Contrast Agents: Hemodynamics, Electrolytes and Acute Kidney Injury

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

Transcatheter Cardiovascular Therapeutics 2007

Washington, DC / October 20-25, 2007

According to Dr. Peter A. McCullough, Chief, Preventive Medicine, William Beaumont Hospital, Royal Oak, Michigan, contrast-induced acute kidney injury (AKI) is the new term for what has traditionally been referred to as contrast-induced nephropathy (CIN). The term AKI has been proposed to represent the entire spectrum of acute renal failure, along with diagnostic criteria and a staging system that reflect quantitative changes in serum creatinine and urine output (Mehta et al. Crit Care 2007;11(2):R31).

“Nephrologists are trying to create this nomenclature for how serious renal failure is,” Dr. McCullough told the audience. Contrast-induced AKI is generally defined as an increase of 25% in serum creatinine or an absolute increase from baseline of 0.5 mg/dL.

Dr. McCullough reviewed the results of a meta-analysis comparing effects of iso-osmolar vs. low-osmolar contrast agents, for which he was primary investigator. The meta-analysis pooled individual patient data (n=2727) from 16 double-blind, randomized, controlled trials in which renal-impaired patients received either the iso-osmolar contrast medium (CM) iodixanol (n=1382) or a low-osmolar CM (n=1345) intra-arterially. Patients were stratified according to chronic kidney disease (CKD), diabetes mellitus (DM) or both.

Results showed that the maximum creatinine increase within three days after CM administration was significantly smaller in the iodixanol group compared with the group receiving low-osmolar CM (0.06 mg/dL vs. 0.10 mg/dL, P<0.001), particularly in patients with CKD (0.07 mg/dL vs. 0.16 mg/dL, P=0.004) and CKD with DM (0.10 mg/dL vs. 0.33 mg/dL, P=0.003) (J Am Coll Cardiol 2006;48:692-9).

Contrast-induced AKI, defined as an increase in creatinine ³0.5 mg/dL within three days after CM administration, occurred less than half as frequently in the iso-osmolar group as in the low-osmolar group in all patients (1.4% vs. 3.5%, P<0.001), roughly one-fourth as frequently in CKD patients (2.8% vs. 8.4%, P=0.001), and approximately one-fifth as frequently in patients with combined CKD plus DM (3.5% vs. 15.5%, P=0.003). These results suggest the choice of an iso-osmolar over a low-osmolar contrast agent is most critical in patients at highest risk.

The RECOVER (Renal Toxicity Evaluation and Comparison Between Visipaque and Hexabrix in Patients with Renal Insufficiency Undergoing Coronary Angiography) trial, which was published soon after the meta-analysis, also demonstrated a significantly lower incidence of CIN with the iso-osmolar contrast agent iodixanol vs. the low osmolar contrast agent ioxaglate (P=0.021) (J Am Coll Cardiol 2006;48:924-30).

“This is something we can definitely draw on,” Dr. McCullough noted. “It is relatively clear that in the high-risk group of patients who have CKD and diabetes, there is a marked reduction in the rate of AKI in patients who receive iodixanol compared with patients receiving any low-osmolar contrast agent.”

Since the meta-analysis, the CARE (Cardiac Angiography in Renally Impaired Patients) and ICON (Ionic Versus Nonionic Contrast to Obviate Worsening of Nephropathy in Chronic Renal Failure Patients) trials in lower-risk patients showed no differentiation in the risk of contrast-induced AKI based on type of CM. But both trials are widely regarded as having been underpowered, and Dr. McCullough expressed skepticism over their results. “That they failed to find a benefit from one agent over another could be because they don’t have complete enough follow-up in terms of creatinine measurements, or they had a too low-risk group,” he commented. “For the average patient coming into your hospital or mine, who has kidney disease and diabetes, there’s a lower rate, lowest of all, with iodixanol.”

Along with choice of CM, data show that volume expansion is a useful strategy for minimizing contrast-induced AKI (Stacul et al. Am J Cardiol 2006; 98(6A):59K-77K).


The new American College of Cardiology/American Heart Association guidelines support this finding. These guidelines established as a Class I indication the need to obtain evidence of creatinine clearance and estimated glomerular filtration rate (GFR) in patients being treated for unstable angina and acute coronary syndrome (ACS), and for dosing adjustments based on evidence of renal insufficiency. As another Class I indication in patients undergoing angiography, iso-osmolar contrast agents are preferred (Anderson et al. J Am Coll Cardiol 2007;50(7):E1-E157).

The most vulnerable patients are those whose renal systems are already compromised by chronic renal disease and/or diabetes, who appear to have a threefold greater risk of dialysis brought about by contrast-induced AKI compared to patients with normal baseline renal function (Am J Cardiol 2006;98(6A):5K-13K). However, even patients with normal creatinine clearance levels and GFRs are at increased risk for contrast-induced AKI from low-osmolar agents.

Those patients who experience a contrast-induced rise in creatinine have an accelerated mortality risk, whether or not they use dialysis. “Even if the creatinine returns to normal, the kidneys are taking a hit, and even after recovery of glomerular filtration, those kidneys are still damaged,” Dr. McCullough remarked. “In a perfect world, we’d move our patients in and out of the catheterization laboratory with not a whit of kidney injury.”

He estimated that about half of all coronary laboratory imaging occurs in the context of ACS, while about half is elective. “In the ACS cases, based on the totality of evidence, it’s very reasonable to use iso-osmolar agents—and in the US, that would be iodixanol,” Dr. McCullough confirmed.

A number of European and global cardiology specialty societies have issued guidelines calling for an iso-osmolar CM in patients at high risk for contrast-induced AKI, and the National Kidney Foundation calls for use of iodixanol in coronary computed tomographic angiography (CTA) involving dialysis patients.

Cardiac Data

Dr. Charles J. Davidson, Professor of Medicine, Division of Cardiology, Northwestern University, Chicago, Illinois, discussed certain benefits of iso-osmolar agents in terms of patient comfort (heat sensation) and heart rate, both of which contribute to motion artifacts that carry the risk of disrupting image quality. These hemodynamic and ECG changes were more frequent with high-osmolar than low-osmolar CM and are minimized with iso-osmolar CM use (Bergstra et al. Catheter Cardiovasc Interv 2000; 50:314-21, Dacher et al. Catheter Cardiovasc Interv 2007; 69:S61, Leschka et al. Radiology 2006;241:378-85).

In addition, he discussed the COURT (Randomized Trial of Contrast Media Utilization in High-Risk PTCA) and VICC (Visipaque vs. Iopamidol Contrast Media Comparison) trials, both demonstrating statistically significant advantages of iodixanol over low-osmolar agents in reducing periprocedural risk.

COURT was a multicentre, prospective, randomized double-blind trial performed in 856 high-risk patients using iodixanol (n=410) or the low-osmolar agent ioxaglate (n=410) in high-risk percutaneous transluminal coronary angioplasty. The primary end point, a composite variable of in-hospital major adverse clinical events (MACE), was half as frequent in patients receiving iso-osmolar CM compared with ioxaglate (5.4% vs. 9.5%, respectively; P=0.027) (Circulation 2000;101(18):2172-7).

As secondary end points, core laboratory-defined angiographic success was more frequent in patients receiving iodixanol (92.2% vs. 85.9%, P=0.004) and there was a trend toward lower total clinical events at 30 days in patients randomized to the iso-osmolar CM (9.1% vs. 13.2% for ioxaglate, P=0.07). Subsequent analyses have indicated that use of the glycoprotein IIb/IIIa agent abciximab “may have been a leveler,” Dr. Davidson revealed, and that without abciximab, there was a fourfold difference in the frequency of in-hospital MACE with iodixanol vs. ioxaglate (1.7% vs. 8.1%, P=0.001).

In the VICC trial involving 1276 patients, iodixanol was compared with the low osmolar agent iopamidol with a similar approximately 50% reduction in MACE, including non-Q-wave myocardial infarctions (4.8% vs. 9.0%, P=0.003). “What was amazing is that they reached almost identical conclusions,” Dr. Davidson reported (Circulation 2003;108(suppl IV, abst 1660):IV-354).

A third speaker, Dr. James K. Min, Assistant Professor of Medicine and Radiology, and Director, Cardiac CT Laboratory, Weill Cornell Medical College, New York, New York, recommended the application of the Bayes theorem, or the construction of positive and negative likelihood ratios, to assess which patients might benefit most from coronary CTA.

Under its current risk profile and given its high negative predictive value, the procedure can be valuable in excluding significant coronary artery disease in individuals at low pre-test risk and those with equivocal stress testing. The procedure also shows benefits for individuals at intermediate pre-test risk for coronary stenosis, while the least likely to benefit are those with high pre-test likelihood of significant coronary disease, according to Dr. Min.

Patient Burden and Medical Care Cost of CIN

New research presented here at TCT supports the need to reduce risk of contrast-induced AKI because of its high cost, frequency and mortality risk.

It has been argued that the higher cost of the iso-osmolar agent iodixanol can be justified based on the fact that it poses less risk of contrast-induced AKI than high- and low-osmolar agents. This assertion is borne out by the findings of a literature review by Teresa Zyczynski, PharmD, and colleagues, which substantiates the high cost of contrast-induced AKI (TCT 2007, Abstract 315).

The authors cite CIN as the third most common cause of hospital-acquired acute renal failure after hypotension and surgery and note there is no systematic assessment of its economic burden. Along with conducting a literature review of short- and long-term clinical consequences, they assessed the economic burden of CIN using a decision analytical model.

As expected, patients with CIN had a higher medical utilization rate and worse short-term and long-term clinical outcomes than patients undergoing percutaneous coronary intervention (PCI) without that complication. In-hospital stays doubled, ICU lengths of stay quadrupled, in-hospital mortality was nearly six times greater, one-year mortality doubled, and MACE at one year were approximately a third higher in patients who experienced CIN than otherwise.

The average in-hospital cost of CIN (in US dollars) was estimated to be $10,345 (range $5032 to $12,959) and the one-year follow-up cost $1467, resulting in an average per-patient one-year cost of $11,812 and a per-procedure cost of about $1000 per PCI. When stratified by patient risk, the per-procedure CIN-associated costs were found to be $886, $1654, $3083 and $6768 for low-, moderate-, high- and very high-risk risk groups, respectively.

With population aging and growth in chronic conditions such as diabetes, an increase in the number of patients with risk factors for CIN is expected. The authors asserted that without targeted interventions to reduce the incidence of CIN, the cost will continue to increase.

They also cautioned that interventions targeted at the high- or very high-risk groups, even with an estimated 10% shift in risk profile, would yield cost savings lower than those achieved when individuals at all risk levels are targeted. Given the overall high economic burden of CIN, even relatively expensive interventions might prove to be cost-effective, according to the authors.

Other Predictors of CIN

The benefit of reducing CIN risk in low-risk individuals was further explored in a poster presentation by Dr. Eric Chong, Heart Institute, National University Hospital, Singapore, and colleagues (TCT 2007, Abstract 309). They followed a cohort of 5086 patients with normal baseline renal function (serum creatinine <1.5 mg/dL) who did not receive prophylactic treatment while undergoing primary or elective PCI at their institute.

The increase in the incidence of CIN among diabetic patients vs. nondiabetics was non-significant (8.2% vs. 6.8%, P=0.18), but within the diabetic group, those who were on insulin were at significantly higher risk of CIN than those on diet control and oral hypoglycemic agents (18.9% vs. 3.6% vs. 6.8%, respectively, P=0.001). Other significant clinical predictors of CIN were advanced age (odds ratio [OR] 6.4, P=0.042), female gender (OR 2.0), abnormal left ventricular ejection fraction (OR 1.02, P=0.01), hypotension defined as systolic blood pressure <100 mm/Hg (OR 1.5, P=0.004), and anemia defined as hemoglobin count <11g/dL (OR 1.5, P=0.044).

Mortality at one month was 14.5% in the CIN group vs. 1.1% in the non-CIN group (P<0.001). Results at six months were even more striking: 17.8% mortality in the CIN group vs. 2.2% in the non-CIN group (P<0.001). These results suggest that even patients with normal baseline renal function should be evaluated carefully for other predisposing factors to CIN and targeted for preventive precautions.

Iso-osmolar vs. Low-osmolar Contrast Media: New CIN Data

A third poster reported on a prospective, controlled, randomized trial conducted at the interventional cardiology unit of Hospital 12 de Octubre in Madrid, Spain (Hernandez et al., TCT 2007, Abstract 312). All 250 patients sequentially assigned to the iso-osmolar CM iodixanol or to the low-osmolar CM ioversol were hydrated with intravenous isotonic solution 1000 mL and received oral N-acetylcysteine 1200 mg b.i.d.

Baseline differences in serum creatinine, creatinine clearance levels and contrast volumes across patient groups were statistically insignificant. Post-procedure serum creatinine measures were taken at 72 hours. CIN was defined as a creatinine increase of 0.5 mg/dL or >25% from baseline.

The incidence of CIN, 5.6% globally, was over twice as frequent in the ioversol group compared with the iso-osmolar cohort (8.3% vs. 2.5%, OR 0.2555, P=0.047). Low creatinine clearance levels served as an independent predictor of CIN and multivariate analysis showed iodixanol and higher creatinine clearance to be protective factors.


Advancement of noninvasive coronary imaging has been accompanied by a risk of CIN, a term that has now been replaced by the more inclusive contrast-induced AKI. An estimated half of all AKI continues to result from iodine CM used in coronary imaging. The evidence supports several keys to prevention, including patient risk evaluation, saline hydration, and targeted use of iso-osmolar contrast agents that are costlier but demonstrate less risk of causing AKI than high- and low-osmolar agents. International authorities have issued guidelines recommending use of the iso-osmolar agent in patients at high risk for contrast-induced AKI.

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