A Novel Blood-Sparing Agent in Cardiac Surgery? First In-Patient Experience with the Synthetic Serine Protease Inhibitor MDCO-2010

Abstract

This first-in-patient study demonstrated dosage-proportional PK for MDCO-2010 and reduction of chest tube drainage and transfusions in patients undergoing primary coronary artery bypass grafting. Antifibrinolytic and anticoagulant effects were demonstrated using various markers of coagulation. MDCO-2010 was well tolerated and showed an acceptable initial safety profile. Larger multi-institutional studies are warranted to further investigate the safety and efficacy of this compound.

Sample-size determination and adherence in randomised controlled trials published in anaesthetic journals

“…Chance corrected inter-observer agreement for trial eligibility was excellent (kappa = 0.82). Twenty-four trials were subsequently excluded for the following reasons: Not randomized (2), 5,6 pilot trial (4), 7-10 cross-over trial (2), 11,12 factorial (2), 13,14 multiple outcomes (5), [15][16][17][18][19] secondary analysis (4), [20][21][22][23] using dynamic sample size calculations (1), 24 non-inferiority trial (2), 25,26 and trial stopped early (2). 27,28 Trial selection process is shown in 0 1, sample-size calculation details of the 28 included trials are reported in Table 1, and a comparison of expected and actual treatment effects are provided in Table 2.…”

Synthesis and Structural Characterization of Macrocyclic Plasmin Inhibitors

“…In spite of the relatively high plasminogen levels between 1.1 and 2 μM in the circulation, clinical studies with different dosages of CU-2010 showed that an inhibitor concentration of approximately 0.5 μM in blood is sufficient to achieve the intended antifibrinolytic efficacy in vivo. [35] Since this concentration would be approximately 250-fold higher than a K i value of 2 nM, an effective inhibition of the activated plasmin in the circulation could be expected. Since these compounds are also very selective plasmin inhibitors, their effective concentration is rather not expected to be affected by targeting other targets.…”

“…Despite a reduced activity in comparison to inhibitor 1 , their inhibitory potency is still in the same range as previously described for the acyclic inhibitor CU‐2010 ( K i =2.2 nM), [12] which had reached clinical phase II development. In spite of the relatively high plasminogen levels between 1.1 and 2 μM in the circulation, clinical studies with different dosages of CU‐2010 showed that an inhibitor concentration of approximately 0.5 μM in blood is sufficient to achieve the intended antifibrinolytic efficacy in vivo [35] . Since this concentration would be approximately 250‐fold higher than a K i value of 2 nM, an effective inhibition of the activated plasmin in the circulation could be expected.…”