The Relative Renal Safety of Iodixanol and Low-Osmolar Contrast Media in Patients Undergoing PCI (Full Title Below)

The Relative Renal Safety of Iodixanol and Low-Osmolar Contrast Media in Patients Undergoing Percutaneous Coronary Intervention Insights from Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2)

ABSTRACT: Contrast-induced acute kidney injury (CI-AKI) is a common complication of percutaneous coronary intervention (PCI). Current guidelines support the use of iodixanol (Visipaque^®, GE Healthcare, Princeton, New Jersey) in patients at high risk for CI-AKI. Recent trials and meta-analyses have shown no difference in CI-AKI when iodixanol is compared to low-osmolar contrast media (LOCM). We evaluated the incidence of CI-AKI, in-hospital dialysis and in-hospital death in 58,957 patients who underwent PCI in 2007 and 2008 in a large regional consortium of 31 hospitals and who were treated with iodixanol (n = 17,814) or LOCM (n = 41,143). Propensity-matched analysis was performed to adjust for differences in baseline variables. Patients treated with iodixanol compared to those treated with LOCM were slightly older, had more medical comorbidities and a higher baseline creatinine (1.35 ± 1.07 mg/dL versus 1.10 ± 0.85 mg/dL; p J INVASIVE CARDIOL 2010;22:467–472 Key words: contrast media, iodixanol, low-osmolar contrast media, contrast-induced nephropathy ——————————————————————————————————— Contrast-induced acute kidney injury (CI-AKI) is a well-described complication of percutaneous coronary intervention (PCI). CI-AKI is associated with increased morbidity, mortality and healthcare cost.^1–3 Conditions which heighten the risk of CI-AKI such as chronic kidney disease, diabetes, congestive heart failure, hemodynamic instability and anemia are not typically modifiable at the time of cardiac catheterization, but other strategies have emerged to minimize the nephrotoxicity of contrast media.^1,4,5 Effective preventative measures against CI-AKI include hydration with normal saline and minimization of contrast volume by use of biplane imaging, limited injections and staging of interventional procedures.^6,7 N-acetylcysteine has shown promise as an adjunctive prophylactic therapy, but has mixed results in randomized, controlled trials.^8,9 Likewise, isotonic sodium bicarbonate remains controversial, although a recent meta-analysis suggests it may be superior to normal saline in reducing CI-AKI.^10–12 The type of contrast agent used also impacts the risk of CI-AKI. Both contemporary low-osmolar contrast media (LOCM) and the iso-osmolar contrast medium, iodixanol (Visipaque^®, GE Healthcare), result in less nephrotoxicity than the older-generation high-osmolar contrast media.^13,14 Early randomized, controlled trials and a 2003 meta-analysis suggested that iodixanol is less harmful to renal function than LOCM.^15–17 The revised ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction gave a Class IA recommendation for the use of iso-osmolar contrast media for coronary angiography in patients with chronic kidney disease.¹⁸ More recently, however, multiple larger randomized, controlled trials have demonstrated no difference in CI-AKI when iodixanol was compared with different types of LOCM.^19–22 In addition, two recent meta-analyses which included contemporary randomized trials showed no difference in the incidence of CI-AKI between iodixanol and a pool of LOCM.^23,24 Given the widespread use of iodixanol and LOCM in PCI, it is important to evaluate how often each type of contrast media is being used, and whether iodixanol improves patient outcomes in common practice — particularly in patients with preexisting chronic kidney disease. Therefore, we evaluated the outcomes of patients undergoing PCI in a regional consortium to analyze the impact of iodixanol compared to various LOCM.

Methods

The study cohort for our analysis included patients undergoing PCI in a large regional registry of contemporary PCI in 31 hospitals in Michigan. The details of the registry and of the data collection process have been described elsewhere.^25–29 Briefly, procedural data on all patients undergoing elective and non-elective PCI at the participating hospitals are collected using standardized data collection forms. Baseline data include clinical, demographic, procedural and angiographic characteristics as well as medications used before, during and after the procedure, and in-hospital outcomes. All data elements have been prospectively defined, and the protocol was approved by the institutional review board at each institution. The data were collected by a dedicated staff member and forwarded to the coordinating center. Medical records of all patients undergoing coronary artery bypass grafting or of patients who died in the hospital were reviewed to ensure data accuracy. A further 2% of cases were randomly selected for audit. The study population for this analysis included patients who underwent PCI in 2007–2008. We excluded patients with a history of renal failure requiring hemodialysis from any outcome analysis related to CI-AKI. All procedures were performed using standard coronary interventional techniques. The choice of contrast media was at the discretion of the operating physician within the realm of each hospital policy. The primary endpoint for this analysis was CI-AKI. Other endpoints evaluated included in-hospital need for hemodialysis and in-hospital death. CI-AKI was defined as a rise in serum creatinine greater than or equal to 0.5 mg/dL. Peak creatinine was collected at least 24 hours post procedure, but varied depending on the length of stay. In-hospital death was defined as death from either a cardiac or non-cardiac cause. Continuous variables are expressed as mean ± standard deviation, and discrete variables are expressed as frequency counts and percentages. The differences in discrete variables between groups were evaluated by the chi-square test and Fisher’s exact test. Continuous variables were analyzed using the t-test and the Wilcoxon rank sum test as needed. To adjust for the non-randomized use of iodixanol and for a possible selection bias in this cohort, a predictive model that adjusted for the propensity to receive iodixanol was also developed.³¹ The probability or a propensity score of receiving iodixanol was calculated using a non-parsimonious logistic regression model. We used Greedy matching techniques to select patients treated with any type of LOCM as counterparts to patients treated with iodixanol by choosing the patient with the nearest propensity score. In-hospital outcome was then compared within this propensity-matched cohort using hierarchical random-effect models. Differences in CI-AKI within the matched population were also analyzed in diabetic patients alone, after stratifying by baseline glomerular filtration rate (GFR) and after stratifying patients into those who did or did not exceed the maximum advised contrast dose.³⁰

Results

A total of 58,957 patients underwent primary PCI during the study period. Patients with end-stage renal disease requiring dialysis were excluded from the analysis. Thus, the study cohort included 57,765 patients, of whom 17,814 patients were treated with iodixanol and 41,143 were treated with LOCM. There was wide variation in the proportion of patients treated with iodixanol versus LOCM in the participating hospitals (Figure 1). Baseline demographics and clinical characteristics of the population are shown in Table 1. Patients treated with iodixanol were, in general, higher-risk patients: older, with more medical comorbidities and more likely to undergo PCI for unstable coronary disease. Baseline creatinine was higher in patients treated with iodixanol than in patients not treated with iodixanol (1.35 ± 1.07 mg/dL vs. 1.10 ± 0.85 mg/dL; p Table 2. There was a higher incidence of CI-AKI in those treated with iodixanol than those not treated with iodixanol (5.10% vs. 2.64%; p (Table 3), except that those patients receiving iodixanol tended to be more obese. The model used for developing the propensity score had a c-statistic of 0.66. In the propensity-matched cohort, in which each patient who received iodixanol was matched with a similar patient who received LOCM, after adjusting for baseline differences and clustering, there was no difference in the incidence of CI-AKI (OR 1.09, CI 0.97–1.23), in-hospital need for dialysis (OR 0.85, CI 0.60–1.20) or in-hospital death (OR 1.05, CI 0.87–1.26) (Table 4). When the propensity-matched cohort was further stratified by baseline GFR, no difference was observed between patients who received iodixanol and those who received LOCM, except in patients with a GFR of 60–89 ml/min/1.73 m² in whom the incidence of CI-AKI was actually higher with iodixanol (Figure 2). Similarly among the matched cohort of patients in whom the maximum advised contrast dose was exceeded, there was a trend toward a lower incidence of CI-AKI with iodixanol, but this was not significant. Among diabetic patients in the propensity-matched cohort, there was no significant difference in the overall incidence of CI-AKI between those patients who received iodixanol or LOCM (9.68% vs. 9.84%, OR, CI; p = 0.79). Since the incidence of CI-AKI peaks at 48–72 hours, we evaluated the propensity-matched cohort by length of stay. Although the overall incidence of CI-AKI increased as length of stay increased from 24 hours, to 48 hours to greater than or equal to 72 hours, there was no significant difference between those who received iodixanol compared to those who received LOCM.

Discussion

In this study, we evaluated the use of contrast media in patients undergoing PCI in current clinical practice. Our data suggest that iodixanol is a widely used contrast medium, particularly in higher-risk patients, but that the use of iodixanol does not seem to influence the risk of CI-AKI, in-hospital hemodialysis, or in-hospital death. Patients receiving iodixanol in this population were slightly older, had more medical comorbidities, and a slightly higher baseline creatinine. It is not surprising, therefore, that this population of patients had worse in-hospital outcomes in nearly every category. The baseline demographic and clinical differences between those patients who did and who did not receive iodixanol underscores the need for appropriate statistical adjustment. Following adjustment for the baseline differences, we did not find any advantage or disadvantage of iodixanol with respect to renal outcome compared with LOCM. Our study also reconfirms the importance of minimizing contrast volume in patients at risk for CI-AKI. As previously reported, patients with baseline renal insufficiency and patients in whom the maximum advised contrast dose was exceeded were at higher risk of CI-AKI.^5,32 It is worth noting that stratification of the matched patients by baseline renal function and by exceeding maximum advised contrast dose did not demonstrate less CI-AKI with iodixanol compared to LOCM, although there was a non-significant trend toward benefit with iodixanol (12.97% vs. 10.16%; p = 0.06). This may merit further investigation since a recent trial also suggests that among patients receiving high contrast volumes, the incidence of CI-AKI may be lower in patients treated with iodixanol.³³ Since CI-AKI tends to peak at 48–72 hours, it is worth examining the incidence of CI-AKI in matched patients with longer lengths of stay. Although the overall incidence of CI-AKI increased in both patient groups with the length of stay, there remained no significant difference between those who received iodixanol and those who received LOCM. The lack of difference of in-house mortality and need for hemodialysis between the matched groups is expected since there was no difference in the risk of more modest renal dysfunction. Modest elevations in serum creatinine after contrast exposure should be respected, however, since they are associated with increased long-term morbidity and mortality in prior studies.² The findings of this analysis corroborate those of two recent meta-analyses which demonstrated that the use of iodixanol does not result in less CI-AKI when compared to a pool of LOCM.^23,24 This analysis, however, evaluated a greater than ten-fold larger patient population treated in a routine practice setting and provides external validation of these meta-analyses. The findings of recent randomized trials, two recent meta-analyses, and now this observational study, provide support to the 2009 Focused Update of the AHA/ACC guidelines, which now recommends iso-osmolar contrast media (Class IA recommendation) or low-osmolar contrast media other than ioxaglate or iohexol (Class IB recommendation) for coronary angiography in PCI.³⁴ Our findings are based on observational data that are not centrally adjudicated. Although the data were analyzed using risk adjustment and propensity analysis, we cannot exclude that we were unable to adjust for other unknown factors that may influence outcome. Propensity matching cannot adjust for unmeasured confounders and thus cannot supplement a clinical trial. We were unable to assess for differences in periprocedural hydration in those who received iodixanol. In addition, our data collection is confined to the patient’s immediate hospital stay. It is likely that we may have underestimated the true incidence of CI-AKI in both arms, because creatinine tends to peak at 48–72 hours after contrast exposure. However, among the patient cohort with a longer length of hospitalization, we did not observe any difference in outcome based on type of contrast. Further, although CI-AKI is associated with worse long-term prognosis, this study focused primarily on short-term elevations in creatinine rather than long-term outcomes of harder endpoints. Iodixanol is a commonly used contrast agent in PCI. Within the limits of the observational nature of our study, there is no evidence to suggest that the use of iodixanol in lieu of other types of LOCM is associated with less CI-AKI in this setting, regardless of baseline renal function or presence of diabetes. Further controlled trials are warranted to assess the renoprotective effects of various types of LOCM in order to identify which are clearly the preferred renal protective agents.

References

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——————————————————————————————————————— From the ^aUniversity of Michigan School of Medicine, Ann Arbor, Michigan; ^bUniversity of Miami, Miami, Florida; ^cBlue Cross Blue Shield of Michigan, Detroit, Michigan; ^dSt. John’s Hospital and Medical Center, Detroit, Michigan; ^eSinai Grace Hospital, Detroit, Michigan; ^fIngham Regional Medical Center, Lansing, Michigan; ^gMeijer Heart Center, Grand Rapids, Michigan; ^hHenry Ford Hospital, Detroit, Michigan. The authors report no conflicts of interest regarding the content herein. Manuscript submitted May 21, 2010, provisional acceptance given June 28, 2010, final version accepted July 27, 2010. Address for correspondence: Hitinder S. Gurm, MD, Division of Cardiovascular Medicine, University of Michigan, 2A394, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-5853. E-mail: hgurm@med.umich.edu