Routine use of protamine increases the rate of hemostasis success, with a shorter time to hemostasis (TTH) observed, in a study that compares the medication’s routine versus selective administration. In the August 14 issue of JAMA Cardiology, the ACE-PROTAVI double-blind, placebo-controlled, randomized clinical trial details protamine’s additional benefits, such as reductions in minor vascular complications, procedural time and duration of postprocedural hospital stay. Describing protamine’s administration, which was prior to large sheath removal and arteriotomy closure after transfemoral transcatheter aortic valve implantation (TAVI), the paper’s authors said the study, “emphasize(s) the potential benefit of heparin reversal.” “The use of protamine at the time of large sheath removal is highly dependent on individual operators and even varies within the same implanter teams,” said the paper’s authors, led by Pieter A. Vriesendorp MD, PhD, from The Alfred Hospital in Melbourne, Australia. “We anticipate that the results of this study will provide robust evidence to guide decision-making by TAVI teams.” Full results Findings from the study, which was published Monday online, revealed that patients receiving up-front protamine administration had a higher rate of hemostasis success (188 of 192 patients (97.9%)). This compares to the patients in the placebo group (186 of 203 patients (91.6%); absolute risk difference, 6.3%; 95% confidence interval [CI]: 2.0%-10.6%; P=0.006). Further findings revealed that patients receiving up-front protamine had a shorter median interquartile range (IQR): TTH (181 (120-420) seconds vs 279 (122-600) seconds; P=0.002). Routine protamine administration resulted in a reduced risk of the composite outcome in the protamine group (5.2%) vs the placebo group (12.8%); odds ratio [OR]: 0.37; 95% CI: 0.1-0.8; P=0.01). According to the research team, this difference was predominantly driven by the difference in the prevalence of minor vascular complications. The study also noted a lack of adverse events associated with protamine use. “Heparin reversal might improve closure and hemostasis and reduce minor vascular complications, but it is unlikely to affect catastrophic vascular complications, such as the rupture or perforation of arteries,” said the paper’s authors. “However, a reduction in minor bleeding and vascular complications will lead to earlier mobilization and less nursing requirement on the ward and is associated with reduced length of stay, as demonstrated in this trial. Controversial use Discussing the implications of the findings, the researchers highlighted the controversial use of protamine in interventional cardiology, where there was a lower need for heparin reversal post procedure. It’s questionable use also extended to the minimally invasive approach with smaller sheath sizes and, perhaps, fear of thrombotic complications. In contrast, the study also cited recent research in which the routine administration of protamine and its beneficial effects were apparent in 873 patients. Significantly reduced bleeding and vascular complications (4.1%) were noted when compared with no protamine (11.8%). The research also found no increase in ischemic events, such as stroke and myocardial infarction, with administration of protamine (1.8%) compared with no protamine (3.6%). Moving the discussion on to the study’s limitations, the research team acknowledged the infrequent adverse effects of protamine, with the risk of an anaphylaxis reaction ranging from 0.19% to 0.69%. The small sample size was also an issue worth highlighting by the team. The study included 410 enrolled patients and 226 patients receiving protamine (192 in the protamine group and 34 in the placebo group who required the use of syringe B). They concluded that the sample size may have been too small to conclude that there was no additional risk involved with protamine use. “On the other hand, protamine is well documented and established in cardiac surgery, and the rare risk of severe complications does not preclude using routine protamine in that setting,” they said. Study methods The ACE-PROTAVI trial was an investigator-initiated, double-blind, placebo-controlled randomized clinical trial performed at 3 Australian hospitals with a 1-year follow-up period. The study population consisted of 410 patients: 199 patients in the protamine group and 211 in the placebo group. The median (IQR) patient age in the protamine group was 82 (77-85) years, and 68 of 199 patients receiving protamine (34.2%) were female. The median (IQR) patient age in the placebo group was 80 (75-85) years, and 89 of 211 patients receiving the placebo (42.2%) were female. Eligible patients were randomized 1:1 between routine protamine administration and placebo. The coprimary outcomes were the rate of hemostasis success and TTH. Source: Vriesendorp PA, Nanayakkara S, Heuts S, et al. Routine Protamine Administration for Bleeding in Transcatheter Aortic Valve Implantation: The ACE-PROTAVI Randomized Clinical Trial. JAMA Cardiol.2024. Published Online: August 14, 2024. doi:10.1001/jamacardio.2024.2454 Image Credit: Op Creator – stock.adobe.com