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A meta‐analysis and cost‐minimization analysis of bivalirudin versus heparin in high‐risk patients for percutaneous coronary intervention

Abstract This meta‐analysis was performed to compare the safety, efficacy, and pharmacoeconomic of bivalirudin versus heparin in high‐risk patients for percutaneous coronary interventions (PCI). Earlier meta‐analysis comparing bivalirudin and heparin during PCI demonstrated that bivalirudin caused less bleeding with more stent thrombosis. However, little data were available on the safety of bivalirudin versus heparin in high‐risk patients for PCI. Thus, we performed a meta‐analysis to evaluate the efficacy and safety in the “high‐risk” patients. A systematic search of electronic databases was conducted up to July 30, 2020. The Cochrane Risk of Bias assessment tool was used to assess the quality of included studies. The primary outcomes were all‐cause death and major adverse cardiac events (MACE); secondary outcomes were major and minor bleeding, followed by a cost‐minimization analysis comparing bivalirudin and heparin using a local drug and medical costs reported in China. Subgroup analysis was based on the type of disease of the high‐risk population. Finally, a total of 10 randomized controlled trials involved 42,699 patients were collected. The Cochrane Risk of Bias Tool was employed to appraise the research quality. No significant difference was noted between bivalirudin and heparin regarding all‐cause death and MACE. However, subgroup analysis showed that bivalirudin caused less major bleeding in female (OR:0.65, 95% CI:0.53–0.79), diabetes (OR:0.55, 95%CI:0.42–0.73), and CKD (OR:0.59, 95%CI:0.63–1.65). The scatterers of the included literature were approximately symmetrical, and no research was outside the funnel plot. Additionally, cost‐minimization analysis showed that heparin was likely to represent a cost‐effective option compared with bivalirudin in China, with potential savings of 2129.53 Chinese Yuan (CNY) per patient for one PCI. Overall, the meta‐analysis showed that although bivalirudin appeared to have a lower risk of major bleeding rate, the overall effectiveness and safety between the two groups showed no significant difference in high‐risk patients for PCI. But the results of the cost‐minimization analysis showed that heparin could be a potential cost‐saving drug than bivalirudin in patients for PCI in China.

conducted up to July 30, 2020. The Cochrane Risk of Bias assessment tool was used to assess the quality of included studies. The primary outcomes were all-cause death and major adverse cardiac events (MACE); secondary outcomes were major and minor bleeding, followed by a cost-minimization analysis comparing bivalirudin and heparin using a local drug and medical costs reported in China. Subgroup analysis was based on the type of disease of the high-risk population. Finally, a total of 10 randomized controlled trials involved 42,699 patients were collected. The Cochrane Risk of Bias Tool was employed to appraise the research quality. No significant difference was noted between bivalirudin and heparin regarding all-cause death and MACE. However, subgroup analysis showed that bivalirudin caused less major bleeding in female (OR:0.65, 95% CI:0.53-0.79), diabetes (OR:0.55, 95%CI:0.42-0.73), and CKD (OR:0.59, 95%CI:0.63-1.65). The scatterers of the included literature were approximately symmetrical, and no research was outside the funnel plot. Additionally, cost-minimization analysis showed that heparin was likely to represent a cost-effective option compared with bivalirudin in China, with potential savings of 2129.53 Chinese Yuan (CNY) per patient for one PCI. Overall, the meta-analysis showed that although bivalirudin appeared to have a lower risk of major bleeding rate, the overall effectiveness and safety

| INTRODUC TI ON
Percutaneous coronary intervention (PCI) refers to recanalization of stenosed or occluded coronary arteries by cardiac catheterization to improve myocardial perfusion. 1 As compared with fibrinolytic therapy and medical treatment measures, PCI has substantially improved the prognosis of patients presenting with acute coronary syndrome (ACS). 2 Data show that the total number of PCI treatments for coronary heart disease in mainland China in 2018 was 915,256. Compared with 2017, it increased by 21.5%. 3 The early characteristics of ACS are the increased risk of thrombotic complications, emphasizing the need for fast, safe, and effective antithrombotic therapy, especially in patients undergoing PCI. 4,5 Patients for PCI are bound to receive antithrombotic therapy to prevent thromboembolic events.
Bivalirudin and heparin are the two adjunctive antithrombotic therapies used during primary PCI. 6 Heparin is currently the most commonly used antithrombotic agent in patients with ACS. 7 Bivalirudin is a direct intravenous thrombin inhibitor. ESC/EACTS guidelines recommend it as an alternative to heparin in patients with ACS, in particular non-ST-segment elevation myocardial infarctions (NSTEMI). Unfractionated heparin is traditionally regarded as the mainstay anticoagulant strategy in PCI. A study published by Steg et al. 8 indicated that bivalirudin was equally efficacious with less bleeding than heparin, despite its predilection for stent thrombosis.
Although several meta-analyses [9][10][11] have been performed comparing the safety and efficiency of bivalirudin versus heparin, there are few studies for high-risk patients.
In this meta-analysis, women, patients with anemia, CKD, and diabetes were regarded as high-risk groups to explore the effectiveness and safety of bivalirudin and heparin. In the REPLACE-2 experiment, patients with diabetes, women, and CKD were considered as high-risk patients for subgroup analysis to observe the effectiveness and safety of bivalirudin and heparin. Chinese PCI interventional treatment guidelines point out that for some special ACS patients, those with diabetes and CKD, the risk of thrombosis or bleeding is relatively high. Antithrombotic drugs should be used to fully weigh their efficacy and safety. The American AHA/ACC guidelines also indicated that the characteristics of the diseases could affect the effectiveness of PCI, such as diabetes, CKD, anemia, and female patients. Reducing bleeding rates in patients with high-risk features can be clinically more relevant and have a higher impact on prognosis. For patients in high-risk, for example, compared with men, women undergoing PCI have a higher probability of suffering from comorbidities, such as hypertension and chronic kidney disease. 12,13 Patients with kidney dysfunction often have impaired coagulation and abnormal platelet function that increase the tendency of bleeding events when anticoagulants are used. 14 Therefore, the weighted risk versus benefit of the type of anticoagulation used is extremely important and deserves careful evaluation.
At present, bivalirudin is considered to have a similar effect as heparin in clinical application. 15 Several clinical studies have shown that bivalirudin has significant advantages in reducing perioperative complications, improving medical quality, and reducing medical cost. There have been some cost-effect clinical trials that compare the difference of economic evaluation. [16][17][18] One study in China based on a randomized, double-blind, multicenter phase III clinical trial, BRIGHT trial, showed that under the current economic conditions in China, bivalirudin is proved to have higher significant cost-effectiveness compared with heparin. It is recommended to use bivalirudin instead of heparin in ACS patients for PCI. Other studies draw a similar conclusion mostly that bivalirudin saves clinical cost. At this stage, China has gradually begun to further promote the use of bivalirudin in clinical treatment. 19 between the two groups showed no significant difference in high-risk patients for PCI. But the results of the cost-minimization analysis showed that heparin could be a potential cost-saving drug than bivalirudin in patients for PCI in China.

K E Y W O R D S
bivalirudin, economic evaluation, heparin, meta-analysis, PCI

What is already known about this subject
• Heparin and bivalirudin are currently the most commonly used antithrombotic agents in patients with the acute coronary syndrome (ACS).
• The meta-analysis and economic evaluation of high-risk patients for percutaneous coronary intervention (PCI) are still controversial.
• There is no economic evaluation of the Chinese population based on meta-analysis.

What this study adds
• This meta-analysis evaluated the safety and efficacy reported in randomized controlled trials (RCTs) on the use of bivalirudin versus heparin in high-risk patients for PCI.
• Heparin has better economic benefits than bivalirudin in Chinese patients for PCI.
To ensure the rational promotion of the clinical use of bivalirudin, more clinical staff, researchers, and payment policymakers are required to formulate relevant policies according to clinical evidence and health economics evidence.
Thus, the objectives of this meta-analysis were to (1) compare the efficacy and safety reported in randomized controlled trials (RCTs) on the use of bivalirudin versus heparin for high-risk patients for PCI; (2) use the meta-analysis result to compare the economic benefits in heparin and bivalirudin (from a healthcare system perspective) for patients planned for PCI in China.

| Selection criteria
We searched for studies reporting data on the safety and efficacy in patients for PCI in the following specific subgroups of "high-risk" patients according to the AHA/ACC Guideline: female, anemia patients, diabetes patients, and chronic kidney disease.
Inclusion criteria were (a) RCTs including further analyses, (b) individuals with planned PCI were randomly assigned to two groups, one group was treated with bivalirudin and the other with heparin plus either routine or provisional GPI, (c) studies reporting clinical outcomes in both groups, d) a subgroup analysis of a certain high-risk population included in the RCT experiment.
Studies with any of the following conditions were excluded: (a) lack of data for detailed analysis results; (b) reviews, editors, observational studies, and small sample trials (n < 50).

| Data extraction and quality assessment
The following data from each study were extracted by two independent authors: baseline characteristics of study patients, countries, interventions, diseases, drug dose, mean age, and outcomes.
The quality evaluation and risk of bias of each RCT study were separately assessed by two reviewers with application of Cochrane Collaboration's risk of bias assessment tool. The evaluation contents mainly included: (1) generation of random sequence (selection bias); (2) concealment of distribution sequence (selection bias); (3) blind method for research object and implementer (implementation bias);

| Outcome measures
The primary endpoints were all-cause mortality and MACE. MACE rate included myocardial reinfarction and stroke and thrombosis rate. Secondary outcomes included major bleeding rate and minor bleeding rate. Major bleeding was defined as Bleeding Academic Research Consortium (BARC) type 3 or 5. The minor bleeding rate was defined as BARC type 1 or 2. According to the definition of the World Health Organization (WHO), the baseline hemoglobin value of anemia males is <130 g/L, and of females <120 g/L.

| Statistical analysis
The data were calculated by random-effects models and expressed as odds ratios (ORs) and 95% confidence intervals (CI). Heterogeneity across trials was evaluated using the Cochran Q test and the Higgins I 2 test. I 2 < 25% was considered low heterogeneity, and I 2 > 75% high between studies. Publication bias was assessed using a funnel plot and the Egger test. All statistical analyses were made by using STATA statistical software version 12.0 (Stata Corp).

| Cost analysis
According to the results of the meta-analysis, the appropriate economic evaluation method was selected. If there was no significant difference in the efficacy and safety of bivalirudin and heparin, the "cost-minimization analysis" is selected to analyze the economy of the two schemes; if there was a significant difference in the efficacy or safety of the two drugs, the "cost-effectiveness analysis" is se-

| RE SULTS
Subsequently, 2380 related articles were searched, and 10 RCTs satisfied our predefined inclusion criteria after screening (Figure 1).

| Female patients
As shown in Figure 2, women receiving bivalirudin during PCI dem-

| Diabetes patients
In the overall analysis, no significant difference was detected

| Quality accesses and publication bias
The results of 10 RCT studies were analyzed by the Cochrane evaluation system as shown in Figure 6. In six studies stratifying

| Cost analysis
According to the comprehensive evaluation of 10 included RCTs, there was no significant difference between the mortality and MACE of bivalirudin and heparin in high-risk groups. The forest plots were shown in Figure 8. The cost difference results between the two groups in China was presented in Table 3.

F I G U R E 7
Funnel plot of the mortality stratified according to gender The sensitivity results for drugs and adverse reactions showed that the minimum cost analysis results of bivalirudin and heparin did not change when the price was within the range of changes. The sensitivity analysis results, as given in Table 4, were consistent with the cost-benefit analysis results, indicating that the pharmacoeconomic analysis of this study is stable and reliable.

| DISCUSS ION
To the best of our knowledge, this is the first meta-analysis focusing on high-risk patients for PCI to compare the efficacy and safety of bivalirudin versus heparin. Using high information from 10 RCTs, we provided, for the first time, high-quality data including 1984 women, 2494 anemia patients, 5242 diabetes patients, and 3633 CKD patients on the relative risk of bleeding events in these specific subgroups of patients receiving PCI. In this study, we found that bivalirudin is associated with a lower risk of major bleeding more significantly compared with heparin in high-risk patients.
Our results indicated that among female high-risk patients, bi- This systematic study confirmed that compared with the combination treatment of the heparin group, CKD patients receiving bivalirudin treatment were associated with a 41% relative risk reduction of major bleeding. There was one meta-analysis published that assesses CKD patients; this study extends previous studies and includes more recent trials. Several factors might explain the safety benefits of bivalirudin: (1) In patients with CKD, the elimination half-life of bivalirudin is prolonged from 25 min to 3.5 h. 37 (2) In PCI patients receiving heparin, chronic kidney disease is associated with a prolonged period of severe, continuously activated partial thromboplastin. 38 There was no significant difference in all-cause death and major bleeding between bivalirudin and heparin in patients with anemia.
Nearly 25% of patients who underwent elective PCI and 40% of patients who underwent PCI due to acute myocardial infarction have been proved to have baseline anemia. 39 Anemia is a common disease in PCI patients and is associated with significant increases in postprocedural death rate, reinfarction, and bleeding. 40   Although bivalirudin appeared to have a lower risk of major bleeding rate, the overall effectiveness and safety between the two groups showed no significant difference. Despite the usefulness of this study, there are still limitations. In our study, bivalirudin was associated with a reduction in the risk of major bleeding but not decreased rates of death or MACE in diabetes patients.
Clinical and methodological differences common to systematic reviews led to inevitable heterogeneity. The follow-up time of most studies was less than 2 years, and the long-term efficacy and safety cannot be observed. This may affect the conclusion to a certain extent, and further subgroup analysis is needed to determine it. Among these were the supplied drugs and administration protocols, procedural techniques, the severity of coagulation and embolism, facility expertise, and patient baseline characteristics. Firstly, the dosage and type of heparin were slightly different in these included clinical trials such as some patients were given enoxaparin and others were given unfractionated heparin.
Secondly, individual patient-level data were difficult to achieve, so that it is hard to further analyze the potential limitations. Finally, our cost data were retrieved from published literature which usually needs further confirmation by chart reviews, clinical trials, or real-world studies. These discrepancies might have been caused by the different including criteria in our meta-analysis. Subgroup analysis should also be performed to verify the final results for patients with or without insulin therapy.

| CON CLUS ION
This study suggests that bivalirudin in high-risk patients is associated with a significant reduction of major bleeding compared with heparin and may be a preferred substitute for heparin plus GPIs in high-risk patients. But heparin could be a potential cost-saving drug than bivalirudin in patients for PCI in China.

ACK N OWLED G EM ENTS
This study was supported by the National Nature Science

D I SCLOS U R E
There are no competing interests to declare.

AUTH O R CO NTR I B UTI O N S
K.X. and Y.D. conceived the study; S.S., F.Y., and Y.D. contributed toward the intellectual conception of the review; K.X. and B.C.
extracted and analyzed the data; K.X., B.C., and Y.D. wrote the first draft of the paper; W.J., J.W., and Y.D. revised the manuscript; F.Y. and J.W. supervised the study and contributed to writing the paper.

E TH I C A L A PPROVA L S TATE M E NT
Ethics approval was not required for this research.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data were derived from public domain resources. The data that support the findings of this study are available from the corresponding author upon reasonable request.