Effect of bivalirudin on myocardial microcirculation and adverse events after interventional therapy in older patients with acute coronary syndrome

Abstract

BACKGROUND

Bivalirudin, a direct thrombin inhibitor, is used in anticoagulation therapies as a substitute for heparin, especially during cardiovascular procedures such as percutaneous coronary intervention.

AIM

To explore the effect of bivalirudin on myocardial microcirculation following an intervention and its influence on adverse cardiac events in elderly patients with acute coronary syndrome (ACS).

METHODS

In total, 165 patients diagnosed with acute myocardial at our hospital between June 2020 and June 2022 were enrolled in this study. From June 2020 to June 2022, elderly patients with ACS with complete data were selected and treated with interventional therapy. The study cohort was randomly divided into a study group (n = 80, administered bivalirudin) and a control group (n = 85, administered unfractionated heparin). Over a 6-mo follow-up period, differences in emergency processing times, including coronary intervention, cardiac function indicators, occurrence of cardiovascular events, and recurrence rates, were analyzed.

RESULTS

Significant differences were observed between the study cohorts, with the observation group showing shorter emergency process times across all stages: Emergency classification; diagnostic testing; implementation of coronary intervention; and conclusion of emergency treatment (P < 0.05). Furthermore, the left ventricular ejection fraction in the observation group was significantly higher (P < 0.05), and the creatine kinase-MB and New York Heart Association scores were notably lower than those in the control group (P < 0.05).

CONCLUSION

In elderly patients receiving interventional therapy for ACS, bivalirudin administration led to increased activated clotting time achievement rates, enhanced myocardial reperfusion, and reduced incidence of bleeding complications and adverse cardiac events.

Key Words: Bivalirudin, Heparin, Acute coronary syndrome, Corrected thrombolysis in myocardial infarction flow frame count, Thrombolysis in myocardial infarction, myocardial perfusion classification

Core Tip: Effective anticoagulation management is essential for older patients with acute coronary syndrome, especially in those with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. Bivalirudin may be an innovative drug for achieving this goal.

INTRODUCTION

Acute coronary syndrome (ACS) represents a range of critical heart conditions with diverse clinical presentations, including unstable angina, non-ST-elevation myocardial infarction, and ST-elevation myocardial infarction (STEMI)[1]. These conditions collectively contribute to over half of the global coronary heart disease cases and cause significant concern owing to their abrupt onset and potentially high rates of morbidity and mortality. Data from the Global Registry of Acute Coronary Events highlight a grim statistic: Approximately 15% of patients with ACS die within the first year following the initial episode, with the mortality rate escalating to 25% by the third year and soaring up to 40% by the fourth year.

Among elderly patients with ACS, coronary artery lesions tend to be more intricate and severe and are often characterized by multiple vessel involvement and left main stem lesions, such as diffuse, tortuous, and calcified lesions. This level of severity exacerbates the mortality rate and worsens the overall prognosis[2]. Percutaneous coronary intervention (PCI) is one of the most efficacious treatments for these syndromes[3,4], effectively relieving coronary narrowing or blockage and promptly restoring blood flow to the myocardium. It is widely endorsed by numerous domestic and international clinical practice guidelines[5] and serves as a central therapeutic approach for the management of ACSs.

Despite its benefits, PCI can encounter complications in approximately 30%-40% of patients, where there is either no or slow blood flow through the affected vessel. These complications can result in microvascular dysfunction, acute stent thrombosis, and even sudden cardiac death, thereby posing a significant independent risk factor for both immediate post-PCI outcomes and the likelihood of long-term cardiovascular incidents, including sudden cardiac death.

This study investigated the potential benefits of bivalirudin in enhancing myocardial perfusion and reducing adverse events in elderly patients with ACS undergoing interventional therapy. By scrutinizing the safety and effectiveness of bivalirudin specifically in this demographic, our aim was to refine the post-PCI treatment protocol to mitigate complication risks and ultimately enhance the long-term prognosis of senior patients afflicted with ACSs.

MATERIALS AND METHODS

General information

With the approval of the hospital’s Ethics Committee, 165 patients with ACS who were admitted to the emergency department of our hospital between June 2020 and June 2022 were selected for the study. From June 2020 to June 2022, elderly patients with ACS with complete data were selected and treated with interventional therapy. The study cohort was randomly divided into a study group (n = 80, administered bivalirudin) and a control group (n = 85, administered unfractionated heparin). The inclusion criteria were as follows: (1) Patients with a confirmed diagnosis of ACS who received PCI; (2) Patients with ACS aged 65 years or older; (3) Normal communication ability; (4) Time from onset of illness to admission to the hospital to receive treatment of not more than 12 h; and (5) Patients and their families providing signed informed consent. The exclusion criteria were as follows: (1) ACS combined with severe liver, kidney, and other organ function abnormalities; (2) ACS combined with malignant tumors and other serious diseases; (3) ACS combined with hematologic diseases; (4) Existence of immune function and coagulation abnormalities; and (5) Other miscellaneous reasons for dropping out of the study. Patients with extensive bleeding tendencies, contrast allergies, or other contraindications were excluded.

Research methodology

All patients underwent elective coronary angiography and rapamycin-coated or paclitaxel-coated stents via the radial or femoral arteries. The preoperative preparation consisted of patients taking 600 mg of clopidogrel once and chewing 300 mg of enteric aspirin to achieve antiplatelet therapy. Patients in the observation group were additionally treated with the following regimen: A peripheral intravenous bivalirudin loading dose of 0.75 mg/kg was administered before coronary angiography. A continuous intravenous drip of bivalirudin 1.75 mg/(kg-h) was administered intraprocedurally and continued for 3-4 h after the procedure. The dose of bivalirudin was adjusted according to the activated clotting time (ACT), which ranged from 250-350 s. The treatment regimen in the control group was 3000 U of plain heparin (100 U/kg), which was supplemented with an arterial sheath prior to PCI. If the procedure lasted for more than 1 h, an additional 1000 U of heparin was administered hourly, and the heparin dose was adjusted again according to the ACT value. In both groups, the decision to perform thrombus extraction and apply glycoprotein IIb/IIIa receptor antagonists was made by the operator during the procedure and was based on the thrombus load. After the procedure, all patients received clopidogrel 75 mg/day (for 12 mo) and aspirin 100 mg/day for a prolonged period and were treated with appropriate medications for lipid regulation, glucose reduction, ventricular rate control, and coronary expansion. After admission, all the patients were tested for blood pressure, routine blood and urine tests, blood lipids, liver function, kidney function, blood glucose, markers of myocardial injury, amino-terminal B-type brain natriuretic peptide proximity, and other related indices. In addition, the incidences of no or slow blood flow during the procedure and adverse events during hospitalization and follow-up were recorded. This comparative study assessed the impact of bivalirudin vs plain heparin on myocardial microcirculatory improvement and safety after PCI in older patients with ACS.

Observation indicators

Differences were compared in the times of emergency procedures, such as coronary intervention, cardiac function indices, cardiovascular events, and recurrence between the two groups of patients.

Emergency process time

This is the time required for emergency classification, examination, diagnosis, implementation of coronary intervention, and completion of emergency treatment.

Cardiac function indexes

Left ventricular ejection fraction was detected using cardiac ultrasound (M30, Wuhan Kangbenuo Medical Equipment Co., Ltd.) before and after the intervention. Phosphocreatine kinase isoenzyme (CK-MB) levels were detected using ELISA. The American New York Heart Association Cardiac Function Classification was used to determine CK-MB levels. The New York Heart Association cardiac function classification was used to evaluate the cardiac function of the heart, which was divided into I, II, III, and IV. The scores corresponded to 1-4 points, with higher scores indicating poorer cardiac function.

Cardiovascular events and recurrence

The incidence of arrhythmia, heart failure, cardiac arrest, shock, and recurrent myocardial infarction was recorded during the intervention.

Statistical methods

SPSS 20.0 was used to analyze the data, and the mean ± standard deviation and n (%) were used to express the measurement and count data, respectively, which were analyzed by t and χ² tests, respectively. P < 0.05 indicated that the difference was statistically significant.

RESULTS

Comparison of the general conditions of the two groups of patients

There were 85 patients in the observation group, of whom 45 were male and 40 were female, with a mean age of 67.39 ± 7.53 years. The time from onset to admission was 3.58 ± 0.71 h. Forty-nine of the patients had hypertension, 38 had diabetes mellitus, and 19 had cardiovascular disease. The control group included 40 male and 40 female patients, with a mean age of 67.78 ± 7.62 years. The mean time from onset to admission was 3.46 ± 0.75 h. Forty-four patients had hypertension, 35 had diabetes mellitus, and 17 had cardiovascular diseases. There were no statistically significant differences in the general characteristics of the two groups (P > 0.05; Table 1).

Table 1 Comparison of the general conditions of the two groups of patients.

Group	n	Sex, n (%)		Age, mean ± SD	Time from onset to admission in h, mean ± SD	Comorbidities, n (%)
		Male	Female			High blood pressure	Diabetes	Cardiovascular disease
Observation group	85	45 (52.94)	40 (47.06)	64.29 ± 7.53	3.58 ± 0.71	49 (57.65)	38 (44.71)	19 (22.35)
Control group	80	40 (50.00)	40 (50.00)	63.78 ± 7.62	3.46 ± 0.75	44 (55.00)	35 (43.75)	17 (21.25)
χ2/t	-	0.143		0.432	1.056	0.117	0.015	0.029
P value	-	0.706		0.666	0.293	0.732	0.902	0.864

Observation group: Patients treated with bivalirudin; Control group: Patients treated with unfractionated heparin. SD: Standard deviation.

Comparison of emergency process times

The duration of emergency processes, such as emergency classification, examination and diagnosis, implementation of coronary intervention, and completion of emergency treatment, was shorter in the observation group than in the control group (P < 0.05; Table 2).

Table 2 Comparison of emergency flow times.

Group	n	Emergency classification	Diagnostic examination	Perform coronary interventions	Completion of emergency treatment
Observation group	85	1.82 ± 0.35	4.37 ± 1.12	33.96 ± 3.51	41.76 ± 3.92
Control group	80	3.06 ± 0.71	6.58 ± 2.39	40.46 ± 4.33	54.27 ± 4.76
t value	-	14.357	7.677	10.621	18.473
P value	-	< 0.001	< 0.001	< 0.001	< 0.001

Data are mean ± standard deviation and in minutes. Observation group: Patients treated with bivalirudin; Control group: Patients treated with unfractionated heparin.

Comparison of cardiac function indicators

The left ventricular ejection fraction of patients in the observation group was higher than that in the control group after the intervention (P < 0.05), and the CK-MB and New York Heart Association scores were lower than those in the control group (P < 0.05; Table 3).

Table 3 Comparison of cardiac function indices.

Groups	n	LVEF in %		CK-MB in U/L		NYHA points
		Pre-intervention	Post-intervention	Pre-intervention	Post-intervention	Pre-intervention	Post-intervention
Observation group	85	41.57 ± 3.46	59.18 ± 4.35	114.36 ± 14.32	48.06 ± 4.37	2.86 ± 0.53	1.75 ± 0.42
Control group	80	41.78 ± 3.21	51.24 ± 3.87	112.93 ± 14.84	54.75 ± 5.11	2.83 ± 0.50	2.01 ± 0.53
t value	-	0.403	12.359	0.630	9.055	0.373	3.503
P value	-	0.687	< 0.001	0.530	< 0.001	0.709	0.001

Data are mean ± standard deviation. Observation group: Patients treated with bivalirudin; Control group: Patients treated with unfractionated heparin. CK-MB: Phosphocreatine kinase isoenzyme; LVEF: Left ventricular ejection fraction; NYHA: New York Heart Association.

Comparison of cardiovascular events and recurrences

The cardiovascular event (4.71%) and recurrent myocardial infarction rates (3.53%) were lower in the observation group than in the control group (16.25% and 12.50%, respectively, P < 0.05; Table 4).

Table 4 Comparison of cardiovascular events and recurrences.

Groups	n	Arrhythmia	Heart failure	Cardiac arrest	Shock, loanword	Cardiovascular events	Recurrent myocardial infarction
Observation group	85	2	1	1	0	4 (4.71)	3 (3.53)
Control group	80	5	4	2	2	13 (16.25)	10 (12.50)
χ2 value	-	-	-	-	-	5.943	4.569
P value	-	-	-	-	-	0.015	0.033

Data are n (%). Observation group: Patients treated with bivalirudin; Control group: Patients treated with unfractionated heparin.

DISCUSSION

Although patients with ACS can experience the prompt opening of lesion-related coronary arteries, their condition can also induce myocardial reperfusion injury, which manifests as no reflow or slow flow and leads to poor reperfusion of the myocardial microcirculation. This pathological process triggers myocardial tonus and cardiac electrophysiological abnormalities, which adversely affect cardiac function and patient prognosis[6,7]. Currently, the mechanism of anaplastic and slow reperfusion remains unclear and may interact with various factors, such as plaque debris occluding the microvasculature, platelet overactivation, thrombosis, reperfusion injury, and endothelial dysfunction.

Rational anticoagulation during the perioperative period reduces slow flow and no reflow events during PCI. Plain heparin has traditionally been recognized as the standard perioperative anticoagulant for PCI in patients with ACS. However, owing to the nonspecific binding of normal heparin to plasma proteins and variable dose response, it leads to a low intraoperative ACT attainment rate, unstable anticoagulation effect, evident individual differences, a higher risk of postoperative bleeding, and the risk of inducing heparin-induced thrombocytopenia.

Bivalirudin, a novel anticoagulant drug derived from hirudin derivatives, exerts its anticoagulant effects by directly inhibiting its active site[8]. Compared to ordinary heparin, bivalirudin has direct and specific thrombin inhibitory properties, is not affected by the inactivation of platelet factor 4, and does not require cofactor activation[9]. Its binding to thrombin is transient and reversible[10] and plays a blocking role in both the initial and sustained stages of thrombus formation[11]. Additionally, bivalirudin has a short half-life, rapid onset of action, high bioavailability, and a linear pharmacokinetic-pharmacodynamic relationship, which results in a more stable anticoagulant effect.

Several large multicenter randomized controlled trials[12,13] have reported that the use of bivalirudin in patients with ACS undergoing PCI is more effective in reducing the incidence of ischemic events and has a lower risk of bleeding than plain heparin or combined glycoprotein IIb/IIIa inhibitor regimens. A meta-analysis published in 2016[14] showed that bivalirudin reduced the risk of bleeding compared to plain heparin but had an increased risk of in-stent thrombosis.

For example, one study examined the efficacy and safety of prasugrel in conjunction with bivalirudin against the pairing of clopidogrel with standard heparin in patients with STEMI undergoing PCI. The results indicated no statistically significant difference between the two regimens in terms of the primary endpoint of 30-d in-stent thrombus or ischemic complications[15]. A separate study[16] randomized patients with acute myocardial infarction (inclusive of both STEMI and non-STEMI) who underwent PCI into three categories: Bivalirudin only; heparin only; and heparin combined with tirofiban. Notably, no substantial variation in the 30-d acute in-stent thrombosis was observed among the three groups, which could be attributed to the protocol that extended and escalated the dosage of bivalirudin injections to 4 h post-procedure. Given the inherent antiplatelet properties of bivalirudin, it may offer adequate antithrombotic protection during the early post-PCI phase until the full antiplatelet effect of clopidogrel is established.

Current research also underscores that advancing age independently elevates the risk of bleeding; every extra year of age corresponds to a 2% relative increase in bleeding risk[17]. Elderly patients with coronary artery disease face a heightened vulnerability to detrimental events, such as bleeding, ischemia, and mortality, owing to the complexities of their coronary lesions, calcium deposition issues, and common accompanying health conditions, such as hypertension, diabetes, and hyperlipidemia. Thus, when performing PCI in older patients with ACS, meticulous balancing of bleeding and coagulation risks during the perioperative period is crucial to minimize adverse outcomes and maximize the clinical benefits.

CONCLUSION

The use of bivalirudin in interventional therapy for older patients with ACS achieved higher ACT attainment rates and improved myocardial microcirculatory reperfusion. Moreover, it effectively reduced the incidence of hemorrhage and adverse cardiac events, resulting in improved clinical outcomes.