A Randomized Trial Evaluating the Safety Profile of Sugammadex in High Surgical Risk ASA Physical Class 3 or 4 Participants

W. Joseph Herring; Yuki Mukai; Aobo Wang; Jeannine Lutkiewicz; John F. Lombard; Li Lin; Molly Watkins; David M. Broussard; Manfred Blobner

Disclosures

BMC Anesthesiol. 2021;21(259) 

In This Article

Results

Twenty seven sites in 4 countries screened 393 participants, of whom 331 were enrolled and randomized (Figure 2). Of those randomized, 326 completed all protocol visits. Participants distributed evenly by demographic characteristics across treatment groups (Table 1). Treated participants were 79 years old (median); 67% were ≥ 65 years; mean BMI was 28.6 kg/m2; 40% were female; majority were white non-Hispanic. There was a slight gender imbalance in the neostigmine/glycopyrrolate group that arose by chance following treatment randomization. Cholecystectomy (6%) and prostatectomy (5%) were the most frequently performed procedures. Pre-existing co-morbid conditions displayed adequate balance across groups; overall 73% had hypertension, 27% hyperlipidemia, 25% coronary artery disease, 24% gastroesophageal reflux disease. The most frequently used anesthetics across all treatment groups were propofol, lidocaine and fentanyl administered intravenously, and sevoflurane administered as an inhalant. No clinically meaningful imbalances in the types of anesthetics used was observed across the treatment groups (data not shown), mitigating the concern that differences in types of anesthesia administered may have impacted the outcomes seen in this study. There were three deaths in the study: 2 who died post-operatively and 1 subject in the sugammadex 4 mg/kg group who did not receive study intervention. None of these deaths were deemed related to study medication by the investigators.

TE cardiac events occurred infrequently across the groups (Table 2). The incidence of TE sinus bradycardia was significantly lower in the sugammadex 2 mg/kg group vs neostigmine/glycopyrrolate (P = 0.026). The incidence of TE sinus tachycardia was significantly lower in the sugammadex 2 and 4 mg/kg groups vs neostigmine/glycopyrrolate (P = 0.007 and 0.036, respectively). No significant differences in other TE cardiac arrhythmias were seen between sugammadex and neostigmine/glycopyrrolate intervention groups. The between-group differences in the incidences of TE cardiac arrhythmias seen in the overall population were generally consistent when analyzed across ASA Physical Class status (3 and 4: Table 3) and NMBA stratum (rocuronium, vecuronium; Table 4).

Overall, the numbers/percentages of participants with ECIs were low in all the intervention groups up to 7 days post-treatment (Table 5). No clinically meaningful differences were observed between groups with respect to the ECIs of CR bradycardia, CR tachycardia and other CR cardiac arrhythmias. No cases of adjudicated anaphylaxis or hypersensitivity reactions and no drug-induced liver injury were reported at any time during this study. The incidences of elevated ALT, AST, bilirubin and alkaline phosphates were low and similar across the intervention groups. No participants met the creatinine clearance predetermined criterion of < 30 mL/min up to 14 days post-treatment. No clinically meaningful findings relating to the administration of sugammadex were observed in the mean changes of vital sign assessments or incidences of vital sign findings that met predetermined criteria.

The numbers/percentages of participants with AEs and drug-related AEs reported up to 7 days post-treatment were similar across the 4 intervention groups (Table 6). Although there were numerical differences in the incidence of serious adverse events (SAEs) between the sugammadex and neostigmine/glycopyrrolate intervention groups, there were no imbalances (based on the 95% CIs) and the differences were not clinically meaningful. One drug-related SAE in the sugammadex 16 mg/kg group was reported (i.e., cardiac arrest Day 1), resolved, and no treated participants discontinued due to an AE. One subject in each of the sugammadex 2- and 4-mg/kg groups had a SAE that resulted in death. The subject in the sugammadex 4 mg/kg group had a SAE of cardiac failure on Day 2 and the subject in the sugammadex 2 mg/kg group had a SAE of cardiac arrest on Day 9. No clinically meaningful differences were observed between the sugammadex and neostigmine/glycopyrrolate intervention groups in the analysis of specific AEs (incidence of ≥4). Consistent with expectations in participants undergoing surgery, AEs of procedural pain (45.6 to 54.3%) and incision site pain (17.6 to 29.0%) were reported most frequently across all groups.

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