Hexabrix is an ionic, low-osmolar, low-viscosity contrast media. It has been shown to contain anti-thrombogenic properties. Dr. Manoukian shares his experience and discusses current thinking in this area. What properties are important when we look to differentiate the various contrast media? The primary purpose of contrast media is to opacify the structure of interest, and for most of us in cardiology, that structure is the coronary arteries. Most, if not all, contrast media opacify the coronary arteries well. For that reason, the other important properties of contrast media have not been given much attention. We do know that different contrast media, much like everything else that we use, have several properties beyond opacification that dramatically differentiate them from one another. These properties include ionicity, structure, osmolality, viscosity, and thrombogenicity. Probably one of the earliest properties to receive attention was osmolality. It is generally felt that low-osmolar contrast agents are safer and better tolerated than high-osmolar contrast agents. As a result, most, if not all, cardiovascular invasive procedures are performed with low-osmolar contrast. With regard to the complications of contrast media, most of the attention has centered on the risk of acute renal failure known as contrast- induced nephropathy (CIN). Although some of the safest agents employed in medicine, contrast media carry a risk of CIN and some low-osmolar contrast media were initially felt to have a higher or lower risk. Currently, based upon recent data, key opinion leaders seem to believe that most of the available low-osmolar contrast media generally carry about the same risk of CIN, despite differing levels of osmolality. In addition to the risk of CIN, over the years we have recognized that certain nonionic contrast media may be associated with a higher risk of clotting and thrombotic complications, particularly during percutaneous coronary intervention (PCI), via activation of the coagulation cascade, platelets, or both. By comparison, ioxaglate (Hexabrix, Guerbet), an ionic contrast agent, has favorable experimental and clinical data showing limited or no association with clotting compared to some of the non-ionic contrast agents. In a recent two-article supplement to the Journal of Invasive Cardiology,1 Mark Fisch and Fred Feit presented the experimental, mostly pre-clinical, basic science data, regarding Hexabrix and activation of coagulation.1 In that same supplement, my article focused on clinical trials looking at the risk of thrombosis and coagulation with Hexabrix and other contrast media.2 Interestingly, there seems to be a solid body of evidence supporting the fact that Hexabrix may be associated with a lower risk of thrombosis, especially in high-risk patients. By high risk, I mean patients undergoing either cardiac catheterization for an urgent reason, such as an acute coronary syndrome, unstable angina or ST-segment elevation MI (STEMI), or those undergoing PCI. As I mentioned before, since we tend to look at contrast media merely as agents that help us see the coronaries, I believe we haven’t looked seriously enough at these other properties. It’s my opinion, and, I think, the opinion of many thoughtful interventional cardiologists, that anticoagulant properties in contrast media are very important and that choosing one agent or another might during PCI or even high-risk catheterization might increase or decrease the risk of a thrombotic complication. So it is possible that a contrast agent could be a direct cause of a thrombotic event? Some good trials have looked at that exact question. Although not every trial was conclusive, some randomized trials did show an increased risk of thrombotic complications in patients receiving non-ionic contrast. In fact, the FDA mandates that manufacturers of non-ionic contrast media place a statement on package inserts about the risk of thrombotic events with this type of contrast, which is not the case with the ionic agent, ioxaglate. We give so many anticoagulants during an interventional procedure that we lose sight of the fact that some of the things we are doing could actually increase the likelihood of clotting. In fact, avoiding a nonionic contrast agent that potentially could increase the risk of a thrombotic event means we may be able to achieve superior outcomes with less anticoagulation, at lower cost and with a lower risk of bleeding complications. Can you explain more about the antico- agulant properties of Hexabrix? There is experimental data to support that Hexabrix, an ionic contrast agent, is less likely to activate the coagulation (clotting) cascade, resulting in a greater inhibition of thrombin generation. Furthermore, data suggests that Hexabrix results in less platelet activation. Therefore, in terms of the body’s intrinsic clotting mechanisms, available data indicates that the coagulation cascade and platelets may be less likely to be activated by Hexabrix. By comparison, there are data that non-ionic contrast media may either have less anticoagulant effects or even pro-coagulant effects, possibly resulting in an increased likelihood of a thrombotic complication. What that could mean in the cath lab, or for an interventional procedure specifically, are complications likely to be manifested by a peri-procedural myocardial infarction, slow flow in a coronary vessel, obvious angiographic thrombus, or subacute or acute stent thrombosis. These are the types of the clinical sequelae that we would be considering in terms of thrombotic complications of PCI. How are you using Hexabrix in your practice? Based upon the data, Hexabrix appears well suited for patients in two categories. First, are patients undergoing urgent cardiac catheterization, such as in the setting of an acute coronary syndrome or STEMI. These patients are at increased risk of thrombotic complications and if they undergo PCI, those risks are further increased. Second, patients undergoing PCI, even if elective, could be well-suited for Hexabrix, because of the risk of thrombotic complications during balloon angioplasty or stent placement. Less likely to benefit from Hexabrix — not that they would be harmed, simply that they may not benefit as much — would be patients undergoing low-risk, elective catheterization, where the risk of thrombotic complications or critical coronary disease are less likely. What about peripheral vascular use? Patients with peripheral vascular disease usually have very severe and diffuse atherosclerosis of one or more vascular beds, often including the coronary circulation. When they undergo interventional procedures, there is also a very high risk of thrombotic complications, in part often due to the extensive nature of the plaque and the long and very diffusely diseased vessels. For patients at high risk of thrombotic complications, either during a diagnostic or interventional peripheral procedure, it would be expected that there might be a role for ionic contrast in reducing those thrombotic complications as well. Do you warm contrast media at your institution? No, we use it at room temperature. The benefits of warming contrast primarily relate to reducing viscosity. Simply put, warming contrast reduces its viscosity. To the best of my knowledge, there is no data to support that viscosity reduces thrombotic complications, although Hexabrix is also one of the lowest viscosity contrast media, even at room temperature. We have previously reported that there are advantages of low viscosity contrast media in that lower viscosity allows for higher flow rates of contrast injection and lower injection pressures. A lower viscosity contrast media will allow you to inject it more easily, especially through small French catheters, and also allows for injection with a lot less force. Flow rate is important for opacification. Generally speaking, the higher the flow rate, the better the visualization. The ability to use a lower injection pressure makes it easier to inject for those that hand inject, especially for cath lab staff and physicians with small hands. It also allows you to inject with less force or less pressure, even when using a power injector. Reducing the injection pressure exerted by contrast on the vessel wall can improve safety. The higher the injection pressure, the greater the potential for catheter-induced trauma to the coronary vessels. What about cost? In some centers, Hexabrix might be more expensive than other contrast media. However, it is very seldom that the actual cost of a product is the only cost involved. Reducing cost by preventing costly events is a significant factor. You have to factor in that the patient might have had a complication that might have cost $10,000, or $20,000 or more. Generally, contrast media are in the 20-60 cents per cc range. Any incremental increase in cost could be partially or completely offset by a reduction in complications. Cost is always an issue, but it shouldn’t supersede the use of what might result in the highest quality outcome for the patient. Any final thoughts? When it comes to contrast media, there hasn’t been much in the way of active decision-making on the part of practitioners. It’s unfortunate, because there are many areas in cardiology where we work very hard to select the best product for an individual patient, based upon that particular patient’s profile; that doesn’t appear to be the case with contrast media. What’s interesting is this data is not all that new. Data regarding ionic contrast media like Hexabrix has been around for several years, if not well over a decade. For that reason, it is data that perhaps has been forgotten by practitioners as they have begun to focus on other components of invasive or interventional procedures in their quest to optimize outcomes. Today, there is an increasing focus on reducing complications related to invasive procedures, and with that in mind, practitioners should make sure that they are exploring every possible component of the procedure to result in the best outcomes. Much like we give strong consideration to various oral and intravenous anticoagulants during the course of interventional procedures, interventionalists and cardiologists in general should not over-look one relatively easy, therapeutic change — the use of a contrast media that might be associated with the lower risk of thrombosis. Dr. Manoukian can be contacted at firstname.lastname@example.org References
1. Fisch M, Feit F. Mechanisms of Thrombosis Induction and Mitigation with Contrast Media: Comparative Effects and Implications for Percutaneous Coronary Intervention. J Invasive Cardiol 2010; 22(Suppl A):4A-9A.
2. Manoukian SV. Experimental and clinical evidence for ionic, low-osmolar contrast media for thrombosis and major adverse cardiac event reduction in the setting of percutaneous coronary intervention. J Invas Cardiol 2010; 22(Suppl A): 10A-14A.