the effects of probucol with hydration were comparable to those of only hydration in the subgroup analyses (Table 2 and Figs. 4 and 5).

Table 2 - Summary outcomes of the meta-analysis.

	No. of trials [No. of Ref.}	No. of participants	Heterogeneity		Statistical method	Effect estimates
			P value	I 2		Effect size (95% CI)	P value
Incidence of CI-AKI in total	14[12–25]	3306	.26	17%	Fixed	0.33 (0.25, 0.44)	<.001
Incidence of CI-AKI in subgroups:
volume of CM <200 mL	12[12–15,18–25]	3040	.19	26%	Fixed	0.35 (0.26, 0.46)	<.001
volume of CM ≥ 200 mL	2[16,17]	266	.99	0%	Fixed	0.22 (0.08, 0.60)	.003
IOCM	7[18–20,22–25]	1532	.07	49%	Fixed	0.52 (0.34, 0.81)	.003
LOCM	7[12–17,21]	1774	.71	0%	Fixed	0.37 (0.27, 0.51)	<.001
SCr at 24 h	4[12,13,16,17]	649	.81	0%	Fixed	−6.09 (−9.67, −2.51)	.001
SCr at 48 h	6[12,13,16,17,21,24]	1510	<.001	91%	Random	−13.78 (−22.08, −5.49)	.001
SCr at 72 h	12[12,13,16–25]	2822	<.001	82%	Random	−8.76 (−12.25, −5.26)	<.001
eGFR at 72 h	5[18,19,21,22,25]	1621	0.39	2%	Fixed	5.94 (3.70, 8.17)	<.001

CM = contrast medium, eGFR = estimated glomerular filtration rate, IOCM = iso-osmolality contrast medium, LOCM = low-osmolality contrast medium, Scr = serum creatinine.

Figure 3: . Forest plot of incidence of CI-AKI. CI-AKI = contrast-induced acute kidney injury.

Figure 4: . Forest plot of incidence of CI-AKI in subgroup according to volume of contrast medium exposure. CI-AKI = contrast-induced acute kidney injury.

Figure 5: . Forest plot of incidence of CI-AKI in subgroup according to types of contrast medium exposure. CI-AKI = contrast-induced acute kidney injury.

3.4. Other outcomes

1.3.4. Scr.

Four trials reported the Scr concentration 24 hours after administering the contrast medium. The Scr level 24 hours after administration was significantly lower in the probucol with hydration group than in the hydration-only group (MD: –6.09, 95% CI: –9.67 to –2.51, P = .001; I² = 0%, P = .81, fixed effect model, 4 trials^{[12,13,16,17]}; Table 2 and Fig. 6A). The same results were observed for the Scr level after 48 hours (MD: –13.78, 95% CI: –22.08 to –5.49, P = .001; I² = 91%, P < .001; random effect model, 6 trials^{[12,13,16,17,21,24]}; Table 2 and Fig. 6B) and 72 hours (MD: –8.76, 95% CI: –12.25 to –5.26, P < .001; I² = 82%, P < .001, random effect model, 12 trials^{[12,13,16–25]}; Table 2 and Fig. 6C). The heterogeneities of Scr after 48 hours and 72 hours were significant; thus, we performed sensitivity analyses by omitting 1 trial at a time. A specific study was not identified as the source of heterogeneity for either timepoint, indicating robust pooled outcomes.

Figure 6.: (A) Forest plot of Scr 24 h after contrast medium exposure. (B) Forest plot of Scr 48 h after contrast medium exposure. (C) Forest plot of Scr 72 h after contrast medium exposure. Scr = serum creatinine.

2.3.4. eGFR.

Five trials^{[18,19,21,22,25]} reported the eGFR 72 hours after contrast medium exposure. The eGFR was higher in the probucol with hydration group than the hydration-only group (MD: 5.94, 95% CI: 3.70–8.17, P < .001; I² = 2%, P = .39, fixed effect model; Table 2 and Fig. 7).

Figure 7: . Forest plot of eGFR 72 h after contrast medium exposure. GFR = estimated glomerular filtration rate.

3.3.4. Incidence of dialysis.

Seven trials^{[14,18–21,23,24]} reported the dialysis incidence during the hospital stay. Only 1 participant required temporary dialysis in the hydration-only group. No participants required permanent dialysis.

4.3.4. Major clinical adverse events and ADR.

Three trials^[21,23,24] reported major clinical adverse events, including cardiovascular events, stroke, cerebral hemorrhage, gastrointestinal bleeding, and temporary dialysis during the follow-up period, ranging from 7 to 180 days (Table 3). We did not pool the dates for assessing the heterogeneity of the follow-up period.

Table 3 - Major clinical adverse events.

	Wang Y 2019[24]	Fu N 2017[21]	Zhao Z 2018[23]
Probucol group	1.8% (2/110)	2.2% (7/321)	6.5% (3/46)
Control group	2.7% (3/110)	2.8% (8/320)	21.7% (10/46)
Follow-up period (d)	7	14	180
P value	.651	.624	<.05

Three trials reported ADR,^[22–24] including mild gastrointestinal discomfort (3 trials^[22–24]) and rash (1 trial^[23]), which disappeared spontaneously without additional therapy. The total ADR rate (OR: 4.7, 95% CI: 1.0–22.3, P = .05; I² = 0%, P = .92, fixed-effect model; Fig. 8A) and the mild gastrointestinal discomfort rate (OR: 3.59, 95% CI: 0.74–17.48, P = .11; I² = 0%, P = .81, fixed-effect model; Fig. 8B) did not differ between the probucol with hydration and hydration only groups.

Figure 8.: (A) Forest plot of total ADR. (B) Forest plot of gastrointestinal discomfort. ADR = adverse drug reaction.

3.5. Publication bias

The funnel charts showed unremarkable asymmetry on both sides of the CI-AKI incidence for the Scr concentration 72 hours after contrast mediums administration (Fig. 9A and B). An Egger test indicated no publication bias (t = –1.31, P = .214; t = –1.36, P = .205). The publication bias for the Scr concentration after 24 and 48 hours and eGFR after 72 hours were not evaluated because there were fewer than ten original trials.

Figure 9.: (A) Funnel plot of incidence of CI-AKI. (B) Funnel plot of Scr 72 h after contrast medium exposure. CI-AKI = contrast-induced acute kidney injury, Scr = serum creatinine.

3.6. Quality of evidence

The quality level of the evidence that probucol with hydration reduces the incidence of CI-AKI was moderate. The selection bias risk downgraded the level of evidence (see Table S2, https://links.lww.com/MD/I669, which reported the quality of evidence).

4. Discussion

The main finding of this meta-analysis is that probucol with hydration reduced the incidence of CI-AKI in patients with coronary heart disease undergoing CAG or PCI compared to only hydration, and the quality level of the evidence was moderate.

Our primary finding is consistent with that of Xin W et al,^[10] but the total sample size of our study is considerably larger. Compared to that meta-analysis, this study included 11 additional trials (2256 participants) performed in China. However, 2 trials^[26,27] included in the study by Xin W et al were excluded from our study; 1 study lacked detailed information on the volume of contrast medium volume, and the other had only 1 patient with CI-AKI. The contrast medium volume is an independent predictor correlated to CI-AKI.^[28] Consequently, volume differences between the probucol with hydration and hydration-only groups might affect the CI-AKI incidence. Therefore, we excluded the 1 trial without this information. The other excluded trial evaluated CI-AKI 24 hours after contrast medium exposure, resulting in only 1 (0.65%) participant with CI-AKI. Therefore, that trial analysis may underestimate the CI-AKI incidence and the renal protection value of probucol. Pranata et al also excluded these 2 trials in their meta-analysis, but their conclusions were inconsistent with ours, likely owing to their smaller sample size.^[11] However, although Pranata et al reported an insignificant P value, the CI suggested a nonsignificant beneficial trend, but this result may have been due to publication bias. Thus, additional studies with a larger sample are needed for a definite conclusion.^[11] Our study pooled the dates of 14 trials then created a funnel chart and performed an Egger test to evaluate publication bias, which supported the result that probucol with hydration reduced the CI-AKI incidence. In addition, the sensitivity analysis demonstrated that the pooled outcome was robust. Finally, we evaluated the quality of evidence based on the Grading of Recommendations Assessment, Development, and Evaluation system; the result was moderate, which was superior to that in the study by Pranata et al.^[11]

We performed subgroup analyses because various contrast medium types and volumes are used in clinical practice. The results were preliminarily similar in all subgroups, but these results should be interpreted with caution due to potential differences in the specific LOCM type. For example, a meta-analysis reported no association between iodixanol (an iso-osmolality contrast medium) and fewer incidences of CI-AKI compared with LOCM overall. However, the relative renal safety of LOCM compared with iodixanol might vary based on the specific LOCM type. For example, the CI-AKI decreased when iodixanol was compared to ioxaglate and iohexol, but no difference was observed when iodixanol was compared with iopamidol, iopromide, or ioversol.^[29] Another meta-analysis reported that iodixanol significantly reduced the CI-AKI incidence compared with iohexol alone but not when compared with LOCMs other than iohexol or with other ionic dimers.^[30] We could not perform subgroup analyses based on the specific LOCM type owing to the limited sample size. Hence, while our subgroup analyses demonstrated the value of probucol for renal protection after iodixanol administration, other studies are still required to elucidate the protective value of probucol after exposure to other LOCM types. Finally, only 2 trials (266 participants) administered more than 200 mL of contrast medium, and no trials administered more than 300 mL; thus, evidence for or against probucol after high-volume contrast medium exposure is insufficient.

Other study outcomes supported the renal protection effect of probucol, including the Scr level and eGFR changes after contrast medium exposure. However, it remains unclear whether probucol reduces the incidence of dialysis in patients with CI-AKI because only 1 dialysis event occurred in this study. Therefore, trials in populations with a dialysis risk, such as those with diabetic nephropathy, are needed.

The pathophysiological mechanisms of CI-AKI are complex, and probucol, which has potent antioxidative properties, might protect the kidneys from CI-AKI.^[31–33] Superoxide dismutase is an oxidative stress indicator, and several human^[21,23] and animal^[34–36] studies have reported higher superoxide dismutase concentrations after contrast medium administration in their probucol groups than in their control groups. Probucol may reduce the typical pathological changes associated with CI-AKI, such as tubular epithelial vacuolar degeneration, brush border disintegration, shedding, and mitochondria swelling, by reducing local renal oxidative stress. Some have also suggested that the renal protective effects of probucol against CI-AKI may be mediated by altering renal GPx activity, an endogenous antioxidant enzyme.^[37]

Meanwhile, studies have suggested a link between apoptosis^[38–40] and the pathogenesis of CI-AKI and that probucol may have an antiapoptotic effect, preventing CI-AKI. Apoptosis is induced through endogenous, exogenous, and endoplasmic reticulum pathways. The endogenous pathway starts with the mitochondria and is one of the most important apoptosis pathways. Furthermore, B-cell lymphoma 2 (Bcl-2) family members have an essential role in the mitochondrial apoptosis pathway, and Bcl-2 and Bcl-2-associated X protein (Bax) are important apoptotic genes in this family. The former inhibits apoptosis, prolongs cell life, and is mainly distributed in the mitochondrial membrane, the inner surface of the cell membrane, and the endoplasmic reticulum; the latter mainly promotes apoptosis. The intracellular Bcl-2 to Bax ratio (Bcl-2/Bax) regulates apoptosis. As the ratio increases, cells tend to survive; in contrast, as the ratio decreases, cells tend to undergo apoptosis. Studies have evaluated these 2 proteins in diabetic rats injected with ionized hypertonic contrast medium, reporting downregulated Bcl-2 protein expression (the antiapoptotic protein) and upregulated Bax protein expression (the pro-apoptotic protein). However, probucol altered this balance, leading to mitochondrial caspase-3 inhibition, reducing renal cell apoptosis.^[35,36,41] Furthermore, probucol downregulated the expression of the apoptotic genes FAS and FASL in rats with CI-AKI and reduced renal cell apoptosis and renal injury.^[42] Moreover, probucol had other beneficial effects, such as on endothelial function,^[33,43] which might also contribute to its protective effect regarding CI-AKI. However, further studies are needed to determine the exact mechanisms underlying these effects.

A previous propensity analysis reported an association between probucol therapy and a significantly reduced long-term all-cause mortality risk in patients with coronary heart disease who had undergone complete revascularization (PCI or bypass surgery).^[44] In contrast, a prospective study reported no differences in the incidence of key composites of primary endpoints related to cerebrovascular and cardiovascular events between the probucol and control groups of patients with coronary heart disease.^[45] In our study, only 3 trials^[21,23,24] reported major clinical adverse events, but the follow-up period was too short to evaluate long-term survival. Additionally, there was considerable heterogeneity regarding the follow-up period; thus, we reviewed the results individually rather than pooling the dates of major clinical adverse events. As a result, none of the trials^[21,23,24] had an increased incidence of major clinical adverse events in the short term. Zhao Z et al also reported a significantly lower incidence of major clinical adverse events in their probucol group than in their control group (6.5% vs 21.7%, P < .05) within 180 days.^[23] However, studies with a larger sample size are needed to verify this result. Finally, the ADR incidence did not differ between the 2 groups in this study, demonstrating the safety of probucol with hydration in patients with coronary heart disease.

4.1. Limitations

This systematic review and meta-analysis has several limitations. First, all the included trials were performed in China. Therefore, trials must be performed in other countries to make a generalized conclusion. Second, the evidence quality was moderate due to the risk of bias. Third, as previously discussed, most trials administered <200 mL of contrast medium, resulting in insufficient evidence on the effects of high-volume contrast administration. In addition, we could not perform a subgroup analysis based on the specific LOCM type because of limited trials. Thus, more double-blinded, large-sample, multicenter randomized trials are needed.

4.2. Conclusions

Probucol with hydration reduced the incidence of CI-AKI in patients with coronary heart disease undergoing CAG or PCI; the quality level of the evidence was moderate. Nevertheless, more high-quality, large-sample, multicenter randomized trials are needed to confirm this finding.

Acknowledgments

Thanks are due to Dr Yushu Wang for assistance with statistical analysis and valuable discussion.

Author contributions

Conceptualization: Xiaojiao Cui, Bo Xie

Data curation: Xiaojiao Cui, Bo Xie, Hao Wang, Fuqiang Liu, Fang Qin, Jun Zhang

Formal analysis: Xiaojiao Cui, Bo Xie, Hao Wang, Fuqiang Liu

Investigation: Xiaojiao Cui, Bo Xie

Methodology: Xiaojiao Cui, Bo Xie, Fang Qin, Jun Zhang, Xiaoqing Yi

Project administration: Xiaojiao Cui, Bo Xie

Resources: Xiaojiao Cui, Bo Xie

Software: Xiaojiao Cui, Bo Xie, Linghan Mei

Supervision: Xiaojiao Cui, Bo Xie

Writing – original draft: Xiaojiao Cui, Bo Xie

Writing – review & editing: Xiaojiao Cui, Bo Xie, Hao Wang, Fuqiang Liu, Linghan Mei, Fang Qin, Jun Zhang, Xiaoqing Yi