Activated protein C as disease-modifying therapy in antenatal preeclampsia: An open-label, single arm safety and efficacy trial

Objectives: Preeclampsia is characterized by maternal systemic inflammation and coagulation activation, akin to the sepsis syndrome. Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) may modify disease progression to safely prolong pregnancies and improve perinatal outcomes. Both maternal and perinatal risks are highest remote from term. Study design: Open-label, single arm safety and efficacy trial of rhAPC in consenting pregnant women with severe early-onset preeclampsia. Disease severity-matched rhAPC-naive controls were identified from an existing database. An additional six women were recruited as biomarker controls. Main outcome measures: Primary safety outcome: incidence of peripartum bleeding; primary efficacy outcome: duration of pregnancy after enrolment. Results: Twelve (31.6%) of 38 eligible women consented; 3 did not receive the infusion due to staffing. Therefore, 9 women received rhAPC (24 mu g/kg/hr for <= 96 h antenatally). No safety issues were identified. There was a marginal prolongation in eligibility-to-delivery intervals for women receiving rhAPC (Mantel-Cox p = 0.052; Gehan-Breslow-Wilcoxon p = 0.049). Compared with both the pre-infusion phase in the rhAPC-treated women themselves and with fullPIERS rhAPC-naive women, rhAPC was associated with increased urine output during the infusion (6/9 vs 1/9 had urine output > 100 mL/h during the infusion, Fisher's exact p = 0.003). Conclusions: These data support further investigation of APC in women with severe early-onset preeclampsia; recombinant and purified human APC is available. In addition, these data will inform the design and implementation of randomized controlled trials aiming to modify and/or moderate the proinflammatory and proacoagulant state of preeclampsia.