The Role of Radiographic Contrast Media in Invasive Angiographic Procedures: Innocent Bystander or Important Player?

During the last two decades, there have been consistent improvements in acute and long-term outcomes of percutaneous coronary intervention (PCI). Dramatic reductions in the rates of serious in-hospital major adverse clinical events (MACE), including death, myocardial infarction, and emergent bypass surgery, have accompanied the introduction of stents and the subsequent optimal use of antithrombotic and antiplatelet agents. Improvements have also been seen in long-term outcomes, with significant reductions in repeat revascularization procedures. Progress in our understanding of the risks and benefits of PCI stem from insightful and fundamental observations concerning the mechanisms of vessel injury and the biology of restenosis. Though great strides have been made in reducing the risk and increasing the benefits of contemporary PCI, these improvements have not been applied uniformly across all patient subgroups or disease categories. Among the latter, two important categories of patients have become known as high-risk: patients presenting with acute ischemic syndromes and those with chronic renal insufficiency. In the case of acute coronary syndromes, it has been known for some time that the increased predisposition to thrombosis, both prior to and during PCI, represented the major risk associated with the procedure. Major adverse clinical events in this setting are just that periprocedural death or myocardial infarction. Consequently, the introduction of potent antithrombotic and antiplatelet agents has been met with great enthusiasm. Physicians could finally feel more comfortable performing such high-risk procedures with the optimized use of these agents. Although MACE rates associated with PCI have fallen significantly, patients with acute ischemic syndromes remain at greater risk for periprocedural MACE. Given our understanding of the inherent thrombogenicity of this setting, and lingering concerns about the role of radiographic contrast media (RCM) used during these procedures, attention has appropriately been focused on improving our understanding of the contribution of RCM to overall outcomes. While there is little dispute that low osmolal nonionic RCM dramatically enhances procedural safety in terms of hemodynamic compromise (when compared to high osmolal ionic RCM), there has been less agreement on the impact of using nonionic low osmolal agents during PCI in patients with acute ischemic syndromes. Early observations on the potential of nonionic RCM to enhance clotting in vitro¹ spawned extensive research on the effects of RCM on the clotting system, platelet function, and the interaction of RCM with the vessel endothelium.^2-6 Not surprisingly, there was considerable disagreement among studies examining the different effects of ionic and nonionic RCM, much of it related to the applicability of in vitro experiments to the clinical setting and to the wide variation in experimental conditions and techniques used. It was the clinical setting that would ultimately decide which RCM method should become the method of choice. Given that the issue centered on the potential for nonionic RCM to increase the risk of thrombosis, and that the acutely ischemic patient poses a high risk for periprocedural thrombosis, early randomized controlled trials of various RCM were met with keen interest. Unfortunately, differences in definitions and end points, as well as underpowered trials and the rapidly changing technology of PCI, have precluded arriving at any consensus. That is, until recently. A double-blind, randomized trial, the COURT (COntrast media Utilization in high Risk PTCA-Percutaneous Transluminal Coronary Angioplasty) Trial, evaluated the effect of a low osmolal ionic dimer (ioxaglate) versus an iso-osmolar nonionic dimer (iodixanol), on the rate of in-hospital MACE following PCI. In 856 high-risk patients, MACE was reduced by 45% with iodixanol. The COURT trial⁷ provided convincing evidence that the use of nonionic RCM was certainly safe and, in fact, superior to ionic RCM during high-risk PCI. The mechanism for the observed benefit with iodixanol could not be elucidated from this clinical study. However, a striking reduction in the rate of periprocedural myocardial infarction, a decidedly thromboembolic event, seen with iodixanol suggests a beneficial effect of this agent on thrombosis and/or vascular integrity. More recently, the results of the VICC trial (Visipaque [iodixanol] vs. Isovue® [iopamidol] in Cardiac Complications) were presented at the American Heart Association meeting (Orlando, Florida, November 8-12, 2003). The VICC trial compared the effects of iodixanol with those of iopamidol (a low osmolal nonionic RCM) in terms of in-hospital and 30-day MACE.⁸ The results of this study support and extend the observations of the COURT trial, and confirm the ever-increasing safety of PCI in high-risk patients. Although the COURT and VICC trials differ in the prevalence of patients that are truly high risk, the observation of a striking reduction in the frequency of periprocedural myocardial necrosis with iodixanol is notable, notwithstanding the more stringent definition of myocardial infarction in the COURT study (Table 1). This significantly reduced incidence of peri-procedural myocardial infarction seen with iodixanol compared to iopamidol extended to the 30-day assessment (iopamidol, 9.4% vs. iodixanol, 5.3%; P=0.005) and sends a powerful message to the interventionalist. Specifically, RCM should no longer be viewed as innocent bystanders in these procedures. Rather, their beneficial effect on clinically relevant outcomes must be factored into our decision-making and practice patterns. At the outset of this article, we mentioned an additional high-risk group of patients, those with chronic renal insufficiency. A considerable body of literature has accumulated over the past several years confirming the widely held medical precept that such patients are inherently sicker and therefore predisposed to poor outcomes. However, the role that RCM may play in influencing such outcomes, at least for invasive angiographic procedures, derives from the risk of contrast nephropathy. Not only are patients with underlying renal insufficiency at increased risk of adverse events when compared to those with preserved renal function, but those patients with super-imposed contrast nephropathy on a background of chronic renal insufficiency are also at extremely high risk of fatal and nonfatal cardiovascular events.⁹ Because underlying renal insufficiency is a major risk factor for contrast nephropathy, the appropriate use of an RCM with a decreased likelihood of perturbing already compromised renal function is self-evident. Unfortunately, neither the COURT nor the VICC trials provides insight into this issue, as neither was specifically designed to investigate contrast nephropathy. Nevertheless, the results of the recently published NEPHRIC study (NEPhrotoxicity in High-Risk Patients Study of Iso-Osmolar and Low Osmolar Nonionic Contrast Media) may be of some relevance.¹⁰ This latter trial established the superiority of iodixanol compared to iohexol during invasive angiographic procedures, including PCI, in high-risk patients with underlying renal insufficiency. By extension, a diminished rate of contrast nephropathy should translate into a reduced risk of in-hospital and longer-term adverse cardiovascular events. In this regard, ongoing clinical studies may elucidate the importance of the type of RCM used, and its effect on outcomes, during invasive angiographic procedures. In conclusion, radiographic contrast media can no longer be viewed as innocent bystanders with inert properties. They possess the potential to promote both deleterious and beneficial outcomes during invasive angiographic procedures. Convincing evidence has accumulated to support the safety of low osmolal nonionic agents compared to ionic agents during invasive angiographic procedures. Equally cogent evidence is accumulating to support the use of the iso-osmolal nonionic agent, iodixanol, during such invasive procedures in truly high-risk patients.