Objectives

To determine the time to occurrence of a composite triple endpoint (death, limb amputation/gangrene, and new thrombosis) after a positive heparin PF-4 antibody test.

Background

Heparin-induced thrombocytopenia (HIT) is a common and often severe complication of heparin therapy. HIT is an immunologic drug reaction mediated by the IgG antibodies against the heparin-platelet factor 4 (PF4) complex. Thrombocytopenia is the cardinal, yet least worrisome, complication of HIT. The major complications are arterial and venous thrombi. Patients who are positive for thrombosis and a heparin-PF4 antibody test, with or without thrombocytopenia, categorize further as HIT-Thrombosis (HIT-T). Conversely, patients with no clinical evidence for thrombosis, but positive for thrombocytopenia and heparin-PF4 antibody test are clinically categorized as isolated HIT.

The incidence of HIT ranges from 0.3-5.0%, and is dependent on population, type and route of heparin used. The treatment of HIT-T with anticoagulation is well established, but the risks and treatment of isolated HIT are unclear. Recent ACCP (“CHEST”) current standard of care guidelines for isolated HIT is the institution of a direct thrombin inhibitor until the platelet count is greater than 100,000 (usually for 3-4 days), the overlap of the direct thrombin inhibitor with Coumadin for at least 5 days, and an unspecified total duration of anticoagulation (although 28 days from the onset of this complication is often recommended). These guidelines are based upon a sparse amount of data, with no randomized placebo-controlled studies, and few prospective studies. Unfortunately, treatment of isolated HIT often results in major increases in hospital length of stays, and financial obligations.

An observational study, HOT, Heparin-Induced Thrombocytopenia Observational Thromboembolism Study, was designed to address the incidence of isolated HIT, and whether such patients had an increased rate of symptomatic or asymptomatic clots. The study was unsuccessful due to shortcomings in the number of eligible subjects identified with isolated HIT. Nevertheless, a large cohort of consecutive patients with a positive heparin-PF4 antibody test were identified. The HIT-RADIO study would be the largest multi-site retrospective study of this patient population in many years. The intent of this study was to obtain large samples of positive heparin-PF4 antibody subjects to perform specific, descriptive, and hypothesis-generating outcomes.

Participants

Subjects were a combination of participants from the previous HOT Study and/or any patients at selected hospitals associated with the Transfusion Medicine/Hemostasis Clinical Trials Network. Approximately 500 patients were estimated to be enrolled in the study.

A positive heparin-PF4 antibody test occurred in 668 patients. Of those 668 patients, 442 were eligible subjects and 226 were excluded due to lack of recent heparin exposure. Eligible subjects were further divided into three reporting groups: HIT-T (71), Isolated HIT (284), and No HIT (87).

In order to be included in this study, the medical record had to be available for the hospital admission when the positive heparin-PF4 antibody test was obtained. No exclusion criteria were recorded.

Design

Retrospective chart review was conducted at the U.S. centers that participated in the HIT Trial and were part of the NIH Transfusion Medicine and Hemostasis Network. Medical records were reviewed by the study personnel for abstraction of data onto case report forms. Records from other institutions were included only if they were already part of the medical record for the visit that reported the positive antibody test. Reference time for all measurements was the date the assay was sent. The review was not to include dates more than 28 days prior or 45 days after the assay was sent.

Subjects were categorized into four groups: group 1 was HIT-T with thrombocytopenia, group 2 HIT-T, group 3 isolated-HIT, and group 4 positive for heparin-P4 antibody with neither thrombocytopenia nor thrombosis. Various analyses were performed on baseline characteristics, the primary composite triple endpoint, and secondary endpoints. Baseline characteristics included demographics, medical history, optical density of the positive HIT ELISA test, the type of heparin exposure, and the indication for heparin.

Conclusions

The statistical analysis of the primary composite triple endpoint was measured by the mean time to occurrence. The mean time to the primary endpoint for subjects with HIT-T was 17.5 days; for subjects with Isolated HIT was 27.8 days; and for subjects with No HIT was 31.4 days. This difference in time to the primary outcome was found to be statistically significant when comparing subjects with HIT-T to those with No HIT, but was not significant when comparing subjects with Isolated HIT to those with No HIT.

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