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Ioxaglate Versus IoDixanol for the Prevention of Contrast-induced Nephropathy: The IDPC Trial
Abstract
Background. Despite the potential benefits of percutaneous procedures for the assessment and treatment of coronary artery disease, these interventions require the use of iodine contrast, which might lead to contrast-induced nephropathy (CIN) and increased risk of dialysis and major adverse cardiac events (MACE). Aims. We sought to compare two different iodine contrasts (low vs. iso-osmolar) for the prevention of CIN among high-risk patients. Methods. This is a single-center, randomized (1:1) trial comparing consecutive patients at high risk for CIN referred to percutaneous coronary diagnostic and/or therapeutic procedures with low (ioxaglate) vs iso-osmolarity (iodixanol) iodine contrast. High risk was defined by the presence of at least one of the following conditions: age >70 years, diabetes mellitus, non-dialytic chronic kidney disease, chronic heart failure, cardiogenic shock, and acute coronary syndrome (ACS). The primary endpoint was the occurrence of CIN, defined as a >25% relative increase and/or >0.5 mg/dL absolute increase in creatinine (Cr) levels compared with baseline between the 2nd and 5th day after contrast media administration. Results. A total of 2268 patients were enrolled. Mean age was 67 years. Diabetes mellitus (53%), non-dialytic chronic kidney disease (31%), and ACS (39%) were highly prevalent. The mean volume of contrast media was 89 ml ± 48.6. CIN occurred in 15% of all patients, with no significant difference regarding the type of contrast used (iso = 15.2% vs low = 15.1%, P >.99). Differences were not observed in specific subgroups such as diabetics, elderly, and ACS patients. At 30-day follow-up, 13 patients in the iso-osmolarity group and 11 in low-osmolarity group required dialysis (P =.8). There were 37 (3.3%) deaths in the iso-osmolarity cohort vs 29 (2.6%) in the low-osmolarity group (P =.4). Conclusion. Among patients at high risk for CIN, the incidence of this complication was 15%, and independent of the use of low- or iso-osmolar contrast.
J INVASIVE CARDIOL 2023;35(6):E281-E290. doi: 10.25270/jic/21.00249. Epub May 18.
Key words: nephropathy, contrast media, percutaneous coronary intervention, osmolarity
Introduction
Contrast-induced nephropathy (CIN) is a relatively frequent, costly, and potentially serious complication following intravascular administration of iodinated contrast material. Although the overall incidence of CIN is reported to be <2%, it may occur in up to 30% of patients with multiple risk factors.1-3 Previous registries have related its occurrence to an increased length of hospital stay and costs.4 Furthermore, CIN is associated with a higher risk of mortality and need for dialysis in the short to midterm follow-up.5
Although the pathophysiological mechanisms by which contrast agents cause CIN have not been completely understood, direct and indirect effects to the kidney, as well as hemodynamic perturbations, have been implicated.6
Despite a large number of preventive therapies tested, including renal replacement therapy and pharmaceutical agents (eg, acetylcysteine, statins, etc.), periprocedural intravenous saline infusion and a use of contrast volume as low as reasonably achievable, is the only proven strategy to minimize the risk of CIN.7-14
Compared with the high-osmolality contrast agents, low-osmolality and iso-osmolality agents are associated with a lower risk of CIN, and their use is therefore recommended.15 However, controversy remains whether iso- or low-osmolarity contrast media types are associated with a lower risk of CIN.16-22 However, differences in the osmolality of the contrast or in the ionic composition might result in superiority of iso vs low-osmolarity agents in the prevention of CIN.1 This issue has not been adequately tested in previous randomized trials.
The Ioxaglate versus IoDixanol for the Prevention of Contrast-induced nephropathy (IDPC) trial compared the use of iso- to low-osmolarity contrast for the prevention of CIN, among patients at high risk for this complication.
Methods
Trial design. The IDPC is a single center, prospective, open-label, randomized trial enrolling consecutive, high risk patients, undergoing diagnostic or therapeutic percutaneous coronary procedures in a public, tertiary institution, between September 2016 and October 2018. The trial was registered on http://www.clinicaltrials.gov (NCT02991742) and approved by the research ethics board of our institution. There was no external funding for this research.
Population. Patients undergoing coronary diagnostic angiography or percutaneous intervention were eligible for the trial if they had at least 1 risk factor for CIN: age >70 years, CKD (CrCl <60 mL/min according to the CKD-EPI formula), diabetes mellitus, congestive heart failure, left ventricular ejection fraction <50%, cardiogenic shock, use of intra-aortic balloon pump, or acute coronary syndrome referred to urgent procedures. We chose the inclusion criteria on the basis of independent risk factors validated by previous observational studies, including the ACT trial.13
Patients on dialysis and those with ST-segment elevation myocardial infarction undergoing primary or rescue angioplasty were excluded because of the inability to administer the study hydration protocol for at least 6 hours before the procedure.
Study procedures. Data were obtained at baseline, on the day of the angiography, and between 48 to 96 hours and at 30 days after angiography. Baseline data were collected immediately after randomization and before administration of hydration scheme and the study contrast media. Data collected at baseline included demographic and clinical characteristics and the most recent serum creatinine level measured within the past 48 to 96 hours. On the day of the procedure, we collected data regarding the administration of the iodine contrast, hydration scheme, and angiographic procedure. Between 48 to 96 hours after angiography, we assessed vital status, need for dialysis, need for another angiogram, and collected a blood sample for serum creatinine measurement. Whenever >1 measurement was available during the period of 48 to 96 hours, the highest was used. Patients were contacted 30 days after the intracoronary procedure to assess the need for dialysis and the vital status.
Patients with CrCl ≤ 45mL/min were hospitalized one day prior to the procedure for intravenous hydration with 0.9% saline (0.5-1 mL/kg per hour according to left ventricular function), which was maintained for 12 hours after the procedure. Patients with CrCL between 45 and 60 mL/min were also hydrated for 4 hours before and after to the procedure.
Trained investigators and study coordinators collected the data using a web-based system. Data quality control was guaranteed by automated data entry checks and on-site monitoring.
Randomization. After providing written informed consent, patients were randomized in a 1:1 ratio to receive iso- (Iodixanol) or low-osmolarity (Ioxaglate) contrast. To guarantee concealment of the allocation list, randomization was implemented through a 24-hour web-based automated randomization system. In order to reduce the likelihood of systematic errors and allow the use of statistical tests, simple randomization was performed on the day of the coronary procedure at the exam scheduling center using the Excel program with the generation of the sequence of the type of contrast to be used. Patients who met the inclusion criteria were randomized sequentially, regardless of the type of coronary procedure to which it was indicated (catheterization or PCI). This information was entered into the IDPC electronic medical record called GESTHOS.
Endpoints. The primary endpoint was the occurrence of CIN, defined as a >25% relative increase and/or >0.5 mg/dL absolute increase in creatinine (Cr) levels compared with baseline, between the 2nd and 4th day after contrast media administration.
Secondarily, we evaluated the incidence of CIN at 30 days, the composite of death or need for dialysis at 48 to 96 hours and at 30 days. Additionally, we aimed to identify independent predictors of death/need for dialysis among this population.
Sample size calculation. For sample size calculation we estimated an incidence of CIN of 25% at 96 hours after the procedure in patients receiving low-osmolarity contrast. We anticipated a 20% reduction in the risk of CIN with iso-osmolar contrast. Assuming a 10% loss of the sample, the inclusion of 2262 patients provided the study with 80% power, with a type-one error of 0.05.
Statistical analysis. All analyses were performed on an intention-to-treat basis and no post randomization exclusions were performed. Differences in discrete variables were evaluated by the χ2 test or Fisher exact test. Continuous variables with skewed distributions were analyzed using the Wilcoxon rank-sum test. The results of comparisons of proportions are presented as relative risks and their respective 95% confidence intervals. Secondary outcomes at 30 days after randomization were analyzed with Cox proportional hazards regression. The composite outcome death or need for dialysis were presented as a Kaplan–Meier curve. Missing values were not imputed.
Results
Between September 2016 and October 2018, a total of 16,244 patients underwent percutaneous coronary procedures at our Institution, and 14% met the inclusion/exclusion criteria and agreed to participate in the IDPC trial (n = 1,134 patients in each randomized arm). Figure 1 reports the flowchart for this trial.
*CROSS = local government regulation system.
Table 1 summarizes the main clinical characteristics of the study population at baseline. There were more males (63.5%) with more than half of the population being diabetics (52.9%). Acute coronary syndrome was the initial clinical presentation in 38.9% of patients, 32.4% had previous CKD (ClCr <60 mL/min/1.73m2) and 6.5% had previous left ventricular dysfunction (ejection fraction <50%). Overall, there were no significant differences between the two cohorts, except for a slightly higher prevalence of smokers in the low osmolarity group (56.9% vs. 48.5%, P<.01).
The mean number of risk factors for CIN per patient was 2.4, with more than half having ≥ 2 study inclusion criteria. According to the Mehran score, the enrolled patients were at moderate risk for CIN (8.9 ± 3.7).
The majority of the procedures were diagnostic (85.2%) and the amount of contrast used was 89.5 ±48.6 mL, with no difference between groups.
There was a significant variance in the creatinine levels from baseline to post procedure (Δ= 0.05 mg/dl, P=.045), which was more evident in the ioxaglate cohort (Δ= 0,06 mg/dl vs. Δ= 0,03 mg/dl, P=.001)
The incidence of the primary endpoint CIN was 15.1% and it did not differ between the randomized group (15.1% with ioxaglate vs. 15.2% with iodixanol, P=.953). Independent predictors of CIN in this population were: male gender (OR 1.26, 95% CI 0.99-1.63), basal creatinine (OR 1.42, 95% CI 1.10-1.81), LV dysfunction (OR 1.56, 95% CI 1.00-2.35), use of pacemaker (OR 4.9, 95% CI 1.64-14.6), cardiogenic shock, or use of IABP (OR 14.9, 95% CI 4.03-7.08),
The composite outcome of 30-day death or dialysis occurred in 3.4% of the total sample, without differences between the groups (3.2% vs. 3.7%, P=.489) (Figure 2). Independent predictors of death/dialysis were ACS as initial clinical presentation (OR 1.9, 95% CI: 1.21–2.98), LV dysfunction (OR 3.19, 95% CI 1.78–5.73) and occurrence of CIN (OR 5.66, CI 95% 3,64–8,79). Noteworthy, the type of contrast media was not a predictor of these adverse events (Figure 3).
Discussion
This is the largest trial to date comparing iso-osmolarity vs low-osmolarity contrast media for CIN prevention following percutaneous coronary procedures. The incidence of CIN among this high-risk population was lower than anticipated, possibly reflecting the relatively low amount of contrast media used. The type of contrast media (iso- vs. low-osmolarity) did not impact on the occurrence of CIN.
As previously mentioned, the overall incidence of CIN varies from 0.15% to 2.3%. However, it might increase up to 35% depending on the presence of risk factors and procedure characteristics. In trials with patients with similar characteristics to ours, the incidence of CIN varied from 12.3% to 15.9%.1,2,4,5,23
It is essential to identify patients at higher risk of this complication. In the literature, presence of congestive heart failure, chronic renal dysfunction, and advanced age are commonly associated with its occurrence, as well as the presence of cardiogenic shock.2 This last variable was rare in our casuistic (0.4%), but the remaining three were frequently observed.
Iso-osmolar iodine contrasts have osmolarity close to the blood osmolarity (around 280-290 mOsm/Kg), while the “so called” low osmolarity ones have osmolarity between 300-900 mOsm/Kg. In fact, they received this denomination due to the lower osmolarity as compared to the first generation of iodine contrast, which had osmolarity ≥1500 mOsm/Kg. However, it is important to understand that contrasts also differentiate based on other properties such as viscosity, iodine concentration, and ionicity. Therefore, even contrasts classified in the same osmolarity range might result in different renal damage.24 Contrary to many previous trials and meta-analysis, the present study evaluated only one type of contrast from each group, minimizing this possible bias.
Finally, despite being a serious adverse event, which eventually results in prolonged hospitalization and increased costs, in the present report the occurrence of CIN resulted in relatively low rates of death or dialysis.
Limitations. There are other properties beyond osmolarity which might impact the occurrence of CIN, therefore the results should not be extrapolated to other contrasts than the two tested in the present study. The incidence of CIN was lower than anticipated, therefore the study power might be reduced. Finally, this is a single center trial, which limits extrapolations of our findings.
Conclusions
Among high-risk patients, the occurrence of CIN remains high, despite the use of a small amount of contrast and prophylactic hydration. The type of contrast (ioxaglate [low-osmolarity] vs. iodixanol [iso-osmolarity]) was not associated with the occurrence of CIN.
Although infrequent in this sample, the occurrence of the composite endpoint of death or dialysis was more often observed in patients with acute coronary syndrome, LV dysfunction, and those who presented CIN after the percutaneous coronary procedure.
References
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Affiliations and Disclosures
From the 1Department of Interventional Cardiology, Instituto Dante Pazzanese de Cardiologia, São Paulo, SP, Brazil; 2Department of Interventional Cardiology, Mount Sinai, New York, New York; and the 3Hospital São Domingos -DASA.
Clinicaltrials: NCT02991742
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript accepted February 7, 2023.
Address for correspondence: J Ribamar Costa Jr, Instituto Dante Pazzanese de Cardiologia, Av. Dr Dante Pazzaensse, 500, Ibirapuera, São Paulo – SP, Brazil. Email: rmvcosta@uol.com.br
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