DyeVert System and Contrast-induced Acute Kidney Injury
DyeVert System and Contrast-induced Acute Kidney Injury
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).
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.
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):

 1. Refractory angina,

 2. Signs or symptoms of heart faiklure or new or worsening mitral regurgitation,

 3. Hemodynamic instability,

 4. Recurrent angina or ischemia at rest or with low-level activities despite intensive
 medical therapy,

 5. Sustained ventricular tachycardia or ventricular fibrillation,

 6. 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.