Beneficial Effects of Complement Inhibition With Soluble Complement Receptor 1 (TP10) During Cardiac Surgery

Abstract

and the TP10 Cardiac Surgery Study GroupBackground-TP10, a potent inhibitor of complement activation during cardiopulmonary bypass (CPB) has been shown to significantly reduce the incidence of death and myocardial infarction (MI) in high-risk male patients undergoing cardiac surgery. However, the effect of TP10 in females was undefined because of the limited number of females studied. To examine the possibility of a gender effect, this phase 2 multi-center trial was undertaken to determine whether TP10 would also limit ischemic damage in a larger sample size of high-risk females undergoing cardiac surgery on cardiopulmonary bypass (CPB). Methods and Results-This prospective, double-blind, placebo-controlled, multi-center trial involved 297 high-risk (urgent surgery, CABG ϩ Valve, reoperations, ejection fraction Ͻ30%) female patients randomized to receive a 5 mg/kg dose of TP10 (nϭ150) or placebo (nϭ147) as a 30-minute intravenous infusion before surgery. The primary end point was the incidence of death or MI at 28 days after surgery. Complement activation was assessed by levels of CH50 and SC5b-9 during and after CPB. TP10 was well tolerated and there were no differences in the safety profiles of the 2 groups. Although TP10 effectively suppressed complement activation (at 2 hours after CPB CH50 (meanϩSD % change from baseline) 50Ϯ17% placebo versus 4Ϯ14% TP10; Pϭ0.0001; SC5b-9 (ng/mL) 917Ϯ1067 placebo versus 204Ϯ79 TP10; Pϭ0.0001), there was no difference in the primary end point between the groups (17% placebo versus 21% TP10; Pϭ0.2550). Conclusions-The benefits of TP10 appear to be gender-related. and mechanisms other than complement activation may be responsible for myocardial injury in high-risk female patients during cardiac surgery on CPB.

Soluble CR1 Therapy Improves Complement Regulation in C3 Glomerulopathy

“…However, super-physiologic singledose treatment with sCR1 has been used in .500 patients (infants and adults) undergoing a variety of cardiac surgeries or after myocardial infarctions to arrest complement activation. [23][24][25][26] These studies showed that sCR1 was well tolerated with no adverse events clearly or consistently associated with its use. Importantly, the possible development of anti-sCR1 antibodies was monitored but never observed in .350 patients.…”

A vital role for complement in heart disease

“…Lazar et al studied the effects of TP10 in high-risk patients undergoing cardiac surgery, but even if complement activation was effectively suppressed by TP10, there was no reduction in the clinical composite primary endpoint (Lazar et al, 2004). However, there was a reduction in mortality and myocardial infarction size in males but not in females (Lazar et al, 2004;Lazar et al, 2007), suggesting that the effects of TP10 may be gender-related. These observations have not been further explored.…”

Anticomplement therapy

“…The TP10 group showed a lower primary endpoint event rate by 30% only in male patients. In a follow-up study of 297 female patients randomized to treatment with TP10 or placebo, it was shown that TP10 suppressed complement activation but did not reduce the incidence of death or MI by 28 days after surgery (Lazar et al 2007). A possible reason for this lack of difference is that the number of adverse events in the control arm of this trial was quite low to begin with, at 17%.…”