Efficacy and safety of rivaroxaban plus clopidogrel versus aspirin plus clopidogrel in patients with coronary atherosclerotic heart disease and gastrointestinal disease undergoing percutaneous coronary intervention: study protocol for a non-inferiority randomized controlled trial

The study is a prospective, single-center, non-inferiority, randomized controlled trial. A total of 1020 subjects will be recruited at the Section V of the Cardiology Department of the General Hospital of Northern Theater Command in China. To evaluate the efficacy and safety of rivaroxaban plus clopidogrel versus aspirin plus clopidogrel in patients with CHD and GID undergoing PCI. The study flow diagram is shown in Fig. 1. The SPIRIT Checklist is shown in Supplemental file 1 [12].

Eligible criteria are as follows: Patients 18 to 75 years of age with stable coronary atherosclerotic heart disease or non-ST segment elevation acute coronary syndromes (NSTE-ACS) combined with GID, Global Registry of Acute Coronary Events (GRACE) scores < 140 points, are considered to be enrolled. Patients with GIB or gastrointestinal ulcers that have healed for more than 12 months or the patients who take aspirin accompanied by uncomfortable but tolerable symptoms (e.g., stomachache, abdominal distension) are included. The diagnosis of gastrointestinal disease is determined by the physician based on the patient’s clinical symptoms, the result of the endoscopy, and previous medical history. GID is defined as acute or chronic gastritis, gastric mucosal erosion, GIB or gastrointestinal ulcer healing for 1–12 months, gastrointestinal dysfunction diagnosed by a specialist, or gastrointestinal tumor planning surgery. Patients who met any of the exclusion criteria are excluded. Main exclusion criteria include a GRACE score > 140 points in patients with non-ST segment elevation myocardial infarction (NSTEMI) or ST-segment elevation myocardial infarction (STEMI), severe renal insufficiency (creatinine clearance < 30 mL/min), and previous aspirin or rivaroxaban allergy.

Detailed inclusion and exclusion criteria are listed in Table 1. The subjects met all inclusion criteria and no exclusion criteria are eligible for this study after signing the informed consent form. The informed consent form is provided in Supplemental file 2. To ensure the safety of patients, we will continue to monitor and care for until the end of the study regardless of the reason why participants withdrew from the study. This trial will be terminated in case of any abundance of adverse events or intervention-related complications.

Advertisement through posters and an outpatient publicity board is used to identify potential participants to reach the required sample size.

Before randomization, all enrolled subjects are assessed for randomization. Subjects with any of the following conditions shall not be randomized: withdrawal of informed consent, voluntarily withdrawal from the trial, the investigator determining that random antithrombotic regimens cannot be accepted, and unwilling or unable to undergo PCI.

After the assessment, the subjects are getting a random number. Based on the number, subjects are randomized (1:1) to the experiment arm (rivaroxaban plus clopidogrel) or the control arm (aspirin plus clopidogrel) by the block randomization table. Two investigators enroll subjects. The random number was generated by an independent professional statistician using the SPSS 25.0 software. According to the order generates a random number and informs the number to the authorized doctor who obtains informed consent and decides the intervention. This trial is an open-label design. The investigators and the subjects know which drugs the subjects are using, but the independent event assessment committee and data analysts do not know which drugs the subjects are using.

Subjects assigned to the experiment arm should receive rivaroxaban 10 mg plus clopidogrel 75 mg daily. Subjects assigned to the control arm should receive aspirin 100 mg plus clopidogrel 75 mg daily. All subjects are given medication routinely for 6 months. If subjects had never or not routinely taken clopidogrel or aspirin in the pastor taken clopidogrel 75 mg or aspirin 100 mg daily routinely less than five days before inclusion, a loading dose of clopidogrel 300–600 mg or aspirin 300–600 mg should be given within 12 h before coronary angiography.

If GIB occurs during the study, antiplatelet drugs should be discontinued, endoscopic hemostasis under the condition of stable hemodynamics, and Proton Pump Inhibitors (PPI) drug treatment are performed. Three days after hemostasis, subjects are given clopidogrel 75 mg monotherapy daily as soon as possible if the gastric injury is localized or completely hemostatic, no active bleeding relapses, and hemoglobin remains above 90 g/L after blood transfusion. Five days after hemostasis, they return to the original treatment strategy after randomization. But if there is still a small range of active or occult bleeding and the hemoglobin fluctuates above 100 g/L on different days, subjects are given low molecular weight heparin. Seven days after hemostasis, they restore to the original treatment strategy after randomization, and low molecular weight heparin was discontinued at the same time.

After subjects provided informed consent and were enrolled in the study, the data collection is initiated. Investigators should collect information including demographic information, admitting examination, and laboratory tests.

At the follow-up visit of 30 days by telephone contact, investigators need to know about and record information as follows: (1) bleeding events, including location, time, treatment, hospitalization, and duration of hospitalization; (2) MACCE, including time of occurrence, treatment, hospitalization, and length of hospitalization; (3) reviewing concomitant medication with subjects; (4) informing subjects of the importance of compliance with study medication; (5) scheduling the next visit; (6) informing subjects and/or guardians to notify investigators of any adverse events.

At the follow-up visit of 6 months on-site, investigators should collect data as follows: (1) assessing MACCE; (2) assessing bleeding events, including location, time, treatment, hospitalization, and duration of hospitalization; (3) proceeding routine blood test and fecal occult blood test to observe whether the patient has gastrointestinal bleeding and other diseases; (4) reviewing concomitant medication with subjects. In terms of patient compliance with medication, the medication compliance of patients was judged by regular follow-up. At the follow-up visit of 30 days by telephone contact, investigators checked the amount of pills left by the subjects. During a 6-month on-site follow-up, pill boxes would be handed by subjects to check their medication compliance. At the end of the study, the physician decides whether subjects should be received which antithrombotic treatment and whether they should be received PPI and H2 receptor antagonists. Detailed schedule content is listed in Table 2. We will request consent for the review of participants’ medical records, and for the collection of blood samples to assess hematology (RBC, WBC, HGB, HCT, Plt) and fecal occult blood. Biological specimens collected from subjects will be used only for laboratory testing and will be destroyed safely when the test ends. No genetic or molecular analysis is scheduled.

The primary endpoint of the study is Bleeding Academic Research Consortium (BARC) type 2–5 bleeding events requiring medical intervention. The secondary endpoint is a composite of MACCE including all-cause death, cardiac death, nonfatal myocardial infarction, stent thrombosis, ischemia-driven target vessel revascularization, and stroke. Other endpoints include the separate components of the MACCE and BARC 3–5 bleeding. Detailed definitions of all study endpoints are provided in Supplemental file 3.

Adverse events (AEs), serious adverse events (SAEs), and harms from interventions will be collected and reported to CEC. Those events include bleeding events (BARC) and other serious adverse events (e.g., death, ischemia-driven target vascular revascularization, stent thrombosis, and myocardial infarction). Furthermore, the investigator will be reported to relevant regulatory bodies as needed, indicating expectedness, seriousness, severity, and causality.

Case Report Form (CRF) and entering the information into an electronic database will be completed by two investigators. They are double-checked by them each other. All the CRF on paper will be stored in a locked cabinet, using the phonetic initials of the name as the code name and access to the data is only available to those who are authorized by the principal investigator. All information collected in this study will be strictly protected to ensure the privacy of participants.

Based on the incidence of BARC type 2–5 bleeding in the GEMINI-ACS-1 [11] trial and OPT-CAD trial, provided that the incidence of BARC type 2–5 bleeding in the experiment arm and the control arm are both 6% at 6 months. A non-inferiority margin of 4.7% was estimated and based on a one-sided type 1 error of 2.5%, power of 85%, and a 10% drop-out rate, a total of 1020 patients was needed for adequate analysis. Sample-size determination was performed with SAS version 9.3.

The analysis of the primary endpoint that BARC type 2–5 bleeding events require medical intervention for 6 months based on intention-to-treat (ITT) and per-protocol (PP) population. The ITT population is all randomized subjects. All randomized subjects without major protocol violations, subjects who did not receive the assigned treatment, or did not receive any treatment belong to the ITT population. The PP population is fully in line with the study. The study will conduct subgroup analyses of primary and secondary endpoints based on gender, age, and diabetes in the ITT population. Multiple imputation will be performed to handle missing data. The main endpoints of the ITT population are analyzed and then reanalyzed in the PP population to support the results. The analysis of the composite of MACCE is based on the ITT population. Unless otherwise stated, all hypothesis tests are carried out at a bilateral significance level of 5%. To determine whether the efficacy and safety of rivaroxaban plus clopidogrel in patients with CHD and GID are not inferior to aspirin plus clopidogrel. The difference in the incidence of endpoints between the experiment group and the control group is less than or equal to the non-inferior effect value means an invalid hypothesis (H0, P0–P1 ≤  − 4.7%). The difference in the incidence of the primary endpoint between the two groups is greater than the non-inferior effect value remains an alternative hypothesis (H1, P0–P1 >  − 4.7%). The non-inferiority test is carried out at a significance level of 0.025 on one side. Statistical analyses were performed with SAS version 9.3.

The Clinical Events Committee (CEC) is composed of medical experts in the field of cardiology and gastroenterology. Committee members are responsible for reviewing all reported events and classifying those events. If necessary, CEC can request original information from the research center. Members are remaining blind to treatment assignments.

The study is monitored by an independent Data and Safety Monitoring Board (DSMB). All adverse events in this study will be reported to the DSMB, and they can request additional information as required. The DSMB will regularly check the endpoint events to identify the safety of the study. DSMB will supervise and manage the research scheme and data before the start of the study, mid-study, and after the end of the study. Based on the result of the review, the DSMB will provide a report about the safety of the study to the lead investigator. And based on safety data, the DSMB may recommend that the lead investigator modify or terminate the trial.

During the course of the trial, any formal modifications to the protocol or informed consent form will be agreed by the research team, approved by the Ethics Committee to implementation, and reported to participants if necessary. It will also be updated in the Clinical Trials Registry.

The results of the study will be disseminated to participants, the public, and other relevant groups through publications and presented at scientific conferences.