Abstract
Background : The FRALE compound, S-303, effectively inactivates contaminating pathogens in RBC concentrates. Phase I trials in healthy subjects showed recovery of S-303-treated RBCs (SRBC) stored for 35 days (d) to be comparable to conventional RBCs (CRBC). Phase III trials were initiated to evaluate SRBC for transfusion (tx) support of acute anemia in cardiac surgery and of chronic anemia for sickle cell anemia or thalassemia.
Methods : A randomized, controlled, double-blind, parallel group, non-inferiority design trial of SRBC vs. CRBC tx for support of acute anemia in cardiac surgery patients (pts) was conducted at 5 study sites. RBCs were txed during and for up to 6 d post surgery; pts were followed to d 13 for adverse events (AEs), and to d 27 for serious AEs (SAEs). The primary endpoint was selected to measure adverse sequelae associated with inadequate tissue oxygenation by RBCs: a composite endpoint of myocardial infarction (MI), acute renal failure (ARF), and death. The trial had 80% power with 200 pts to show non-inferiority with an absolute difference of 15% in the primary endpoint compared to CRBC. Secondary endpoints were: RBC and other blood product use, change in hemoglobin (Hb), and AEs.
Results : While this trial was enrolling, 2 asymptomatic pts in the chronic trial developed antibodies to SRBC, leading to early termination of both trials. At time of termination, 148 pts in the acute anemia trial had been txed. Despite the reduced sample size, the trial still has >70% power to show non-inferiority at the 0.05 significance level, assuming a common primary endpoint incidence of 20% for both groups. The 2 groups were balanced for demographics (mean age 68 yrs; 62% male; 95% Caucasian), type of surgery (68% intermediate risk group: repeat surgery or multiple procedures) and baseline characteristics. The primary endpoint was achieved: SRBC were not inferior to CRBC, with 1-sided 95% CI for treatment difference (SRBC-CRBC) of 12%. Results were similar by surgery and study site. Study RBCs only were received by 91% of pts; 41% of RBCs were txed during surgery. Other blood product use (see table) and AEs were similar in both groups. Tx reactions were uncommon. No antibodies to SRBC were detected in the acute trial.
Endpoint SRBC CRBC p-Value* (n=74) (n=74) *2-sided p-value, testing for treatment difference. Composite endpoint (%) 22 21 1.00 MI (%) 0 2.7 0.25 ARF (%) 22 19 0.84 Death (%) 0 1.4 0.50 Mean change in Hb (g/dL) Pre vs. post-tx 1.4 1.5 0.74 Pre-surgery up to d 6 −2.6 −2.2 0.17 Mean no. RBC tx/units 2.1/4.4 1.9/3.8 0.49/0.20 Other blood product tx (% pts/mean no. units) FFP 47/2.1 45/2.5 0.87/0.55 Platelets 45/1.7 40/1.4 0.62/0.59 Cryo 6.8/0.5 11/0.5 0.40/0.94
Conclusions : Although enrollment was not completed, efficacy endpoints for S-303-treated RBCs were comparable to conventional RBCs in this trial for support of acute anemia in cardiac surgery; no antibodies to S-303 RBC were detected; and the safety profile for S-303 RBCs was comparable to conventional RBCs. Processing improvements are being evaluated to reduce the immunogenicity potential associated with chronic exposure to S-303-treated RBCs.
The Impact of Perioperative Viscoelastic Test Application on Blood Product Usage and Outcome in Cardiac Surgery; Regional Cardiac Surgery Center Experience