GTC Biotherapeutics (fka GTCB)

[DewDiligence]

Antithrombin for Severe Sepsis?
Try It Again, but Without Heparin!

[This is an old (2006) editorial in the Journal of Thrombosis and Haemostasis that I finally found a way to access. It provides an introduction to the paper by Hoffmann (see #msg-10993909 for abstract), one of several recent papers that revisited the Kybersept study with a fresh point of view about the use of heparin. Bernd Jilma, the author of this editorial, conducted a study that tested the PK/PD of ATryn in healthy human volunteers subjected to a “model” of endotoxemia.]

http://www.google.com/search?q=%22bernd+jilma%22+antithrombin+sepsis+heparin

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Thromb Haemost. 2006 May;95(5):755.

Jilma, B

Department of Clinical Pharmacology, Medical University of Vienna, Austria and Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA

Recent studies revealed novel anti-inflammatory actions of antithrombin (AT) in vitro as well as in vivo, but also suggested that heparin antagonizes anti-inflammatory and microcirculatory effects of AT.

The Kybersept trial was a pivotal phase III trial for AT in sepsis. In this issue of Thrombosis and Haemostasis, Hoffmann et al. present a further analysis of this study, which many of us have been looking forward to. The safety and efficacy analyses compare the a priori defined subgroups of patients with and without heparin treatment. Patients receiving concomitant heparin were defined as patients receiving any heparin during the AT treatment period of four days.

Increased efficacy is supported by a 6% lower mortality in patients treated with AT but without concomitant heparin. The effect size was fairly consistent or even increased from days 28 to 90.

Two safety analyses are provided, one for spontaneously reported thrombosis, the other for bleeding risk. The incidence of thrombotic events during the four days of antithrombin treatment was 0.3–0.6% in any of the four groups (placebo or AT with or without heparin). With all the caveats of the non-randomized heparin treatment, these data indicate that there is no justification to use heparin for prophylactic reasons when AT is infused over four days.

Any bleeding was associated with a high risk of mortality (60–88%) in all groups at 90 days. This also indicates that bleeding in septic patients who receive placebo appears to be a detrimental feature of sepsis (mortality 70–88%). While bleeding events were increased by AT treatment, bleeding patients under AT treatment had a lower mortality as compared to bleeding patients on placebo. Again, heparin treatment was not beneficial.

These findings as well as further analysis from that trial have important implications for the planning of future clinical trials with AT. First and foremost, concomitant treatment with heparins should be prohibited at least until one day after the end of AT therapy. Secondly, this requirement in the protocol should be strictly enforced by vigorous monitoring during the trial.

It is notable, that in contrast to protein C or activated protein C [i.e. Xigris], supra-physiological levels of AT have marked dose-dependent anticoagulant efficacy on their own, as demonstrated in a human model of endotoxin-induced, tissue factor-triggered coagulation. Also, it should be emphasized that there is no evidence from randomized controlled clinical trials to support the use of heparin in septic patients.
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