In this single-center, retrospective study involving patients with ACS undergoing elective PCI, we found that 80% of the recommended dose without post-procedure infusion of bivalirudin can also achieve clinical effects. Both groups were pretreated with DAPT before PCI and treated with non-infusion of bivalirudin after PCI. Our data suggest that the rates of NACE, MACE, and bleeding events were not significantly different between the two groups. Subgroup analysis also suggested that there was no significant difference in the incidence of all bleeding events and NACE within 30 days between the two groups in terms of sex, age, BMI ≥ 30, diabetes, anemia, medium and high risk of bleeding, and renal function.
The anticoagulant effect of bivalirudin was monitored using the ACT. The bivalirudin dose was adjusted using the 5 min ACT value during PCI. Bivalirudin, a commonly used anticoagulant in clinical practice, does not activate platelets and does not bind to plasma proteins; it has linear pharmacokinetics with a short half-life of 25 min (18, 19), compared with heparin. Bivalirudin has no inhibitors, and once bleeding occurs, there is no option aside from discontinuation of the drug. Therefore, physicians should carefully evaluate the application of bivalirudin and ensure an ACT value > 250 s in clinical practice. Previous studies were designed to seek a better administration strategy for bivalirudin treatment, including loading doses, maintenance doses, infusion methods, and usage of the special population. In the present study, there was no significant difference in the ACT value between the two groups after 5 min (99.2% vs. 98.7%, P = 0.315), indicating that 80% of the bivalirudin dose can also achieve an anticoagulant effect during elective PCI.
The MATRIX study (20) showed that the clinical efficacy of postoperative normal dose infusion in patients with ACS is superior to that of low-dose infusion and non-infusion in patients after operation. However, there is no difference in the clinical efficacy between the continuous infusion and non-infusion groups after PCI, which may be due to the fact that more clinical events of low-dose infusion offset the advantages of normal dose infusion. Therefore, we designed this study based on the rationale of the previous MATRIX study with non-infusion.
The EUROMAX study (21), HORIZONS-AMI study (22), and meta-analysis (23) reported that bivalirudin reduced the incidence of bleeding events but increased the incidence of acute stent thrombosis in patients with primary PCI. The BRIGHT study (24) enrolled Chinese patients who had undergone primary PCI for acute myocardial infarction. The results showed that continuous infusion of bivalirudin for 3–4 h after PCI could reduce the incidence of NACE by reducing the incidence of bleeding events without increasing the incidence of MACCE. Studies (25–26) have suggested that the possible reason for the increased incidence of stent thrombosis in the bivalirudin group after primary PCI is that antiplatelet drugs have not yet reached the effective blood concentration, and the short half-life period of bivalirudin results in the existence of an antithrombotic window, which requires continuous postoperative infusion to reduce thrombotic events. In summary, these studies suggest that attention should be paid to the antithrombotic time window for anticoagulant therapy with bivalirudin. To evaluate the efficacy of intraoperative application of 80% bivalirudin, patients with ACS were included in this study. In the BRIGHT study (24), the recommended dose infusion was used for 3–4 h after PCI. However, in our study, the preoperative aspirin and P2Y12 receptor antagonist reached the effective blood concentration for patients who underwent elective PCI to render a non-blank antithrombotic window.
In terms of the safety of using an 80% dose of bivalirudin during PCI, the incidence of all bleeding events in the bivalirudin group without infusion after PCI in the MATRIX study (11) was 10.6%, and the incidence of BARC 2–5 bleeding events was 5.2%. In our study, the incidence of all bleeding events in the reduced-dose group was 4.8%, and the incidence of BARC 2–5 bleeding events was 0.3%, both of which were significantly lower than those in the MATRIX study (10.6% vs. 4.8%, P < 0.001; 5.2% vs. 0.3%, P < 0.001). In the BRIGHT study (24), the incidence rate of all bleeding events was 4.1%. In our study, the bleeding rate in the reduced-dose group was 4.8%, which was similar to that in the bivalirudin group in the BRIGHT study (P = 0.498). The incidence of BARC 2–5 type bleeding events in the reduced-dose group in our study was significantly lower than that in the BRIGHT study (0.3% vs. 1.2%, P = 0.025). The incidence of all bleeding events in our study was higher than that in the BRIGHT study due to the increase in BARC 1 bleeding. The CRUSADE score of the bivalirudin group in the BRIGHT study was (19.6 ± 11.9), that of the reduced-dose group was (26.79 ± 11.32), and that of the recommended-dose group was (27.26 ± 11.57), both of which in our study were higher than those in the BRIGHT study (all P < 0.001). Although all bleeding events increased, the incidence of major bleeding decreased.Studies (27–29) have shown that reducing the incidence of major bleeding in patients undergoing PCI is associated with postoperative adverse events. In our study, the proportion of ACT values ≥ 350 s in the recommended-dose group was significantly higher than that in the reduced-dose group (56.7% vs. 48.2%, P = 0.001), and there was a greater tendency for major bleeding (0.5% vs. 0.3%, P = 0.687). It has been suggested that 80% of the recommended dose of bivalirudin is safe during PCI.
Several limitations of the present study should be noted. First, this was a single-center, retrospective study with a multi-center, large sample size. Prospective, randomized controlled studies are needed to further verify the reliability of the conclusions. Second, bivalirudin is excluded by both the renal and protease pathways, and its clearance is closely related to the glomerular filtration rate. The recommended dose is not applicable to patients with severe renal impairment (creatinine clearance of < 30 mL/min) or those on dialysis. Therefore, these patients were excluded from this study. An 80% dose of bivalirudin for elective PCI is indicated for patients with creatinine clearances of > 30 mL/min and those who do not require dialysis. Finally, in this study, patients with UA (81.3–82.2%) and NSTEMI (16.2–17.2%) accounted for a high proportion, while the proportion of patients with STEMI (1.5–1.6%) was relatively lower, as STEMI generally undergoes primary PCI through the green channel. Therefore, the results of this study were applicable to patients with NSTEMI and UA who underwent elective PCI, and further studies are needed regarding the safety and efficacy of reduced-dose bivalirudin in patients with STEMI.