Bivalirudin infusion in patients with acute coronary syndrome after stenting

The recent review by Laine et al. adds important information regarding the use of bivalirudin during percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) [1]. Most of bivalirudin clinical trials were discussed in this review. We wish to consider some viewpoints not emphasized.

Whether anticoagulation with bivalirudin can improve the prognosis of ACS patients undergoing PCI when compared with unfractionated heparin (UFH), with or without glycoprotein IIb/IIIa inhibitors (GPI), is still controversial. Most studies showed that the risk of major bleeding was reduced; however, the incidence of major adverse cardiac events (MACE) was not improved, and the risk of acute stent thrombosis was significantly increased [2]. Since the increased risk of stent thrombosis may be, at least in part, explained by the short half-life of bivalirudin (only 25 min), it was suggested that prolonging bivalirudin infusion after PCI could mitigate the risk of acute stent thrombosis [3]. However, this remains a highly controversial topic.

The EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) study showed that acute stent thrombosis occurred very early (median time 2.3 h) and was not mitigated by the novel P2Y12 inhibitors. Prolonging the bivalirudin infusion at the PCI dose (1.75 mg/kg/h) but not at a lower dose (0.25 mg/kg/h) can mitigate the risk of acute stent thrombosis [4]. These results showed that the dose as well as infusion duration of bivalirudin are very important in preventing stent thrombosis during PCI.

Similarly, the BRIGHT (Bivalirudin in Acute Myocardial Infarction vs Heparin and GPI Plus Heparin) Trial showed that in ACS patients undergoing primary PCI, the use of bivalirudin with a median 3 h post-procedure PCI-dose (1.75 mg/kg/h) infusion resulted in a decrease in net adverse clinical events, compared with UFH, with or without GPI, primarily driven by a reduction in bleeding events with bivalirudin, without significant differences in MACE, cerebral events, or stent thrombosis [5].

In contrast, a multicentre, randomized, registry-based, open-label clinical trial, VALIDATE-SWEDEHEART (Bivalirudin versus Heparin in ST-Segment and Non-ST-Segment Elevation Myocardial Infarction in Patients on Modern Antiplatelet Therapy in the Swedish Web System for Enhancement and Development of Evidence-based Care in Heart Disease Evaluated according to Recommended Therapies Registry Trial), which included >6000 patients undergoing PCI for myocardial infarction, the rate of the composite of death from any cause, myocardial infarction, or major bleeding was not lower among those who received bivalirudin than among those who received UFH monotherapy [6]. In the VALIDATE-SWEDEHEART study, although continuation of the bivalirudin infusion after PCI was strongly recommended, only 65% of patients in the bivalirudin group received a post-PCI infusion, with an average duration <1 h. Whether further prolongation of bivalirudin infusion (e.g. 3 h in the BRIGHT trial) can improve the outcomes is unclear.

Gargiulo et al. reported that in patients with ACS, a prolonged full-dose bivalirudin infusion after PCI was associated with improved outcomes when compared with no or low-dose bivalirudin post-PCI infusion, using data from the MATRIX (Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX) study [7]. In the accompanied editorial, Montalescot et al. suggested that anticoagulation (with either enoxaparin, fondaparinux, or bivalirudin) may be needed for a short period after PCI [8]. We think that this suggestion should be considered with caution. The half-life is significantly different among anticoagulants (25 min for bivalirudin; 3–5 h for enoxaparin), data from bivalirudin cannot be extended to other anticoagulation strategies. Nowadays, there are no studies supporting the prolonged use of enoxaparin in ACS post-PCI. In contrast, we found that in the patients undergoing PCI for non-ST-segment elevation ACS, anticoagulation therapy was not associated with improved outcomes but higher risk of bleeding [9].

In conclusion, studies support the use of a post-PCI bivalirudin infusion regimen to further optimize outcomes in ACS patients. However, a full dose and adequate infusion duration (up to ~3–4 h) may be needed. Further studies should compare different infusion strategies of bivalirudin in ACS patients.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

The authors are supported by the Scientific Research Fund of Foshan, Guangdong, China [No: 2016AB003353], the National Natural Science Foundation of China [No: 81600239], the Science and Technology Innovation Project from Foshan, Guangdong [FS0AA-KJ218-1301-0006, FS0AA-KJ218-1301-0010], and the Clinical Research Startup Program of Shunde Hospital, Southern Medical University [CRSP2019001].