Rationale and Design of a Randomized Controlled Trial of Bivalirudin with a Prolonged High-Dose Infusion Versus Heparin Monotherapy During Primary Percutaneous Coronary Intervention in Patients with Acute ST-Segment Elevation Myocardial Infarction: The BRIGHT-4 Trial : Cardiology Discovery

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Rationale and Design of a Randomized Controlled Trial of Bivalirudin with a Prolonged High-Dose Infusion Versus Heparin Monotherapy During Primary Percutaneous Coronary Intervention in Patients with Acute ST-Segment Elevation Myocardial Infarction: The BRIGHT-4 Trial

Liang, Zhenyang1; Li, Yi1; Stone, Gregg W.2; Han, Yaling1,*

Author Information
Cardiology Discovery 2(4):p 226-230, December 2022. | DOI: 10.1097/CD9.0000000000000068
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Abstract

Rationale

Bivalirudin is a direct thrombin inhibitor, and its effective anticoagulant component is a hirudin derivative fragment.[1] By directly and specifically inhibiting the activity of factor IIa, bivalirudin exerts a reversible and transient anticoagulant effect, which has been associated with a lower incidence of bleeding events in many studies compared with traditional heparin therapy.[2,3] Early randomized trials in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) reported that bivalirudin has significant bleeding benefits and even lowered the cardiac death rate when compared with heparin.[4,5] However, more recent clinical trials and meta-analyses have shown conflicting results, with bivalirudin associated with similar or higher ischemic risk including myocardial infarction and stent thrombosis, and the bleeding benefit was no longer seen when platelet membrane glycoprotein inhibitors (GPI) were not routinely used.[6–9] Thus, recommendations for bivalirudin use were lowered to class IIb in the 2018 European Society of Cardiology/European Association of Cardio-Thoracic Surgery (ESC/EACTS) Guidelines on myocardial revascularization.[10]

This potential detrimental risk of bivalirudin may be associated with its short half-life (approximately 25 minutes).[11] Patients with STEMI have delayed absorption and bioavailability of P2Y12 receptor inhibitors including both clopidogrel and the more potent agents ticagrelor or prasugrel, not reaching their maximum platelet inhibition effects until 6 to 8 hours after administration.[12,13] Therefore, a “window period” with lack of antithrombotic effect may exist if the bivalirudin infusion is stopped immediately as it was in the early clinical trials in PPCI, placing patients in a hypercoagulable state. A meta-analysis preliminarily verified the above hypothesis, showing that most bivalirudin-related acute ST events occurred during the first few hours after PCI.[14] To address this issue, our team conducted the Bivalirudin in Acute Myocardial Infarction versus Heparin and GPI Plus Heparin Trial (BRIGHT) to explore the impact of peri-procedural bivalirudin administration on clinical outcomes for patients undergoing PPCI.[15] With 2194 recruited patients from 82 sites, our study pioneered the continuous high-dose (1.75 mg/(kg·h)) bivalirudin maintenance infusion treatment for 2 to 4 hours after the procedure, and found that with this regimen bivalirudin substantially reduced major bleeding events without increasing the risk of stent thrombosis compared with heparin with or without the routine use of a GPI, providing an important benefit for patients undergoing emergency PCI.[15] Although this strategy was also demonstrated in a post-hoc analysis of the randomized European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) and Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) trial (which examined multiple different bivalirudin and heparin regimens), it has not previously been tested in a randomized trial with sufficient sample size.

The BivaliRudin with prolonged high-dose Infusion durinG PPCI versus Heparin Trial 4 (BRIGHT-4) therefore aims to investigate whether bivalirudin with a 2- to 4-hour post-PCI high-dose infusion is superior to heparin monotherapy among STEMI patients undergoing PPCI with radial artery access (which further decreases major bleeding rates), with GPI in both arms reserved for procedural thrombotic complications, in reducing all-cause death or major bleeding in these high-risk patients.

General study design

BRIGHT-4 is a large-scale, prospective, multicenter, active drug-control, parallel-group, open-label, randomized trial. Bivalirudin will be used in STEMI patients undergoing an invasive PPCI strategy, with a prolonged high-dose infusion for 2 to 4 hours after PCI. Approximately 6000 patients will be enrolled in the current trial, and the control therapy will be heparin monotherapy. The use of GPI in both arms will be reserved for procedural thrombotic complications (provisional use). Follow-up will be performed at 30 days, 6 months, and 12 months after the randomization. The study flow chart is shown in Figure 1. The study is registered at Clinicaltrials.gov (Identifier: NCT03822975).

F1
Figure 1::
Study flow chart. BARC: Bleeding Academic Research Consortium; PCI: Percutaneous coronary intervention; STEMI: ST-segment elevation myocardial infarction.

Study population

The study will enroll 6000 STEMI patients undergoing PPCI who met the criteria for enrollment. Specific study inclusion and exclusion criteria are shown in Table 1.[16] Written informed consent will be obtained before screening. The trial was approved by the ethics committee at the General Hospital of Northern Theater Command (Shengyang, China) (NO. k-2018-3).

Table 1 - Inclusion and exclusion criteria of BRIGHT-4 trial.
Inclusion criteria
(1) Any age
(2) STEMI patients with symptom onset ≤48 h and planned primary PCI (STEMI defined as ST-segment elevation ≥1 mm in ≥2 contiguous leads or new LBBB, or persistent ischemic symptoms occurring in the presence of RBBB[17])
(3) Patients requiring staged revascularization of non-culprit vessels within 30 d may also be enrolled. In such cases, the antithrombotic agents and procedures in the staged PCI must be consistent with the index PCI, especially the peri-procedural antithrombotic agents including assigned heparin vs. bivalirudin, and the GPI tirofiban
(4) No contraindications for dual antiplatelet therapy, and dual antiplatelet agents must be administered according to current guidelines before PCI (loading doses and maintenance doses of aspirin and clopidogrel orticagrelor)
(5) The subject or legal representative has been fully informed, and written informed consent obtained
Exclusion criteria
(1) Not suitable for primary PCI as judged by the local physicians
(2) STEMI treated by thrombolysis
(3) Patients received heparin, LMWH, fondaparinux, bivalirudin, or GPI within 48 h before the index PCI
(4) Mechanical complications (such as ventricular septal rupture, papillary muscle rupture, or acute mitral regurgitation)
(5) Known allergy or contraindications to heparin, bivalirudin, aspirin, clopidogrel, or ticagrelor
(6) Patients are participating in other drug or device trials
(7) Patients whom the investigators consider inappropriate to participate in the study or those likely to be nonadherent to the study protocol during the follow-up period due to psychiatric disorders, alcoholism, or drug addiction
BRIGHT-4: BivaliRudin with high-dose Infusion durinG primary percutaneous coronary intervention versus Heparin Trial 4; GPI: Glycoprotein IIb/IIIa inhibitors; LBBB: Left bundle branch block; LMWH: Low-molecular weight heparin; PCI: Percutaneous coronary intervention; RBBB: Right bundle branch block; STEMI: ST-segment elevation myocardial infarction.

Randomization

Patients meeting all the inclusion criteria and none of the exclusion criteria will be assigned to the bivalirudin or heparin group via centralized randomization system after signing the informed consent.

Patients will be randomized to the bivalirudin or heparin group using a 1:1 allocation ratio with randomly varied block sizes of 4 and 6. The block sizes will not be revealed to the study sites. The electronic data capture (EDC) system will be used to randomize subjects. The EDC will assign a treatment arm for patients and specify the appropriate medication number for the package of investigational treatment to be dispensed to the patient.

Enrolled patients who do not meet the eligibility for randomization will not receive study drugs, and subsequent management strategies will be administered at their attending physicians’ discretion in accordance with the local standard of care.

Blinding

The trial is open-label. An independent clinical events committee (CEC) will adjudicate all relevant clinical events. The committee members and the CEC management team will be completely blinded to the randomized therapy, as well as any patient identifying information. The CEC will adjudicate the events based on pre-determined definitions. The study statistician will be blinded for the primary analyses.

Study medications and treatments

Study medications are listed in Table 2.

Table 2 - Study medications of BRIGHT-4 trial.
Study drug The form and dosage of drug Manufacturer
Zelang (bivalirudin) 0.25 g/bottle Jiangsu Hansoh Pharmaceutical Group Co., Ltd., Jiangsu, China
Heparin sodium injection (heparin) 12,500 U/2 mL Shanghai Pharma No.1 Biochemical Pharmaceutical Co., Ltd., Shanghai, China
BRIGHT-4: BivaliRudin with high-dose Infusion durinG primary percutaneous coronary intervention versus Heparin Trial 4.

Bivalirudin group

In the cardiac catheterization laboratory, an intravenous loading bolus dose of bivalirudin 0.75 mg/kg will be started before angiography, immediately followed by intravenous infusion of 1.75 mg/(kg·h) until 2 to 4 hours after PCI. Activated thrombin time (ACT) will be monitored 5 minutes after the first administration, and if the ACT is <225 seconds (Hemotec assay), an additional intravenous injection of 0.3 mg/kg of bivalirudin will be administered to ensure the re-checked ACT is ≥225 seconds.

The bivalirudin bolus loading dose is not affected by renal function. The bivalirudin maintenance infusion dose is reduced to 1.0 mg/(kg·h) for patients with estimated glomerular filtration rate (eGFR) <30 mL/min and to 0.25 mg/(kg·h) for patients on dialysis.

Heparin group

In the cardiac catheterization laboratory, an intravenous bolus injection of heparin 70 U/kg will be started before angiography. The ACT will be monitored 5 minutes after the first administration, and if the ACT <225 seconds (Hemotec assay), an additional intravenous injection of 1000 U heparin is administered, to ensure the re-checked ACT is ≥225 seconds.

Concomitant medications

Routine use of GPI during the procedure is not allowed. Intravenous or intra-coronary tirofiban is only allowed for target vessel slow blood flow, no-reflow, refractory thrombus or thrombosis complication during PCI. If necessary, intravenous tirofiban should be started with 10 to 25 μg/kg bolus infusion (>5 minutes) followed by 0.15 μg/(kg·min) maintenance infusion for up to 18 hours. For patients with eGFR <60 mL/min, maintenance dose is reduced to 0.075 μg/(kg·min). Intra-coronary injection of tirofiban should be 500 to 750 μg per injection, with repeated injection interval of 3 to 5 minutes with a cumulative dose no more than 1500 to 2250 μg.

Low-molecular weight heparin (LWMH) after PPCI can be administered at the operator’s discretion. A loading dose of aspirin 300 mg, and P2Y12 receptor inhibitor clopidogrel 300 or 600 mg or ticagrelor 180 mg shall be administered before the index PCI. Other medications will be prescribed according to current guidelines. Transradial or transfemoral approach and stent type will also be at the operator’s discretion (transradial preferred, the current standard of care for PPCI in STEMI in China).

Clopidogrel 75 mg per day or ticagrelor 90 mg twice per day for the 12-month maintenance dose will be administered. Aspirin 100 mg per day for chronic maintenance dose will be administered. Other medications shall be prescribed according to current guidelines.

Follow-up

Data collection will commence after the subject has provided informed consent. Data will include patients’ demographic information, laboratory tests, procedural characteristics, and medications. Follow-up visits or telephone contacts will be conducted by an investigator or site coordinator trained for the protocol and case report forms (CRF). Data required for analysis will be obtained as outlined in Table 3.

Table 3 - Data collection schedule of BRIGHT-4 trial.
Study procedures Visit 1 (PCI) Visit 2 (discharge) Visit 3 (30 days after PCI) Visit 4 (6 months after PCI) Visit 5 (12 months after PCI)
Window period 0 day ±7 days ±14 days ±30 days
Eligibility criteria X
Patient informed consent X
Randomization X
Medical history/demographics X
Vital signs X
Blood and urine routine test* X
Blood biochemical examination* X
Cardiac markers (including TnT or TNI/CK/CK-MB)* X
ACT test X
12-Lead ECG* X
Key symptom inspection X X X X X
Clinical assessment X X X X X
Concomitant medications X X X X X
Coronary artery angiography X
Cardiovascular events X X X X X
Adverse events X X X X X
*Routine tests; repeated tests during in-hospital period are at physicians’ discretion. “X” represents that the corresponding procedure has been carried out during this visit.
ACT: Activated thrombin time; BRIGHT-4: BivaliRudin with high-dose Infusion durinG primary percutaneous coronary intervention versus Heparin Trial 4; CK: Creatine kinase; CK-MB: Creatine kinase isoenzyme; ECG: Electrocardiogram; PCI: Percutaneous coronary intervention; TNI: Troponin I; TnT: Troponin T.

Primary and secondary endpoints and safety evaluations

The primary endpoint is the composite of all-cause death or Bleeding Academic Research Consortium (BARC) types 3 to 5 bleeding at 30 days. The definition of BARC bleeding types have been published elsewhere.[17] In brief, BARC types 3 to 5 bleeds are major bleeds defined as those requiring transfusion, surgical intervention, or are associated with a hemoglobin drop of at least 3 g/dL (type 3) or fatal events (type 5). The key secondary endpoints at 30 days, 6 months, and 12 months after randomization are listed in Table 4.

Table 4 - Primary and secondary endpoints of BRIGHT-4 trial.
Primary endpoints
All-cause death or BARC types 3–5 bleeding at 30 days after randomization
Secondary endpoints
(1) Net adverse clinical events (defined as a composite of all-cause death, recurrent myocardial infarction, ischemia-driven target vessel revascularization, stroke or BARC types 3–5 bleeding) at 30 days and 6 and 12 months after randomization
(2) The incidence of a composite of all-cause death or BARC types 2–5 bleeding at 30 days and 6 and 12 months after randomization
(3) Stent thrombosis (defined as definite or probable stent thrombosis according to Academic Research Consortium definition) at 30 days and 6 and 12 months after randomization
(4) Major adverse cardiac and cerebral events (defined as a composite of all-cause death, recurrent myocardial infarction, ischemia-driven target vessel revascularization, or stroke) at 30 days and 6 and 12 months after randomization
(5) BARC types 3–5 bleeding at 30 days and 6 and 12 months after randomization
(6) BARC types 2–5 bleeding at 30 days and 6 and 12 months after randomization
(7) Thrombocytopenia (defined as post-PCI platelet counts <150 × 109/L for patients with baseline platelet count >150 × 109/L) at 30 days after randomization
(8) The incidence of each individual event, including all-cause death, cardiac death, non-cardiac death, recurrent myocardial infarction, ischemic-driven target vessel revascularization, ischemia-driven target lesion revascularization, or stroke at 30 days and 6 and 12 months after randomization
BARC: Bleeding Academic Research Consortium; BRIGHT-4: BivaliRudin with high-dose Infusion durinG primary percutaneous coronary Intervention versus Heparin Trial 4; PCI: Percutaneous coronary intervention.

Adverse events of interest will be collected throughout the study period. All serious adverse events will be recorded from the time of obtaining informed consent throughout the study. Section 8 in the protocol gives more detailed information on adverse event data collection.

Sample size and statistical analysis

The study hypothesis is that a 2- to 4-hour post-PCI high-dose bivalirudin is superior to heparin monotherapy for the 30-day primary endpoint, a composite of all-cause death or BARC types 3 to 5 bleeding after PPCI in patients with STEMI. H0: PI = PC; H1: PI ≠ PC, α = 0.05 (2-sided); where PI denotes the primary endpoint rate in the bivalirudin group and PC is the primary endpoint rate in the control group. Power calculations are based on a superiority comparison for the primary endpoint, a composite of all-cause death or BARC types 3 to 5 bleeding at 30 days after primary PCI in patients with STEMI. Assuming the incidence of the primary endpoint in the heparin group is 3.3%[15] and assuming 1% loss to follow-up at 30 days, 3000 evaluable patients in each group (6000 in total) are planned to be enrolled and randomly assigned in a 1:1 ratio, to provide 80% power to detect a 1.2% absolute risk reduction (35% relative risk reduction) in the bivalirudin group compared with the heparin group with a 2-sided type I error of 0.05.[15]

Data will be analyzed using SPSS 22.0 (IBM Corporation, Armonk, New York, USA) software package. Two-sided t test with alpha level of 0.05 will be used. (1) Efficacy analysis: Intention-to-treat analysis set is used for efficacy analysis. Time-to-first event analyses will be performed with groups compared by the log-rank test. Between the 2 groups, all hypotheses will be tested using a 2-sided test at α = 0.05. P ≤ 0.05 will be considered statistically significant. Hazard ratios and 95% confidence intervals will be determined by Cox regression. Additional analyses will be performed in the per-protocol and PCI-treated populations. (2) Safety analysis: The safety analysis set will be used. All patients who receive any dose of study medications (heparin and bivalirudin) will be included.

Study organization and status

This trial is a physician-initiated study and is supported by the Chinese Society of Cardiology’s Foundation, and an investigator-initiated grant from Hengrui Pharma (Jiangsu, China). The sponsor is not involved in the study design or study processes, including site selection and management, data collection, and analysis or decision to submit for publication. The executive and steering committee of the study will be responsible for all the design and conduct of this study, all study analyses, drafting and editing of the manuscript, and its final contents.

The randomized control trial (RCT) was registered with the https://clinicaltrials.gov/ (Identifier: NCT03822975) on January 30, 2019, and the first patient was randomized on February 14, 2019. This RCT is expected to be completed by May 2023.

Ethical considerations

This trial was approved by the ethics committee and institutional review board at General Hospital of Northern Theater Command (Shenyang, China). The ethics review boards of each participating hospital agreed to their participation. The data collected will be held centrally in a specific database, only de-identified information can be used for analysis. Informed consent will be conducted by investigators with clinical research qualifications. After being fully informed of the protocol, the patient will sign the informed consent form. The protocol will be executed strictly according to Good Clinical Practice.

Conclusion

BRIGHT-4 is a large-scale, prospective, multicenter RCT that aims to compare the safety and efficacy of bivalirudin with a 2- to 4-hour post-PCI high-dose infusion versus heparin monotherapy in STEMI patients undergoing PPCI with radial artery access, with the goal of providing essential clinical evidence to select the optimal peri-procedural anticoagulation strategy for these high-risk patients. The findings of this trial will inform the global practice for the PPCI treatment of STEMI.

Funding

This trial is supported by the Chinese Society of Cardiology’s Foundation.

Author contributions

Zhenyang Liang participated in the writing and review of this article and approved the final draft of the protocol.

Yi Li participated in the research design and review of this article and approved the final draft of the protocol.

Gregg W. Stone participated in the research design and review of this article and approved the final draft of the protocol.

Yaling Han participated in the research design, writing, and review of this article and approved the final draft of the protocol.

Conflicts of interest

This study received an investigator-initiated grant from Hengrui Pharma (Jiangsu, China).

Dr. Stone has received speaker honoraria from Medtronic, Pulnovo, Infraredx; has served as a consultant to Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Abiomed, Ancora, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Cardiomech, Gore, Amgen, Adona Medical, Millennia Biopharma; and has equity/options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, Xenter. Dr. Stone’s daughter is an employee at IQVIA. Institutional disclosure: Dr. Stone’s employer, Mount Sinai Hospital, receives research support from Abbott, Abiomed, Bioventrix, Cardiovascular Systems Inc, Phillips, Biosense-Webster, Shockwave, Vascular Dynamics, Pulnovo and V-wave. The other authors have no disclosures.

Editor note: Yaling Han is the Editor-in-Chief of Cardiology Discovery. Gregg W. Stone is an Associated Editor of Cardiology Discovery. Yi Li is an Editorial Board Member of Cardiology Discovery. The article was subject to the journal’s standard procedures, with peer review handled independently by these editors and their research groups.

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Keywords:

Heparin; Bivalirudin; ST-segment elevation myocardial infarction; Primary percutaneous coronary intervention

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