Association of immune globulin intravenous and thromboembolic adverse events
Authors: Mikhail V. Ovanesov, Mikhail D. Menis, Dorothy E. Scott, Richard Forshee, Steven Anderson, Wilson Bryan, Basil Golding
Journal: American Journal of Hematology (2017)

The recent article by Ammann et al.1 is a meta-analysis of randomized controlled trials (RCTs) performed to determine whether thromboembolic events (TEEs) are more frequent in patients receiving immune globulin intravenous (IGIV). The conclusion of the study is that TEEs are not more frequent after IGIV compared with placebo or no treatment. The authors caution that their results should not be generalized "to older and otherwise higher risk patients" and that "patients with immune deficiencies were under-represented." However, physicians and healthcare providers should not read the paper and conclude that the risk of TEEs following IGIV treatment is so small or non-existent that careful monitoring of patients for thrombosis is not necessary. Based on earlier published studies and analyses conducted by the Food and Drug Administration (FDA), FDA considers the risk of TEEs following IGIV treatment is small but not zero and the benefits for indicated therapeutic uses outweigh the risks. IGIV is regulated by the FDA Center for Biologics Evaluation and Research, Office of Tissues and Advanced Therapies. In 2010, FDA became aware of a cluster of TEEs associated with certain lots of Octagam, an IGIV product. An FDA investigation showed high levels of coagulation factor XIa (FXIa), a procoagulant impurity, in the TEEs-associated lots of Octagam, and other IG products.2, 3 The procoagulant FXIa-contaminated Octagam lots were promptly withdrawn from the U.S. market, and multiple regulatory and corrective actions were taken. Specifically, FDA informed manufacturers of the potential issue with FXIa in IG products. FDA, working with the World Health Organization, National Institute for Biological Standards and Control (UK), and European Medicines Agency implemented corrective actions, including developing assays and standards for measuring FXIa, transferring knowledge of these assays to manufacturers, encouraging manufacturers to test their products at lot release, and to consider introduction of dedicated steps to remove FXIa. In addition, FDA required all manufacturers to introduce class labeling changes with a Boxed Warning to highlight the risk of thrombosis and advice to increase monitoring for TEE in treatment of patients with underlying risks factors. FDA web-postings informed users of IG products of the risk. Additionally, the FDA Office of Biostatistics and Epidemiology performed large healthcare database retrospective studies that provided evidence that certain IG products were associated with higher thrombosis risk on the first day of infusion.4, 5 The findings were consistent with laboratory analyses of products which showed an association of high TEE risk with high levels of FXIa impurity.5 In addition to the elevated TEE risks with specific products, these studies identified underlying recipient risk factors. What accounts for the discrepancy between Ammann et al.'s conclusion that there is no increased risk of thrombosis,1 and FDA's and manufacturers' laboratory investigations and healthcare database analyses showing an increased risk? The recent study pooled data from multiple study centers involving multiple IGIV products.1 Since thrombosis is relatively rare and is typically observed in certain lots from a few products, it is likely that pooled RCT data would not detect the risk, as the RCTs were based on smaller sample sizes (enrollment from 40 to 624 participants) and not tailored to detect rare adverse events. In contrast, an earlier study by Amman et al. with a larger number of patients (8035 non-users and 2724 users of IG) involving chronic lymphocytic and multiple myeloma patients, showed a threefold higher rate of arterial TEEs in the first day of IG infusion.6 Both of FDA's epidemiological studies4, 5 were based on substantially greater numbers of exposed persons (11 000 and 101 000 exposures, respectively), and thus could detect rare adverse events. FDA studies, unlike the study by Ammann et al.1 also represent the use of products in clinical practice, as all IG users were included regardless of age, indications, and underlying risk factors. In summary, FDA acknowledges that the analyses conducted by Ammann et al. are an appropriate scientific investigation of an important issue. However, the data from the Ammann et al.1 paper should not be considered in isolation from previous studies. FDA continues to evaluate and better quantify TEE risks for IG products for different patient populations and indications as part of a large chart confirmed Sentinel BloodSCAN study. The FDA conclusion from the available data is that the risk of thrombosis from IG products is small but not zero. Accordingly, continued vigilance on the part of the agency, the manufacturers, the healthcare providers, and the patients is warranted. All the authors wrote and approved the manuscript.