Contrast Nephropathy Clinical Trial
Official title:
Renal Insufficiency Following Contrast Media Administration Trial III (REMEDIAL III): Renalguard System Versus Left-ventricular End-diastolic Pressure-guided Hydration in High-risk Patients for Contrast-induced Acute Kidney Injury
The urine flow rate (UFR)-guided and the left-ventricular end-diastolic pressure
(LVEDP)-guided hydration regimens have been proposed to prevent contrast-induced acute kidney
injury (CI-AKI). The REnal Insufficiency Following Contrast MEDIA Administration TriaL III
(REMEDIAL III) trial is a randomized, multicenter, investigator-sponsored trial aiming to
compare these 2 hydration strategies in high risk patients.
Patients with estimated glomerular filtration rate <45 ml/min/1.73 m2 and/or a high risk for
CI-AKI (as defined according to both Mehran's score ≥11 and/or Gurm's score >7) will be
enrolled. Patients will be divided in high (>12 mm Hg) and normal LVEDP, non-invasively
estimated by transmitral flow velocity to annular velocity ratio (E/E' index). Patients in
each group will be randomly assigned to 1) LVEDP-guided hydration with normal saline
(LVEDP-guided group). The fluid infusion rate will be adjusted according to the LVEDP as
follows: 5 mL/kg/hr for LVEDP <12 mmHg; 3 mL/kg/hr for 13-18 mmHg; and 1.5 mL/kg/hr for >18
mmHg. 2) UFR-rate guided hydration (RenalGuard group). In this group, hydration with normal
saline plus low-dose of furosemide is controlled by the RenalGuard system, in order to reach
and maintain a high (>300 mL/h) UFR. In all cases iobitridol (an low-osmolar, non ionic
contrast agent) will be administered. The primary endpoint is the composite of CI-AKI (i.e.,
serum creatinine increase ≥ 25% and ≥ 0.5 mg/dl from the baseline value at 48 hours after
contrast media exposure) and/or acute pulmonary edema.
Contrast-induced acute kidney injury (CI-AKI) is a powerful predictor of unfavorable early
and late outcome. Hydration represents the cornerstone in CI-AKI prevention1. However, at
present there is no consensus on how hydration should be carried out. The most recommended
hydration regimen is normal saline infusion at 1 mL/kg/h 12 hours before and 12 hours after
CM exposure. Limitations of this hydration regimen include 1) preclusion in urgent/emergent
settings, and 2) suboptimal efficacy in high- and very high risk patients. Indeed, in high
and very-high risk patients the rate of CI-AKI may be still high, whereas a forced hydration
regimen may increase the risk of pulmonary edema.
In order to clarify how to carry out optimal hydration, 2 regimens have been recently
proposed: 1) left ventricular end-diastolic pressure (LVEDP)-guided hydration and 2) urine
flow rate (UFR)-guided hydration. The POSEIDON trial demonstrated that the left ventricular
end-diastolic pressure (LVEDP)-guided hydration is superior to the conventional hydration
regimen in preventing CI-AKI. In the LVEDP-guided hydration, the fluid infusion rate was
adjusted according to the LVEDP as follows: 5 mL/kg/hr for LVEDP <12 mmHg; 3 mL/kg/hr for
13-18 mmHg; and 1.5 mL/kg/hr for >18 mmHg. The reported rate of pulmonary edema was 1.5%.
Another theory for CI-AKI prophylaxis suggests to induction and maintenance of a high UFR.
This high UFR should allow the body to rapidly eliminate contrast media, reducing contact
time within nephron. The RenalGuard™ System (PLC Medical Systems, Inc.) in combination with
limited (0.25 mg/kg) dose of furosemide induces an maintains a high UFR (>300 mL/h) safely by
maintaining the intravascular blood volume and minimizing the risk of over or
under-hydration. Furthermore, the reported rate of pulmonary edema was <1%.
The purpose of the present study is to compare the LVEDP-guided hydration and the UFR-guided
hydration in patients at high risk for CI-AKI.
Following enrollment, patients will be randomly assigned to one of the following treatments:
1) LVEDP-guided group, and 2) RenalGuard group. Enrolled patients will be stratified,
according to the estimated LVEDP value, into high LVEDP and normal LVEDP group. LVEDP will be
non-invasively estimated by the transmitral flow velocity to annular velocity ratio (E/E'
index). Estimated LVEDP pressure >12 mm Hg will be considered high. Patients allocated in
both groups will receive intravenous 0.9% sodium chloride for at least one hour prior to
cardiac catheterization. In both groups the fluid rate will be adjusted according to the
non-invasive LVEDP estimate as follows: 5 mL/kg/hr for LVEDP ≤12 mmHg; 3 mL/kg/hr for 13-18
mmHg; and 1.5 mL/kg/h for >18 mmHg, as suggested in the POSEIDON trial. Invasive LVEDP
measurement will be also estimated in all patients by placing an angled 5 or 6-French pigtail
catheter in the mid-cavity of the left ventricle at the beginning of the procedure and before
contrast media injection in order to confirm the non-invasive estimated value.
The sample size was calculated to demonstrate the superiority of the RenalGuard therapy over
the LVEDP-guided hydration regimen. The investigators expect a reduction in the primary
composite endpoint from 9% in the LVEDP-guided group to 5% in the RenalGuard group. Using a
two-sided Chi-square test with a significance level of 0.05, a total of at least 750
randomized patients (350 in each arm) afforded the study 80% power. The endpoints will be
analyzed in the global population and also in the subgroups stratified according to the LVEDP
value.
Serum creatinine, cystatin C, blood urea nitrogen, sodium and potassium will be measured the
day before, 12, 24, 48 hours and 1 week after administration of the contrast agent;
additional measurements will be performed in all cases of deterioration of baseline renal
function. CI-AKI is defined as an increase of serum creatinine >=0.3 mg/dl at 48 hours after
contrast media exposure.
Patient demographic details, medical history, current medication, eGFR, risk score for
CI-AKI, and left ventricular ejection fraction are recorded at baseline. Total hydration
volume administered according to the prophylaxis and during the 24 and 48 hours following the
procedure as well as the total urine volume will be recorded. The pre-procedure sCr level is
considered as the sCr concentration before the initiation of any prophylaxis. End-point data
and adverse events are collected during the in-hospital stay and at 1-month. Six-month and
12-month MAE will be also collected. All adverse events are recorded in the case report form
and the data coordinating center will be informed by facsimile within 72 hours of any events.
Serious events and any other safety issues will be reviewed by an independent Data Monitoring
and Safety Committee. All events will be adjudicated by a Clinical Events Committee (CEC),
who is blinded to treatment assignment. At least 2 members of the CEC review clinical data
and relevant documentation and determine whether end points have occurred according to the
study definitions. In case of disagreement between reviewers, a third member of the CEC will
adjudicate and the data will be considered by the entire committee if 2 of the 3 reviewers do
not agree.
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| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Withdrawn |
NCT00313807 -
Study of Intravenous Amino Acid Infusion to Prevent Contrast Dye Mediated Renal Damage
|
Phase 2 |