Rivaroxaban in patients with abdominal aortic aneurysm and high-sensitivity C-reactive protein elevation (BANBOO): study protocol for a randomized, controlled trial

doi:10.21203/rs.3.rs-2200813/v1

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Research Article

Rivaroxaban in patients with abdominal aortic aneurysm and high-sensitivity C-reactive protein elevation (BANBOO): study protocol for a randomized, controlled trial

https://doi.org/10.21203/rs.3.rs-2200813/v1

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published 19 Jun, 2023

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Background

Abdominal aortic aneurysm (AAA) is a fatal disease due to the propensity to rupture. The drug treatment for small AAA without surgical indications has been controversial. Previous studies showed that high-sensitivity C-reactive protein (hs-CRP) had become a potential biomarker of the disease, and the anti-inflammatory effect of rivaroxaban for AAA has been corroborated. Thus, we hypothesized that rivaroxaban could control the progression of AAA in patients with hs-CRP elevation.

Methods

The study is a prospective, open-label, randomized, controlled clinical trial. Sixty subjects are recruited from the General Hospital of Northern Theatre Command of China. Subjects are randomly assigned (1:1) to the intervention arm (rivaroxaban) or control arm (aspirin). The primary efficacy outcome is the level of serum hs-CRP at six months. The secondary outcomes include imaging examination (the maximal diameter of AAA, the maximal thickness of mural thrombus, and the length of aneurysm), major adverse cardiovascular and cerebrovascular events (MACCE, including AAA transformation, non-fatal myocardial infarction, acute congestive heart failure, stent thrombosis, ischemia-driven target vessel revascularization, vascular amputation, stroke, cardiovascular death, and all-cause death), other laboratory tests (troponin T, interleukin 6, D-dimer, and coagulation function).

Discussion

The BANBOO trial tested the effect of rivaroxaban on the progression of AAA in patients with elevated Hs-CRP for the first time.

Trial registration: ChiCTR2100051990, ClinicalTrials.gov, registered October 12, 2021.

Abdominal aortic aneurysm

High-sensitivity C-reactive protein

Rivaroxaban

Randomized controlled trial

Protocol

Abdominal aortic aneurysm (AAA) is a chronic progressive disease that occurs mainly among males above 65 [1]. The incidences of AAA for males and females over 60 years were shown to be 5% and 1% [2]. Smoking and hypertension could promote the rupture risk of an aneurysm. Mortality could rise to 50–80% once rupture [3]. The drug treatment for "small" AAA, defined as the maximal aortic external diameter between 30 and 55 millimeters, has been controversial for individuals without surgical indications [4]. There are two main controversial points: whether the progression of AAA can be delayed or prevented and whether the fatal rupture incidence of AAA can be reduced by medical treatment.

A large number of evidence indicate that aortic wall inflammation is pivotal to the pathogenesis of AAA [5]. To regulate the expression of inflammation-related genes is a promising strategy for inhibiting the progression of AAA. The inflammatory cytokine high-sensitivity C-reactive protein (hs-CRP) has been corroborated as a potential biomarker of AAA.⁵ Hs-CRP has been verified to predict cardiovascular risk and holds a positive correlation with the size of AAA [6]. The progression, expansion, and rupture of AAA could be diminished successfully by the exogenous anti-inflammatory drug [7–9].

Studies have shown that the average level of hs-CRP decreased significantly by rivaroxaban treatment from baseline to the endpoint of research [10, 11]. In addition, for the pro-inflammatory activity of factor Xa in arterial thrombosis, the direct inhibition of factor Xa by rivaroxaban may particularly benefit antithrombosis [12]. Rivaroxaban inhibits tissue factors, which induce platelet aggregation via inhibiting thrombin production [13]. G Monux et al. showed that factor Xa inhibitor rivaroxaban exerted anti-inflammatory and anti-oxidative stress properties in human AAA sites, suggesting a role of factor Xa in mechanisms associated with the pathogenesis of AAA [14].

Many preclinical studies suggested that rivaroxaban may have a beneficial effect on AAA.¹⁵ There have been extensive randomized controlled trials (RCTs) to evaluate the safety and efficacy of rivaroxaban in cardiovascular and cerebrovascular diseases (stroke prevention, venous protection, and vascular protection) [15]. For example, in the EINSTEIN study [16–18]. The risk of a recurrent event was significantly lower in the rivaroxaban group (10 to 20mg) than in the aspirin group, without a significant increase of bleeding events [19]. In the ATLASACS-TIMI46 study [20], the rivaroxaban group was superior in terms of net clinical outcomes (death, myocardial, stroke, or TIMI hemorrhage).

New oral anticoagulant rivaroxaban has the advantages such as convenient usage, predictable pharmacokinetic characteristics, no requirement for regular monitoring, accurate anticoagulant effect, and low risk of bleeding, especially intracranial hemorrhage [21, 22]. However, no specific medical therapy has been proven to slow the expansion rate of an abdominal aortic aneurysm, and therefore is not recommended (III, A) [23]. And blood pressure control, statins and antiplatelet therapy should be considered in all patients with abdominal aortic aneurysm (IIa, B) [23]. So we chose aspirin as comparator of rivaroxaban in this trial.

We hypothesized that rivaroxaban had a good control effect on the progression of AAA in patients with elevated hs-CRP, but there is no clinical study in this field from our current knowledge. The BANBOO study, a randomized controlled trial, will test this hypothesis and its results will guide clinical applications. (Fig. 1. Study concept.)

2.1 Objective

The primary objective is to explore the anti-inflammatory efficacy of rivaroxaban in the treatment of AAA with hs-CRP elevation, to investigate the application value of rivaroxaban for AAA. The secondary objectives are to analyze the safety of rivaroxaban for AAA and the efficacy of rivaroxaban on antithrombosis and alleviating inflammatory lesion.

2.2 Study design and setting

2.2.1 Study design

The BANBOO trial is a prospective, single-center, open-label, randomized, controlled clinical trial, conducted in the General Hospital of Northern Theatre Command of China. The protocol was designed to adhere to the recommendations of Standard Protocol Items for Randomized Trials statement (SPIRIT) [24]. The study is blind to statistical investigators. The research flowchart of the BANBOO trial is detailed in Fig. 2.

2.2.2 Timeline

The study is expected to last 18 months, including a 12 months enrollment period and a 6 months follow-up period.

2.2.3 Setting

Initial baseline assessment includes contact information, physical examination, vital signs, demographical data, previous history, clinical characteristics, admission diagnosis, imaging examination, and laboratory test data. Once a standardized interview is performed, the data will be recorded in the case report form (CRF) for each subject. Follow-up visits will occur at entry, 1-month, and 6-month after treatment initiation, and outcome data will be collected. Detailed collecting information on visits are listed in Table 1. An imaging subgroup is set up to analyze the effect of rivaroxaban on AAA morphology. All subjects screened, regardless of whether they are eligible for randomization, are provided with follow-up calls twice at 1 month and 6 months. Any interruption of treatments due to personal reason is required to report within 24 hours. Treatment should be discontinued immediately for the emergent situation, including trauma or urgent invasive procedures for the benefit of subjects.

Table 1

Collecting information on visits.
Follow-up	Baseline (Visit 1)	1 month (Visit 2, ± 7 days)	6 months (Visit 3, ± 7 days)
Inclusion/exclusion criteria	X
Physical examination	X
Vital signs	X
Inform Consent Form	X
Contact information	X
Demographic data	X
Previous history	X
Admitting diagnosis	X
Subject guidance	X
Drug therapy	X	X	X
hs-CRP	X	X	X
Imaging examination	X		X
MACCE		X	X
Other laboratory tests	X	X	X
Bleeding events (BARC)	X	X	X
Liver function	X	X	X
Renal function	X	X	X
Subject compliance		X	X
hs-CRP, high-sensitivity C-reactive protein; MACCE, major adverse cardiovascular and cerebrovascular event; BARC, Bleeding Academic Research Consortium.

2.2.4 Withdrawal

Subjects may voluntarily discontinue the study at any time. Other conditions that may lead to treatment suspension will be evaluated and determined by investigators.

2.3 Patient and public involvement

All patients screened, regardless of whether they are eligible for randomization, are documented in the patient database of the trial center, and provided with regular follow-up calls or face-to-face visits even post-trial. Before randomization, a training scheme for the eligible subjects and their relatives is initiated by professional investigators. The training covers the purpose and process of the BANBOO trial, possible benefits and potential risks, medication guidance, symptoms of adverse events (AEs), the necessity to contact doctors actively, subject's rights and responsibilities, and methods of disseminating the trial to other AAA patients. Researchers will answer the relevant questions from the subjects. Social media, such as Wechat, facilitate communication and connection between researchers and patients.

2.4 Training

Investigators and monitors will be trained in the research program, CRF, and regimen of research drugs. All training must be documented, including the revision of training materials, trained members, and training dates.

2.5 Recruitment

Via the internet (http://www.chictr.org.cn/index.aspx) and public places (such as the hospital bulletin board) to recruit, the purpose is to publicize the study so that suitable patients can be enrolled in time and smooth completion of this research and technical promotion can be ensured. The BANBOO trial began to recruit in October 2021.

2.6 Inclusion and exclusion criteria

The BANBOO study is designed to enroll 60 AAA subjects with hs-CRP elevation. Subjects aged 18 to 85 years, 30–50 mm in diameter of the aneurysm, serum hs-CRP ≥ 2mg/L are eligible for enrollment. Each enrolled subject should write informed consent before randomization. Complete inclusion and exclusion criteria are listed in Table 2 and Table 3.

Table 2

Inclusion criteria
Inclusion criteria
1. 18–85 years old;
2. AAA diagnosed by CTA, the maximal diameter of aneurysm is 30–50 mm;
3. Serum hs-CRP ≥ 2mg/L;
4. Written Informed consent.
AAA, abdominal aortic aneurysm; CTA, Computed Tomography Angioplasty; hs-CRP, high-sensitivity C-reactive protein.

Table 3

Exclusion criteria
Exclusion criteria
1. ACS (unstable angina and acute myocardial infarction); 2. Dual antiplatelet therapy for stable CHD less than six months after PCI or ACS less than 1 year after PCI; 3. Acute congestive heart failure or left ventricular ejection fraction ≤ 40%; 4. Suffer from infectious diseases within 2 months before screening and infection has not been controlled more than 1 month; 5. Active hepatitis, the elevation of alanine aminotransferase (ALT) value > 5×the upper limit of normal; 6. Severe renal failure (CrCl < 30 ml/min); 7. Life expectancy is less than 1 year; 8. Any situation may interfere with the research process, such as dementia, paralysis, alcoholism etc.; 9. Pregnancy or women during the suckling period; 10. Suffered from hereditary connective tissue disease, such as Marfan’s syndrome, etc.; 11. Known allergies or intolerance to aspirin or rivaroxaban; 12. AAA tends to rupture or has ruptured, and abdominal pain aggravates; 13. Major surgery within 1 month; 14. Active stage of severe peptic ulcer or previous bleeding events (including retinal or vitreous hemorrhage, urinary tract hemorrhage etc.) within 6 months; 15. Have participated in other ongoing clinical studies; 16. Refuse to write an informed consent; 17. Other unsuitable conditions adjudicated by investigators.
ACS, acute coronary syndrome; CHD, coronary heart disease; PCI, Percutaneous Coronary Intervention; CrCl, creatinine clearance rate, CrCl = Body weight(kg)×(140-age)/[0.818×CREA(µmol/L)][Serum creatinine (CREA) is tested by Enzymatic method. Female: Above data results ×0.85].

2.7 Screening and randomization

Asymptomatic AAA is screened by computed tomography angiography (CTA) to determine the diameter of aortic aneurysm (30-50mm). The maximal orthogonal AAA diameter on CTA is a measurement of infrarenal aortic diameter perpendicular to the lumen to avoid overestimation of the tortuous aorta. And then, the serum hs-CRP tests are performed in subjects with an eligible diameter of aortic aneurysm. Values of serum hs-CRP will be recorded at entry, 1 month, and 6 months. Immuno-turbidity is used to detect serum hs-CRP concentration. Eligible subjects are randomly assigned to the intervention arm (rivaroxaban) or control arm (aspirin) in a 1:1 ratio. The randomized numbers are generated by computer and placed in opaque envelopes. The subject who decides to withdraw from the study will no longer be admitted to enter, and the subject number will not be assigned again.

2.8 Treatment regimen

The study used aspirin as a control group, as recommended by the AAA guidelines. In the control arm, aspirin (100mg q.d.) is started at the time of randomization for 6 months. In the intervention arm, rivaroxaban (15mg q.d.) is formed at the time of randomization for 6 months; the rivaroxaban dose will be reduced to 10mg q.d. for the subjects aged over 75 years old. Both arms receive standard background therapy with pitavastatin 2mg daily orally, according to clinical guidelines.

2.9 Outcomes

The primary efficacy outcome is the level of serum hs-CRP at 6 months. The secondary outcomes include imaging examination (the maximal diameter of AAA, the maximal thickness of mural thrombus and the length of aneurysm), major adverse cardiovascular and cerebrovascular events (MACCE, including AAA transformation, non-fatal myocardial infarction, acute congestive heart failure, stent thrombosis, ischemia-driven target vessel revascularization, vascular amputation, stroke, cardiovascular death, and all-cause death), other laboratory tests (troponin T, interleukin 6, D-dimer, and coagulation function). Blood will be taken at entry, 1, 6 months to assess changes in circulatory indexes. CTA will be performed at entry and 6 months depending on local ethics guidelines. The safety outcomes include bleeding events defined according to the Bleeding Academic Research Consortium criteria (BARC), liver function (determined by alanine aminotransferase), and renal function (determined based on the creatinine clearance rate). Detailed endpoints are listed in Appendix A, and detailed definitions of endpoints are shown in Appendix B. Results of the BANBOO trial will be interpreted based on all endpoints.

2.10 Adverse events or harms

All AEs related to cardio-cerebrovascular, bleeding, liver, and renal damage were collected from the time subjects signed informed consent to the end of the study. The doctor should adopt the best treatment immediately after discovery and report to the Ethics Committee within 2 days of the occurrence.

2.11 Dissemination policy

Findings will be disseminated via peer-reviewed journals and conferences. The BANBOO trial was registered and recruited on the Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx).

2.12 Statistical considerations and sample size calculation

The primary endpoint analysis will be performed according to the intention-to-treat principle. The main aim of this study is to investigate whether rivaroxaban is superior to aspirin in reducing the level of serum hs-CRP in patients with AAA and hs-CRP elevation at 6 months. The null hypothesis (H0) for this analysis is that the level of the primary endpoint in the intervention arm is the same as that of the control arm, namely P0 = P1. The alternative hypothesis (H1) is that the levels of the primary endpoint in the two arms is not equal, namely P0 ≠ P1, and the superiority test is conducted at the 2-sided significance level of 0.05.

Continuous variables are presented as the mean ± standard deviation or the median with interquartile range and compared between two arms via T-test or Mann-Whitney-U test. Categorical variables are presented as counts and percentages and compared between two arms via χ² test. Kaplan-Meier curves and Log-rank tests are used to describe the cumulative incidences of MACCE and bleeding events. The differences in the risk of AAA between the two arms are estimated using a Cox proportional hazards model. A two-sided P < 0.05 is considered to be statistically significant. All statistical analyses are performed using SAS (Version 9.3) software.

Power calculations are based on a superiority comparison of the primary endpoint. Assuming the level of serum hs-CRP in the aspirin arm (control) is 4.79 ± 3.2 mg/L at 6 months, and taking the drop-out rate is 10%, 30 patients in each arm (60 in total) are planned to be enrolled and randomly assigned in a 1:1 ratio, to provide 90% power to detect a 2.54 mg/L absolute value reduction in rivaroxaban arm (intervention) in comparison with that in aspirin group with a 2-sided type I error of 0.05.

2.13 Data monitoring, collection, validation, and management

The data monitor was served by clinical trial experts who were not involved in this study. The monitor will check the data obtained from the trial and evaluate the arms of treatment. Monitors ensure that the trial team is conducting the study per the protocol. CRF is used for data collection. Data is entered into the database, and all data need to be entered by two investigators. All missing data needs to be accounted for and recorded in CRF. Investigators are required to sign off after completing the CRF. All data will be uploaded and updated on the Clinical Trial Management Public Platform (http://www.medresman.org.cn/ login.aspx).

2.14 Other expected conditions

2.14.1 Drug overdose

Suppose an overdose occurs during the study period. In that case, the investigator shall immediately notify the study leader and the principal investigator within 24 hours of the discovery of the overdose but no later than the second business day.

2.14.2 Pregnancy

Based on study-eligible criteria, pregnant or would-be pregnant women are excluded from the study population. If unplanned pregnancy occurs during the study period, all pregnancies should be reported to the study leader and principal investigator; pregnant women should immediately discontinue research drugs and drop out of the study.

2.14.3 Biological specimens

Biological specimens should be exhausted or destroyed after statistical analysis.

2.15 Current status

The BANBOO trial was initiated to recruit patients in October 2021. The estimated duration period of the BANBOO trial is 18 months. The study is ongoing.

All subjects must be fully informed of the trial process and provide written informed consent. (Appendix C) The trial is being conducted in accordance with the Declaration of Helsinki of the World Medical Association. The BANBOO trial has been approved by the Medical Ethics Committee of the General Hospital of Northern Theatre Command of China [Ethics Approval Number: Y(2021)090, Appendix D]. Any amendments of protocol must be approved by Ethics Committee.

Researchers, ethics committees, monitors, and drug regulators will be allowed access to medical records and results. To protect patient privacy, subjects' personal information shall not be disclosed in any public report of this study results or to a third party without authorization.

Life-threatening AAA requires monitoring or treatment depending on the size of the aortic aneurysm and/or symptomatology [25]. The current research on conservative treatment of AAA involves several aspects, such as lifestyle change, exercise therapy, medications, etc. Quit smoking is critical to current smokers; regular aerobic exercise does not reduce AAA growth and rupture [26]. There is an urgent need for drugs to control aneurysm growth or rupture, but the results of RCTs have been disappointing. Several preclinical studies on statins suggested potential benefits for AAA, but the results have not been verified by RCT [27]. Regarding antiplatelet medication, ticagrelor showed no difference in growth rates compared with placebo in RCT [28]. Propranolol has not been corroborated as useful to reduce the growth rate of the aneurysm but increases side effects in the treatment arm [29]. There was no difference in growth rates among the perindopril, placebo, placebo plus amlodipine group in a randomized trial, even though a decrease of blood pressure was detected in both perindopril and amlodipine group [30]. RCTs of macrolides in the treatment of AAA have yielded conflicting results, and more further studies are required [31–33].

Lacking effective drugs to prevent the progression of AAA, the status quo has plagued researchers in this field [34]. Researchers continue to explore possible drugs to control AAA, and we are looking forward to exciting news from pending clinical studies (NCT04224051, NCT04723888, NCT02225756). Current guidelines, such as the National Institute for Health and Care Excellence (NICE) 2020 guideline on AAA: diagnosis and management of European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the Management of Abdominal Aorto-iliac Artery Aneurysms [35, 23], are limited in recommendations for conservative medical treatment for lack of solid evidence. Therefore, more data are needed to support the conventional treatment of AAA.

There has been increasing evidence that aortic wall inflammation is the primary pathogenesis of AAA [5]. Studies showed that elevated hs-CRP positively correlates with AAA diameter size [36–38]. The concept that “lower is better” for hs-CRP influenced current guidelines [39, 40]. A study of 75 male patients and a study of 435 patients corroborated the serum hs-CRP as a marker of progression and expansion of AAA [41, 42]. A research suggested that hs-CRP is a valuable biomarker to assess the evolution of calcification [43]. Wang Y et al. evaluated the correlation between hs-CRP and AAA through systematic review including prospective studies, retrospective studies, and cohort studies. The results suggested that hs-CRP may possibly be used as a diagnostic biomarker in AAA patients with medium to small aortic diameter but not in AAA patients with large aortic diameter [44]. Hs-CRP could be a potential biomarker of AAA and a promising strategy to control the progression of AAA [8].

Studies showed a significant decrease in mean hs-CRP levels from baseline to the end of rivaroxaban treatment [10, 11]. The role of factor Xa in arterial thrombosis is considered due to its pro-inflammatory activity. The anti-inflammatory effects of rivaroxaban, a direct factor Xa inhibitor, may be particularly beneficial in inhibiting arterial thrombosis [12]. Rivaroxaban indirectly inhibits tissue factor-induced platelet aggregation by inhibiting thrombin production.¹³ We hypothesize that rivaroxaban is a promising treatment strategy for small AAA with hs-CRP elevation. However, no clinical study of rivaroxaban in this field has been reported to date [45].

This study is a prospective, single-center, open-label, randomized controlled trial with a total sample size of 60 cases based on statistical calculation and the admission volume of patients with AAA in the research center. The study is blinded to the statistical investigator. The BANBOO trial is the first research to assess the efficacy and safety of rivaroxaban compared with aspirin in AAA patients with hs-CRP elevation.

AAA, Abdominal aortic aneurysm; hs-CRP, high-sensitivity C-reactive protein; RCT, randomized controlled trial; SPIRIT, Standard Protocol Items for Randomized Trials statement; CRF, case report form; CTA, computed tomography angiography; MACCE, major adverse cardiovascular and cerebrovascular event; BARC, Bleeding Academic Research Consortium criteria; AE, adverse event; NICE, National Institute for Health and Care Excellence; ESVS, European Society for Vascular Surgery.

Acknowledgment

None.

Disclosure

All researchers declare no conflicts of interest. Each author has approved the final article manuscript they have contributed to the research, design, preparation, and execution.

Author’s contribution

Xiaozeng Wang and Jingyuan Li conceived and designed the protocol. Tienan Zhou and Lei Zhang reviewed and commented on the intellectual content. Jingyuan Li, Sicong Ma, Xiu Jia, and Yingzhen Bu contributed to the development of the original study protocol. Miaohan Qiu and Sicong Ma analyzed and executed the statistical method and sample size calculation. Jingyuan Li drafted the protocol manuscript. All authors revised and approved the final version of the manuscript. Xiaozeng Wang is the study leader.

Data statement

All data of the BANBOO trial will be uploaded and updated on the Clinical Trial Management Public Platform (http://www.medresman.org.cn/login.aspx). All data will be reserved and analyzed in the database of the contract research organization.

Funding

The BANBOO trial was funded by the “Xingliao Talents” Program of Liaoning Province (No. XLYC2008004, Appendix E).

Wang Y, Ait-Oufella H, Herbin O, Bonnin P, Ramkhelawon B, Taleb S, et al. TGF-beta activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II-infused mice. J Clin Investigat. 2010;120(2):422–32.
Ijaz T, Sun H, Pinchuk IV, Milewicz DM, Tilton RG, Brasier AR. Deletion of NF-kappaB/RelA in Angiotensin II-sensitive mesenchymal cells blocks aortic vascular inflammation and abdominal aortic aneurysm formation. Arterioscl Thromb Vascul Biol. 2017;37(10):1881–90.
Isoda K, Akita K, Kitamura K, Sato-Okabayashi Y, Kadoguchi T, Isobe S, et al. Inhibition of interleukin-1 suppresses angiotensin II-induced aortic inflammation and aneurysm formation. Int J Cardiol. 2018;270:221–7.
Song H, Xu T. Itaconate prevents abdominal aortic aneurysm formation through inhibiting inflammation via activation of Nrf2. E Bio Medicine. 2020;57:102832.
Jones GT, Phillips LV, Williams MJ, van Rij AM, Kabir TD. Two C-C, Family, Chemokines. Eotaxin and RANTES, Are Novel Independent Plasma Biomarkers for Abdominal Aortic Aneurysm. J Am Heart Assoc. 2016;5:e002993.
Paul M, Ridker. A Test in Context High-Sensitivity C-Reactive Protein. J Am Coll Cardiol. 2016;67:712–23.
Miralles M, Wester W, Sicard GA, Thompson R, Reilly JM. Indomethacin inhibits expansion of experimental aortic aneurysm via inhibition of the COX2 isoform of cyclooxygenase. J Vasc Surg. 1999;29:884–92.
Curci JA, Petrinec D, Liao S, Golub LM, Thompson RW. Pharmacologic suppression of experimental aortic aneurysms: a comparison of doxycycline and four chemically modified tetracyclines. J Vasc Surg. 1998;28:1082–93.
Bigatel DA, Elmore JR, Carey DJ, Cizmeci-Smith G, Franklin DP, Youkey JR. The matrix metalloproteinase inhibitor BB-94 limits expansion of experimental abdominal aortic aneurysms. J Vasc Surg. 1999;29:130–8.
Miyazawa K, Pastori D, Hammerstingl C, Cappato R, Meng IL, Kramer F, et al. Left atrial thrombus resolution in non-valvular atrial fibrillation or flutter: biomarker substudy results from a prospective study with rivaroxaban (X-TRA). Ann Med. 2018;50:511–18.
Kirchhof P, Ezekowitz MD, Purmah Y, Schiffer S, Meng IL, Camm AJ, et al. Effects of Rivaroxaban on Biomarkers of Coagulation and Inflammation: A Post Hoc Analysis of the X-VeRT Trial. TH Open. 2020;4:e20–32.
Charles T. Esmon. Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost. 2014;111:625–33.
Perzborn E, Heitmeier S, Laux V. Effects of Rivaroxaban on Platelet Activation and Platelet-Coagulation Pathway Interaction: In Vitro and In Vivo Studies. J Cardiovasc Pharmacol Ther. 2015;20:554–62.
Moñux G, Zamorano-León JJ, Marqués P, Sopeña B, García-García JM, Laich de Koller G, et al. FXa inhibition by rivaroxaban modifies mechanisms associated with the pathogenesis of human abdominal aortic aneurysms. Br J Clin Pharmacol. 2017;83:2661–70.
Camm AJ. The Rivaroxaban Program and the Management of Unmet Needs in Thromboembolic Disease. Thromb Haemost. 2018;118(S 01):2–11.
Buller HR, Lensing AW, Prins MH, Agnelli G, Cohen A, Gallus AS, et al. Einstein-DVT Dose-Ranging Study investigators. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT Dose-Ranging Study. Blood. 2008;112:2242–7.
Buller HR. Oral rivaroxaban for the acute and continued treatment of symptom-matic venous thromboembolism. The Einstein-DVT and Einstein Extension Study (Abstract 187). ASH Annual Meeting Abstracts [online], http://ash.confex.com/ash/2010/webprogram/Paper32683.html (2010).
The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. New Engl J Med. 2010;363:2499–510.
Weitz JI. Rivaroxaban or Aspirin for Extended Treatment of Venous Thrombo- embolism. N Engl J Med. 2017;376:1211–22.
Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R, Misselwitz F, et al. ATLAS ACS-TIMI 46 study group. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet. 2009;374(9683):29–38.
ESC EACTS. European Association for Cardio-Thoracic Surgery. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. European Heart Journal. 2017,1–48.
Ding Y, Li X, Zhou M, Cai L, Tang H, Xie T, et al. Factor Xa inhibitor rivaroxaban suppresses experimental abdominal aortic aneurysm progression via attenuating aortic inflammation. Vascul Pharmacol. 2021 Feb;136:106818.
Wanhainen A, Verzini F, Van Herzeele I, Allaire E, Bown M, Cohnert T et al Editor's Choice - European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the Management of Abdominal Aorto-iliac Artery Aneurysms. Eur J Vasc Endovasc Surg. 2019 Jan;57(1):8–93.
Chan A-W, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin J, Dickersin K, Hróbjartsson A, Schulz KF, Parulekar WR, Krleža-Jerić K, Laupacis A, Moher D. SPIRIT 2013 Explanation and Elaboration: Guidance for protocols of clinical trials. BMJ. 2013;346:e7586.
Shaw PM, Loree J, Gibbons RC. Abdominal Aortic A. 2020 Nov 18. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan.
Myers J, McElrath M, Jaffe A, Smith K, Fonda H, Vu A, et al. A randomized trial of exercise training in abdominal aortic aneurysm disease. Med Sci Sports Exerc. 2014 Jan;46(1):2–9.
Wemmelund H, Høgh A, Hundborg HH, Thomsen RW, Johnsen SP, Lindholt JS. Statin use and rupture of abdominal aortic aneurysm. Br J Surg. 2014;101(8):966–75.
Golledge J, Pinchbeck J, Tomee SM, Rowbotham SE, Singh TP, Moxon JV, et al. TEDY Investigators. Efficacy of Telmisartan to Slow Growth of Small Abdominal Aortic Aneurysms: A Randomized Clinical Trial. JAMA Cardiol. 2020 Dec 1;5(12):1374-81.
Propanolol Aneurysm Trial Investigators. Propranolol for small abdominal aortic aneurysms: results of a randomized trial. J Vasc Surg. 2002;35(1):72–9.
Bicknell CD, Kiru G, Falaschetti E, Powell JT, Poulter NR, AARDVARK Collaborators. An evaluation of the effect of an angiotensin converting enzyme inhibitor on the growth rate of small abdominal aortic aneurysms: a randomized placebo-controlled trial (AARDVARK). Eur Heart J. 2016;37(42):3213–21.
Wang YD, Liu ZJ, Ren J, Xiang MX. Pharmacological therapy of abdominal aortic aneurysm: an update. Curr Vasc Pharmacol. 2017;16(2):114–24.
Karlsson L, Gnarpe J, Bergqvist D, Lindbäck J, Pärsson H. The effect of azithromycin and Chlamydophilia pneumonia infection on expansion of small abdominal aortic aneurysms – a prospective randomized double-blind trial. J Vasc Surg. 2009;50(1):23–9.
Anagnostakos J, Lal BK. Abdominal aortic aneurysms. Prog Cardiovasc Dis. 2021 Mar-Apr;65:34–43.
Golledge J, Moxon JV, Singh TP, Bown MJ, Mani K, Wanhainen A. Lack of an effective drug therapy for abdominal aortic aneurysm (Review Symposium). J Intern Med. 2020; 288: 6–22.
NICE guideline. Published: 19 March 2020. .
Folsom AR, Yao L, Alonso A, Lutsey PL, Missov E, Lederle FA, et al. Circulating Biomarkers and Abdominal Aortic Aneurysm Incidence: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2015 Aug 18;132(7):578 – 85.
Qin Y, Yang Y, Liu R, Cao X, Liu O, Liu J, et al. Combined Cathepsin S and hs-CRP predicting inflammation of abdominal aortic aneurysm. Clin Biochem. 2013 Aug;46(12):1026–9.
Wanhainen A, Bergqvist D, Boman K, Nilsson TK, Rutegård J, Björck M. Risk factors associated with abdominal aortic aneurysm: a population-based study with historical and current data. J Vasc Surg. 2005 Mar;41(3):390–6.
Ridker PM, Narula J. Will Reducing Inflammation Reduce Vascular Event Rates? JACC Cardiovasc Imaging. 2018 Feb;11(2 Pt 2):317–9.
Ridker PM, Koenig W, Kastelein JJ, Mach F, Lüscher TF. Has the time finally come to measure hs-CRP universally in primary and secondary cardiovascular prevention? Eur Heart J. 2018 Dec;7(46):4109–11. 39(.
Parry DJ, Al-Barjas HS, Chappell L, Rashid ST, Ariëns RA, Scott DJ. Markers of inflammation in men with small abdominal aortic aneurysm. J Vasc Surg. 2010 Jul;52(1):145–51.
De Haro J, Acin F, Bleda S, Varela C, Medina FJ, Esparza L. Prediction of asymptomatic abdominal aortic aneurysm expansion by means of rate of variation of C-reactive protein plasma levels. J Vasc Surg. 2012 Jul;56(1):45–52.
Garrafa E, Giacomelli A, Ravanelli M, Dell'Era P, Peroni M, Zanotti C, et al. Prediction of abdominal aortic aneurysm calcification by means of variation of high-sensitivity C-reactive protein. JRSM Cardiovasc Dis. 2016 Dec;6:5:2048004016682177.
Wang Y, Shen G, Wang H, Yao Y, Sun Q, Jing B, et al. Association of high sensitivity C-reactive protein and abdominal aortic aneurysm: a meta-analysis and systematic review. Curr Med Res Opin. 2017 Dec;33(12):2145–52.
Gurung R, Choong AM, Woo CC, Foo R, Sorokin V. Genetic and Epigenetic Mechanisms Underlying Vascular Smooth Muscle Cell Phenotypic Modulation in Abdominal Aortic Aneurysm. Int J Mol Sci. 2020;21:6334.

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published 19 Jun, 2023

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Editorial decision: Minor revision
07 Jun, 2023
Reviewers agreed at journal
11 Nov, 2022
Reviewers invited by journal
11 Nov, 2022
Editor assigned by journal
10 Nov, 2022
First submitted to journal
25 Oct, 2022

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Rivaroxaban in patients with abdominal aortic aneurysm and high-sensitivity C-reactive protein elevation (BANBOO): study protocol for a randomized, controlled trial

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Journal Publication

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Abstract

Figures

1. Background

2. Methods/design

2.1 Objective

2.2 Study design and setting

2.2.1 Study design

2.2.2 Timeline

2.2.3 Setting

2.2.4 Withdrawal

2.3 Patient and public involvement

2.4 Training

2.5 Recruitment

2.6 Inclusion and exclusion criteria

2.7 Screening and randomization

2.8 Treatment regimen

2.9 Outcomes

2.10 Adverse events or harms

3. Ethics Statement

4. Discussion

Abbreviations And Acronyms

Declarations

References

Supplementary Files

Status:

Journal Publication

Version 1