Since 2013, the U.S. Food and Drug administration (FDA) has required that intravenous immune globulin (IGIV) products carry a boxed warning concerning the risk of thromboembolic events (TEEs). This study assessed the incidence of TEEs attributable to IGIV in a large population-based cohort. A self-controlled risk interval design was used to quantify the transient increase in TEE risk during the risk interval (days 0–2 and 0–13 following IGIV for arterial and venous TEEs, respectively) relative to a later control interval (days 14–27 following IGIV). Potential IGIV-exposed TEE cases from 2006 to 2012 were identified from the FDA-sponsored Sentinel Distributed Database and confirmed through medical record review. Inpatient IGIV exposures were not included in the venous TEE analysis due to concerns about time-varying confounding. 19,069 new users of IGIV who received 93,555 treatment episodes were included. Charts were retrieved for 62% and 70% of potential venous and arterial cases, respectively. There was a transient increase in the risk of arterial TEEs during days 0–2 following IGIV treatment (RR = 4.69; 95% CI 1.87, 11.90; absolute increase in risk = 8.86 events per 10,000 patients, 95% CI 3.25, 14.6), but no significant increase in venous TEE risk during days 0–13 following outpatient IGIV treatments (RR = 1.07, 95% CI 0.34, 3.48). Our results suggest there is a small increase in the absolute risk of arterial TEEs following IGIV. However, lower-than-expected chart retrieval rates and the possibility of time-varying confounding mean that our results should be interpreted cautiously. Continued pharmacovigilance efforts are warranted.
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Many thanks are due to those who participated in this project: Sentinel Operations Center: Carolyn Balsbaugh, Jennifer Popovic, Katherine Yih, Tiffany Woodworth, Noelle Cocoros, PRISM Chart Validation Team. IGIV-TEE Workgroup: Joshua Gagne, Mike Mueller, Casey Covarrubias, Carly Comins, Elena Letuchy, Vinutha Vijayadeva, Cynthia Nakasato. Programmers: Rick deFreisse, StatLog, Robert Jin.
The results reported herein correspond to the objectives of Mini-Sentinel contract HHSF223200910006I from the U.S. Food and Drug Administration (FDA) and Department of Health and Human Services (HHS). This work was also supported by the Sentinel Coordinating Center, which is funded by the FDA through HHS contract number HHSF223201400030I.
Conflict of interest
E. Ammann is currently employed by Johnson & Johnson; the study analyses were completed, and manuscript drafted before his start in this role. C. Leonard serves on the Executive Committee of the University of Pennsylvania's Center for Pharmacoepidemiology Research and Training; the Center receives funds to support education from Pfizer and Sanofi. A. Cuker has served as a consultant for Synergy CRO; his institution has received research support on his behalf from Alexion, Bayer, Novo Nordisk, Pfizer, Sanofi, Spark, and Takeda. J. Robinson reports grants to her institution from Acasti, Amarin, Amgen, Astra-Zeneca, Eli Lilly, Esperion, Medicines Company, Merck, Novartis, Novo-Nordisk, Regeneron, Sanofi, and Takeda, and consulting fees from Amgen, Medicines Company, Merck, Novartis, Novo-Nordisk, Pfizer, Regeneron, and Sanofi. The other authors report no disclosures.
Data Partners who provided medical records and data used in the analysis: Aetna, a CVS Health company, Blue Bell, PA; Harvard Pilgrim Health Care Institute, Boston, MA; HealthCore, Inc., Translational Research for Affordability and Quality, Alexandria, VA; HealthPartners Institute, Minneapolis, Minnesota; Humana, Inc., Healthcare Research, Miramar, FL; Kaiser Permanente Colorado Institute for Health Research, Denver, CO; Kaiser Permanente Center for Health Research Hawai’i, Honolulu, HI; Kaiser Permanente Northern California, Division of Research, Oakland, CA; Kaiser Permanente Northwest Center for Health Research, Portland, OR; Kaiser Permanente Washington Health Research Institute, Seattle, WA; Meyers Primary Care Institute, Worcester, MA; OptumInsight Life Sciences Inc., Boston, MA; Vanderbilt University Medical Center, Department of Health Policy, Nashville, TN, through the TennCare Division of the Tennessee Department of Finance & Administration which provided data.
Sentinel uses a distributed data approach in which Data Partners maintain physical and operational control over electronic health data in their existing environments after transforming their data into a common data model. This analysis utilized the Sentinel Distributed Database [and standardized data querying tools. Code for Sentinel standardized data querying tools, query specifications, and related documentation are shared via the Sentinel website, which allows for transparency and potential replicability of this study on other data sources.] To preserve patient privacy, Sentinel generally does not save, maintain, or post individual level datasets. Sentinel Data Partners update data at varying intervals and retain a limited number of iterations of their historical data, which may affect replication of this assessment.
This Sentinel manuscript is a public health surveillance activity conducted under the authority of the Food and Drug Administration and, accordingly, is not subject to Institutional Review Board oversight.
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Ammann, E.M., Chrischilles, E.A., Carnahan, R.M. et al. Self-controlled assessment of thromboembolic event (TEE) risk following intravenous immune globulin (IGIV) in the U.S. (2006–2012). J Thromb Thrombolysis 53, 264–272 (2022). https://doi.org/10.1007/s11239-021-02610-4
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