Gadolinium and nephrogenic systemic fibrosis.

AJR 2009; 192:W1 0361–803X/09/1924–W1 © American Roentgen Ray Society Gadolinium and Nephrogenic Systemic Fibrosis I read with great interest the recent nephrogenic systemic fibrosis (NSF) review by Drs. Shellock and Spinazzi [1] and the accompanying editorial by Dr. Colletti [2]. I applaud the AJR for presenting detailed safety information to the radiology community at a time when such information is desperately needed. After reading Dr. Colletti’s accompanying editorial, I thought it would be prudent to point out that to date no prospective well-designed study has ever shown a significant difference in the reported adverse reaction rates among the available gadolinium chelates, either for nuisance reactions, such as headache or nausea, or for serious adverse events, such as anaphylaxis [3]. Although evaluation of certain more recently developed gadolinium contrast agents has shown substantially higher rates of reaction than agents approved earlier (e.g., OptiMARK [gadoversetamide, Covidien AG 31% reaction rate] and Vasovist [gadofosveset trisodium, EPIX Pharmaceuticals; 23% reaction rate]), I believe that even these findings are likely the result of changing standards for the conduct of clinical trials and do not necessarily imply a worse safety profile (as assessed by minor adverse reactions) for these agents [4, 5]. The best study design for comparing two treatments (in this instance, two contrast agents) is the crossover study in which both treatments are given to the same patient with a suitable interval between applications to allow washout of the compound. Several such studies have compared the safety and efficacy of Magnevist (gadopentetate dimeglumine, Bayer Schering Pharma) and MultiHance (gadobenate dimeglumine, Bracco Diagnostics), for example. As recently summarized by Shellock et al. [6], the reported reaction rates for Magnevist and MultiHance in nearly 300 patients enrolled in crossover studies with these two agents were 8.5% and 8.0%, respectively. Similarly, a crossover study comparing ProHance (gadoteridol, Bracco Diagnostics) to Magnevist found comparable reaction rates between the two agents: 2% after ProHance and 4% after Magnevist [7]. This is not to say that the commercial companies involved, and in particular the local sales representatives, have not tried (often successfully) to use scare tactics in condemning one or another agent on the basis of minor adverse events. Such tactics are, by the way, very much an American tradition, with large markets such as Japan having very different market shares of each agent, due in part to the lack of such negative advertising. The agent most commonly singled out for these tactics in the United States has been ProHance. That remains so even today despite—or if one is negative, perhaps because of—the fact that this agent has made recent major gains in market share because of the advent of NSF, a very serious disease. To place value on such rumors and statements (not based on scientific data) is extremely counterproductive. I recall the time in the early months after NSF and its connection to gadolinium chelate administration became known, that the sales force for Magnevist aggressively sought to sell their agent at our institution, stating definitively that there were no cases of NSF with Magnevist. Considering the evidence of gadolinium chelate stability in the scientific literature, this was very much unlikely to be true (as, of course, time confirmed). The scientific literature, and specifically all prospective, controlled clinical trials, confirm that the five gadolinium chelates currently on the U.S. market with extracellular distribution—in order of their FDA approval, Magnevist, ProHance, Omniscan (gadodiamide, GE Healthcare), OptiMARK, and MultiHance—cannot be differentiated on the basis of nausea, vomiting, or hives, the most common nuisance reactions. This truth is confirmed, interestingly enough, by recent, personal, first-hand experience. After the recognition of NSF and its link to gadolinium chelate administration (in mid 2006), I was charged with the difficult task of converting our very large clinical practice to exclusive ProHance use. This was done at the direction of the chair of the department, despite that both he and two of the 10 technologists (the most senior technologist and the chief technologist) held the belief that ProHance had a substantially greater number of minor adverse reactions. More than 2 years later, we are still happily using this agent and, in terms of liability, are very glad of our early switch [8]. Both of the aforementioned technologists now believe, on the basis of their experience of the past 2 years, that there is no difference in minor adverse reactions between these two agents (when injected in the same manner). To summarize, as I did in a letter to the editor in AJR in 2001 [9]: • “To the best of current scientific knowledge, all of the gadolinium chelates approved clinically for use in the United States.have the same incidence of severe anaphylactoid reactions. ” • “This is also true for minor adverse reactions, the two most notable being nausea and hives. ” • “Let us not add to the problem.by permitting unsubstantiated rumors to circulate.but continue to promote science. ” Of course, in the NSF era, considerations other than traditionally assessed adverse events may weigh more heavily in the selection of a gadolinium contrast agent. The connection between the stability of gadolinium complexes and spurious laboratory interferences [10, 11] and the link between chelate stability and the incidence of NSF [12–16] would argue for use of the most stable agents, if not in all patients at least in those patients at risk. I would also caution against relying too heavily on screening to identify all patients with advanced renal failure. As we have learned with cardiac pacemakers, some patients inadvertently get past rigorous screening for MRI each year, despite each site’s best attempts. This again argues for a renewed emphasis on the safety profile of the gadolinium chelates and specifically their stability in vivo.