Comparison of net adverse clinical events between bivalirudin and heparin as anticoagulants for percutaneous coronary intervention in Chinese patients
- Authors:
- Published online on: September 27, 2023 https://doi.org/10.3892/etm.2023.12229
- Article Number: 530
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Copyright: © Chai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Percutaneous coronary intervention (PCI) alleviates coronary artery stenosis or occlusion and restores blood flow by implanting stents; this has been one of the key methods used in the treatment of coronary artery diseases (1,2). Notably, patients who undergo PCI exhibit an unstable hypercoagulable state in their blood, resulting in a high risk of thrombosis (3-5). In order to prevent the occurrence of thrombosis, treatment with anticoagulants is also usually applied simultaneously in patients who undergo PCI, (6,7). However, bleeding and even mortality may occur during or after receiving anticoagulants in patients who undergo PCI (8,9). Therefore, it is critical to select appropriate anticoagulants in order to both effectively prevent thrombosis and minimize the risk of bleeding events.
Generally, bivalirudin, unfractionated heparin, enoxaparin and fondaparinux are the most commonly applied anticoagulant drugs used during PCI (10). Bivalirudin, as a direct thrombin inhibitor with a rapid onset and a short half-life, has been reported to be safer for use compared with heparin in several previous studies (11-14). For example, a previous study demonstrated that bivalirudin decreases the incidence of net adverse clinical events (NACEs) and major bleeding within 1 year compared with heparin plus a glycoprotein IIb/IIIa inhibitor (GPI) in patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary PCI (13). Moreover, another study indicated that in patients with coronary artery disease complicated with diabetes who undergo PCI, bivalirudin decreases the risk of 30-day major adverse cardiac and cerebral events (MACCEs) compared with heparin (14). In addition, another study demonstrated that compared with heparin alone and heparin plus tirofiban, bivalirudin achieves a reduction in bleeding event rates in patients with acute myocardial infarction who undergo primary PCI (15). However, the aforementioned studies were both conducted in countries other than China. Due to the short time period since bivalirudin has begun to be been marketed in China, the safety of the use of bivalirudin among Chinese patients who undergo PCI remains unclear; thus, this is a key issue which needs to be resolved.
Therefore, the present study aimed to compare the incidences of NACEs, MACCEs and bleeding events between the use of bivalirudin and heparin in Chinese patients who underwent PCI.
Patients and methods
Patients
The present cohort study reviewed 2,377 patients [mean age: 64.8±11.3 years; males: 1,644 (69.2%)] who underwent primary PCI and received bivalirudin or heparin as anticoagulants in HanDan Central hospital (Handan, China) between December, 2017 and February, 2022. The screening criteria were as follows: i) An age >18 years; ii) patients who underwent primary PCI; iii) patients who had the clinical manifestation of STEMI, unstable angina (UA), non-STEMI (NSTEMI) or stable coronary artery disease (SCAD); and iv) patients who received bivalirudin or heparin [low molecular weight heparin (LMWH) or unfractionated heparin (UFH)] as anticoagulants. Patients who had the following conditions were ineligible: i) Had incomplete clinical data for study use; ii) were complicated with cancers or severe hematological diseases; and iii) women who were pregnant or breastfeeding. The present study was approved by the Ethics Committee of HanDan Central Hospital (Handan, China; approval no. 20230816001). Patients or their families provided written informed consent. Clinical characteristics of patients are given in Table I.
Treatment
Bivalirudin or heparin (LMWH or UFH) were administered to the eligible patients for anticoagulant treatment. The treatment was not intervened with in the present study; the appropriate medication was selected was based on the actual clinical status of the patient. Furthermore, there were no restrictions on the addition of GPIs. As a result, patients who received bivalirudin were considered as the bivalirudin group (n=944) and patients who received LMWH or UFH were considered as the heparin group (n=1,433). The detailed regimens of bivalirudin and heparin were the same as those described in a previous study (16).
Data collection and assessment
Demographics, comorbidities, disease features and treatment-related information were obtained for analysis. The Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA guidelines (CRUSADE) score was evaluated based on 8 predictors and ranged from 1-100 points (17). Patients were classified into 5 categories of bleeding risk based on CRUSADE score: Very low, ≤20 points; low, 21-30 points; moderate, 31-40 points; high, 41-50 points; and very high risk, ≤51 points (17). Additionally, within 30 days after PCI, NACEs, MACCEs, Bleeding Academic Research Consortium grades 2-5 (BARC 2-5) bleeding events and BARC 3-5 bleeding events were assessed. NACEs was defined as the composite of MACCEs and BARC 2-5 bleeding events (18). MACCEs was defined as the composite of all-cause death, cardiac mortality, recurrent myocardial infarction, ischemia-driven target vessel revascularization and stroke (18). BARC 2-5 bleeding events and BARC 3-5 bleeding events were assessed according to BARC criteria (19).
Statistical analysis
Statistical analysis was carried out using SPSS V22.0 software (IBM Corp.). Graph plotting was performed using GraphPad Prism V6.1 software (GraphPad Software Inc.). Comparisons between the two groups were performed using the unpaired Student's t-test, χ2 test or Wilcoxon rank sum test. Factors associated with NACEs, MACCEs, BARC 2-5 bleeding events or BARC 3-5 bleeding events were assessed using logistic regression analysis, and all factors analyzed in the univariate logistic regression analysis were included in the multivariate logistic regression analysis with the forward stepwise mode. A value of P<0.05 was considered to indicate a statistically significant difference.
Results
Clinical features
The heparin group included 458 (32.0%) females and 975 (68.0%) males with a mean age of 65.1±11.3 years. Moreover, the bivalirudin group included 275 (29.1%) females and 669 (70.9%) males with a mean age of 64.4±11.3 years. The median value [interquartile range (IQR)] of the CRUSADE score in the bivalirudin group was lower compared with that in the heparin group [27.0 (20.0-36.0) vs. 28.0 (21.0-38.0); P=0.019]. Moreover, the bleeding risk stratified by the CRUSADE score revealed a significant difference between the bivalirudin and heparin groups (P=0.013). In terms of demographics, comorbidities, other disease features and treatment-related information, there were no significant differences between the groups (all P>0.05). The detailed clinical features of the patients are presented in Table I.
Incidences of NACEs, MACCEs, BARC 2-5 bleeding events and BARC 3-5 bleeding events
The incidence of NACEs in the bivalirudin group was significantly lower compared with that in the heparin group (9.3 vs. 13.4%; P=0.003). Moreover, no significant difference was found in the incidence of MACCEs between the bivalirudin and heparin groups (5.9 vs. 7.6%; P=0.116). Furthermore, among the MACCEs, the incidences of all-cause mortality (3.7 vs. 4.5%; P=0.325), cardiac mortality (3.0 vs. 3.4%; P=0.541), recurrent myocardial infarction (1.6 vs. 2.0%; P=0.442), ischemia-driven revascularization (1.9 vs. 1.3%; P=0.263) and stroke (1.6 vs. 1.5%; P=0.809) did not vary significantly between the groups. Of note, the incidences of BARC 2-5 bleeding events (4.8 vs. 8.7%; P<0.001) and BARC 3-5 bleeding events (1.9 vs. 4.4%; P=0.001) in the bivalirudin group were lower compared with those in the heparin group (Table II).
 | Table IIComparison of NACEs, MACCEs, BARC 2-5 bleeding events and BARC 3-5 bleeding events between groups. |
Independent factors for NACEs
Univariate logistics regression analysis revealed that bivalirudin treatment (vs. heparin treatment; P=0.003) predicted a lower risk of NACEs. Age (≥65 years vs. <65 years; P=0.017), a history of hypertension (yes vs. no; P=0.013), clinical manifestation of SCAD (vs. UA; P<0.001), NSTEMI (vs. UA; P<0.001), STEMI (vs. UA; P<0.001), CRUSADE score (≥41 vs. <40; P=0.001), operative timing (emergency operation vs. elective operation; P<0.001) and total stent length (>33.0 vs. ≤33.0 mm; P=0.020) forecasted higher risks of NACEs (Table III).
According to forward stepwise multivariate logistic regression analysis, bivalirudin treatment [vs. heparin treatment; odds ratio (OR), 0.587; P<0.001] independently estimated a lower risk of NACEs. However, age (≥65 years vs. <65 years; OR, 1.455; P=0.008), a history of hypertension (yes vs. no; OR, 1.447; P=0.016), clinical manifestation of SCAD (vs. UA; OR, 2.054; P=0.005), NSTEMI (vs. UA; OR, 2.164; P=0.001), operative timing (emergency operation vs. elective operation; OR, 2.352; P<0.001), lesional vessel (multiple vs. single; OR, 1.561; P=0.010) and total stent length (>33.0 vs. ≤33.0 mm; OR, 1.405; P=0.015) independently predicted higher risks of NACEs (Table III).
Independent factors for MACCEs
Based on univariate logistic regression analysis, bivalirudin treatment (vs. heparin treatment; P=0.117) was not associated with risk of MACCEs. Age (≥65 years vs. <65 years; P=0.028), a history of hypertension (yes vs. no; P=0.034), clinical manifestation of SCAD (vs. UA; P<0.001), NSTEMI (vs. UA; P=0.007), STEMI (vs. UA; P=0.001), CRUSADE score (≥41 vs. <40; P=0.024), operative timing (emergency operation vs. elective operation; P<0.001) and lesional vessel (multiple vs. single; P=0.044) estimated higher risks of MACCEs (Table IV).
According to forward stepwise multivariate logistic regression analysis, bivalirudin treatment (vs. heparin treatment; OR, 0.689; P=0.041) independently predicted a lower risk of MACCEs. Age (≥65 years vs. <65 years; OR, 1.531; P=0.016), a history of hypertension (yes vs. no; OR, 1.460; P=0.047), operative timing (emergency operation vs. elective operation; OR, 1.982; P<0.001) and lesional vessel (multiple vs. single; OR, 1.613; P=0.019) independently forecasted higher risks of MACCEs (Table IV).
Independent factors for BARC 2-5 bleeding events
In accordance with univariate logistic regression analysis, bivalirudin treatment (vs. heparin treatment; P<0.001) estimated a lower risk of BARC 2-5 bleeding events, whereas clinical manifestation of SCAD (vs. UA; P<0.001), NSTEMI (vs. UA; P<0.001), STEMI (vs. UA; P<0.001), CRUSADE score (≥41 vs. <40; P=0.001) and operative timing (emergency operation vs. elective operation; P<0.001) predicted higher risks of BARC 2-5 bleeding events (Table V).
Based on further forward stepwise multivariate logistic regression analysis, bivalirudin treatment (vs. heparin treatment; OR, 0.459; P<0.001) independently forecasted a lower risk of BARC 2-5 bleeding events. However, age (≥65 years vs. <65 years; OR, 1.498; P=0.024), a history of diabetes mellitus (yes vs. no; OR, 1.568; P=0.019), clinical manifestation of SCAD (vs. UA; OR, 2.356; P=0.009), NSTEMI (vs. UA; OR, 2.632; P=0.002), operative timing (emergency operation vs. elective operation; OR, 2.535; P<0.001) and total stent length (>33.0 vs. ≤33.0 mm; OR, 1.431; P=0.040) independently predicted higher risks of BARC 2-5 bleeding events (Table V).
Independent factors for BARC 3-5 bleeding events
According to the univariate logistic regression analysis, bivalirudin treatment (vs. heparin treatment; OR, 0.423; P=0.001) was related to a lower risk of BARC 3-5 bleeding events. Nevertheless, a history of diabetes mellitus (yes vs. no; OR, 1.798; P=0.013), the clinical manifestation of SCAD (vs. UA; OR, 3.470; P=0.001), NSTEMI (vs. UA; OR, 2.275; P=0.036), STEMI (vs. UA; OR, 2.128; P=0.017), CRUSADE score (≥41 vs. <40; OR, 3.100; P<0.001), operative timing (emergency operation vs. elective operation; OR, 1.859; P=0.007) and stent diameter (≥3.5 vs. <3.5 mm; OR, 1.743; P=0.018) were associated with a higher risk of BARC 3-5 bleeding events (Table VI).
Additionally, forward stepwise multivariate logistic regression analysis demonstrated that bivalirudin treatment (vs. heparin treatment; OR, 0.386; P=0.002) was independently associated with a lower risk of BARC 3-5 bleeding events. Nevertheless, a history of diabetes mellitus (yes vs. no; OR, 1.805; P=0.024), the CRUSADE score (≥41 vs. <40; OR, 2.313; P=0.001), operative timing (emergency operation vs. elective operation; OR, 2.379; P=0.001) and stent diameter (≥3.5 vs. <3.5 mm; OR, 1.635; P=0.048) were independently associated with a higher risk of BARC 3-5 bleeding events (Table VI).
Discussion
Bivalirudin plays an anticoagulant role by inhibiting thrombin directly, repressing circulating and clot-bound thrombin, but not combining antithrombin III, which is considered to have certain clinical advantages over heparin in patients receiving PCI (20-22). For example, a previous study suggests that among patients with STEMI who undergo primary PCI and receive aspirin and ticagrelor, bivalirudin reduces the incidence of NACEs compared with heparin (23). Moreover, another study indicated that in patients with STEMI who undergo PCI, bivalirudin decreases all-cause mortality compared with heparin (24). These findings are similar to those of the present study, which revealed that among patients who underwent PCI, bivalirudin decreased the incidence of NACEs compared with heparin, and bivalirudin treatment (vs. heparin treatment) was an independent factor for predicting a low risk of NACEs. This may be due to the following: i) Bivalirudin directly inhibited thrombin, while heparin indirectly inhibited thrombin through antithrombin III activation; thus, bivalirudin decreased the incidence of bleeding events compared with heparin in patients who underwent PCI (22,25). ii) Bivalirudin exerted a regulatory effect on inflammation in patients who underwent PCI, thereby inhibiting atherosclerosis and further decreasing the incidence of MACCEs to a certain extent compared with heparin in those patients (14,26,27). For the aforementioned reasons, bivalirudin decreased the incidence of NACEs compared with heparin.
However, the incidence of MACCEs in patients who undergo PCI continues to be a matter of concern. A previous study demonstrated that, compared with heparin, bivalirudin decreases the risk of 30-day MACCEs in patients with coronary artery disease complicated by diabetes who undergo PCI (14). Another study disclosed that the incidence of MACCEs does not vary between bivalirudin and the unfractionated heparin in patients with STEMI undergoing primary PCI (23). Moreover, in female patients with acute myocardial infarction who undergo emergency PCI, no discrepancy is observed in the incidence of MACCEs between bivalirudin and heparin (28). In the present study, bivalirudin numerically reduced the incidence rate of MACCEs compared with heparin, although there was no significant difference. Moreover, bivalirudin treatment (vs. heparin treatment) was not associated with a risk of MACCEs in univariate logistic regression analysis, while it was independently related to a low risk of MACCEs in forward stepwise multivariate logistic regression analysis. This result may be due to the fact that the result of the univariate logistic regression analysis was affected by some confounding factors, resulting in the concealment of the true effect of bivalirudin treatment. Following adjustment by forward stepwise multivariate logistic regression analysis, the influence of these confounding factors was eliminated, and it was found that bivalirudin treatment (vs. heparin treatment) was independently related to a lower risk of MACCEs. The result from forward stepwise multivariate logistic regression analysis was explained as follows: Compared with heparin, bivalirudin inhibited inflammation in patients who underwent PCI, and thus reduced the MACCEs to a certain extent (14,26,27).
In addition, a previous study has demonstrated that in patients with STEMI who undergo primary PCI, bivalirudin reduces the 30-day incidence of BARC 3-5 major bleeding events compared with heparin (24). In another study on elderly patients with STEMI who underwent primary PCI, bivalirudin decreases the incidence of BARC 2-5 bleeding events compared with unfractionated heparin (29). These findings are partly in accordance with the findings of the present study, which revealed that bivalirudin reduced the incidence of BARC 2-5 and 3-5 bleeding events compared with heparin. In addition, bivalirudin treatment (vs. heparin treatment) was independently associated with low risks of BARC 2-5 and 3-5 bleeding events. The possible reasons for this were the following: i) Compared with heparin, bivalirudin had a shorter half-life and it was metabolized more rapidly in the plasma of patients undergoing PCI, which may lead to a lower risk of bleeding in these patients (21); and ii) the reduction in the risk of bleeding with the use of bivalirudin might be related to its direct inhibition of thrombin, its non-union with platelet factor 4 and its linear pharmacokinetics (25).
As aforementioned, the present study showed that bivalirudin reduced the risks of NACEs, MACCEs and bleeding events compared with heparin in patients who underwent PCI. Notably, bivalirudin is 10-50 times more expensive compared with heparin (30), thus for clinical management, the cost-effectiveness of the two drugs is also an issue worth taking into consideration. Currently, the results of the comparison of cost-effectiveness between bivalirudin and heparin are inconsistent in previous studies. For example, one study revealed that bivalirudin is less cost-effective compared with heparin in patients who undergo PCI (31). Another study showed that bivalirudin is more cost-effective for only a minority of patients who undergo PCI with a high bleeding risk compared with heparin (32). Nevertheless, one study illustrated that the use of bivalirudin in patients with STEMI who undergo primary PCI is cost-effective compared with the use of heparin (33). These controversial results may be due to the existence of some confounding factors (34). Taken together, the comparison of cost-effectiveness between bivalirudin and heparin is uncertain and required to be verified in further studies.
There were several limitations to the present study, which should be mentioned: i) The present study was a single-center study, which may have led to bias in the selection process. ii) The present study only evaluated NACEs within 30 days after PCI. Thus, the long-term safety of bivalirudin in patients who undergo PCI remains to be further explored. iii) In the present study, the included patients selected medication based on their actual clinical status rather than randomization, which may have led to potential confounders between groups.
In conclusion, the present study demonstrated that bivalirudin reduced the incidence of NACEs (particularly bleeding events) compared with heparin in Chinese patients who underwent PCI, which may serve as a safer anticoagulant in these patients. However, further validation in larger-scale, multi-center and randomized controlled studies is necessary.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
LC, JL, YW and ZB contributed to the conception and design of the study. LC, MZ, ZW, JL and ZB were involved in data collection. YZ, YW and ZQ contributed to data analysis. LC and JL confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.
Ethics approval and consent to participate
The study was approved by the Ethics Committee of Handan Central Hospital (Handan, China; approval no. 20230816001). The patients or their families provided written informed consent.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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