Cardiovascular disease, as the most common cause of mobility and mortality, is a critical issue affecting global human health (1). Pleasingly, along the introduction and advancement of percutaneous coronary intervention (PCI), the outcomes and long-term prognosis of patients with cardiovascular disease have been improved a lot, while its concomitant complications still worry the physicians and patients (2, 3). Among PCI-related complications, thrombotic complication such as stent thrombosis, is one of the prior concerns to be handled; then for years, unfractionated heparin (UFH) (with or without glycoprotein IIb/IIIa inhibitors) was considered as the anticoagulant choice during PCI, while it exhibits several limits: unpredictability of biological efficiency, platelets activation, heparin-induced thrombopenia, and bleeding (4–7). Therefore, exploration of better adjunctive anticoagulant during PCI is of great importance.

Bivalirudin, a synthetic analog of natural anticoagulant hirudin which consists of 20 amino acid peptides, is an explicit and irreversible thrombin inhibitor with concentration-dependent competitive and non-competitive thrombin repressing effect (8, 9). Unlike the UFH, bivalirudin not only realizes expectable anticoagulant outcome with linear pharmacokinetic and pharmacodynamic properties, it also achieves quicker onset and has a shortened action period; but also reduces the influence of platelet function and bleeding, which makes it a potentially alternative option for anticoagulant during PCI (8–12). Clinically, several randomized trials have demonstrated the non-inferiority of bivalirudin vs. UFH plus glycoprotein IIb/IIIa inhibitors regrading ischemic events, but the superiority of lower bleeding risk in PCI procedures as anticoagulant (6, 12–14). However, since its application in China, it still lacks comprehensive evaluation of adverse events (AEs) or adverse drug reactions (ADRs) under the real-clinical setting conditions with a larger-sample-size population, especially for the exploration of severe, rare, or new ones; furthermore, identification of their risk factors is deficient as well.

Therefore, the current prospective, multi-center, intensive monitoring study enrolled 3,049 patients who underwent PCI with bivalirudin as anticoagulant from 27 Chinese medical centers, then aimed to comprehensively investigate the occurrence and risk factors of AEs and ADRs, especially for bleeding and thrombocytopenia.

Accumulating reports demonstrate that anticoagulant use of bivalirudin during PCI is of very good tolerance, while some minor AEs or ADRs still need attention, such as bleeding (especially major bleeding), cardiac/cardiovascular events (such as heart failure, cardiogenic shock, recurrent myocardial infarction, etc.), cerebrovascular events (such as stroke, etc.), stent thrombosis, and so on (16–21). It was reported that bleeding events occur in 5.0–11.3% patients, among which major bleeding events affect 0.9–7.8% patients who are undergoing PCI with bivalirudin as anticoagulant (16, 19, 22). Furthermore, safety related major adverse cardiac events (MACEs) appear in 7.6–13.4% patients (17, 19); safety related stroke events happen in 0.2–1.7% patients who perform bivalirudin-involving PCI procedure (16, 17, 22). In addition, 0.7–2.4% bivalirudin-involving PCI treated patients suffer from stent thrombosis events (19, 22, 23). However, the general, detailed evaluation of AEs regarding bivalirudin application as anticoagulant in PCI is still limited; not to mention that it also lacks comprehensive assessment of AEs under the real-clinical setting conditions with a large sample size population in China. In the current prospective, multi-center, large sample size, intensive monitoring study, we observed that 13.58% patients underwent PCI with anticoagulant bivalirudin occurred AEs, among which 1.02% cases suffered from SAEs and 0.26% cases died due to AEs. Since no previous report discusses the comprehensive AEs regarding PCI with anticoagulant bivalirudin, the percentage could not be compared or referred to. Then after categorization by SOC, the most common AEs were gastrointestinal disorders (3.58%), general disorders and administration site conditions (3.31%), respiratory, thoracic, and mediastinal disorders (3.18%), and then blood and lymphatic system disorders (2.66%). These data inspired us to pay attention to and even prevent these AEs in advance. In terms of bleeding, 4.13% studied patients experienced bleeding events, which was numerically lower compared to that in previous studies (16, 19, 22), which might result from: (1) the improved knowledge of the studied drug and advanced procedure technology and skills; and (2) the different study design, enrolled patients, observational period, and so on.

In order to provide the precise and strict information about the adverse events/adverse reactions related to bivalirudin application as anticoagulant during PCI for further drug choice guiding, we evaluated ADRs of bivalirudin during PCI, which were defined as the harmful reaction of qualified drugs that was irrelevant to the purpose of medication under normal usage and dosage. It was discovered that 3.87% patients experienced bivalirudin related ADRs, among which 0.23% cases suffered from SADRs, while no case died due to ADRs. However, there has been no previous study analyzing the bivalirudin related ADRs during PCI. This current study is the first to provide the overall information about it (16–23). Generally speaking, we observed that bivalirudin was well-tolerated as an anticoagulant for PCI. Then to identify potential risk factors of ADRs induced by bivalirudin during PCI, logistic regression analysis was performed which discovered that older age, renal function impairment, and CRUSADE high risk stratification independently correlated with ADRs occurrence. The possible explanations were as follows: (1) Patients with older age might have more complications and worse metabolism ability for drugs, leading to increased ADRs (24, 25); (2) renal function impairment affected the drug metabolism directly, which resulted in ADRs (26); (3) CRUSADE high risk stratification reflected higher possibility of bleeding, which was one of the most common ADRs of bivalirudin. In the current study, one patient died of acute heart failure, two patients died of acute myocardial infraction, two patients died of tachycardia, one patient died of hypotension, one patient died of hypoxemia, and two patients died of systematic syndromes. After assessment, it is considered that none of these patients died of bivalirudin-related adverse reactions.

Furthermore, 0.23% patients showed new ADRs of bivalirudin, 1.12% patients experienced bivalirudin related bleeding, and 2.59% patients had bivalirudin related thrombocytopenia during PCI. These informed us that the occurrence of bleeding and thrombocytopenia, directly induced by bivalirudin, were less than the previous opinions (16, 19, 22). Moreover, apart from CRUSADE high risk stratification, operative timing (emergency vs. elective), and full dose use of bivalirudin also independently correlated with increased bivalirudin related bleeding events risk during PCI. These might result from: (1) an emergency operation reflected the acute and severe disease condition or short preparation time for complication prevention therefore led to increased bleeding risk; (2) full dose vs. reduced dose use of bivalirudin suggested the increased anticoagulant effect, generating increased bleeding possibility. When looking at thrombocytopenia, older age and renal function impairment were independently associated with its increased risk, with the possible explanations the same as their contributions to total ADRs risk (24–26). In addition, it is of note that a previous HEAT-PPCI study observes that bivalirudin does not decrease bleeding risk while increases acute stent thrombosis risk compared to UFH in STEMI patients (27). However, it brings about great dispute resulting from the following issues: (1) HEAT-PPCI is a single-center study; (2) the assessment of AEs by a third party is not carried out; and (3) activated clotting time (ACT) during operation is quite accidentally lower compared to previous studies. The findings of this study confirmed that bivalirudin as an anti-coagulant during PCI was a safe regimen. Meanwhile, the recognition of risk factors related to ADRs, bleeding, and thrombocytopenia might help to improve the administration of bivalirudin as anti-coagulant during PCI.

Despite these interesting findings, the current study still faces some limitations. First, the sample size of this study was calculated and set to 3,049 based on the purpose to observe the ADR with at least 0.1% incidence, while some SADRs or even deadly ADRs might be below 0.1% incidence. Therefore, these SADRs might not be easily discovered in this study. Hence, an even larger sample size population study would be needed in the future. Second, the medical centers participating in this study were almost first-class hospitals in China which could not represent all-level hospitals, therefore the physicians' skill and patients' bias would exist. Third, since the total ADRs, especially bivalirudin related bleeding events and bivalirudin related thrombocytopenia, rarely occurred, the risk factors analyzed by logistic regression analysis might have relatively low statistical power. Fourth, a long-term follow-up could be conducted to explore the safety of bivalirudin.

In conclusion, bivalirudin is well-tolerated as anticoagulant for a PCI procedure; meanwhile, older age, renal function impairment, and CRUSADE high risk stratification serve as independent risk factors of bivalirudin related ADRs.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Ethics Committee of Beijing Anzhen Hospital Affiliated to Capital Medical University (KS2019012) and Peking University People's Hospital (2018PHA092-001). The patients/participants provided their written informed consent to participate in this study.

PL and HZ made substantial contributions to the design of the present study. Data acquisition and interpretation were performed by PL, HZ, CL, ZJ, ZZ, ZL, FW, JL, and LH. PL, HZ, JL, and LH critically revised the manuscript for important intellectual content. All authors approved the final version of the manuscript. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of the work are appropriately investigated and resolved.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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