High-risk patients who did not receive guidelines-recommended prophylactic hydration prior to procedures requiring iodinated contrast media had the same rate of contrast-induced nephropathy (CIN) as patients who received usual care, according to results from the phase 3 AMACING trial published online ahead of print in The Lancet.1
CIN refers to the decline in renal function that can occur as an adverse reaction to the intravascular administration of iodinated contrast media. Various international guidelines state that in order to prevent CIN, patients at high risk should receive intravascular volume expansion with isotonic saline prior to contrast media administration, a recommendation that the AMACING investigators say is based on expert opinion, not clinical trials.
Study investigators Estelle C. Nijssen, MSc, and colleagues from Maastricht University Medical Centre, The Netherlands, randomly assigned 660 high-risk patients undergoing elective procedures involving iodinated contrast material to receive no prophylaxis (n=332) or intravenous hydration (n=328).
High-Yield Data Summary
- Clinical practice should not be changed based on a single study. However, the results of this study raise the question as to whether the guidelines should have introduced this group of patients to prophylactic hydration as standard care, since its efficacy has not been shown.
Patients were defined as high-risk on the basis of criteria described in The Netherlands and European guidelines. Patients with an estimated glomerular filtration rate (eGFR) lower than 30 mL per min/1.73 m2, a history of dialysis, or no referral for intravenous hydration were not eligible for the study.
Results showed that 8 out of 307 patients (2.6%) who received no prophylactic hydration and 8 of 296 patients (2.7%) who did receive prophylactic hydration developed CIN, an absolute difference of −0.10% (one-sided 95% CI −2.25 to 2.06; one-tailed P =.4710). Mean total costs were €1455 for the hydration patients and €792 for non-hydration patients (mean difference H– minus H+: −€663, 95% CI –€1234 to −€191).
In an accompanying editorial, Peter A McCullough, MD, and colleagues criticized the study’s methodology.2 “The method of computation of the non-inferiority margin and the revision of this statistical approach was unconventional and in the end had the assumptions that the contrast-induced acute kidney injury rate in the normal saline group would be 2.4% and the rate in the no saline prophylaxis group could be as high as 4.5% with relative risk or hazard ratio of less than 1.88 to meet non-inferiority. The upper bound of the 95% confidence limit for this construction is about 4.50, which exceeds all conventions for non-inferiority trials,” they wrote.
Dr. McCullough and colleagues also expressed the opinion that the field is not ready for non-inferiority trials due to the absence of a proven standard for prophylactic hydration that can be applied in control groups. However, Ms Nijssen stated in an email interview with Rheumatology Advisor that a non-inferiority design was the only appropriate choice for evaluating the cost-effectiveness of prophylaxis.
“The efficacy of prophylaxis had not been shown, and it was not known what CIN incidence would be in patients not receiving any prophylaxis. We assumed that the prophylaxis might be better in reducing CIN than not giving any prophylaxis but that the costs and patient burden imposed would also be much greater, as well as the risk of complications due to prophylaxis,” she commented.
Ms Nissen added: “Because in most cases CIN is a transient rise in serum creatinine — a biochemical event which resolves by itself within a few weeks and which only rarely leads to lasting clinically relevant effects — we determined that a non-inferiority margin of 2.1% would be acceptable. That is, we determined that not giving prophylaxis would be non-inferior to prophylaxis in that it saves costs and reduces burdens on patients, as long as the difference in CIN between the two groups was not greater than 2.1%.”
Summary and Clinical Applicability
Ms Nijessen told Rheumatology Advisor that physicians could consider not giving prophylactic hydration to the population described in the study, assuming optimal contrast administration. “It must be noted that clinical practice should not be changed based on a single study,” she stated.
“However, in this case one could ask the question whether the guidelines should have introduced this prophylactic hydration as standard care, since its efficacy had not been shown. Also, we found complications of the prophylactic hydration occurring in 5.5% of patients, which poses the question whether it is ethical to continue giving prophylaxis. Lastly, there are several studies in recent years that generate some doubt as to cause and consequences of CIN.”
- The study took place at a single center
- The sample size was smaller than planned
- The design of the study was open-label, by necessity
- Post-contrast serum creatinine measurements were not available in all patients
- 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 [published online February 21, 2017]. The Lancet. doi:10.1016/S0140-6736(17)30057-0
- McCullough PA, Zhang J, Ronco C. Volume expansion and contrast-induced acute kidney injury [published online February 21, 2017] The Lancet. doi:10.1016/S0140-6736(17)30540-8