The main findings of our study, with a total of 160 patients undergoing transfemoral PCI for complex lesions, are as follows: (1) immediate administration of protamine resulted in significantly lower rates of the composite of in-hospital death, MI, stent thrombosis, stroke/systemic embolism, bleeding requiring blood transfusion, and vascular access complications; (2) use of protamine after PCI was safe with lower rates of hematoma and without increasing any stent thrombosis and MI; and (3) patients with protamine administration had significantly shorter hospital stays than patients without protamine.

Although the incidence of bleeding complications after PCI has been decreasing, it remains the main challenge in complex PCI, which requires a femoral approach, larger sheath size, and more prolonged ACT. Stent thrombosis is a rare but serious complication of complex PCI due to procedure-related factors, such as bifurcation, long calcified lesions, and CTO [10].

Protamine has been used clinically for prompt reversal of the anticoagulant effect of heparin. Although protamine has been widely used in cardiovascular surgery [11] for a long time, it is underused for PCI because of the possible increase in the chances of hyperacute stent thrombosis, heparin rebound, and the potential for allergic or anaphylactic reactions [12]. Nevertheless, some studies have investigated the safety of protamine use following PCI. De Luca et al. [5] performed a meta-analysis of randomized and non-randomized trials from 1990 to 2009 to evaluate the safety and benefits of protamine administration after coronary angiography, including bare-metal stents and first-generation DES. In this meta-analysis of 6762 patients, the rates of short-term mortality and MI were similar in both groups, with a significant reduction in major bleeding complications in patients receiving protamine. Yamamoto et al. [6] showed the safety of protamine following elective transfemoral PCI with the second-generation DES. They showed that the use of protamine after manual compression following elective transfemoral PCI was associated with fewer bleeding complications and protamine-treated patients did not sustain higher rates of stent thrombosis than non-protamine-treated patients, despite using DES. However, Yamamoto et al. [6] excluded patients with ACS who had a higher risk of bleeding and thrombosis than those with stable angina and did not describe the complexity of the lesion. In our study, we included patients who underwent only complex PCI, and more than 90% of the patients had ACS. Our study suggests that the administration of protamine is safe and does not increase the risk of stent thrombosis or MI.

Despite the inclusion of patients who underwent complex PCI with high anatomical risk, the reasons for the absence of stent thrombosis events in the protamine group should be considered. First, at the time of PCI, we only included patients who were already treated with DAPT, including new-generation P2Y12 inhibitors such as ticagrelor or prasugrel. DAPT has been established as a standard-of-care treatment for preventing stent- and non-stent-related ischemic events after PCI with DES [13,14,15]. Stent thrombosis appears to be significantly affected by the potency and rapidity of antiplatelet therapy, and the lack or delayed effect of antiplatelet agents has consistently been associated with a higher risk of stent thrombosis [16]. Compared with clopidogrel, ticagrelor and prasugrel, which have greater potency and faster action in inhibiting adenosine diphosphate–induced platelet aggregation; thus, they can reduce stent thrombosis regardless of stent type, the timing of stent thrombosis, and ACS [17, 18]. Second, all patients in our study used second-generation DES, which has a lower rate of stent thrombosis than first-generation DES. First-generation DES platforms, which have relatively thick struts, durable polymer coating that can cause peri-strut inflammation, and paclitaxel that may cause delayed endothelial recovery, were associated with late and very late stent thrombosis [19, 20]. However, second-generation DES platforms have lower thrombogenicity due to more flexible and thinner struts, more biocompatible or biodegradable polymers, and limus drugs decrease neointimal response and increase re-endothelialization [21, 22]. Third, IVUS-guided PCI was performed in all patients in our study. PCI for complex lesions such as small-vessel disease, bifurcation, and long or highly calcified lesions is associated with a higher risk of malapposition, incomplete lesion coverage, under-expansion, and the likelihood of a slower or non-uniform pattern of endothelialization compared with simple PCI. In our study, optimal PCI with proper stent sizing and stent deployment using pre-intervention and post-intervention IVUS contributed to the reduction of stent thrombosis by aiming at no residual narrowing, absence of dissections, complete stent expansion, and good stent apposition [10, 23, 24].

This study had several limitations that should be addressed. This was a retrospective, non-randomized, single-center study. However, to the best of our knowledge, this is the first study to evaluate patients receiving heparin reversal with protamine for complex PCI. In addition, the relatively small study population may have affected the outcome. The cumulative incidence of stent thrombosis with DES at one year was very low at less than 1% [24]; therefore, the incidence of stent thrombosis may have been underestimated due to the small number of patients in this study. Anaphylactic reactions to protamine may also have been underestimated due to the small study population because they were very rare (< 1%) and less likely to occur without protamine-containing insulin [25].

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