1.Introduction

2. Body

2.1. Pharmacological properties:

Iodixanol is a water-soluble iso-osmolar non-ionic dimeric iodinated contrast agent for intravascular administration. Chemically, it is 5,5’-[(2-hydroxy-1,3-propanediyl) bis (acetylamino)]bis[N,N’-bis(2,3-dihydroxypropyl)-2,4,6- triiodo-1,3- benzenedicarboxamide] (Figure 1), with a molecular weight of 1550.20 and iodine content of 49.1%. It has six iodine atoms per molecule, no carboxyl groups and has nine hydroxyl groups evenly distributed around the molecule ⁸.

Figure 1. Chemical structure of Iodixanol (Visipaque).

Figure 1. Chemical structure of Iodixanol (Visipaque).

Iodixanol has a similar pharmacokinetic profile as other ICAs. Peak serum concentrations are rapidly achieved, followed by an exponential decrease, with almost no detectable levels in 24 hours. Iodixanol distributes only in the extracellular fluid. Mean distribution half-life (0.43 hours), elimination half-life (2.18 hours) and apparent volume of distribution (0.275 L/kg) are not dose-dependent³. Around 97% of the administered dose is excreted without being metabolized through the urine in 24 hours, and the rest through feces in 72 hours. This changes to 76% of the dose excreted via urine over five days in patients with stable but severely impaired renal function (creatinine clearance <20ml/min), due to prolonged elimination half-life. Nonionic contrast media does not directly affect glomerular filtration rate. In healthy individuals, iodixanol acts as a diuretic and produces a dose-dependent increase in urine volume³. Iodixanol is available as a solution for injection, at concentrations corresponding to 270 and 320 mg of iodine/mL (mgI/mL). It is mixed with sodium and calcium chloride, which renders it an isotonic solution.

2.3. Tolerability and safety:

ICAs differ in their tolerability profiles. Iso-osmolarity and lower iodine content have been proven to be safer and more tolerable in humans ¹⁰. The toxicity of poly-iodinated contrast media is a function of the molecule’s physicochemical properties: notably ionicity, higher osmolality and viscosity, and the chemical interaction of reactive iodine anions with biological sites¹².

2.3.1. Pain and discomfort:

Pain and discomfort following contrast administration is not only inconvenient for the patient but can also compromise image quality due to motion artifacts produced by the patient’s body movements during imaging. If the motion artifacts are significant enough to render the study non-evaluable, repeating the study would lead to additional contrast and radiation exposure to the patient and increased cost to the healthcare system. Earlier studies by Klow et al., and Hill et al. in patients undergoing invasive cardiac angiography, the patients receiving iodixanol had a significantly lower incidence of moderate to severe discomfort than those receiving iohexol^19,21. In a more recent study with patients receiving iodixanol or iopamidol for CCTA, there was no difference in the number of patients having moderate to severe symptoms. However, a subgroup analysis of patients >55 years of age showed lower rates of moderate to severe symptoms in the iodixanol group (8.5% vs. 24.6%, p=.01)²². In another study, while 27% of patients receiving iodixanol 320 reported pain or warmth, the rate was 13.1% for iodixanol 270, 21.3% for iopamidol and 16.7% for iohexol (p<0.05)¹⁰.

When compared to a hyperosmolar agent, an iso-osmolar agent has greater vascular stability in arterioles that supply the skeletal muscles and skin over the extremities. Hence, there is no activation of vascular endothelium, and no vasodilation followed by vasoconstriction.^54,55 The activation of nociceptors in nerves supplying the neurovascular bundles is also less by iso-osmolar agents. This vascular stability and attenuated nociceptor activation may result in less pain and discomfort when iodixanol is used¹². A study by Murphy et al. showed that diatrizoate, a high-osmolar agent, had higher pain and discomfort rates than low-osmolar iohexol and ioxaglate, thus proving iodine content was not responsible for adverse effects²³. Hence, it can be hypothesized that osmolarity of the ICA is the determinant of pain and discomfort after contrast injection, and not viscosity or iodine content.

2.3.2. Flushing:

Flushing is the most common side effect after intravenous contrast injection. Iodixanol 270 had the lowest incidence of flushing (46%; 95% CI 36–56%) in 513 patients undergoing CCTA when compared to iopamidol (78%; 95% CI 59–87%) and iohexol (72%; 95% CI 55–85) (p<0.001)]¹⁰. Patients receiving iodixanol had a lower incidence of moderate to severe flushing (3.0% vs. 12.8%, p=.005) than iopamidol in another study. The difference was more profound in patients over 55 years of age (8.5% for iodixanol vs. 24.6% iopamidol, p=0.01)²². Other adverse effects reported, but very infrequently with iodixanol include chest or leg pain, visual disturbance, dizziness, hypotension, vasovagal reaction, headache, nasal symptoms, taste disturbances, coughing, dyspnea, skin reactions, nausea, vomiting, and shivering³.

2.3.3. Heart rate variability:

The patient’s heart rate and its variation play a vital role in cardiac CT imaging due to the limitations in temporal resolution ^24-26. Besides mean heart rate, significant variations in heart rate per minute (due to significant R-R interval variations) also causes misregistration of ECG-gated data, hence causing artifacts in the reconstructed image. These if severe, may render the study non-evaluable. Heart rate variability might also potentially increase overall radiation dose, due to longer scan times.

Giesler et al.²⁷ and Hoffmann et al.²⁸ showed that a multitude of quality measures of CCTA including sensitivity, image quality, and evaluable coronary artery segments was inversely proportional to heart rate. Median HR change was higher with iohexol when compared to iodixanol, in a CCTA study by Choi et al. (p<0.001)^15,27,28. While iodixanol showed more HR variation < 3 beats/min (86% v/s 72%, p=0.03) HR variability >4 beats per min were noted more with iohexol (p=0.003)¹⁵. In another study, HR variability was lowest for CCTA subjects with iodixanol 320 (2.5 ± 3.0), followed by iodixanol 270 (3.4 ± 5.2), and was highest with iopamidol 370 (4.9 ± 5.8), (p< 0.001)¹⁰. Studies have shown no difference in heart rate variability between iodixanol and iopidamol in patients undergoing CCTA (p=0.56) ²², as well as non-gated chest CT angiography (p=0.72)²⁹ No significant difference was seen in the mean deviation of HR in patients undergoing CCTA, receiving iodixanol versus iomeprol (1.4 beats/min v/s 4.4 beats/min, p value not significant). However, the latter group showed a greater number of arrhythmic heartbeats during the scan (p<0.001)³⁰. Ioxaglate has been shown to induce a greater increase in mean heart rate than iodixanol in patients undergoing cardiac angiography and ventriculography (p<0.05). Both agents caused significant QT interval prolongation (p<0.005), but the changes were more marked with ioxaglate³¹. When compared with iomeprol, no significant differences were seen in terms of mean changes in HR during left coronary arteriography (p=0.8), right coronary arteriography (p=0.9), or left ventriculography (p=0.8) by Schmid et al³². The contrast injection during cardiac catheterization could presumably imply more susceptibility to reflex tachycardia, secondary to direct and nondiluted contrast agent injection, than during left ventriculography. Other factors such as the volume of contrast media used, image acquisition time and route of administration vary during these procedures which might influence the ICA’s effect on cardiac parameters³³. This could perhaps explain the results from studies where there was no difference in HR variability during left ventriculography between groups who received iodixanol and other ICAs^20,35 (Table 1)

Table 1. Major trials of tolerability.

Table 1. Major trials of tolerability.

Authors	Randomized	Numb of patients	Mean Age	Contrast	Endpoints	Results
Lily Honoris et al, 201710	Yes	N=513	57 ±11	Iodixanol Iohexol Iopamidol	Flushing	Iodixanol superior
Xiao et a, 201664	Yes	N=2000	52 ± 13.3	Iodixanol 320 Iohexol	Urticaria&Nausea	Iodixanol superior
Carlartrand-Lefebvre et al, 201129	Yes	N=130	52±16	Iopamido Iodixanol 320	HR	No difference
Jared D. Christensen et al, 20117	Yes	N=60	53.5±15.1	Iodixanol-320 Iopamidol370	HR	No difference
Ryo Nakazato, et al, 201622	Yes	N=266	57.2 ± 11.7	Iodixanol Iopamidol	HR Flushing	No difference No difference
Choi et al,201215	Yes	N=300	62±11	Iodixanol 320 Iohexol 350	HR	Iodixanol superior

2.4. Outcomes:

2.4.1. Hemodynamic changes and Cardiovascular side effects:

Contrast media have been associated with several cardiovascular adverse effects. Iodixanol had a lesser effect (p<0.01) on left ventricular end diastolic pressure when compared to ioxaglate, in patients with reduced ejection fraction undergoing ventriculography. Large reductions (>20mm Hg) in diastolic blood pressure occurred in more iodixanol than iohexol recipients during left coronary angiography ( 13% v/s 3%, p=0.025). Although 62% of patients receiving iodixanol had systolic blood pressure reduction >20 mm Hg, when compared to 49% receiving iohexol, it was not statistically significant (p=0.07). No differences were noted between the two agents during right coronary angiography or ventriculography¹⁹.

The impact of contrast media with different osmolality on cardiac preload was studied in 90 patients with congestive heart failure (CHF) and Chronic Kidney Disease (CKD), undergoing invasive cardiac angiography with hemodynamic monitoring. The CHF patients were at higher risk when hyperosmolar agents are used, due to the fluid shifts that occur. Increase in extravascular lung water index was seen only when iopromide was used (p<0.001), but global end-diastolic index and central venous pressure significantly increased in both groups (p<0.001 respectively). The overall incidence of acute heart failure was more frequently observed in the iopromide than the iodixanol group (12 v/s 4 events, p=0.027)³⁶.

As osmotic pressure was significantly higher in LOCM iopromide than in IOCM iodixanol; the increase in plasma osmolality following LOCM injection could consequently result in an increase in blood volume and cardiac preload.

2.4.2. Major Adverse Cardiovascular Event (MACE)

In a study conducted by Budoff et al. in patients receiving iodixanol as contrast agent for CCTA, the rate of MACE (cardiac death, non-fatal myocardial infarction or unstable angina requiring hospitalization) was 5.7% in patients with a positive CCTA (one ormore ≥50% stenosis) and 0.1% (1/683) patients with a negative CCTA (99.9% MACEfree survival rate) at 12 months follow up¹⁶.

In a comparison between iodixanol and ioxaglate for angioplasty, the VIP (Visipaque in Percutaneous Transluminal Coronary Angioplasty) trial investigators did not find any significant difference in MACE neither at 2 days (iodixanol, 4.7%; ioxaglate, 3.9%; p=0.45, nor between the 2-day and 1-month follow-ups (p=0.27) in 1141 patients³⁷. In the COURT(Contrast Utilization in High-Risk Patients Undergoing PTCA) trial, the inhospital MACE was 5.4% for iodixanol and 9.5% for ioxaglate (p=0.027). Total events at 30 days in patients randomized to iodixanol were lower as well (9.1% versus 13.2%, p=0.07)³⁸. In the ICON (Ionic versus non-ionic Contrast to prevent worsening nephropathy after angioplasty in chronic kidney disease patients) trial, however, the use of ioxaglate was associated with a lower mortality at l year as compared to iodixanol (2.7% v/s 9.1%, p=0.07) in patients who underwent cardiac catheterization³⁹. In a single-center study, patients undergoing percutaneous coronary angioplasty who received iodixanol had more MACE than those who received ioxaglate (4.8% vs. 0.3%, p<0.005). Although the difference was mainly related to the appearance of a large thrombus during PCI (6% with iodixanol vs. 0.3% with ioxaglate, p<0.0001), use of iodixanol was one of the independent predictors of in-hospital MACE (p<0.001) on multivariate analysis⁴⁰.

In the CONTRAST-AMI (Contrast Media and Nephrotoxicity Following Primary Angioplasty for Acute Myocardial Infarction) trial, no significant difference was found in 1-month MACE in patients who were administered iodixanol and iopromide for the procedure⁴¹. No significant difference in 1-month major adverse cardiac events was observed (8% in iopromide v/s 6% in iodixanol, p=0.37).

In Cardiac Catheterization (VICC) trial, 1276 patients were randomized, in a double-blind, U.S. multicenter trial comparing the use of iodixanol to iopamidol during percutaneous coronary intervention (PCI)⁴². The primary outcome of the trial was in-hospital major adverse cardiac events (MACE). All events were adjudicated by a clinical events committee blinded to the contrast used. Patients undergoing PCI using iodixanol had 46.7% lower in-hospital MACE (iopamidol 57/630 events vs. 31/646 in iodixanol group, p=0.003), due to lower rates of non-Q MI (7.5% iopamidol vs. 3.4% with iodixanol, p=0.002). The difference in MI remained significant at 30 days (9.4% vs. 5.3% respectively, p=0.005).

McCullough et al. reviewed 333,533 inpatient coronary or peripheral angioplasties from 357 hospitals⁴³. The overall incidence of Major Adverse Renal and Cardiac Event (MARCE) was 7.41%. There was a 0.69% absolute risk reduction and a 9.32% relative risk reduction in MARCE rate with iodixanol in comparison to LOCM (iohexol, ioversol, iopamidol, ioxaglate, ioxilan, and iopromide). In comparison with LOCM, use of iodixanol had a 9% decrease in the overall MARCE rate, 50% decrease in the renal composite end point, 34% decrease in the risk for AMI, 38% decrease in the risk for angina and 21% decrease in the need for repeat stent implantation⁴³. (Table 2) Further larger RCTs in patients undergoing CCTA are warranted to avoid the effect of confounding variables that arise with invasive angiography.

Table 2. Major trials of MACE(major adverse cardiac events).

Table 2. Major trials of MACE(major adverse cardiac events).

study	Numb of Pts	Mean Age	Contrast	Endpoint	Results
Qian et al, 201736	N=90	62±13	Iodixanol Iopromide	90-Day cardiac event Acute heart failure	Iodixanol superior No difference
Bertrand et al, 200037	N=1411	61.6 ±10.6	Iodixanol Ioxaglate	Acute renal failure	No difference
Davidson et al, 200038	N=810	61±12	Iodixanol Ioxaglate	During hospital stay 30-Day cardiac event	Iodixanol superior No difference
Harrison et al, 200342	N=1276	-	Iodixanol Iopamidol	In- hospital 30- Day cardiac event	Iodixanol superior No difference
Giustino et al, 201639	N=146	71.6±9.9	Iodixanol Ioxaglate	ARF 30-Day events	No difference No difference
Song T2 et al, 201765	N=220	54.1±9.8	Iodixanol Iohexanol	ARF	Iodixanol superior

2.4.3. All-cause mortality

In a study conducted by Wang et al. comparing long-term adverse effects between iodixanol and low osmolar contrast media, patients who received LOCM had comparable all-cause mortality (n=6,992) with iodixanol, after multivariate regression analysis with adjustments done for confounding variables. However, in CKD patients, LOCM group had higher mortality rates than iodixanol cohort (regression adjusted HR 1.80, 95% CI 0.95 to 3.42)¹². However, in another study by From et al., there was no difference in all-cause mortality or contrast nephropathy that was seen between iodixanol and iohexol⁴⁴.

2.4.4. Contrast-induced nephropathy (CIN):

CIN is defined as an acute decline in renal function, expressed as a relative increase in serum creatinine (SCr) concentration of at least 25% or an absolute increase in SCr of 0.5 mg/dl (44.2 mol/l) in the absence of other etiologies²³. The incidence ranges from 5% 49in patients with no risk factors to 11- 50% in patients with risk factors like renal impairment, congestive heart failure, reduced arterial volume and use of nephrotoxic medications. Studies have been done to investigate the nephrotoxic potential of different ICAs⁴⁵.

A randomized trial conducted by Chalmers et al. showed that 15% of patients who received iodixanol for angiography had a rise in creatinine of > 10% in the week following angiography compared with 31% in the iohexol group (p<0.05)⁴⁶. Another RCT by Aspelin et al. for the NEPHRIC (Nephrotoxicity in High-Risk Patients Study of Iso-Osmolar and Low-Osmolar Non-Ionic Contrast Media) study group, in high-risk patients with diabetes and serum creatinine concentrations of 1.5- 3.5 mg/dl showed that the mean creatinine concentration change from day 0-7 was 0.07 mg/dl in the iodixanol group and 0.24 mg/dl in the iohexol group (p=0.003). The incidence of CIN, defined as a peak rise > 0.5 mg/dL, was decreased from 26% to 3%, (p<0.002) when iodixanol was used. They hence concluded that iodixanol might have a safer renal profile in high-risk patients than low osmolar ICAs like iohexol⁴⁷.

The Renal Toxicity Evaluation and Comparison Between Visipaque and Hexabrix in Patients with RECOVER (Renal Insufficiency Undergoing Coronary Angiography) study compared the nephrotoxicity of iodixanol and ioxaglate used as contrast media in patients undergoing coronary angiography. The incidence of CIN was lower with iodixanol (7.9%) than with ioxaglate (17.0%; p 0.021), with an odds ratio (OR) of CIN of 0.415 (95% CI 0.194 to 0.889) for iodixanol. The incidence of CIN was lower with iodixanol in patients with severe renal failure (p=0.023) or associated diabetes (p=0.041) or patients given more volume of contrast media (p=0.038)⁴⁸. Though the ICON study investigators found no statistically significant difference in AKI rates in the iodixanol group (20%) and ioxaglate group (24.3%), it is to note that the study was underpowered⁴⁹.

In a meta-analysis with a pooled data from 2,727 patients, McCullough et al. concluded that the maximum increase in creatinine within three days post-ICA administration was significantly smaller in the iodixanol group when compared with LOCM group (0.06 mg/dl vs. 0.10 mg/dl, p<0.001). This was furthermore remarkable in CKD patients (0.07 mg/dl vs. 0.16 mg/dl, p=0.004) and CKD combined with DM patients (0.10 mg/dl vs. 0.33 mg/dl, p=0.003). Contrast-induced nephropathy as defined as increase in creatinine > 0.50 mg/dl within 3 days of contrast use, was less in the iodixanol group than in the LOCM group in all patients (1.4% vs. 3.5%, p<0.001), in CKD patients (2.8% vs. 8.4%, p=0.001), and in CKD combined with DM patients (3.5% vs. 15.5%, p=0.003)⁴³. Another meta-analysis with 3,129 patients showed that intra-arterial iodixanol significantly reduced the risk of contrast-induced acute kidney injury (CI-AKI) when compared with LOCM (RR = 0.68; 95% CI, 0.50-0.92; Z=2.47; p=0.01)⁴³. Nie et al. also found that CIN incidence was significantly lower with iodixanol than iopromide (5.7% vs. 16.7%; p=0.011) in CKD patients undergoing coronary angiography⁵⁰. No difference in nephrotoxicity was found between iopromide, and iodixanol was found in the DIRECT study⁵¹. The rate of contrast-induced nephropathy was not statistically different after the intra-arterial administration of iopamidol or iodixanol to high-risk patients, with or without diabetes mellitus in the CARE (Cardiac Angiography in Renally Impaired Patients) study as well⁵².

When the data of 57,925 patients from the Swedish Coronary Angiography and Angioplasty Registry was compared with the Hospital Discharge Register, clinically significant kidney failure was greatest for patients receiving the iodixanol (1.7%), when compared to ioxaglate (0.8%) (p<0.001). The odds ratio for renal failure in patients with diabetes or prior renal failure was also higher in patients who received iodixanol (p <0.01). The risk associated with iohexol was similar to ioxaglate. The rate of patients needing dialysis was also higher in the iodixanol group. (2% v/s 1%, p<0.01)⁵³. Contrast media cause transient endothelium-dependent vasodilation mediated by the release of nitric oxide.^54,55 In the renal blood vessel network, this transient dilation can be followed by sustained vasoconstriction that lasts for several hours, as opposed to the peripheral vasoconstriction that lasts for seconds to minutes. In the setting of CKD and DM, there is already a reduction in the renal parenchymal mass and the number of nephrons at baseline. The prolonged vasoconstriction and reduction in blood flow can then impair oxygenation to the medulla, resulting in tubular ischemia. Additionally, the proximal tubular cells are involved in the uptake and release of the ICA in the kidney due to its water solubility. These tubular cells undergo swelling, blebbing and apoptosis and lead to stasis of the contrast within the kidneys. Also, 3-hydroxy-3-methyl-glutaryl- CoA reductase (HMG Co-A) regulates the production of isoprenoid pyrophosphates, which further play a key role in the proper function of guanosine triphosphate (GTP)- binding protein-mediated endocytosis. The high concentration of contrast within and surrounding renal tubular cells causes direct cellular toxicity. This results in loss of the tubular structure breakdown, loss of cell membrane, and removing of material into the urinary tubule (Tamm-Horsfall protein), which leads to more stasis of contrast in the urine, resulting in increased movement of contrast into the tubulointerstitial space, where there is no ready form of clearance. A combination of both ischemic and chemotoxic injury to the proximal tubules triggers tubuloglomerular feedback, which signals the glomerulus to reduce filtration. This results in the rise of the plasma concentration of creatinine, that is seen approximately 24 to 48 hours after there has been a significant reduction in filtration⁵⁴.

In such high-risk patients, even using the average dose of ICA for routine coronary angiography can cause CI-AKI. There might also be sufficient destruction to some nephrons that recovery might not be possible and fibrosis ensues. In patients with advanced CKD (eGFR<30ml.min/1.73m2), CI-AKI can result in a larger reduction in the kidney function, with azotemia, volume overload and hyperkalemia following. The process culminates in progression to ESRD⁵⁴.

Another mechanism that has been proposed for CIN is embolism. As kidneys get 25% of the cardiac output, micro-embolism could account for CI-AKI. The fact that intravenous administration of ICAs have a lower rate of CI-AKI compared to intra-arterial administration, possibly because there is a greater admixture of contrast in the blood pool before it reaches the kidney and there is a lesser chance of athero-embolism, supports this theory⁵⁴ As iodinated contrast is water soluble, it is amenable to prevention strategies that expand intravascular volume, increase glomerular filtration and tubular flow of urine into collecting ducts, and on into the ureters and bladder⁵⁴.

2.4.5. Hematological SDE:

Contrast agents are known to cause hemolysis and micro-circulation disturbances as well. The high viscosity of iodixanol causes an insignificant short-term effect on the microcirculation compared to other agents⁵⁵. In a study conducted by Gerk et al., iodixanol did not cause an increase in free hemoglobin, indicating no hemolysis⁵⁶. In vitro studies conducted by Kerl et al. showed that RBC morphology is less affected by iodixanol when compared with LOCM. This was more significant at higher temperatures at which it is administered, thus not affecting the smooth flow of RBCs in the blood vessels⁵⁷.

2.4.6. Neurological SDE:

Studies in animals have shown that iodixanol is associated with similar or lesser changes to the blood-brain barrier and neurological function than nondimeric nonionic contrast media, and this is attributed to the hydrophilicity⁵⁸.

The primary reason that Iodixanol has lower toxicity is that Iodexanol is an iso-osmolar, dimeric, nonionic contrast medium. This lower osmolality and reduced chemotoxicity has generally led to lower osmotic diuresis as compared to those induced by low-osmolar mediums. ^2,47, This increased diuresis associated with low osmolar agents enhance distal sodium delivery, increasing medullary work and potentially inducing hypoxia and volume depletion, with consequent activation of vasoregulatory hormones. This vasoregulatory mechanism difference is likely the cause of increased heart rate variability with low osmolar agents and potentially the differences in CV outcomes discussed above.^41,42,43 Iodixanol has a lower osmolality and a higher iodine ratio than other non-dimeric contrast media. Further, the presence of hydroxyl groups and the absence of carboxyl groups in iodixanol contributes to reduced toxicity.

3. Conclusions

Table 3. Summary of comparison between Iodixanol and low osmolar contrast media.

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