safety, tolerability, pharmacokinetics and pharmacodynamics of mdco-2010 in patients undergoing elective coronary artery bypass graft surgery

Conditions: Coronary Artery Bypass Graft; Cardiopulmonary Bypass

Summary: the purpose of this study is to demonstrate that periprocedural infusion of escalating doses of mdco-2010 is safe and tolerated in patients undergoing elective cabg surgery, to characterize the single dose pharmacokinetics of mdco-2010, to investigate the effect of mdco-2010 on pharmacodynamics (biomarkers of fibrinolysis and coagulation parameters), and to investigate the effect on exploratory clinical endpoints of bleeding, transfusion requirements and reexploration.

this protocol describes a study of the investigational drug mdco-2010 as a haemostasis modulator in patients undergoing elective coronary artery bypass graft (cabg) surgery involving a cardiopulmonary bypass (cpb). perioperative bleeding is a serious complication that adversely affects the morbidity and mortality of cardiac surgery. to alleviate this complication, prophylactic antifibrinolytic therapies are now widely accepted as a strategy to inhibit excessive fibrinolysis. mdco-2010, a synthetic small molecule, is a direct inhibitor of plasmin and plasma kallikrein. both of these have been implicated with impaired haemostasis. in addition, potent inhibition of coagulation factors xa, xia and activated protein c has been demonstrated. thus, mdco-2010 has the potential to mitigate excessive fibrinolysis and thrombin generation during cardiac surgery involving a cardiopulmonary bypass. in particular the latter is supposed to provide additional benefits beyond reducing transfusion requirements.

Eligibility criteria:
inclusion criteria * men, aged 18 to 80 years or * post-menopausal women, aged up to 80 years. postmenopausal status defined as ≥ 1 year since last menstruation in women with no medical history of hysterectomy or women with a medical history of bilateral oophorectomy * planned elective, isolated primary cabg surgery with more than 1 graft, including the use of cardiopulmonary bypass * written informed consent prior to any study-related procedure not part of normal medical care exclusion criteria patients may not meet any of the following exclusion criteria: * planned concomitant surgery including atrial septal defect (asd) repair, valve replacement, carotid endarterectomy, aortic surgery, any combined procedure or any repeat sternotomy * planned off-pump cabg * body weight \ 110 kg * planned hypothermia \< 28°c * major surgical procedures within 30 days of entry * placement of drug-eluting stent (des) within 12 months or of bare-metal stent (bms) within 6 weeks of entry in a vessel which is not intended to be grafted * ejection fraction \< 35% * preoperative coagulation abnormalities * platelet count \< 100,000/cubic mm, or * inr \> 1.5 or quick \< 40%, or * activated partial thromboplastin time (aptt) \> 1.5 x upper limit of normal (uln) * preoperative hb \< 11 g/dl for male patients or \< 10 g/dl for female patients * patient refusal to receive donor blood products if necessary * administration of thienopyridines within 5 days prior to surgery administration of warfarin within 5 days prior to surgery * administration of tirofiban or eptifibatide within 24 hours or administration of abciximab within 5 days prior to surgery * administration of fondaparinux within 24 hours prior to surgery * creatinine clearance (calculated using cockroft-gault equation) \< 60 ml/min * planned intraoperative use of tranexamic acid or of ε-aminocaproic acid * history of stroke or transient ischemic attack within 3 months prior to entry * known heparin-induced thrombocytopenia * known history of thrombophilia, eg, deep vein thrombosis (dvt) with pulmonary embolism * active liver disease * any condition requiring chronic immunosuppressive medication * receipt of an investigational drug or device 30 days prior to entry * any other condition which, in the opinion of the investigator, would prevent a patient's participation in the study

Keywords: cardiac surgery coronary artery bypass graft cardiopulmonary bypass haemostasis modulator blood loss direct inhibitor of plasmin and plasma kallikrein cabg cpb