DyeVert System and Contrast-induced Acute Kidney Injury

Study Overview
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Brief Summary
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The aim of the REnal Insufficiency Following Contrast MEDIA Administration TriaL IV (REMEDIAL IV) is to test whether the use of the DyeVert system is effective in reducing CI-AKI rate in ACS patients undergoing urgent/immediate (within 2 hours) invasive diagnostic and/or interventional cardiovascular procedures. The DyeVert™ system (Osprey Medical Inc., Minnetonka, MN, USA) is a novel device designed to reduce CM volume during coronary procedures, while maintaining fluoroscopic image quality. Patients with ACS scheduled for urgent/immediate coronary angiography/angioplasty will be enrolled and randomized into 2 groups: 1) DyeVert group (CM injection will be handled by the DyeVert TM system), and 2) Control group (CM injection will be carried out by a conventional manual injection syringe).

Detailed Description
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Acute kidney injury (AKI) is a common complication in patients suffering from acute coronary syndromes (ACS) and treated by percutaneous coronary intervention (PCI). This complication has been associated with higher early and late adverse events. It has been emphasized that the pathogenesis of AKI in the setting of ACS is multifactorial, including age, unstable hemodynamic conditions, co-morbidities (that is, diabetes mellitus and anemia) pre-existing chronic kidney disease, dehydration and administration of nephrotoxic drugs. However, the role of iodinated contrast media (CM) has been well established. Hydration represents the cornerstone in contrast-induced AKI (CI-AKI) prevention. However, at present there is no consensus on how hydration should be carried out, especially in ACS patients, and all the the recommended hydration regimens have limited applicability in the urgent/emergent settings such as ACS. Several targeted hydration regimens have been proposed, but none has been tested in ACS patients; in the present trial the investigators will adopt the left ventricular end diastolic pressure (LVEDP) -guided hydration because this approach is simple and easy to implement in the current target population. The CM volume used is an independent predictor of CI-AKI and the concept that the lower the CM volume, the lower the CI-AKI risk is generally accepted. The administration of a CM volume >3X glomerular filtration rate (GFR) is suggestive of increased risk of CI-AKI. To date the use of manual injections with a manifold remains the preferred technique in the majority of catheterization laboratories. In particular, manual injection is often favored for interventional procedures, which require low, variable-flow pressure injections. The AVERT trial demonstrated that CM volume is significantly lower in patients randomized to DyeVert™ in comparison to control (36.9 ± 10.9 mL versus 62.5 ± 12.7 mL, p < 0.001) and the observed reduction in CM volume used was most evident in patients undergoing PCI. Therefore, in this scenario is of outmost importance to limit the CM volume in the attempt to prevent CI-AKI. The aim of the REnal Insufficiency Following Contrast MEDIA Administration TriaL IV (REMEDIAL IV) is to test whether the use of the DyeVert system is effective in reducing CI-AKI rate in ACS patients undergoing urgent or immediate (within 2 hours) invasive diagnostic and/or interventional cardiovascular procedures. METHODS All patients with ACS scheduled for urgent/immediate coronary angiography/angioplasty will be screened for inclusion/exclusion criteria. Diagnosis of ACS (both ST-Elevation Myocardial Infarction [STEMI] and high-risk Non-ST-Elevation Myocardial Infarction [Non-STEMI]) will be established in accordance with guidelines, including a typical chest pain history, diagnostic electrocardiographic changes, and serial increase of cardiac biomarkers. All patients with inclusion/exclusion criteria satisfied and who will agree to sign the informed consent will be enrolled into the trial. The REMEDIAL IV trial will be conducted at a pool of Italian interventional cardiology centers, according to the principles of the Declaration of Helsinki and Good Clinical Practice and has been approved by the local Ethic Committees. All the patients included into the study will receive intravenous 0.9% sodium chloride as soon as in the catheterization laboratory; the hydration regimen will be defined according to the hemodynamic conditions, as defined below. The patients will be then randomized into 2 groups: 1) DyeVert group, and 2) Control group. STUDY ENDPOINTS The primary endpoint of the trial is the rate of CI-AKI. CI-AKI is defined as an increase in the serum creatinine (sCr) concentration ≥ 0.3 mg/dL from the baseline value within 5 days after CM administration or the need for dialysis. Secondary end-points will include: 1) differences in the CM volume in the 2 groups; 2) an increase in the sCr concentration ≥25% within 5 days after CM exposure; 4) the severity of AKI assessed according to the Acute Kidney Injury Network criteria: Stage 1, a sCr increase ≥0.3 mg/dL or ≥1.5-1.9 times from baseline; Stage 2, a sCr increase ≥2.0-2.9 times from baseline; and Stage 3, a sCr increase ≥3.0 times from baseline or the need for dialysis; 5) changes in the serum cystatin C concentration at 24 and 48 hours after CM exposure; 6) the rate of acute renal failure requiring dialysis (defined as a decrease in renal function necessitating acute hemodialysis, ultrafiltration or peritoneal dialysis within the first 5 days post-intervention); 7) the rate of in-hospital, 6 and 12-month major adverse events (MAE), including death, renal failure requiring dialysis, acute pulmonary edema, and sustained kidney injury. Sustained kidney injury is defined as a persistent ≥25% GFR reduction compared to baseline at 6 and 12 months; and 8) the length in in-hospital stay, calculated as the sum of the number of days since admission until discharge from the hospital.

Official Title
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Renal Insufficiency Following Contrast Media Administration Trial IV: Contrast Media Volume Control for Limiting Contrast-Induced Acute Kidney in Acute Coronary Syndrome.

Conditions
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Contrast-induced Acute Kidney Injury, Acute Coronary Syndromes

Intervention / Treatment
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* Device: Coronary angiography using DyeVert system
* Procedure: Coronary angiography using conventional manual injection syringe.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Urgent or immediate (within 2 hours) coronary procedure with iodinated contrast media administration in the setting of an acute coronary syndrome: ST-Elevation Myocardial Infarction (according to Fourth Universal Definition of Myocardial Infarction); High-risk Non-ST-Elevation Myocardial Infarction (according to current guidelines): Refractory angina, Signs or symptoms of heart faiklure or new or worsening mitral regurgitation, Hemodynamic instability, Recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy, Sustained ventricular tachycardia or ventricular fibrillation, Recurrent dynamic ST-T wave changes, particularly with intermittent ST-elevation. Exclusion Criteria: Women who are pregnant. Recent contrast media exposure: contrast media exposure within 48 hours. End-stage chronic kidney disease on chronic dialysis: both haemodialysis and peritoneal dialysis. Multiple myeloma. Current enrolment in any other study when enrolment in the REMEDIAL IV would involve deviation from either protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients included into the study will be treated according to the following strategy. Patients will receive intravenous 0.9% sodium chloride as soon as in the catheterization laboratory. The hydration regimen will be defined according to the hemodynamic conditions, as defined below. The patients will be then randomized into two groups: 1) DyeVert group, and 2) Control group.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: DyeVert group<br>Patients will receive intravenous 0.9% sodium chloride as soon as in the catheterization laboratory. The hydration regimen will be defined according to the hemodynamic conditions and modulated according to the left ventricular end diastolic pressure (LVEDP). During the PCI the CM injection will be handled by the DyeVert TM system. | Device: Coronary angiography using DyeVert system<br>* Invasive diagnostic and/or interventional cardiovascular procedures in the setting of acute coronary syndrome using DyeVert system.<br>|
| Sham Comparator: Control group<br>Patients will receive intravenous 0.9% sodium chloride as soon as in the catheterization laboratory. The hydration regimen will be defined according to the hemodynamic conditions and modulated according to the left ventricular end diastolic pressure (LVEDP). During the PCI the CM injection will be carried out by a conventional manual injection syringe. Strategies for limiting CM volume are: angiograms will be performed with injection of contrast using a 3-cm 3 syringe; this provides strict control of CM delivery by limiting the volume of contrast that can be administered in a single injection; catheters with sideholes will be strictly avoided during percutaneous intervention; when exchanging catheters, unused contrast is withdrawn from the catheter lumen (e.g., by back-bleeding through an opened ''Y''-connector or by aspirating residual contrast from the catheter using a syringe) ''tests'' with ''puffs'' of CM are discouraged. | Procedure: Coronary angiography using conventional manual injection syringe.<br>* Invasive diagnostic and/or interventional cardiovascular procedures in the setting of acute coronary syndrome using conventional manual injection syringe.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of contrast-induced Acute Kidney Injury (CI-AKI). | Serum creatinine (mg(dL) is assessed at baseline (before coronary intervention) and then every day during the hospital stay. CI-AKI is defined as a change in the serum creatinine concentration ≥0.3 mg/dL from the baseline value within 5 days after contrast media administration or the need for dialysis. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences in the contrast media volume in the 2 groups. | Volume of contrast media utilized (mL) is assessed in all enrolled patients at the end of the procedure | 30 days | 
| Change in the sCr concentration ≥ 25 percent within 5 days after CM exposure. | Serum creatinine (mg(dL) is assessed at baseline at baseline (before coronary intervention) and therefore every day during the hospidal stay | 30 days | 
| Severity of AKI assessed according to the Acute Kidney Injury Network criteria. | Stage 1, a sCr change ≥0.3 mg/dL or ≥1.5-1.9 times from baseline; Stage 2, a sCr change ≥2.0-2.9 times from baseline; Stage 3, a sCr change ≥3.0 times from baseline or the need for dialysis. | 30 days | 
| Changes in the serum cystatin C concentration at 24 and 48 hours after CM exposure. | Serum Cystatin C (mg/dL) is assessed at baseline (before the coronary procedure) and at 24 and 48 hours after the procedure | 48 hours | 
| Rate of acute renal failure requiring dialysis. | Change in renal function necessitating acute hemodialysis, ultrafiltration or peritoneal dialysis within the first 5 days post intervention. | 5 days | 
| Rate of in-hospital, 6 and 12 month major adverse events (MAE). | MAE include death, renal failure requiring dialysis, acute pulmonary edema, and sustained kidney injury (defined as a persistent ≥25% GFR change compared to baseline at 6 and 12 months | 12 months | 
| Length of in-hospital stay. | In-hospital stay calculated as the sum of the number of days since admission until discharge from the hospital. | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute kidney injury, Device: DyeVert™ system, percutaneous coronary intervention