Prevention of Contrast-Induced Nephropathy After Emergency Percutaneous Coronary Intervention With a Single Bolus Administration of High-Concentrate Sodium Bicarbonate　― Rationale and Design of a Single-Arm Study Compared With Historical Controls ―

Abstract

Background: Contrast-induced nephropathy (CIN) is clinically important because of its poor prognosis. The incidence of CIN is higher in emergency than elective percutaneous coronary intervention (PCI) because there is no established method to prevent CIN. The aim of this study is to evaluate whether bolus administration of a concentrated solution of sodium bicarbonate can prevent CIN in patients undergoing emergency PCI.

Methods and Results: This multicenter prospective single-arm trial with historical controls will include patients who are aged ≥20 years and will undergo cardiac catheterization for suspected acute myocardial infarction (AMI). Patients will receive an intravenous bolus administration of concentrated sodium bicarbonate solution (7% or 8.4%, 20 mEq) and will be observed for 72±12 h. Data for the control group, comprising all patients who underwent PCI for AMI between January 1, 2020 and December 31, 2020 across participating hospitals, will be extracted. The primary endpoint is the incidence of CIN, defined as an increase in serum creatinine of >0.5 mg/dL or >25% from baseline within 48±12 h. We will evaluate the endpoints in the prospective group and compare them with those in the historical control group.

Conclusions: This study will evaluate whether a single bolus administration of concentrated sodium bicarbonate can prevent CIN after emergency PCI.

Contrast agents are the fourth most common drug causing kidney injury. Contrast-induced nephropathy (CIN) accounts for 5.7% of all drug-induced kidney injuries and is an important clinical problem in terms of long-term outcomes and medical costs.¹

Hydration with isotonic saline or a low concentration (1.26%) of sodium bicarbonate several hours before the administration of contrast agent is known to prevent CIN and is commonly performed in clinical practice.² However, this prophylactic treatment cannot be performed in advance in patients who are administered contrast agent in an emergency setting. Moreover, there are no established methods to effectively prevent CIN in an emergency setting, besides limiting the amount of contrast agent administered. Therefore, there is a need to develop a prophylactic treatment that can be performed rapidly in emergency settings to prevent CIN.³

A previous study reported that bolus administration of low-concentrate sodium bicarbonate immediately before the use of contrast agent significantly reduced the incidence of CIN in an emergency setting. However, that study had a small sample size and used low-concentrate sodium bicarbonate. Moreover, continuous infusion of sodium bicarbonate, which may have a negative effect on heart failure, was administered after bolus administration.⁴ Therefore, we propose to conduct the Bolus Administration of Sodium Bicarbonate to Prevent Contrast-Induced Nephropathy after Emergency Percutaneous Coronary Intervention (BOLUS-pCINC) study to evaluate the efficacy of single bolus administration of only concentrated sodium bicarbonate (7% or 8.4%, 20 mEq) in preventing CIN in patients who undergo emergency percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI).

Methods

Design

This is a multicenter single arm study in 10 hospitals. We will prospectively evaluate the efficacy of bolus administration of concentrated sodium bicarbonate in preventing CIN in patients with AMI who undergo emergency PCI and compare the results with those of historical controls retrospectively enrolled from the same hospitals from January 1, 2020 to December 31, 2020.

Inclusion criteria for patients include age ≥20 years with suspected AMI based on electrocardiographic changes, elevated myocardial enzymes, or echocardiography, and patients judged by the attending physician to require urgent coronary angiography (CAG), heading directly to the cardiac catheterization laboratory from the emergency room or patients with in-hospital onset. The inclusion and exclusion criteria are presented in Table 1. Eligible patients will receive an intravenous bolus administration of 20 mEq of concentrated sodium bicarbonate (24 mL of MEYLON Injection 7%^® [Otsuka Pharmaceutical Factory, Inc., Japan] or Sodium Bicarbonate Injection 7% “NS”^® [Nissin Pharmaceutical Co., Ltd, Japan]; 20 mL of intravenous MEYLON Injection 8.4%^® [Otsuka Pharmaceutical Factory, Inc.] or Sodium Bicarbonate Injection 8.4% “NS”^® [Nissin Pharmaceutical Co., Ltd]) immediately before the administration of contrast agent. After completion of the procedure, patients will be administered isotonic saline (0.9% sodium chloride, ≥1 mL/kg/h for 12 h after the procedure) and observed for 72±12 h after contrast agent administration (Figure). An overview of all the visits and test schedules is presented in Table 2. As the historical control group, all patients who underwent PCI for AMI between January 1, 2020 and December 31, 2020 across the participating hospitals and did not meet the control group exclusion criteria (Table 1) will be included.

Table 1. Inclusion and Exclusion Criteria

Sodium bicarbonate group

Inclusion criteria

1. Age ≥20 years

2. Patients heading directly to the cardiac catheterization laboratory from the emergency room or patients with in-hospital onset

3. Patients with suspected AMI based on ECG changes, elevated myocardial enzymes, or echocardiography

4. Patients judged by the attending physician to require urgent CAG

5. Patients or their legal acceptable representatives who consent to participate in the study

Exclusion criteria

1. Patients with shock or cardiopulmonary arrest upon arrival at the emergency department

2. Patients with impaired consciousness, orthopnea, or needing tracheal intubation and non-invasive positive pressure ventilation upon arrival at the emergency department

3. Patients who received oral or intravenous sodium bicarbonate before CAG was performed

4. Patients allergic to contrast agents at the time of registration

5. Patients undergoing dialysis

6. Patients with uncontrolled hyperthyroidism or hypothyroidism

7. Patients who received contrast media within 7 days of CAG or PCI

8. Patients who did not undergo PCI as the result of CAG

9. Patients not diagnosed with AMI

Historical control group

Inclusion criteria

1. Patients who underwent PCI for AMI between January 1, 2020 and December 31, 2020

Exclusion criteria

1. Patients with shock or cardiopulmonary arrest upon arrival at the emergency department

2. Patients with impaired consciousness, orthopnea, or needing tracheal intubation and non-invasive positive pressure ventilation upon arrival at the emergency department

3. Patients who received oral or intravenous sodium bicarbonate before CAG was performed

4. Patients allergic to contrast agents at the time of registration

5. Patients undergoing dialysis

6. Patients with uncontrolled hyperthyroidism or hypothyroidism

7. Patients who received contrast media within 7 days of CAG or PCI

8. Patients lacking SCr data at the 24±12 and 48±12 h time points

AMI, acute myocardial infarction; CAG, coronary angiography; ECG, electrocardiogram; PCI, percutaneous coronary intervention; SCr, serum creatinine.

Figure.

Design of the Bolus Administration of Sodium Bicarbonate to Prevent Contrast-Induced Nephropathy after Emergency Percutaneous Coronary Intervention (BOLUS-pCINC) study. PCI, percutaneous coronary intervention.

Table 2. Overview of All Visits and Test Schedules

	Enrollment	Observation period
		Baseline	PCI	24±12 h	48±12 h	72±12 h
Informed consent	●
Patient characteristics	●
Registration	●
Medical examination	●
Blood test		●		●	●	●
Urinalysis		●
Lesion and procedure characteristics			●
Adverse event			●	●	●	●

PCI, percutaneous coronary intervention.

The present study will be conducted in compliance with the World Medical Association’s Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects established by the Ministry of Health, Labor, and Welfare in Japan. The investigator will provide sufficient explanation to each patient or their legally acceptable representative and obtain written informed consent. Informed consent for patients in the historical control group will be obtained using an opt-out approach. The research protocol has been approved by independent ethics committees at participating each site. The research period will be from February 7, 2022 to December 31, 2022.

Endpoints

The primary endpoint is the incidence of CIN, defined as an increase in serum creatinine (SCr) of ≥0.5 mg/dL or ≥25% relative to the SCr value at enrollment within 48±12 h. Secondary endpoints include: (1) the incidence of acute kidney injury (≥1.5-fold or ≥0.3 mg/dL increase in SCr within 48±12 h relative to SCr at enrollment); (2) an increase in SCr of ≥0.5 mg/dL or ≥25% relative to the SCr value at enrollment within 72±12 h; and (3) the change in SCr, calculated as the difference between SCr at 24±12, 48±12, or 72±12 h after the procedure and SCr at enrollment.

The safety analysis will record adverse events (AEs), defined as any unfavorable or unintended signs, symptoms, or disease, including abnormal laboratory values. Details of other measurements and AEs are provided in the Supplementary File.

Sample Size

The overall incidence of CIN was 1.5% among all patients enrolled in the study on Prevention of Contrast-Induced Nephropathy After Cardiovascular Catheterization and Intervention with High-Dose Strong Statin Therapy in Japan (PREVENT CINC-J),⁵ in which most patients (92%) received a bolus of concentrated sodium bicarbonate immediately before contrast agent administration in addition to standard saline hydration. Ueda et al reported that in emergency PCI, the incidence of CIN was 3.3% among patients who received a bolus administration of low-concentrate sodium bicarbonate (1.26%, 0.5 mL/kg) before contrast administration followed by continuous infusion of sodium bicarbonate.⁴ In contrast, in a meta-analysis of patients undergoing PCI for ST-segment elevation myocardial infarction (STEMI), the reported incidence of CIN was 13.3%.⁶ A Japanese retrospective cohort study reported that the incidence of CIN was 10.7% in unstable angina pectoris/non-STEMI (NSTEMI) and 16.7% in STEMI.³

Based on these studies, we assumed a 5% incidence of CIN in the sodium bicarbonate group. Furthermore, considering the high incidence of CIN in AMI patients and a 10% incidence of CIN with standard treatment, the sample size for the sodium bicarbonate group at a significance level (2-sided) of α=0.05 with 90% power was estimated to be at least 244 patients. With an estimated dropout rate of 5%, we will target the enrollment of 260 patients in the sodium bicarbonate group.

In addition, approximately 800 patients per year are expected to undergo PCI for AMI at all hospitals participating in this study. Approximately 70% of the 126 patients admitted to the Nara Medical University Hospital for AMI from January 1, 2020 to December 31, 2020 were eligible to be included the control group. Therefore, we can estimate that 560 patients per year will be eligible for the control group at all participating hospitals.

Statistical Analysis

The full analysis set (FAS) and per-protocol set (PPS) conforming to the study protocol will be analyzed. The FAS will include both discontinued and untraceable cases. Patients with no SCr values measured at any time since enrollment will not be included in the FAS. The PPS will be a subset of the FAS and exclude cases with unmeasured SCr values at 24±12 and 48±12 h. Patients who withdraw consent will not be included in the population for analysis.

For the primary endpoint, the proportion of patients with CIN will be estimated with 95% confidence intervals (CIs; Clopper–Pearson type).

In addition, the effectiveness of sodium bicarbonate will be assessed based on the result that the 95% upper confidence limit will be <10%, which is assumed to be the rate of CIN with standard treatment (saline administration). Secondary endpoints 1–3 will be compared between the sodium bicarbonate and control groups using Fisher’s exact test for endpoints 1 and 2 and an unpaired t-test for endpoint 3. The 95% CI for each endpoint will be calculated. In addition, analyses of matched pairs for several factors will be performed.

Discussion

This study will evaluate whether bolus administration of concentrated sodium bicarbonate immediately before the administration of contrast agent prevents CIN in patients undergoing emergency PCI for AMI.

Although several methods for preventing CIN have been reported, the most common method described in the 2018 guidelines from the Japanese Society of Nephrology and Japan Radiological Society, and Japanese Circulation Society is intravenous hydration with isotonic saline (0.9% sodium chloride, 1 mL/kg/h for 6–12 h before and after contrast administration).⁷ Alternatively, intravenous hydration of low-concentrate sodium bicarbonate (1.26% sodium bicarbonate, 3 mL/kg/h for 1 h before and 1 mL/kg/h for 6 h after contrast administration) is also used. However, although these prophylactic treatments can be used in patients with scheduled contrast studies and treatments, they are difficult to apply to emergency cases, such as STEMI or high-risk NSTEMI (persistent or recurrent chest pain refractory to drug therapy, complications of heart failure, hemodynamic instability, fatal arrhythmia or cardiac arrest, mechanical complications [e.g., acute mitral regurgitation], transient ST elevation, recurrent dynamic ST-T changes).⁸ Moreover, the current guidelines do not describe any prophylactic treatment for preventing CIN in emergency cases. Therefore, it is necessary to develop a prophylactic treatment for CIN that can be rapidly performed in emergency cases.

There have been 2 randomized control trials on the efficacy of bolus administration of sodium bicarbonate to prevent CIN. Tamura et al reported that for patients who underwent elective PCI, the incidence of CIN was significantly lower in those who received an intravenous bolus administration of concentrated sodium bicarbonate (8.4%, 20 mEq) in addition to standard saline hydration immediately before contrast administration than in those who received standard saline hydration alone.⁹ Ueda et al reported that intravenous bolus administration of low-concentrate sodium bicarbonate (1.26%, 0.5 mL/kg) immediately before emergency PCI followed by continuous infusion of low-concentrate sodium bicarbonate significantly reduced the incidence of CIN compared with intravenous bolus administration of isotonic saline (0.5 mL/kg) followed by continuous infusion of isotonic saline.⁴ Moreover, the PREVENT CINC-J study, in which most patients (92%) received a bolus of concentrated sodium bicarbonate immediately before contrast agent administration in addition to standard saline hydration, reported an extremely low incidence of CIN of 1.5%.⁵ Therefore, bolus administration of concentrated sodium bicarbonate may be a prophylactic treatment for CIN that can be performed rapidly in emergency settings. In this study, all patients will be scheduled for intravenous bolus administration of concentrated sodium bicarbonate immediately before the administration of contrast agent, in addition to standard saline hydration.

A bolus administration of concentrated sodium bicarbonate may be more effective than low-concentrate sodium bicarbonate because it leads to rapid alkalinization of urine and may be an appropriate prophylactic treatment for CIN in emergency PCI because of its simplicity. The pathophysiology of contrast-induced renal injury is not fully understood, but it may have direct and indirect effects, such as hemodynamic disturbances.^10,11 Contrast agents are toxic to tubular epithelial cells and cause apoptosis and necrosis. An indirect mechanism is ischemic injury due to altered vasomotor activity mediated by vasoactive substances such as endothelin, nitric oxide, and prostaglandins.¹² Ischemic injury is thought to increase the production of oxygen free radicals, leading to renal injury.¹³ The Harber-Weiss reaction, which produces hydroxide ions, plays an important role in free radical production and is activated in acidic environments.¹⁴ As a mechanism for the prevention of CIN with sodium bicarbonate, alkalinization of the tubular fluid is thought to inhibit the development of free radical-induced renal injury. In emergency PCI, rapid alkalinization by bolus infusion of sodium bicarbonate may strongly inhibit the formation of free radicals.

This study has some limitations. It is a single-arm study with a historical control and a short observation period. Because some cases may not be included in the intervention group because of a doctor’s judgment or a patient’s will, potential selection bias cannot be avoided compared with the historical control.

This study aims to explore the possibility of preventing CIN by administering a single bolus of concentrated sodium bicarbonate immediately before contrast agent administration in patients undergoing emergency PCI. The results of this study will confirm whether this is an effective treatment during emergencies.

Acknowledgments

The authors thank the staff at the Clinical Research Center, Nara Medical University Hospital.

Sources of Funding

This research is supported by the Nara Medical University Clinical Research Grant Program (Grant no. 20-008) and a grant from the Otsuka Pharmaceutical Factory, Inc.

Disclosures

Y. Saito has received research funds from Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Bristol-Myers Squibb Company, Actelion Pharmaceuticals Japan Ltd., Kyowa Kirin Co., Ltd., Kowa Pharmaceutical Co., Ltd, Shionogi & Co., Ltd, Dainippon Sumitomo Pharma Co., Ltd., Teijin Pharma Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Nihon Medi-Physics Co., Ltd., Novartis Pharma K.K., Pfizer Japan Inc., and Fuji Yakuhin Co., Ltd.; research expenses from Novartis Pharma K.K., Roche Diagnostics K.K., Amgen Inc., Bayer Yakuhin, Ltd., Astellas Pharma Inc., and Actelion Pharmaceuticals Japan Ltd.; speakers’ bureau fees/honoraria from Alnylam Japan K.K., AstraZeneca K.K., Otsuka Pharmaceutical Co., Ltd., Kowa Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Tsumura & Co., Teijin Pharma Ltd., Toa Eiyo Ltd., Nippon Shinyaku Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Bayer Yakuhin Ltd., Pfizer Japan Inc., Bristol-Myers Squibb Company, and Mochida Pharmaceutical Co., Ltd.; and consultation fees from Ono Pharmaceutical Co., Ltd. and Novartis Pharma K.K.

K. Kuwahara is a member of Circulation Reports’ Editorial Team. The remaining authors have no conflicts of interest to disclose.

IRB Information

This study was approved by the Ethics Committee of Nara Medical University (Reference no. CRB5200002).

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circrep.CR-22-0105

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