Biotech Values

[DewDiligence]

Antithrombin to treat DIC / sepsis:
Benefit/Risk Profile of High-Dose
Antithrombin in Patients with Severe
Sepsis Treated With And Without
Concomitant Heparin

[These are the KyberSept data that have created a buzz about the use of antithrombin to treat DIC associated with sepsis and were responsible for GTCB and partner, Leo Pharma, selecting DIC/sepsis as the *acquired* AT deficiency in which to pursue development in Europe. When heparin was not co-administered, antithrombin treatment resulted in a strong reduction in 90-day mortality relative to placebo: the hazard ratio was 0.85, and the upper bound of the 95% confidence interval on the HR was <1.0, which implies that the p-value was <0.05. The mortality benefit seen at 45 days was slightly smaller than at 90 days with HR = 0.86. (Because there were multiple data looks, I’ve refrained from calling these results “statistically significant” despite the fact that the 90-day mortality endpoint had a p-value<0.05.) Please see the abstracts in #msg-10321910 for related studies of AT in sepsis.]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_...

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Thromb Haemost. 2006 May;95(5):850-6.

Hoffmann JN, Wiedermann CJ, Juers M, Ostermann H, Kienast J, Briegel J, Strauss R, Warren BL, Opal SM; for the KyberSept investigators.

Professor of Medicine, Brown Medical School, Chief, Infectious Disease Division, Memorial Hospital of Rhode Island, 111 Brewster Street, Pawtucket, Rhode Island, 02860 USA.

A randomised, prospective, placebo-controlled phase III multicentre clinical trial (KyberSept) has been performed to test the efficacy of high-dose antithrombin therapy in patients with severe sepsis. Concomitant low-dose heparin has been routinely given in two thirds of patients for deep vein thrombosis prophylaxis. This study analyses heparin - antithrombin interactions in terms of long-term mortality, adverse events, and thromboembolic events.

From a total of 2,314 patients with severe sepsis (placebo: n = 1,157; antithrombin: n = 1,157) 1,616 patients (placebo: 811, antithrombin: 805) received heparin concomitantly with study drug (antithrombin 30,000 IU) over four days, whereas 698 patients (346 and 352, respectively) did not.

In patients with no concomitant heparin, 28-day mortality was lower with antithrombin than with placebo (37.8% vs. 43.6%; absolute reduction: 5.8%; risk ratio: 0.860 [0.725-1.019]), which increased until day-90 (44.9% vs. 52.5%; absolute reduction: 7.6%; risk ratio: 0.851 [0.735-0.987]).

In patients with concomitant heparin, no effect of antithrombin on mortality was seen (28-day mortality: 39.4% vs. 36.6%; absolute increase: 2.8%; risk ratio: 1.08 [0.96-1.22]). Frequency of use of concomitant heparin increased during conduct of the study. Increased bleeding incidences were reported with antithrombin plus concomitant heparin as compared to antithrombin alone. Rates of thromboembolic events were similar when antithrombin was given with or without concomitant heparin.

In the treatment of severe sepsis, high-dose antithrombin may sufficiently protect against development of venous thromboembolism when no concomitant heparin is given. Combined administration of the two increases bleeding risk and probably abolishes efficacy of antithrombin.
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