intervention – Systematic review and meta-analysis of randomized controlled trials including GRADE qualification

Journal Pre-proof Nicorandil Reduces the Incidence of Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography/ Intervention – Systematic Review and Meta-Analysis of Randomized Controlled Trials Including GRADE Qualification

Raymond Pranata, Rachel Vania, Amir Aziz Alkatiri, Doni Firman, Antonia Anna Lukito PII:

S1553-8389(20)30019-1

DOI:

https://doi.org/10.1016/j.carrev.2020.01.010

Reference:

CARREV 1811

To appear in:

Cardiovascular Revascularization Medicine

Received date:

6 November 2019

Revised date:

28 December 2019

Accepted date:

9 January 2020

Please cite this article as: R. Pranata, R. Vania, A.A. Alkatiri, et al., Nicorandil Reduces the Incidence of Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography/Intervention – Systematic Review and Meta-Analysis of Randomized Controlled Trials Including GRADE Qualification, Cardiovascular Revascularization Medicine(2020), https://doi.org/10.1016/j.carrev.2020.01.010

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© 2020 Published by Elsevier.

Journal Pre-proof Title: Nicorandil Reduces the Incidence of Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography/Intervention – Systematic Review and Meta-Analysis of Randomized Controlled Trials Including GRADE Qualification Running Title: Nicorandil Reduces CIN

Raymond Pranata MD, Faculty

of

Medicine,

Universitas

Pelita

Harapan,

Tangerang,

Indonesia;

email:

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[email protected], +6282112918892, ORCID: https://orcid.org/0000-0003-

Rachel Vania MD, of

Medicine,

Universitas

Pelita

Harapan,

Tangerang,

Indonesia;

email:

e-

Faculty

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3998-6551

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[email protected] , ORCID: https://orcid.org/0000-0002-4780-6592 Amir Aziz Alkatiri MD, FSCAI

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Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Indonesia, National Cardiovascular Center Harapan Kita, Jakarta, Indonesia; email:

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[email protected] , ORCID: https://orcid.org/0000-0001-8588-2871

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Doni Firman MD, PhD, FSCAI

Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Indonesia, National Cardiovascular Center Harapan Kita, Jakarta, Indonesia; email: [email protected], SCOPUS ID: 6701649707 Antonia Anna Lukito, MD, PhD, FSCAI Department of Cardiology and Vascular Medicine, Siloam Hospitals Lippo Village, Tangerang, Indonesia Faculty

of

Medicine,

Universitas

Pelita

Harapan,

Tangerang,

Indonesia;

[email protected]; email: [email protected] , ORCID: https://orcid.org/00000001-8519-8949

Journal Pre-proof Corresponding Author: Raymond Pranata MD Faculty

of

Medicine,

Universitas

Pelita

Harapan,

Tangerang,

Indonesia;

E-mail: [email protected] 2206 words (excluding title page and references)

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Authors Contribution

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Raymond Pranata conceived and designed the study and drafted the manuscript. Raymond Pranata and Rachel Vania acquired the data and drafted the manuscript. Raymond Pranata

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and Antonia Anna Lukito performed data extraction. Raymond Pranata, Antonia Anna Lukito,

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Amir Aziz Alkatiri, and Doni Firman interpreted the data. Amir Aziz Alkatiri and Doni Firman performed extensive research and critically revise the manuscript. All authors contributed to

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the writing of the manuscript. Raymond Pranata performed the statistical analysis.

Journal Pre-proof Abstract Background Contrast-induced nephropathy (CIN) is associated with increased mortality and morbidity in patients undergoing coronary angiography (CAG) and percutaneous coronary intervention (PCI). We aimed to assess the latest evidence on the effect of nicorandil on the incidence of CIN in patients undergoing CAG/PCI. Methods

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We performed a comprehensive search on topics that assessed nicorandil and CIN in CAG/PCI patients from inception up until November 2019 through several electronic

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databases.

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Results

There were a total of 1532 subjects from 7 randomized controlled trials. Nicorandil was

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associated with decrease CIN incidence (OR 0.31 [0.20, 0.46], p<0.001; I 2: 0%). Funnel plot was asymmetrical, indicating the risk of publication bias. Oral administration (OR 0.29 [0.18,

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0.46], p<0.001; I2: 0%) has a greater efficacy compared to intravenous route (OR 0.40 [0.17, 0.93], p<0.001; I2: 73%). Pooled analysis of adjusted OR revealed that nicorandil reduced CIN

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incidence independent to other factors in the respective studies (OR 0.34 [0.16, 0.74],

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p=0.006, I2: 75%). Protection against CIN (OR 0.37 [0.22, 0.61], p<0.001; I 2: 22%) was also demonstrated in renal dysfunction subgroup, pooled adjusted OR showed that the effect is independent (OR 0.30 [0.10, 0.90], p=0.03, I2: 86%). GRADE assessment showed moderate level of certainty for the CIN reducing effect of nicorandil in both unadjusted and adjusted models with an absolute reduction of 85 per 1,000 and 87 per 1,000. Harbord test showed no evidence of small-study effects (p=0.866). Conclusion Nicorandil is associated with a lower risk of CIN in patients undergoing CAG/PCI with a moderate level of certainty. Keywords: nicorandil; contrast-induced nephropathy; coronary angiography; percutaneous coronary intervention; coronary artery disease

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Journal Pre-proof Introduction Contrast-induced nephropathy (CIN) or contrast-induced acute kidney injury (CI-AKI) is characterized by worsening of renal function after contrast administration which occurs in 3 to 14% of the patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI), the incidence is even higher in patients with renal dysfunction.[1–3] The definition of CIN varies, but one of the widely used is European Society of Urogenital Radiology which defined CIN as an increase of the serum creatinine level ≥ 0.5 mg/dL (44.2 mmol/L) or > 25% of the baseline value 48–72 h after contrast media (CM) administration.[4]

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This condition is associated with increased morbidity and mortality following CAG/PCI.[5] Adequate hydration still remained as the cornerstone of CIN prevention, there have been

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attempts to use additional agents, but the results are mostly disappointing.[6] Nicorandil is a combination of nicotinamide vitamins and nitrates that acts by opening ATP-sensitive

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potassium channel and cytoplasmic guanosine cyclase in the kidneys resulting in improved

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blood flow.[7,8] Furthermore, nicorandil has been shown to reduce all-cause mortality and cardiac events in patients treated with PCI, which provides additional benefit to nicorandil use.[9] Nicorandil is yet to be approved by the United States Food and Drug Administration

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(FDA) and the results of randomized controlled trials (RCTs) on the use of nicorandil to

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prevent CIN are conflicting.[10,11] In this systematic review and meta-analysis, we aimed to assess whether the administration of nicorandil is associated with decreased risk of CIN and

Methods Search Strategy

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evaluate its certainty of the evidence.

We performed a comprehensive search on topics that assesses nicorandil and CIN in CAG/PCI patients with keywords [“nicorandil” and “contrast-induced nephropathy”] and its synonym from inception up until November 2019 through PubMed, EuropePMC, ScienceDirect, ProQuest, Clinicaltrials.gov, and hand-sampling from potential articles cited by other studies. The records were then systematically evaluated using inclusion and exclusion criteria. We also perform hand-sampling from references of the included studies. Two researchers (R.P and R.V) independently performed an initial search, discrepancies

Journal Pre-proof were resolved by discussion. A Preferred Reporting Items for Systematic Reviews and MetaAnalyses flowchart of the literature search strategy of studies was presented in Figure 1. Selection criteria The inclusion criteria for this study are all studies that assess nicorandil and CIN in patients undergoing CAG and/or PCI. We include all related clinical researches/original articles and exclude case reports, review articles, and non-English language articles. Data Extraction Data extraction and quality assessment were done by two independent authors (R.P and

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A.A.L) using standardized extraction form which includes authors, year of publication, study

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design, fundings, subject characteristics, CAG/PCI procedure, sample size, nicorandil protocol details, proportion of males, age, CIN definition, CIN incidence, and major adverse

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events.

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Statistical analysis

To perform the meta-analysis, we used RevMan version 5.3 software (Cochrane

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Collaboration) and STATA/MP 14.0 (StataCorp LP). We used the odds ratio (OR) and a 95% CI as a pooled measure for dichotomous data. Inconsistency index (I 2) test, which ranges from

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0 to 100%, was used to assess heterogeneity across studies. A value above 50% or p<0.05 indicates statistically significant heterogeneity. We used the Mantel-Haenzsel method for

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OR with a fixed-effect model for meta-analysis, and a random-effect model was used in case

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of heterogeneity. Adjusted odds ratio from the studies were pooled using Inverse Variance. Small study effect was assessed using a regression-based test (Harbord test) for binary outcomes. All P values were two-tailed with a statistical significance set at 0.05 or below. The certainty of the evidence was assessed by using Guideline Development Tool by GRADEpro GDT.

Results We found a total of 377 results. There were 296 records after removal of duplicates. 285 records were excluded after screening the title/abstracts. After assessing 11 full-text for eligibility; we excluded 4 because these abstracts have duplicate data (found on other studies). We included seven studies in qualitative synthesis and meta-analysis. (Figure 1) All 7 studies were RCTs.[8,10–15] There were a total of 1532 subjects from 7 studies. (Table 1)

Journal Pre-proof Characteristics of Included Studies All of the studies were done on patients undergoing elective CAG/PCI. Five studies were designed to evaluate the effect of nicorandil in patients with renal dysfunction defined moderate-high risk as patients with estimated glomerular filtration rate (eGFR) ≤60 ml/min/1.73 m2 in four studies and Cystatin C level ≥0.95 mg/L in males and ≥0.87 mg/dL in females in one study. All but one study was an open-labelled RCTs. Nicorandil was administered via oral route in five studies and intravenous route in two studies. All studies used serum creatinine elevation ≥0.5 mg/dL or ≥25% within 72 hours after CM exposure for

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the definition of CIN. The safety outcome was major adverse events, and four studies

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included this endpoint in addition to CIN.

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Effect of Nicorandil on the incidence of Contrast-induced Nephropathy

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Nicorandil was associated with decrease CIN incidence (OR 0.31 [0.20, 0.46], p<0.001; I2: 0%, p=0.45) [Figure 2A]. Funnel plot was asymmetrical, indicating the risk of publication bias

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[Figure 2B]. Pooled analysis of adjusted OR revealed that nicorandil reduced CIN incidence independent to other factors in the respective studies (OR 0.34 [0.16, 0.74], p=0.006, I2: 75%,

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p=0.003) [Figure 2C].

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Subgroup Analysis based on the mode of administration demonstrated that the oral nicorandil (OR 0.29 [0.18, 0.46], p<0.001; I2: 0%, p=0.82) has a greater efficacy compared to

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intravenous route (OR 0.40 [0.17, 0.93], p=0.03, I2: 73%, p<0.001) in reducing the CIN incidence [Figure 2D]. Pooled analysis of adjusted OR showed that nicorandil independently reduced CIN incidence with oral administration (0.30 [0.10, 0.90], p<0.001; I2: 86%, p<0.001). Subgroup analysis on patients with renal dysfunction, defined as eGFR ≤60 mL/min/1.73 m2 revealed that nicorandil reduce the risk of CIN (OR 0.37 [0.22, 0.61], p<0.001; I2: 22%, p=0.28) [Figure 2E]. Pooled analysis of adjusted OR demonstrated that nicorandil reduced CIN incidence independently (OR 0.30 [0.10, 0.90], p=0.03, I2: 86%, p<0.001). Effect of Nicorandil on the incidence of Major Adverse Events Nicorandil was not associated with major adverse events [Figure 3], subgroup analysis on oral administration only also show a non-significant association with major adverse events. Zhang 2019 study observes the major adverse events at 1-year follow up and the other 3

Journal Pre-proof studies assessed in-hospital rate. Upon subgroup analysis on in-hospital major adverse events, the result was not significant. However, Zhang 2019 demonstrated that nicorandil remained a significant predictor of decreased major adverse events after adjustment (adjusted hazard ratio 0.881 [0.781, 0.993], p=0.037). Risk of Bias Assessment The risk of bias assessment showed that the risk was high in blinding of participants due to the open-label nature of the studies. The risk of bias assessment for the studies is presented in Figure 4A. There were no statistically significant small-study effects for the effect of

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nicorandil and CIN incidence upon analysis using Harbord’s test (p=0.866) [Figure 4B].

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GRADE Qualification

Grading of Recommendations, Assessment, Development and Evaluations (GRADE)

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qualification showed a moderate level of certainty for the CIN reducing effect of nicorandil in both unadjusted (85 fewer per 1,000) and adjusted models (87 fewer per 1,000) [Table 2].

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Oral route for nicorandil administration has a moderate level of certainty; in contrast, a very low level of certainty was found in intravenous subgroup analysis. There were only two

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Discussion

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no significant result.

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studies for intravenous route, one study has a wide confidence interval, and the other has

Nicorandil was shown to be effective in reducing the incidence of CIN in patients undergoing CAG/PCI with a moderate level of certainty. The major adverse events were similar in both groups, indicating no major safety concern. Pathophysiology of CIN is yet to be elucidated, it is thought to be a combination of contrast mediated vasoconstriction of renal vasculature with subsequent ischemia, along with inflammatory response and free radicals induced damage.[16,17] Nicorandil acts by opening K-ATP channel in the kidney and acting as a nitric oxide donor to cause vasodilation, improving microvascular circulation.[18] Furthermore, it promotes endogenous ischemic preconditioning mechanism that causes tissues to become more resistant to ischemia.[19] It has also been shown to reduce free radicals induced damage during hypoxia.[7] The protective effect on cardiovascular outcome has been demonstrated recently in clinical

Journal Pre-proof settings.[20,21] Similar protective mechanisms might be involved in renal vasculature that leads to alleviation of CM induced damage, by providing ischemic preconditioning, vasodilation, and suppression of free radical-induced damage. Such actions reduce renal damage and ischemia possibly leading to reduced incidence of CIN. The intravenous route seemed to be less effective than the oral route on meta-analysis, however, a closer observation showed that there is insufficient evidence to draw such conclusion. Intravenous administration of nicorandil yielded a different result with high heterogeneity. Ko et al. study showed that intravenous nicorandil was ineffective, contrast

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to Nawa et al. report. One of the fundamental differences was the nicorandil administration

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protocol, Nawa et al. gave infusion 4 hours before procedure and continue for 24 hours which is different to Ko et al. who administer nicorandil just before the procedure.

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Nicorandil has a short half-life of approximately 1 hour and might be washed out from

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serum early, leaving no protection for CM which has a longer half-life, this difference might explain Nawa et al. protocol success in reducing CIN.[22] The CM may persist for 24

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hours[23], and in order for nicorandil to provide maximum protection, it has to be given for at least 24 hours. Nawa et al. suggested that continuous infusion should be administered for

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24 hours after CM exposure. In patients with renal dysfunction, CM clearance may be up

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to >40 hours[23], which may necessitate nicorandil administration beyond 24 hours. Recent studies were more focused on oral nicorandil three times daily administered as early as 2

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days before procedure and continued up to 3 days after procedure. There was a lack of evidence on whether intravenous or oral route is better since only Nawa et al. can provide a proper comparison to the oral route protocol (continuing post-procedure). Overall, oral nicorandil provide similar benefits to intravenous route with less hassle of intravenous administration. Clinical Implications Nicorandil can be administered before coronary procedures to reduce the risk of CIN, which is valuable in patients with renal dysfunction, who may have more than 20% risk of CIN. The oral route is preferred due to more available studies and higher certainty of evidence. Timing of nicorandil administration is yet to be defined, however, it should be started before the procedure and continued for at least 48 hours according to the trials on oral nicorandil. Patients with renal dysfunction are expected to receive nicorandil for a longer

Journal Pre-proof time due to delayed CM clearance. Nicorandil should be used as adjunct to other measures such as adequate hydration. Limitations Limitation of this systematic review includes the publication bias as evidenced by asymmetrical funnel plot, the right side of the funnel plot was relatively empty compared to the left side indicating a lack of studies weaker than the effect size. The most common reason for this phenomena is because the studies with the non-significant outcome is less likely to be published and may overestimate the pooled effect of this systematic review.

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Most of the studies are open-labelled, a double-blinding RCT may reduce the risk of bias and should be conducted in the future to increase the certainty of evidence. Most of the trials

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are conducted in Asia, hence, may not represent the global population. Trials abroad Asia needs to be conducted before implementing nicorandil for routine clinical practice

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worldwide.

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Conclusion

Nicorandil is associated with a lower risk of CIN in patients undergoing CAG/PCI with a

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moderate level of certainty. Further double-blinded trials for oral nicorandil is needed to

None

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Acknowledgements

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increase the certainty of evidence before integrating it to routine clinical practice.

Conflict of Interest

The authors declare that they have no conflict of interests. Funding None

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Post-contrast acute kidney injury – Part 1: Definition, clinical features, incidence, role of contrast medium and risk factors. Eur Radiol 2018;28:2845–55.

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[7]

Shimizu S, Saito M, Kinoshita Y, Ohmasa F, Dimitriadis F, Shomori K, et al. Nicorandil ameliorates ischaemia-reperfusion injury in the rat kidney. Br J Pharmacol 2011;163:272–82. doi:10.1111/j.1476-5381.2011.01231.x.

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Fan Y, Wei Q, Cai J, Shi Y, Zhang Y, Yao L, et al. Preventive effect of oral nicorandil on contrast-induced nephropathy in patients with renal insufficiency undergoing elective cardiac catheterization. Heart Vessels 2016;31:1776–82. doi:10.1007/s00380-0160809-y.

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Zhang X, Yu Q, Yao X, Liu G, Li J, Du L. Effects of nicorandil on all-cause mortality and cardiac events in CAD patients receiving PCI: A systematic review and meta-analysis. Int Heart J 2019;60:886–98. doi:10.1536/ihj.18-337.

[10]

Ko YG, Lee BK, Kang WC, Moon JY, Cho YH, Choi SH, et al. Preventive effect of pretreatment with intravenous nicorandil on contrast-induced nephropathy in patients with renal dysfunction undergoing coronary angiography (PRINCIPLE study). Yonsei Med J 2013;54:957–64. doi:10.3349/ymj.2013.54.4.957.

[11]

Nawa T, Nishigaki K, Kinomura Y, Tanaka T, Yamada Y, Kawasaki M, et al. Continuous

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intravenous infusion of nicorandil for 4 hours before and 24 hours after percutaneous coronary intervention protects against contrast-induced nephropathy in patients with

Fan Z, Li Y, Ji H, Jian X. Efficacy of Oral Nicorandil to Prevent Contrast-Induced

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poor renal function. Int J Cardiol 2015;195:228–34. doi:10.1016/j.ijcard.2015.05.078.

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Coronary Procedure. Kidney Blood Press Res 2019;100125:1–11. doi:10.1159/000503160.

Iranirad L, Hejazi SF, Sadeghi MS, Jang SA. Efficacy of nicorandil treatment for

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doi:10.5603/CJ.a2017.0028.

Zhang P, Li WY, Yang SC, Fu NK, Liu XG, Zhang X, et al. Preventive Effects of Nicorandil Against Contrast-Induced Nephropathy in Patients With Moderate Renal Insufficiency Undergoing Percutaneous Coronary Intervention. Angiology 2019. doi:10.1177/0003319719841733.

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Zhang X, Yang S, Zhang P, Fu N. Efficacy of nicorandil on the prevention of contrastinduced nephropathy in patients with coronary heart disease undergoing percutaneous coronary intervention. Coron Artery Dis 2019:1. doi:10.1097/MCA.0000000000000826.

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Guan XF, Chen QJ, Zuo XC, Guo R, Peng XD, Wang JL, et al. Contrast media-induced renal inflammation is mediated through HMGB1 and its receptors in human tubular

Journal Pre-proof cells. DNA Cell Biol 2017;36:67–76. doi:10.1089/dna.2016.3463. [17]

Geenen RWF, Kingma HJ, van der Molen AJ. Contrast-induced nephropathy: Pharmacology, pathophysiology and prevention. Insights Imaging 2013;4:811–20. doi:10.1007/s13244-013-0291-3.

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Taira N. Nicorandil as a hybrid between nitrates and potassium channel activators. Am J Cardiol 1989;63. doi:10.1016/0002-9149(89)90200-2.

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Dargie H. Role of nicorandil in ischaemic preconditioning. Lancet 2002;360:1888.

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doi:10.1016/s0140-6736(02)11755-7. Yamada K, Isobe S, Ishii H, Yokouchi K, Iwata H, Sawada K, et al. Impacts of nicorandil

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on infarct myocardium in comparison with nitrate: assessed by cardiac magnetic resonance imaging. Heart Vessels 2016;31:1430–7. doi:10.1007/s00380-015-0752-3. Ota S, Nishikawa H, Takeuchi M, Nakajima K, Nakamura T, Okamoto S, et al. Impact of

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nicorandil to prevent reperfusion injury in patients with acute myocardial infarction Sigmart Multicenter Angioplasty Revascularization Trial (SMART). Circ J

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2006;70:1099–104. doi:10.1253/circj.70.1099. Frydman A. Pharmacokinetic profile of nicorandil in humans: An overview. J

Geenen RWF, Kingma HJ, van der Molen AJ. Contrast-induced nephropathy:

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Cardiovasc Pharmacol 1992;20:S34-44. doi:10.1097/00005344-199206203-00008.

Pharmacology, pathophysiology and prevention. Insights Imaging 2013;4:811–20. doi:10.1007/s13244-013-0291-3.

Journal Pre-proof Figure Legends Figure 1. Study Flow Diagram Figure 2. Nicorandil and Contrast-Induced Nephropathy. Nicorandil was associated with a lower incidence of CIN (2A), however, the result of funnel plot analysis revealed an asymmetrical distribution (2B). Nicorandil effect on CIN was shown to be independent to other factors in the respective studies (2C). Intravenous administration seemed to be more effective than oral administration (2D). The effect of nicorandil of CIN was also

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demonstrated to be effective in patients with renal dysfunction (2E).

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Figure 3. Nicorandil and Major Adverse Events. Forest-plot showing no significant

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association between nicorandil and major adverse events.

Figure 4. Risk of Bias Assessment. Assessment using Cochrane risk-of-bias tool was shown in

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4A. There were no statistically significant small-study effects according to assessment using

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Harbord’s test (4B).

Journal Pre-proof Table 1. Studies included in the systematic review

Fan 2019

Open Label RCT

Zhan gX 2019

Open Label RCT

Undergoin g PCI

PCI

Zhan g 2019

Open Label RCT

eGFR ≤60 mL/min/1. 73 m2

Iranir ad 2017

Open Label RCT

Cardiac Catheteriz ation

PCI

CIN Definit ion SCr Increas e ≥0.5 mg/dL or ≥25% within 72 hours after CM exposu re SCr Increas e ≥0.5 mg/dL / or ≥25% within 72 hours after CM exposu re SCr Increas e ≥0.5 mg/dL or ≥25% within 72 hours after CM exposu re SCr Increas e ≥0.5 mg/dL / or ≥25% within 72

Nicorand il Protocol Oral; 10 mg t.i.d 2 days before procedur e to 2 days after procedur e

Sampl e Size (n) 252 (127/1 25)

Mal e (%) 59. 84 vs 53. 6

Age (years)

Funding

62.25±1 6.63 vs 65.87±1 7.62

Unclear

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Proced ure

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Patient Characteri stics eGFR ≤60 mL/min/1. 73 m2

Oral; 10 mg t.i.d 1 day before procedur e and for 3 days after PCI

300 (150/1 50)

78. 7 vs 76

67.25±6. 42 vs 67.11±7. 19

Tianjin Municipal Health and Family Planning Commissi on

Oral; 10 mg t.i.d 1 day before procedur e and for 3 days after PCI

250 (125/1 25)

74. 4 vs 71. 2

67.4±6.6 vs 67.0±7.2

Tianjin Municipal Health and Family Planning Commissi on

Oral; 30 min Before procedur e to 3 days after the procedur

128 (64/64 )

60. 9 vs 62. 5

61.35±1 1.77 vs 57.64±1 2.42

Deputy of Research and Education of Qom University of Medical

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Desig n

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Stud y

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PCI

CAG/P CI

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Cystatin PCI C level ≥0.95 mg/L in males and ≥0.87 mg/dL in females

Ko 2013

eGFR ≤60 mL/min/1. 73 m2

Intraveno 213 us; 2 vials (106/1 of 07) nicorandi l (48 mg/V), initiated 4h prior to elective PCI and were continue d for 24 h after the procedur e

SCr Increas e ≥0.5 mg/dL / or ≥25% within 48 hours after CM exposu re

Intraveno 149 us; 12 mg (73/76 nicorandi ) l administ ered over a 30minute period just prior to coronary angiogra phy.

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Nawa Open 2015 Label RCT

Open Label RCT

240 (120/1 20)

73. 33 vs 79. 17

66.07±6. 37 vs 67.37±6. 33

Unclear

81. 6 vs 78. 7

70.4±7.7 vs 70.1±8.1

Unclear

72. 6 vs 67. 1

70.8±9.6 vs 69.1±10. 3

Brain Korea 21 Project for Medical Science, Yonsei University and Korean Institute of Medicine, the Cardiovas

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Oral; 10 mg t.i.d 2 days before procedur e to 3 days after procedur e

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CAG/P CI

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eGFR ≤60 mL/min/1. 73 m2

Sciences

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Doub leblind ed RCT

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Fan 2016

hours after CM exposu re SCr Increas e ≥0.5 mg/dL / or ≥25% within 72 hours after CM exposu re SCr Increas e ≥0.5 mg/dL / or ≥25% within 72 hours after CM exposu re

CAG/P CI

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Journal Pre-proof cular Research Center, Seoul, Korea, GE Healthcar e Korea, and the Korea Healthcar e Technolog y R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea

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CAG: Coronary Angiography; CIN: Contrast-induced Nephropathy; eGFR: estimated Glomerular Filtration Rate; PCI: Percutaneous Coronary Intervention; RCT: Randomized Controlled Trial; SCr: Serum Creatinine

Journal Pre-proof Table 2. GRADE Assessment Number of patients

Certainty assessment

Number of studies

Study design

Risk of bias

Inconsistency

Indirectness

Imprecision

not serious

not serious

not serious

not serious

not serious

Other considerations

Effect

Relative (95% CI)

Certainty Absolute (95% CI)

Nicorandil

Control

publication bias strongly suspected strong association a

33/757 (4.4%)

97/754 (12.9%)

OR 0.31 (0.20 to 0.46)

85 fewer ⨁⨁⨁◯ per 1,000 MODERATE (from 100 fewer to 65 fewer)

not serious

publication bias strongly suspected strong association a

26/509 (5.1%)

71/510 (13.9%)

OR 0.34 (0.16 to 0.74)

87 fewer ⨁⨁⨁◯ per 1,000 MODERATE (from 114 fewer to 32 fewer)

not serious

publication bias strongly suspected strong association a

62/570 (10.9%)

OR 0.33 (0.20 to 0.54)

70 fewer ⨁⨁⨁◯ per 1,000 MODERATE (from 85 fewer to 47 fewer)

35/184 (19.0%)

OR 0.27 131 fewer ⨁◯◯◯ (0.13 to per 1,000 VERY LOW 0.55) (from 161 fewer to 76 fewer)

Contrast-Induced Nephropathy 7

randomised serious a,b trials

randomised serious a,b trials

not serious

randomised serious trials

not serious

22/573 (3.8%)

Contrast-Induced Nephropathy (Intravenous Nicorandil) randomised serious a,b trials

serious c

not serious

not serious

publication bias strongly suspected a

11/184 (6.0%)

Explanations a. Asymmetrical Funnel Plot b. Open-labeled Study

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CI: Confidence interval; OR: Odds ratio

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Contrast-Induced Nephropathy (Oral Nicorandil)

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Contrast-Induced Nephropathy (Adjusted)

c. Nawa et al. study has wide confidence interval. Ko et al. study showed no significant associated with the risk of CIN

Journal Pre-proof CRediT author statement Raymond Pranata: Conceptualization, Methodology, Formal analysis, Investigation, Writing Original Draft Rachel Vania: Data Curation, Investigation, Writing - Original Draft, Project administration Amir Aziz Alkatiri: Investigation, Writing - Review & Editing Doni Firman: Investigation, Writing - Review & Editing

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Antonia Anna Lukito: Data Curation, Investigation, Writing - Original Draft

Journal Pre-proof Highlights

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1. Nicorandil decrease the risk of CIN independent to other factors with moderate level of certainty 2. Nephroprotective effects of nicorandil are also observed in patients with renal dysfunction 3. Oral nicorandil has a higher level of certainty compared to intravenous route in reducing CIN 4. Nicorandil should be given for at least 24 hours

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