Use of Intravenous Immunoglobulin G in HIT: Impact on Thrombosis and Mortality in a Population-Based Study
Authors: Dhakal Binod , Lisa Rein , Szabo Aniko , Aster Richard H. , Padmanabhan Anand 
Published: October 2019

Abstract
Introduction: Heparin-induced thrombocytopenia (HIT) is a severe prothrombotic syndrome with a mortality rate of 10% (Lancet Haematol. 2018 May; 5(5):e220-e231). Case reports show that Intravenous Immunoglobulin G (IVIg) can rapidly and durably counteract HIT antibody-mediated platelet activation in the setting of severe persistent HIT (Chest. 2017 Sep;152(3):478-485 and others). While this data supports use of IVIg in severe HIT, it is well documented that "positive result bias" enhances the likelihood of publication of studies that demonstrate salutary effects of interventions. IVIg has a black box warning for thrombosis which lists a number of potential predisposing states for this complication including hypercoagulable conditions (such as HIT). Thus, one concern is that of new/worsening thrombosis in HIT patients treated with this drug, something that is not evaluable with the limited publications in this area. The Nationwide Inpatient Sample (NIS) is the largest publicly available patient discharge database in the US that includes ~7 million discharges per year representative of discharges from all hospital types in the country. The goal of this study was to evaluate thrombosis, bleeding and mortality outcomes associated with IVIg use in HIT using the NIS database.
Methods: Hospital discharges with an ICD-9-CM code for HIT (289.84) in the NIS were used to compare outcomes in adult patients (≥18yrs) who did and did not receive IVIg treatment (ICD-9-CM code 99.14) from October 1, 2008 to December 31, 2014. Discharges with diagnoses suggestive of a history of thrombosis (ICD-9-CM codes V12.51, V12.52, V12.55), idiopathic thrombocytopenic purpura (287.31), or secondary thrombocytopenia (287.4) were excluded. Patient characteristics included age, sex, all patient refined diagnosis related groups (APR-DRG) severity index, and APR-DRG mortality index. Outcomes included arterial thrombosis, venous thrombosis, bleeding, mortality, and a composite of all outcomes. Variables were compared by IVIg treatment status using survey weighted Chi-squared tests for categorical variables and ANOVA for continuous variables. Survey weighted multiple logistic regression was used to model each binary outcome by IVIg treatment status while adjusting for age, gender, APR-DRG severity index and mortality index. A matched analysis was performed as a sensitivity analysis for the multiple logistic regression results. Controls were matched with IVIg cases by exact gender, APRDRG severity index, and mortality index. Five matching controls were selected for each case based on nearest age. Conditional logistic regression was used to analyze each outcome using the matched dataset.
Results: HIT patients treated with IVIg and those without were no different in age and sex (Table 1). Consistent with the limited published experience of IVIg use in HIT, those who received IVIg had more severe disease with greater likelihood of dying as indicated by their APR-DRG severity and mortality indices (Table 1). Multiple logistic regression showed that the adjusted odds ratio (aOR) was lower for all outcomes except bleeding in the IVIg-treated group, although this did not reach statistical significance (Fig 1; aOR of 0.766, 0.922, 1.049, 0.685 and 0.703 for arterial thrombosis, venous thrombosis, bleeding, death and composite outcome, respectively). Similar results were obtained in conditional logistic regression of matched data (Fig 2).
Conclusions: Use of IVIg was not associated with worse thrombotic outcomes or mortality in HIT. On the contrary, results suggest a possible protective effect on these outcomes, but results did not achieve statistical significance possibly due to small numbers of IVIg-treated patients. The aOR was higher (but not significantly so) for bleeding in IVIg-treated HIT patients, however, this finding is consistent with the possibility that IVIg was used more frequently in patients who had more severe disease (and had already hemorrhaged), as suggested by worse APR-DRG severity and mortality indices in IVIg-treated patients. A prospective randomized treatment study may be necessary to provide conclusive data on IVIg efficacy and risk in HIT.

Disclosures
Dhakal: Amgen: Honoraria; Celgene: Consultancy, Honoraria; Takeda: Honoraria. Aster:BloodCenter of Wisconsin: Patents & Royalties. Padmanabhan:Janssen Pharmaceuticals: Consultancy; GE Healthcare: Other: Material support for Clinical Quality Improvement Initiative; Retham Technologies LLC: Equity Ownership, Other: Retham seeks to develop HITDx(TM), a new assay for HIT diagnosis; BloodCenter of Wisconsin: Patents & Royalties: Patent/royalties for HIT diagnostic testing; Veralox Therapeutics: Other: Advisory Board; TerumoBCT: Consultancy.