Teprasiran Reduces Risk for Early Acute Kidney Injury After Cardiac Surgery

Teprasiran, a small interfering RNA, significantly reduced the incidence of early acute kidney injury (AKI) among patients at high risk for AKI after undergoing cardiac surgery, according to findings published in Circulation.

For the prospective, multicenter, double-blind, randomized, controlled phase 2 trial (ClinicalTrials.gov Identifier: NCT02610283), researchers enrolled patients aged 45 years or older, who were scheduled for an elective cardiac surgical intervention and had at least 1 AKI risk factor. They conducted the study across 41 sites in the United States and Germany between 2016 and 2017. Stratified by estimated glomerular filtration rate (eGFR; 20-60 vs > 60 mL/min/1.73m²), use of cardio-pulmonary bypass, and circulatory arrest status, patients were randomly assigned 1:1 to receive a single intravenous bolus of 10 mg/kg teprasiran or placebo 24 hours prior to surgery. Patients were assessed for instance of AKI and safety at 90 days after surgery.

Patients’ mean age was 73.3±7.47 years, 72.4% were men, and body mass index (BMI) was 30.3±6.36. More patients assigned to receive placebo had diabetes (34.7% vs 22.4%).

The primary study outcome was the proportion of patients who developed AKI determined by serum creatinine by postoperative day 5. AKI occurred among 36.9% in the intervention and 49.7% in the placebo cohorts (odds ratio [OR], 0.58; 95% CI, 0.37-0.92). Stratified by AKI stage, teprasiran decreased risk for stage 1 AKI by 18%, stage 2 AKI by 33%, and stage 3 AKI by 63%.

Secondary outcomes included AKI severity and duration. Among patients who developed AKI, the placebo group tended to have a longer duration (³5 days; 13.3% vs 7%).

At 90 days, major adverse kidney events were not different between cohorts (OR, 1.1; 95% CI, 0.6-1.9; P =.71) nor were deaths (OR, 0.8; 95% CI, 0.3-2.2; P =.72), use of eGFR serum cystatin C (OR, 0.8; 95% CI, 0.5-1.2; P =.2065), or need for renal replacement therapy (OR, 0.6; 95% CI, 0.3-1.6; P =.34).

Adverse events were similar between the 2 cohorts and were experienced by 98.8% of teprasiran and 97.7% of placebo recipients. Most common events were pleural effusion (36.4%), atrial fibrillation (33.7%), AKI (27.0%), and nausea (21.1%).

This study was limited by power, in which significant differences of stage 2 or 3 AKI were not evaluable.

This novel silent interfering RNA for p53 was found to be well-tolerated and to reduce instances of early AKI among patients at high risk for AKI undergoing elective cardiac surgery.

“The results of this study suggest potential renal-protective effects of teprasiran and formed the basis of a larger phase 3 study (NCT03510897) that has recently completed enrollment and follow-up in [more than] 1000 high-risk, on-pump, patients undergoing cardiac surgery to explore the safety and efficacy of teprasiran to reduce MAKE90 in this setting,” the study authors noted.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.

Reference

Thielmann M, Corteville D, Szabo G, et al. Teprasiran, a small interfering RNA, for the prevention of acute kidney injury in high-risk patients undergoing cardiac surgery: a randomized clinical study. Circulation. 2021;144(14):1133-1144. doi:10.1161/CIRCULATIONAHA.120.053029