Soluble Human Complement Receptor 1 Limits Ischemic Damage in Cardiac Surgery Patients at High Risk Requiring Cardiopulmonary Bypass

Abstract

the TP10 Cardiac Surgery Study GroupBackground-This study was undertaken to determine whether soluble human complement receptor type 1 (TP10), a potent inhibitor of complement activation, would reduce morbidity and mortality in high-risk patients undergoing cardiac surgery on cardiopulmonary bypass (CPB). Methods-This was a randomized multicenter, prospective, placebo-controlled, double-blind study in which 564 high-risk patients undergoing cardiac surgery on CPB received an intravenous bolus of TP10 (1, 3, 5, 10 mg/kg) or placebo immediately before CPB. The primary endpoint was the composite events of death, myocardial infarction (MI), prolonged (Ն24 hours) intra-aortic balloon pump support (IABP), and prolonged intubation. Results-TP10 significantly inhibited complement activity after 10 to 15 minutes of CPB and this inhibition persisted for 3 days postoperatively. However, there was no difference in the primary endpoint between the 2 groups (33.7% placebo versus 31.4% TP10; Pϭ0.31). The primary composite endpoint was, however, reduced in all male TP10 patients by 30% (Pϭ0.025). TP10 reduced the incidence of death or MI in males by 36% (Pϭ0.026), the incidence of death or MI in CABG males by 43% (Pϭ0.043) and the need for prolonged IABP support in male CABG and valve patients by 100% (Pϭ0.019). There was, however, no improvement seen in female TP10 patients. There were no significant differences in adverse events between the groups. Conclusion-TP10 effectively inhibits complement activation during CPB; however, this was not associated with an improvement in the primary endpoint of the study. Nevertheless, TP10 did significantly decrease the incidence of mortality and MI in male patients.

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.…”

“…Importantly, the possible development of anti-sCR1 antibodies was monitored but never observed in .350 patients. 23,26 …”

Hemolytic Uremic Syndrome

“…Phase I and phase II clinical trials have shown that the soluble CR1 TP10, administered intravenously both before and during surgery, decreased complement activation and protected vascular function in infants who underwent cardiopulmonary bypass (169). In a randomized, multicenter, prospective study in 564 high-risk patients who underwent cardiac surgery on cardiopulmonary bypass, a bolus of TP10 given immediately before cardiopulmonary bypass significantly inhibited complement activity within 10 min, and this inhibition persisted for 3 d postoperatively (170).…”

Complement activity and pharmacological inhibition in cardiovascular disease

“…This composite end point was significantly reduced in an analysis restricted to men only (P=0.025) as were the rates of death or MI by 36% (P=0.026). No significant excess of side effects occurred with treatment in this study (31).…”

“…In a larger randomized, prospective, double-blind study of high-risk patients undergoing cardiac surgery, 564 patients (408 men and 156 women) received incremental doses of an intravenous bolus of TP10 (1 mg/kg, 3 mg/kg, 5 mg/kg or 10 mg/kg) or placebo immediately before initiating the extracorporeal circulation (31). The serum complement activity (CH50) was almost completely suppressed within 5 min to 10 min, only to recover progressively over the following 72 h. The generation of C3a and SC5b-9 associated with the extracorporeal circulation was also prevented.…”