Acute Renal Failure, Coronary Artery Disease, Kidney Disease
Conditions
Keywords
renal, cardiovascular, kidney, heart, clinical trial, double-blind, multi-site trial, randomized, drug treatment, IV solutions, antioxidant
Brief summary
The purpose of this research study is to compare the effectiveness of intravenous isotonic sodium bicarbonate with intravenous isotonic sodium chloride and oral N-acetylcysteine (NAC) with oral placebo for the prevention of serious adverse outcomes following angiographic procedures in high-risk patients.
Detailed description
The intravascular administration of iodinated contrast media for diagnostic imaging is a common cause of acute kidney injury (AKI) and a leading cause of iatrogenic renal disease. Contrast-induced AKI is associated with serious adverse outcomes including death, need for dialysis, prolonged hospitalization, and acceleration in the rate of progression of underlying chronic kidney disease. The benefit of IV isotonic bicarbonate compared to IV isotonic saline and of N-acetylcysteine for the prevention of contrast-induced AKI and associated adverse outcomes remains unclear. The purpose of this trial is to compare the effectiveness of IV isotonic sodium bicarbonate with IV isotonic sodium chloride and oral NAC with placebo for the prevention of serious adverse outcomes in 7,680 high-risk patients scheduled to undergo coronary or non-coronary angiography. Using a 2 x 2 factorial design, patients will be randomized to receive: 1) either peri-procedural IV isotonic sodium bicarbonate or peri-procedural IV isotonic saline and 2) either oral NAC or oral placebo prior to and for 5 days following the angiographic procedure. The primary study endpoint is a composite outcome comprised of death, need for acute dialysis, or persistent decline in kidney function within 90 days following the index angiogram.
Interventions
DRUGIV isotonic saline
The investigators will administer 3 ml/kg of isotonic saline over 1 hour at an infusion rate of not less than 1 mL/kg per hour and not more than 3 mL/kg per hour prior to the angiographic procedure, 1-1.5ml/kg per hour during angiography, and 6 ml/kg of isotonic saline over 4 hours following the procedure at an infusion rate of not less than 1 mL/kg per hour and not more than 1.5 mL/kg per hour. Providers will retain discretion to administer larger volumes of isotonic saline (up to a maximum of 12 mL/kg) over durations of up to 12 hours pre and 12 hours post-procedure.
DRUGIV isotonic bicarbonate
The investigators will administer 3 ml/kg of isotonic bicarbonate over 1 hour at an infusion rate of not less than 1 mL/kg per hour and not more than 3 mL/kg per hour prior to the angiographic procedure, 1-1.5ml/kg per hour during angiography, and 6 ml/kg of isotonic bicarbonate over 4 hours following the procedure at an infusion rate of not less than 1 mL/kg per hour and not more than 1.5 mL/kg per hour. Providers will retain discretion to administer larger volumes of isotonic bicarbonate (up to a maximum of 12 mL/kg) over durations of up to 12 hours pre and 12 hours post-procedure.
DRUGN-acetylcysteine
NAC will be administered at a dose of 1200mg orally 1 hour prior to angiography, 1 hour following the procedure, and then twice daily for the next 4 days.
DRUGPlacebo
A placebo study drug capsule will be administered orally 1 hour prior to angiography, 1 hour following the procedure, and then twice daily for the next 4 days.
Sponsors
The George Institute
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Planned elective or urgent coronary or non-coronary angiography with iodinated contrast media in which it is anticipated that there will be an interval of 3 hours between the identification of the indication for angiography and the time of the planned procedure. * Pre-angiography eGFR \<60 ml/min/1.73 m2 with diabetes mellitus or pre-angiography eGFR \<45 ml/min/1.73 m2 with or without diabetes mellitus * Ability to provide informed consent
Exclusion criteria
* Stage 5 chronic kidney disease (CKD) (eGFR \<15 mL/min/1.73 m2) * Currently receiving hemodialysis, peritoneal dialysis, continuous renal replacement therapy, or sustained low efficiency dialysis (SLED) * Unstable baseline serum creatinine (SCr) (if known) at the time of angiography defined by an increase in SCr of 25% over the 3 days prior to angiography * Decompensated heart failure requiring any of the following therapies at the time of angiography: * IV milrinone, amrinone, dobutamine, or nesiritide * Isolated ultrafiltration therapy * Intra-aortic balloon pump * Emergent angiography procedures defined as an anticipated duration of \<3 hours between the identification of the indication for angiography and the time of the planned procedure. * Receipt of intravascular iodinated contrast within the 5 days preceding angiography * Receipt of oral or IV NAC within the 48 hours preceding angiography * Known allergy to N-acetylcysteine (NAC) * Known anaphylactic allergy to iodinated contrast media * Prisoner * Age \<18 years * Pregnancy * Ongoing participation in an unapproved concurrent interventional study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious, Adverse, Patient-Centered Events, Including Death, Need for Acute Dialysis, or Persistent Decline in Kidney Function, Comparing Intravenous Sodium Bicarbonate With Intravenous Sodium Chloride. | Within 90 days following angiography | Death will be based on medical record and/or vital status registry documentation Need for acute dialysis will be defined as the initiation of any modality of renal replacement (intermittent hemodialysis, peritoneal dialysis, continuous renal replacement therapy, or sustained low-efficiency dialysis) Persistent decline in kidney function will be defined as an increase in serum creatinine of at least 50% from the baseline value collected pre-angiography to the measurement taken 90 days following the angiography. |
| Number of Participants With Serious, Adverse, Patient-Centered Events, Including Death, Need for Acute Dialysis, or Persistent Decline in Kidney Function, Comparing Oral N-Acetylcysteine With Oral Placebo. | Within 90 days following angiography | Death will be based on medical record and/or vital status registry documentation Need for acute dialysis will be defined as the initiation of any modality of renal replacement (intermittent hemodialysis, peritoneal dialysis, continuous renal replacement therapy, or sustained low-efficiency dialysis) Persistent decline in kidney function will be defined as an increase in serum creatinine of at least 50% from the baseline value collected pre-angiography to the measurement taken 90 days following the angiography. |
Countries
Australia, Malaysia, New Zealand, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Saline & oral placebo IV isotonic saline and oral placebo drug capsule
IV isotonic saline: The investigators will administer 3 ml/kg of isotonic saline over 1 hour at an infusion rate of not less than 1 mL/kg per hour and not more than 3 mL/kg per hour prior to the angiographic procedure, 1-1.5ml/kg per hour during angiography, and 6 ml/kg of isotonic saline over 4 hours following the procedure at an infusion rate of not less than 1 mL/kg per hour and not more than 1.5 mL/kg per hour. Providers will retain discretion to administer larger volumes of isotonic saline (up to a maximum of 12 mL/kg) over durations of up to 12 hours pre and 12 hours post-procedure.
Placebo: A placebo study drug capsule will be administered orally 1 hour prior to angiography, 1 hour following the procedure, and then twice daily for the next 4 days. | 1,244 |
| Saline & oral N-acetylcysteine IV isotonic saline and oral N-acetylcysteine drug capsule
IV isotonic saline: The investigators will administer 3 ml/kg of isotonic saline over 1 hour at an infusion rate of not less than 1 mL/kg per hour and not more than 3 mL/kg per hour prior to the angiographic procedure, 1-1.5ml/kg per hour during angiography, and 6 ml/kg of isotonic saline over 4 hours following the procedure at an infusion rate of not less than 1 mL/kg per hour and not more than 1.5 mL/kg per hour. Providers will retain discretion to administer larger volumes of isotonic saline (up to a maximum of 12 mL/kg) over durations of up to 12 hours pre and 12 hours post-procedure.
N-acetylcysteine: NAC will be administered at a dose of 1200mg orally 1 hour prior to angiography, 1 hour following the procedure, and then twice daily for the next 4 days. | 1,238 |
| Bicarbonate & oral placebo IV isotonic bicarbonate and oral placebo drug capsule
IV isotonic bicarbonate: The investigators will administer 3 ml/kg of isotonic bicarbonate over 1 hour at an infusion rate of not less than 1 mL/kg per hour and not more than 3 mL/kg per hour prior to the angiographic procedure, 1-1.5ml/kg per hour during angiography, and 6 ml/kg of isotonic bicarbonate over 4 hours following the procedure at an infusion rate of not less than 1 mL/kg per hour and not more than 1.5 mL/kg per hour. Providers will retain discretion to administer larger volumes of isotonic bicarbonate (up to a maximum of 12 mL/kg) over durations of up to 12 hours pre and 12 hours post-procedure.
Placebo: A placebo study drug capsule will be administered orally 1 hour prior to angiography, 1 hour following the procedure, and then twice daily for the next 4 days. | 1,254 |
| Bicarbonate & oral N-acetylcysteine IV isotonic bicarbonate and oral N-acetylcysteine drug capsule
IV isotonic bicarbonate: The investigators will administer 3 ml/kg of isotonic bicarbonate over 1 hour at an infusion rate of not less than 1 mL/kg per hour and not more than 3 mL/kg per hour prior to the angiographic procedure, 1-1.5ml/kg per hour during angiography, and 6 ml/kg of isotonic bicarbonate over 4 hours following the procedure at an infusion rate of not less than 1 mL/kg per hour and not more than 1.5 mL/kg per hour. Providers will retain discretion to administer larger volumes of isotonic bicarbonate (up to a maximum of 12 mL/kg) over durations of up to 12 hours pre and 12 hours post-procedure.
N-acetylcysteine: NAC will be administered at a dose of 1200mg orally 1 hour prior to angiography, 1 hour following the procedure, and then twice daily for the next 4 days. | 1,257 |
| Total | 4,993 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | No Endpoint Blood Draw | 38 | 32 | 51 | 43 |
| Overall Study | Procedure Cancelled | 46 | 45 | 25 | 29 |
| Overall Study | Revoked Consent Prior To Procedure | 10 | 9 | 15 | 5 |
| Overall Study | Withdrawal by Subject | 15 | 18 | 13 | 11 |
Baseline characteristics
| Characteristic | Saline & oral placebo | Total | Bicarbonate & oral N-acetylcysteine | Bicarbonate & oral placebo | Saline & oral N-acetylcysteine |
|---|---|---|---|---|---|
| Age, Continuous | 69.6 Years STANDARD_DEVIATION 8.4 | 69.8 Years STANDARD_DEVIATION 8.2 | 70.2 Years STANDARD_DEVIATION 8 | 69.6 Years STANDARD_DEVIATION 8.3 | 69.8 Years STANDARD_DEVIATION 8.3 |
| Race/Ethnicity, Customized Ethnicity Chose Not to Answer | 11 Participants | 48 Participants | 10 Participants | 16 Participants | 11 Participants |
| Race/Ethnicity, Customized Ethnicity Cuban | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Mexican, Mexican American, or Chicano | 17 Participants | 73 Participants | 20 Participants | 27 Participants | 9 Participants |
| Race/Ethnicity, Customized Ethnicity Not Spanish, Hispanic or Latino | 1190 Participants | 4764 Participants | 1197 Participants | 1179 Participants | 1198 Participants |
| Race/Ethnicity, Customized Ethnicity Other Spanish Hispanic, or Latino | 21 Participants | 95 Participants | 27 Participants | 31 Participants | 16 Participants |
| Race/Ethnicity, Customized Ethnicity Puerto Rican | 5 Participants | 12 Participants | 3 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 11 Participants | 35 Participants | 8 Participants | 9 Participants | 7 Participants |
| Race/Ethnicity, Customized Race Asian | 64 Participants | 256 Participants | 65 Participants | 69 Participants | 58 Participants |
| Race/Ethnicity, Customized Race Black or AFrican American | 141 Participants | 570 Participants | 121 Participants | 150 Participants | 158 Participants |
| Race/Ethnicity, Customized Race Indigenous Austrailian | 1 Participants | 4 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race More than one race | 31 Participants | 161 Participants | 50 Participants | 43 Participants | 37 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 19 Participants | 62 Participants | 17 Participants | 16 Participants | 10 Participants |
| Race/Ethnicity, Customized Race Unknown or Not Reported | 6 Participants | 12 Participants | 1 Participants | 5 Participants | 0 Participants |
| Race/Ethnicity, Customized Race White | 971 Participants | 3893 Participants | 993 Participants | 962 Participants | 967 Participants |
| Region of Enrollment Australia | 75 Participants | 317 Participants | 77 Participants | 83 Participants | 82 Participants |
| Region of Enrollment Malaysia | 56 Participants | 230 Participants | 58 Participants | 59 Participants | 57 Participants |
| Region of Enrollment New Zealand | 45 Participants | 179 Participants | 45 Participants | 44 Participants | 45 Participants |
| Region of Enrollment United States | 1068 Participants | 4267 Participants | 1077 Participants | 1068 Participants | 1054 Participants |
| Sex/Gender, Customized Sex Female | 86 Participants | 321 Participants | 73 Participants | 87 Participants | 75 Participants |
| Sex/Gender, Customized Sex Male | 1157 Participants | 4671 Participants | 1184 Participants | 1167 Participants | 1163 Participants |
| Sex/Gender, Customized Sex Unknown/Not Stated | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 28 / 1,300 | 40 / 1,292 | 33 / 1,294 | 28 / 1,291 |
| other Total, other adverse events | 61 / 1,300 | 158 / 1,292 | 83 / 1,294 | 170 / 1,291 |
| serious Total, serious adverse events | 941 / 1,300 | 1,040 / 1,292 | 1,083 / 1,294 | 941 / 1,291 |
Outcome results
Primary
Number of Participants With Serious, Adverse, Patient-Centered Events, Including Death, Need for Acute Dialysis, or Persistent Decline in Kidney Function, Comparing Intravenous Sodium Bicarbonate With Intravenous Sodium Chloride.
Death will be based on medical record and/or vital status registry documentation Need for acute dialysis will be defined as the initiation of any modality of renal replacement (intermittent hemodialysis, peritoneal dialysis, continuous renal replacement therapy, or sustained low-efficiency dialysis) Persistent decline in kidney function will be defined as an increase in serum creatinine of at least 50% from the baseline value collected pre-angiography to the measurement taken 90 days following the angiography.
Time frame: Within 90 days following angiography
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sodium Bicarbonate | Number of Participants With Serious, Adverse, Patient-Centered Events, Including Death, Need for Acute Dialysis, or Persistent Decline in Kidney Function, Comparing Intravenous Sodium Bicarbonate With Intravenous Sodium Chloride. | 111 Participants |
| Saline | Number of Participants With Serious, Adverse, Patient-Centered Events, Including Death, Need for Acute Dialysis, or Persistent Decline in Kidney Function, Comparing Intravenous Sodium Bicarbonate With Intravenous Sodium Chloride. | 116 Participants |
p-value: 0.795% CI: [0.73, 1.24]Wald's Chi-Square
Primary
Number of Participants With Serious, Adverse, Patient-Centered Events, Including Death, Need for Acute Dialysis, or Persistent Decline in Kidney Function, Comparing Oral N-Acetylcysteine With Oral Placebo.
Death will be based on medical record and/or vital status registry documentation Need for acute dialysis will be defined as the initiation of any modality of renal replacement (intermittent hemodialysis, peritoneal dialysis, continuous renal replacement therapy, or sustained low-efficiency dialysis) Persistent decline in kidney function will be defined as an increase in serum creatinine of at least 50% from the baseline value collected pre-angiography to the measurement taken 90 days following the angiography.
Time frame: Within 90 days following angiography
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sodium Bicarbonate | Number of Participants With Serious, Adverse, Patient-Centered Events, Including Death, Need for Acute Dialysis, or Persistent Decline in Kidney Function, Comparing Oral N-Acetylcysteine With Oral Placebo. | 115 Participants |
| Saline | Number of Participants With Serious, Adverse, Patient-Centered Events, Including Death, Need for Acute Dialysis, or Persistent Decline in Kidney Function, Comparing Oral N-Acetylcysteine With Oral Placebo. | 112 Participants |
p-value: 0.8695% CI: [0.78, 1.34]Wald's Chi-Square