Evaluation of Bivalirudin-Associated Major Adverse Cardiac and Hemorrhagic Events in Acute Coronary Syndrome Patients on Chronic Dialysis Following Percutaneous Coronary Intervention

Background and Aim. Patients with chronic dialysis dependency undergoing percutaneous coronary intervention (PCI) are at a greater risk of hemorrhagic and ischemic events. Due to their exclusion from randomized clinical trials, the optimal antithrombotic regimen for this population remains unknown. Bivalirudin has been associated with fewer hemorrhagic complications than unfractionated heparin (UFH) in patients undergoing PCI. We evaluated major adverse cardiac event (MACE) and hemorrhagic event rates for an antithrombotic regimen using bivalirudin or UFH during PCI in acute coronary syndrome (ACS) patients with chronic dialysis dependency. Methods. A retrospective study was performed, including 211 patients on dialysis undergoing PCI due to ACS from January 2014 to April 2019 at the China-Japan Friendship Hospital. Patients were divided into 2 groups based on anticoagulation regimen: the bivalirudin group (86 cases) or the UFH group (125 cases) during and after PCI. Statistical analyses were used to compare MACE and hemorrhagic events between groups at 30 days after PCI. Results. No patients experienced stent thrombosis within 30 days after PCI regardless of anticoagulant. There was no difference in the incidence of MACE in the bivalirudin group compared with the UFH group (6.98% vs 8.80%, respectively; P>.05). The rate of hemorrhagic events in the bivalirudin group was significantly lower than in the UHP group (5.81% vs 18.4%, respectively; P<.05), particularly for rates of mild bleeding (4.65% vs 15.2%, respectively; P<.05). There were no significant differences in rates of severe bleeding between the bivalirudin and UFH groups (1.16% vs 4.00%, respectively; P>.05), although fewer severe hemorrhagic events occurred in the bivalirudin group. Conclusion. Bivalirudin was associated with fewer bleeding events following PCI in individuals with end-stage renal disease on dialysis.

J INVASIVE CARDIOL 2021;33(11):E877-E883. Epub 2021 October 15.

Key words: acute coronary syndrome, bivalirudin, cardiovascular events, dialysis, hemorrhage, percutaneous coronary intervention

Chronic kidney disease (CKD) is a risk factor for cardiovascular disease. According to the Global Registry of Acute Coronary Events (GRACE), one-third of all patients with acute coronary syndrome (ACS) also had CKD.^1,2 Percutaneous coronary intervention (PCI) is an accepted manner of improving cardiac blood flow in patients with ACS. However, the selection of anticoagulants during PCI can impact short-term and long-term patient prognosis. Patients on chronic dialysis are at high risk of ischemia, death, and hemorrhage PCI, in part due to dysregulated coagulation.^3,4 Therefore, for patients with chronic dialysis dependency with ACS, it is important to balance the risk of hemorrhage and coagulation during PCI.⁵

Bivalirudin is a new anticoagulant that works as a direct inhibitor of thrombin. The HORIZONS-AMI studies showed that using bivalirudin during acute PCI treatments can significantly reduce the risk of hemorrhage when compared with conventional unfractionated heparin (UFH).^6-8 Bivalirudin has been widely applied in clinical practice. However, as most clinical trials do not enroll patients with CKD, there is a lack of evidence-based guidelines related to patients with chronic dialysis dependency. Furthermore, little is known about the effects of antithrombotic treatment in dialysis patients undergoing PCI.^9,10 Therefore, we conducted an observational study to explore the safety and efficacy of the anticoagulant bivalirudin in the treatment of patients on dialysis who underwent PCI.

Study participants and grouping. The ongoing registry of catheter-based coronary procedures maintained in our hospital was used in this study. A total of 211 chronic dialysis patients receiving PCI treatment in the China-Japan Friendship Hospital from January 2014 to April 2019 were enrolled. This retrospective study was approved by the ethics committee of the China-Japan Friendship Hospital. The informed consent forms were signed by the patients before we accessed their medical data for analyses.

In total, 130 males and 81 females were recruited, with an age range between 39-81 years (mean age, 69.12 ± 12.36 years). The patients were divided into 2 groups according to the anticoagulative medicine administered during PCI: (1) the bivalirudin group (86 cases); and (2) the UFH group (125 cases).

The inclusion criteria were as follows: (1) a diagnosis of ACS made during hospitalization, including unstable angina pectoris (UAP), acute ST-segment elevation myocardial infarction (STEMI), or acute non-ST segment elevation myocardial infarction (NSTEMI); (2) stent implantation during PCI; and (3) hemodialysis for end-stage renal disease (ESRD) maintained for >3 months.

The exclusion criteria were as follows: patients receiving regular intravenous injections of heparin within 4 hours of surgery, or those who had received subcutaneous low-molecular-weight heparin within 12 hours of surgery; long-term warfarin therapy; venous thrombolysis treatment within 48 hours of surgery; signs of hemorrhage that contraindicated PCI, including a history of gastrointestinal bleeding within 3 months, brain hemorrhage within 6 months, or cerebral infarction within 3 months of surgery; other contraindications for PCI, including severe granulocytopenia, thrombocytopenia or heparin-induced thrombocytopenia; severe, uncontrolled hypertension (>180/110 mm Hg; 1 mm Hg = 0.133 kPa); hepatic function indices that were 1.5 times higher than the upper limit of the normal range (except increased hepatic function indices induced by myocardial infarction); a history of a deep puncture or major surgery over recent months; and a history of allergy to heparin or other biological products.

Prescription pattern of antithrombosis medicine. The bivalirudin group received an intravenous (IV) injection of Chinese-produced bivalirudin Taijianine (Shenzhen Xinlitai Pharmaceutical Company) prior to PCI, with a loading dose of 0.75 mg/kg, followed by an IV drip of 0.25 mg/kg/h. The IV bivalirudin drip was continued for 4 hours after PCI. The activated thrombin time (ACT) was determined 5 minutes after administration. If the ACT was <225 seconds, then IV injection of bivalirudin was titrated to 0.3 mg/kg. In the heparin group, 100 U/kg heparin was administered by IV injection before surgery. The ACT was determined 5 minutes later. If the ACT was <225 seconds, then 300 U of heparin was injected IV. If the PCI procedure time was >1 hour, then 1000 U/h heparin was added (Figure 1).

Both groups were administered aspirin and clopidogrel as dual-antiplatelet therapy. Patients who had not been receiving long-term dual-antiplatelet therapy were administered aspirin (300 mg) and clopidogrel (300 mg) 1-3 hours before PCI. All patients were administered aspirin (100 mg) daily for the long term, and clopidogrel (75 mg) daily for 12 months after PCI.

Angiography and PCI. Patients underwent routine coronary arteriographic examination. Then, a standard stent implant was fitted. Coronary access was via either the radial or femoral artery. The criteria for procedure success included successful implantation and release of the stent, residual stenosis of the target lesion ≤20% of the vessel diameter (by visual examination), grade 3 Thrombolysis in Myocardial Infarction (TIMI) blood flow, and no PCI-associated complications.

Outcomes. The primary outcome was net adverse clinical event (NACE) rate at 30 days after PCI, including major adverse cardiac event (MACE) rate and all hemorrhagic events. The safety endpoint was defined as stent thrombosis 30 days after PCI. MACE included all causes of death, recurrent myocardial infarction, emergent target-vessel revascularization, and stroke. Stent thrombosis was categorized in accordance with the definitions published by the Academic Research Consortium, including “definite” or “possible” stent thrombosis.

Hemorrhagic events were defined in accordance with the criteria published by REPLACE-2.¹¹Mild hemorrhagic events were defined as noticeable bleeding, such as gingival or nose bleeding, macroscopic hematuria, vomiting bright red blood, or brown vomit with positive occult blood, black stools with occult blood, and hematoma at the puncture site. Severe hemorrhagic events were defined as a reduction in hemoglobin >30 g/L, blood transfusion ≥2 units, intracranial hemorrhage, retroperitoneal hemorrhage, lethal hemorrhage, or hemorrhage that required surgical treatment.

Statistical analysis. SAS, version 9.4 was used for all statistical analyses. Measurement data with a normal distribution are expressed as a mean ± standard deviation, and the Student’s t test was used to compare data between the 2 groups. Data that were not normally distributed are expressed as quartiles and the rank-sum test was used to compare data between the 2 groups. Numerical data are expressed as the number of cases, or as a proportion (%), and the Pearson Chi-square test was used to compared data between the 2 groups. Double-tailed tests were used for all analyses, and data were deemed to be statistically significant if P<.05.

Patient demographics. This study recruited 211 chronic dialysis patients who underwent PCI. There were 86 cases in the bivalirudin group and 125 cases in the UFH group (Table 1). There were no significant differences between the 2 groups with regard to gender, age, history of smoking, previous medical history, CRUSADE hemorrhage score, left ventricular ejection fraction, hemoglobin levels, and platelet counts (P>.05 in all cases). The patients in the UFH group were 2 years older than those in the bivalirudin group. There was a significantly higher body mass index (BMI) in the UFH group than in the bivalirudin group (28.2 ± 7.0 kg/m² vs 26.3 ± 5.5 kg/m², respectively; P<.01). Furthermore, the proportion of individuals with STEMI was significantly higher in the bivalirudin group (24.4% vs 11.2% in the UHF group; P<.05), while there were more individuals with UAP in the UFH group (54.4% vs 46.5% in the bivalirudin group; P<.01).

Differences in angiographic and procedural characteristics. Data relating to coronary arteriography and interventional treatment in the 2 groups are shown in Table 2. Twenty-one patients (24.4%) in the bivalirudin group and 34 patients in the UFH group (27.2%) received treatment via the femoral artery. There were no significant differences between the 2 groups (P>.05), and the instant PCI success rate across all patients was 100%. Two patients in the bivalirudin group (2.33%) and 3 patients in the UFH group (2.40%) received intra-aortic balloon pump (IABP) as an adjunctive treatment, which was not significantly different between the 2 groups. Moreover, there were no significant differences in lesion vessel distribution, triple-vessel lesion rate, the proportion of rotational atherectomy for calcification, and the number and length of implanted stents between the 2 groups (P>.05 in all cases).

MACE. A total of 17 MACEs occurred within 30 days after PCI (8.1%), including 6 cases in the bivalirudin group (7.0%) and 11 cases in the UFH group (8.8%). There were no significant differences in the incidence rate for MACE between the 2 groups (P=.63). One patient in the UFH group died from cardiac shock caused by a large anterior myocardial infarction. The incidence rates for recurrent myocardial infarction, stroke, and revascularization of target vessels were 3.49% vs 4.0%, 2.33% vs 3.20%, and 1.2% vs 0.8% between the bivalirudin and UFH groups, respectively. These differences were not significant (P>.05 in all cases). There was no significant difference in the incidence of stent thrombosis during PCI in the 2 groups (P>.05). All data are shown in Table 3.

Hemorrhagic events. Five cases (5.81%) of postoperative hemorrhage occurred in the bivalirudin group, including 4 cases of mild bleeding and 1 case of severe bleeding. In contrast, 24 cases (19.2%) of postoperative hemorrhage occurred in the heparin group, including 19 cases of mild bleeding and 5 cases of severe bleeding. The rate of hemorrhagic events was significantly lower in the bivalirudin group than in the UFH group (5.81% vs 18.4%, respectively; P<.05), particularly in terms of mild bleeding (4.65% vs 15.2%, respectively; P<.05). The rate of severe bleeding trended lower in the bivalirudin group than in the UFH group but was not statistically significant (1.16% vs 4.00%, respectively; P>.05). All data are shown in Table 3.

CKD is an important public health issue in China. CKD leads to end-stage renal disease (ESRD), which requires life-long dialysis treatment. Although the median survival of patients on dialysis is 8 years, the number of chronic dialysis-dependent patients with ACS events is increasing. ACS is associated with a high mortality rate and 18%-20% of patients die from either coronary heart disease or heart failure.² PCI is an important means of coronary revascularization and improves the prognosis of patients with ACS. High-risk patients presenting with NSTEMI, in particular those with CKD, could benefit from revascularization during primary PCI. Furthermore, the clinical course of these patients is associated with adverse events, including PCI-associated hemorrhage, ischemia, and death.¹³ However, most clinical studies have excluded patients with CKD. In particular, there are no clinical studies in China that assess anticoagulant-related adverse events in this group of individuals.

Coronary and peripheral arterial lesions in patients with CKD tend to be more diffuse and severely calcified than those in individuals without renal disease. This increases the complexity of PCI, leading to higher rates of myocardial infarction, stent thrombosis, and other hemorrhagic complications in CKD patients.¹⁴ Perioperative antithrombotic agents enhance the success of PCI and stent patency. Regular heparin and low-molecular-weight heparin are both indirect inhibitors of thrombin. However, both can give an unpredictable anticoagulative response and have a narrow therapeutic window.^15,16 Moreover, regular heparin treatment can lead to severe heparin-induced thrombocytosis (HIT).¹⁷ In recent years, many guidelines worldwide have suggested that the use of bivalirudin during PCI is equivalent to regular heparin in seniors, females, and patients with HIT. Bivalirudin is superior to heparin for patients with a higher risk of hemorrhage.¹⁸ CKD is a risk factor for hemorrhage, suggesting that bivalirudin may be safer in this group. Unfortunately, most large, randomized, controlled clinical studies in patients undergoing PCI have excluded those with CKD. Large-scale clinical studies of dialysis patients treated with bivalirudin during PCI are few,¹⁹ but suggest bivalirudin has similar complication rates as other agents.

Bivalirudin is a specific and reversible inhibitor of thrombin. Compared with heparin, it has a reduced risk of major hemorrhage.²⁰ Heparin alters the morphology and aggregation of platelets, while bivalirudin does not. Bivalirudin had the smallest effect on platelets, compared with heparin alone or heparin combined with eptifibatide.²¹ The BRIGHT study enrolled 2194 patients who were suitable for direct PCI procedures and found that bivalirudin reduced the risk of postoperative acute stent thrombosis in PCI to a greater degree than UFH combined with glycoprotein inhibitor.⁴ Another noted benefit was reduced hemorrhage at non-surgical areas.

Patients with CKD are susceptible to ischemic events and more susceptible to hemorrhagic events when ACS and dual-antiplatelet therapy occur simultaneously.^3-5 Stricter requirements have been placed on the anticoagulation strategies for perioperative PCI, particularly in terms of hemorrhage and stent thrombosis.^9,10 A meta-analysis comprising 16,294 patients reported that the continued use of bivalirudin after direct PCI did not increase the risk of acute stent thrombosis and had a clear advantage over heparin in reducing major hemorrhages.²² There was no incidence of stent thrombosis within 30 days of surgery in the bivalirudin group. The SWEDEHEART trial reported that the bivalirudin group had a 23% reduction in 30-day all-cause mortality rate compared with the heparin group.²³ Meta-analysis of several studies comprising 6405 ACS cases combined with CKD found that bivalirudin reduced NACE and major hemorrhage rates compared with heparin.²⁴

Study limitations. Our study has several limitations. First, it was retrospective, with a small sample size. Second, the optimal comprehensive anticoagulant regimen for dialysis that lowers bleeding risk after PCI is unknown. Specifically, recommendations for females and older patients with ESRD and ACS are lacking. The question remains whether to select non-UFH or to use another type of heparin with a short half-life, such as nadroparin, to complete bedside dialysis. Furthermore, the study was not ethnically diverse, limiting the applicability of the results.

This study showed that bivalirudin is safe and effective to use during perioperative PCI in patients with ACS who are chronically dialysis dependent. Furthermore, bivalirudin use was associated with few bleeding events and no greater cardiovascular complications 30 days after PCI as compared with heparin. These findings support further prospective clinical studies.

Acknowledgment. The authors gratefully acknowledge the participation of all study participants.