By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
SYNOPSIS: This trial randomized 660 patients with chronic kidney disease and a planned procedure requiring intravascular iodinated contrast to prophylactic hydration or to no hydration. No hydration was found to be non-inferior for prevention of contrast-induced nephropathy and saved significant costs.
SOURCE: Nijssen EC, Rennenberg RJ, Nelemans PJ, et al. Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): A prospective, randomised, phase 3, controlled, open-label, non-inferiority trial. Lancet 2017 Feb 20. pii: S0140-6736(17)30057-0. doi: 10.1016/S0140-6736(17)30057-0. [Epub ahead of print].
The number of diagnostic and therapeutic procedures requiring intravascular iodinated contrast continues to grow year after year, and with this has come an increase in patients at risk for contrast-induced acute kidney injury. Although no specific treatment exists for this problem, the number of preventive measures studied to date is impressive. Many treatments have shown early promise in small studies only to fail to show consistent and reproducible results. N-acetylcysteine (Mucomyst) is the archetype of such treatments, but other examples include statins, sodium bicarbonate-containing IV fluid, calcium channel blockers, vitamin C, vitamin E, dopamine, fenoldopam, and remote ischemic preconditioning. However, experts and guidelines have recommended adequate hydration for patients at risk for contrast-induced nephropathy, usually with IV saline administered before and after the procedure.
The near-universal agreement on the value of pre- and post-hydration obscures the relative lack of randomized trial evidence supporting its value. The majority of trials in the literature compare one form of prophylaxis with another, and only three trials have included a group randomized to receive no hydration. No investigators had looked at periprocedural hydration vs. no hydration in the high-risk groups targeted by the guidelines.
Enter the AMACING study. In this prospective, randomized, open-label study, consecutive patients referred for procedures requiring iodinated contrast at Maastricht University Medical Centre in the Netherlands were eligible for enrollment if they had an estimated glomerular filtration rate (eGFR) between 45 and 59 mL per minute combined with a second risk factor, or if they had an eGFR between 30 and 45 mL per minute. Patients with eGFR < 30 were excluded. Patients were assigned 1:1 to either receive IV hydration or to receive no hydration. The specific hydration protocol used in most cases was that recommended by current local guidelines — namely, normal saline at a rate of 3-4 mL/kg per hour for four hours before and four hours after contrast administration. As a standard, patients received pre-warmed iopromide (Ultravist), which is a low-osmolar, non-ionic contrast medium. All patients were subjected to serum creatinine measurements immediately before, two to six days after, and 26-35 days after their contrast procedure. The primary outcome measure was the incidence of contrast-induced nephropathy as determined by rise in serum creatinine at the two-to-six-day blood draw.
Of the 660 consecutive patients who were enrolled, 328 were assigned to receive prophylactic hydration, while 332 received no prophylaxis. In the analysis of day two to six creatinine administration (available in approximately 90% of subjects), contrast-induced acute kidney injury occurred in eight (2.6%) of 307 non-hydrated patients and in eight (2.7%) of 296 hydrated patients. Similarly, there was no significant difference between groups in the day 26-35 creatinine values. No instances of renal failure or requirement for dialysis were recorded. On the other hand, 18 patients in the prophylaxis group (5.5%) experienced complications from hydration, including 13 cases of symptomatic heart failure.
Partly due to the relatively long hydration protocols involved, the hydration group incurred greater hospital costs, and skipping hydration led to significant financial savings.
The authors concluded that forgoing periprocedural hydration in this moderate-risk group of patients was non-inferior to hydration for the prevention of contrast-induced nephropathy. They further reported that using no hydration was less expensive, and was associated with fewer complications than IV hydration.
COMMENTARY
Given that the use of IV hydration is the only measure that has maintained near-universal approval for prevention of contrast nephropathy, it is interesting to note that this recommendation is based as much on expert consensus as on trial data. The AMACING study meets this challenge head on, enrolling patients identified as high risk for CIN and comparing guideline-directed IV hydration with no prophylactic therapy. Doing this took some guts, and the results were striking. Against expectations, the results suggested a cost to this therapy in terms of resource utilization and complications, without apparent benefit. But while some lower-risk patients may benefit from abstaining from IV hydration, it is too early to write off this therapy for many cardiac procedure patients.
Editorialists have criticized the unusual non-inferiority design of the trial and have questioned the method of calculation of the non-inferiority margin. More important is the low reported event rate, which was far lower than comparable studies, and results in loss of discriminatory power. Although a mix of IV and intra-arterial contrast procedures was represented, primarily diagnostic procedures were included, consequently, with relatively low contrast volumes (compared with coronary interventional procedures, for which typical contrast volumes are higher). Patients with eGRF < 30, who are likely at the highest risk of CIN, were specifically excluded from this trial. No knowledge is gained about this group of patients.
Patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention have been studied in two randomized trials that compared no hydration with IV hydration with normal saline. The authors of these trials reported much higher rates of CIN (11-35%) compared with AMACING, and found a significant positive effect of hydration on this outcome.
The idea that IV fluid at a fixed rate and dose is beneficial for every patient without regard to individual volume status is overly simplistic. Hypovolemia is to be avoided, but volume overload, with resulting high renal venous pressure and decreased renal perfusion, can be just as detrimental. For cardiac procedures in particular, the opportunity to individualize prescribed hydration based on measured volume status typically is present. This was the basis of the 2014 POSEIDON trial, which modulated hydration based on measured left ventricular end-diastolic pressure and found a significant beneficial effect on prevention of contrast nephropathy.
More and larger trials are needed to definitively settle this issue. For now, at-risk patients undergoing invasive cardiac procedures should continue receiving peri-contrast hydration, guided by evaluation of volume status.
