Anticoagulation Stability With Bivalirudin: Positioning the Horse Before the Cart.

Abstract

To the Editor: We thank Dr. Seelhammer and colleagues for their interest in our article1 and for the opportunity to expound upon on several key points. With significantly increased use of bivalirudin over the past decade, we acknowledge the need for larger, multicenter collaboration to generate more definitive conclusions in the superiority of bivalirudin used in pediatric Berlin Heart recipients versus unfractionated heparin (UFH). The preferred use of bivalirudin has occurred largely in the absence of robust published evidence. It is our hope that the article is one of many that provides support of this change. We agree that anti-Xa monitoring should be considered over activated partial thromboplastin time (aPTT) in patients anticoagulated on UFH secondary to the impact of inflammation and disseminated intravascular coagulopathy on aPTT. Significant assay variability and center-specific ranges make application across centers challenging. Although inter-reagent differences in anti-Xa have been described,2 we expect more consistent results given that Berlin Hearts (over time) have more pronounced proinflammatory activation compared to other mechanical support devices—translating into greater difficulties with anticoagulation interpretation. This explains some of the discordance of our concurrently drawn aPTT and anti-Xa values, and the difference in our anticoagulation stability findings. We also recognize the limitation of aPTT with bivalirudin use as well and like many centers are working towards access to dilute thrombin time monitoring. We appreciate the request for additional information regarding renal impairment in the bivalirudin group, and have attached Figure 1 which displays the first 21 days of bivalirudin initiation with the infusion rates (mg/kg/hour) plotted alongside estimated glomerular filtration rate (eGFR)-normalized infusion rates for review.Figure 1.: Bivalirudin infusion rates over first 21 days of anticoagulation initiation.Regarding VAD-itis, compared to other devices, Berlin Hearts have a greater perturbation of immune homeostasis, translating into elevated risk for adverse events such as thromboembolism.3,4 These patients are accounted for by the action of treatment with corticosteroids used to attenuate the immune response, and the judgment of the multidisciplinary heart failure team based on elevated laboratory values as recommended by Advanced Cardiac Therapies Improving Outcomes Network’s harmonized protocol rather than any isolated immunologic variable. We are in agreement with Seelhammer et al. that differences in aspirin dosing intensity confers confoundment in thrombotic outcomes, and is accounted for within our limitations. As discussed, higher aspirin utilization with bivalirudin was secondary to the later adoption of the modified Stanford protocol5 and not due to the prevalence of VAD-itis. It is plausible that the UFH patients experienced the same phenomenon of VAD-itis, under-recognized during that era of management, and thus undertreated leading to a greater procoagulant milieu in those patients. At present, this is the only study to compare the use of bivalirudin to UFH in this patient population. Our hypothesis is that greater anticoagulation stability may translate into improved patient outcomes—the former of which we identified in our study. The latter will have to wait for larger, multicenter collaboration. We encourage other centers to publish their experiences in order to reposition the data in front of the practice at-large.