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High relaxivity contrast agent in routine CE-MRA

Roberto Iezzi
19 May, 2015  

Higher contrast agent relaxivity is of fundamental importance in permitting the use of lower doses in contrast-enhanced magnetic resonance angiograms

Roberto Iezzi MD

Department of Radiological Sciences

Catholic University

Rome, Italy

Contrast-enhanced magnetic resonance angiograms (CE-MRA) are now an accepted alternative to diagnostic angiography (DSA) in the evaluation of patients with vascular lesions, with high value in terms of sensitivity and specificity in detecting steno-occlusive disease. It permits non-invasive assessment of the location and extension of a vascular lesion and facilitates not only the planning of interventional or surgical procedures but also offers reliable alternative imaging capabilities for follow-up examinations.

CE-MRA is an extremely powerful imaging tool and relies on the T1 shortening effect of a gadolinium (Gd)-based contrast agent (GBCA) during its first pass through the volume of interest. For effective CE-MRA, imaging should be performed during peak enhancement of the target vessel when overlapping structures and background tissue are not enhanced. For arterial depiction, this means synchronising imaging for the period of preferential arterial enhancement when the arterial Gd concentration is high and no significant venous or background enhancement has occurred.

Since vascular enhancement is a transient and dynamic process, the critical element is timing of the acquisition. Arteries are best visualised if the critical centre of k space data is acquired during the peak arterial enhancement period. Furthermore, it is mandatory to tailor the length of the contrast bolus to the MRA sequence to maintain a high level of Gd in the vessels during much of the higher order phase encoding acquisition to minimise vessel edge blurring, which can reduce vessel detail and visualisation of smaller vessels.

In order to obtain an adequate arterial enhancement and image quality, many authors have used either a double dose of GBCA or a standard volume of 25–30ml (corresponding to 0.17–0.2mmol/kg for a 75kg patient). This reflects concern that lower doses of GBCA may result in compromised spatial resolution and image quality, and lower carrier-to-noise ration (CNR) or signal-to-noise ration (SNR).1 However, the dose of GBCA used in routine CE-MRA procedures is a matter of great concern given the risk of nephrogenic systemic fibrosis (NSF) among patients with severe renal insufficiency. The clinical need is therefore to reduce the dose of GBCA administered while maintaining sufficient contrast enhancement and image quality to achieve an accurate diagnosis and/or to accurately plan interventional procedures.

Based on the need to minimise dose wherever possible, it is mandatory to optimise the contrast medium injection protocol.

MRA contrast agents

Contrast agents based on Gd are by far the most commonly used for MRA procedures. Due to their paramagnetic nature, GBCAs shorten the tissue relaxation time, resulting in increased tissue signal intensity on T1-weighted images. The T1 shortening effects of GBCAs in MRA are dependent on relaxivity (R) and local (arterial) concentration of gadolinium chelate.2

This means that increasing relaxivity would amplify the T1 shortening effects, enabling contrast enhanced MRI to be performed at lower doses with a potential reduction of the risk of Gd induced toxicity. Of the MR contrast agents currently available, MultiHance (gadobenate dimeglumine; Bracco Imaging SpA, Milan, Italy) is unique in that it possesses markedly increased R1 relaxivity relative to conventional GBCAs due to weak and transient interaction of the gadobenate contrast effective molecule with serum albumin.3 This increased R1 relaxivity translates into increased signal intensity enhancement relative to that achieved with conventional GBCAs at equivalent dose.4–11 Based on this assumption, higher relaxivity would theoretically allow lower concentration targets to be detected by MRI.

MultiHance: what is the optimal dose – superiority at equivalent dose?

The study by Schneider et al.1 demonstrated that the optimal dose of MultiHance for CE-MRA applications is 0.1mmol/kg bodyweight. Specifically, the study demonstrated that a dose of 0.1mmol/kg bodyweight (single dose) led to significantly better diagnostic image quality and performance (sensitivity and specificity for detecting significant steno-occlusive disease) compared to MultiHance doses of 0.025, 0.05, and 0.2mmol/kg bodyweight (Figure 1). Given the current widespread concern among the radiological community concerning the use of double and triple doses of GBCAs, particularly in patients with renal insufficiency,12 these results are of considerable interest. Of particular interest was the observation that a higher dose of MultiHance (0.2mmol/kg) is unnecessary and potentially deleterious in terms of image quality and diagnostic performance.

Importantly, a single dose of MultiHance has proven safe for hybrid contrast-enhanced MRA of peripheral arterial occlusive disease (PAOD) even in patients at risk of NSF, as reported by Wang et al.13

With the purpose of confirming the theoretical assumption of superiority of MultiHance at equivalent dose, Gerretsen et al.10 compared two agents with different relaxivity (MultiHance versus Magnevist) at 0.1mmol/kg bodyweight in patients with known or suspected PAOD. Three independent, blinded readers each noted improved vessel visualisation quality and contrast enhancement, reduced technical failure rate and significantly (p<0.002) better diagnostic performance for the detection of >50% stenoses with MultiHance. In common with the conclusions of analogous studies in the brain4–6 and breast,7–8 the superior performance with MultiHance was ascribed to its greater R1 relaxivity in vivo.2–3

MultiHance: does a higher relaxivity MR contrast agent permit a reduction of the dose administered for routine vascular imaging applications?

Given the increased risk of NSF with high dose GBCAs, a potential advantage of using a higher relaxivity MR contrast agent (MultiHance) is that the dose administered can be reduced for CE-MRA procedures on patients at increased risk.

Based on this assumption, Phase III randomised crossover comparisons of 0.1mmol/kg MultiHance and 0.2mmol/kg Magnevist were performed in patients referred for CE-MRA of the supra-aortic arteries (the supra-aortic VALUE study)14 and the peripheral arteries (the peripheral VALUE study).15 All enrolled patients underwent two identical MRA examinations, with a single dose of MultiHance and a double dose of Magnevist randomly administered. Images were evaluated quantitatively (SNR, CNR) and qualitatively (vessel anatomical delineation, global preference) by three independent blinded readers. In addition, diagnostic performance for the detection of significant stenosis was determined with DSA as gold standard.

Supra-aortic VALUE study results

In the supra-aortic VALUE study,14 46 patients with known or suspected steno-occlusive disease of the supra-aortic vessels were enrolled.

Quantitative enhancement in the neck and carotid bifurcation/ICA was similar; although each reader noted slightly greater SNR and CNR with the single-dose of MultiHance in the neck, none of the differences were significant. No significant differences were observed between the two contrast agents in terms of qualitative enhancement. Non-significant superiority for the single-dose of MultiHance was reported for all diagnostic performance indicators (sensitivity: 82.7–88.5% versus 75.0–80.8%; specificity: 96.4–98.6% versus 94.6–98.6%; accuracy: 94.6–96.1% versus 92.4–94.9%; PPV: 81.5–91.5% versus 73.7–90.7%; NPV: 96.8–97.8% versus 95.4–96.4%).

Based on these results, it was concluded that the image quality and diagnostic performance achieved with a single 0.1mmol/kg dose of MultiHance is at least equivalent to that achieved with a double 0.2mmol/kg dose of Magnevist (Figure 2).

Peripheral VALUE study

In this study, 1568 patients with suspected moderate-to-severe PAOD were enrolled.

No differences were noted for any qualitative parameter at any station. Superiority for single dose of MultiHance was reported by all readers for diagnostic performance (sensitivity: 80.4–88.0% versus 75.2–85.8%; specificity: 89.8–96.0% versus 88.7–94.8%; accuracy: 87.4–91.7% versus 84.9–90.6%; PPV: 84.0–92.8% versus 82.3–90.8%; NPV: 88.5–92.4% versus 85.7–91.1%). Quantitative enhancement was similar in the pelvis but significantly (p<0.05) greater with MultiHance in the thigh for two readers.

Based on these results, it was concluded that the image quality and diagnostic performance achieved with a single 0.1mmol/kg dose of MultiHance is at least equivalent to that achieved with a double 0.2mmol/kg dose of Magnevist (Figure 2).


Based on the results of VALUE study, it is clear that higher contrast agent relaxivity is of fundamental importance in permitting the use of lower doses in CE-MRA. Specifically, the higher R1 relaxivity of MultiHance, due to weak, transient interaction of the gadobenate contrast-effective molecule with serum albumin, leads to greater shortening of the T1 relaxation time, substantially increasing SI enhancement. The increase in terms of SI enhancement permits a reduction of the dose, as demonstrated in the VALUE Study, in which a single 0.1mmol/kg dose of MultiHance was able to fully replace a double dose of a “conventional” first-generation GBCA that has no capacity for interaction with serum proteins. It is clear that the possibility to use a lower dose and a lower total volume can be considered an important clinical advantage particularly in patients with renal insufficiency.

In conclusion, with the use of MultiHance it is possible to reduce the dose and volume injected in routine MRA examinations, without compromising contrast enhancement or diagnostic performance.


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