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Surgery
Protocol
Peroperative administration of tranexamic acid in Roux-en-Y and one-anastomosis gastric bypass to reduce haemorrhage in patients with morbid obesity: protocol for randomised controlled trial (PATRY trial)
  1. Judith W H 't Hart1,2,
  2. Bo J Noordman1,2,
  3. Jeannine Palsgraaf-Huisbrink3,
  4. Martin Dunkelgrun2,
  5. Hans F Zengerink2,
  6. Erwin Birnie4,5,
  7. Marc J van Det6,
  8. Evert-Jan G Boerma7,
  9. Steve M M de Castro8,
  10. Eric J Hazebroek9,10,
  11. Barbara S Langenhoff11,
  12. Cornelis Verhoef1,
  13. Jan A Apers2
  1. 1 Department of Surgery, Erasmus University Rotterdam, Rotterdam, Zuid-Holland, The Netherlands
  2. 2 Department of Surgery, Franciscus Gasthuis en Vlietland, Rotterdam, Zuid-Holland, The Netherlands
  3. 3 Hospital Pharmacy, Franciscus Gasthuis en Vlietland, Rotterdam, Zuid-Holland, The Netherlands
  4. 4 Statistics and Education, Franciscus Gasthuis en Vlietland, Rotterdam, The Netherlands
  5. 5 Surgery, University Medical Centre Groningen, Groningen, Groningen, The Netherlands
  6. 6 Surgery, Ziekenhuisgroep Twente, Almelo, Overijssel, The Netherlands
  7. 7 Surgery, Zuyderland Medical Centre Heerlen, Heerlen, Limburg, The Netherlands
  8. 8 Surgery, OLVG Locatie West, Amsterdam, North Holland, The Netherlands
  9. 9 Surgery, Rijnstate Hospital, Arnhem, Gelderland, The Netherlands
  10. 10 Department of Surgery, Wageningen University and Research, Wageningen, Gelderland, The Netherlands
  11. 11 Department of Surgery, Elisabeth-TweeSteden Ziekenhuis, Tilburg, Noord-Brabant, The Netherlands
  1. Correspondence to Judith W H 't Hart; j.hart{at}franciscus.nl

Abstract

Introduction By implementation of Enhanced Recovery After Bariatric Surgery protocols and day-care surgery, early discharge poses a challenge if excessive bleeding occurs after bariatric surgery. Tranexamic acid (TXA) has demonstrated efficacy in other surgical fields and in bariatric pilot studies. This trial aims to assess the efficacy of peroperative administration of TXA in reducing haemorrhage in patients undergoing gastric bypass surgery.

Method and analysis This is a multicentre, phase III, double-blind randomised controlled trial in six high-volume bariatric centres in the Netherlands. A total of 1524 eligible patients, aged 18 years or older, undergoing primary gastric bypass surgery (either Roux-en-Y gastric bypass or one-anastomosis gastric bypass) will be randomised between TXA and placebo (1:1, variable block, stratified for centre, day-care/overnight stay and type of surgery) after obtaining informed consent (2.5% less haemorrhage, power 80%, 2-sided-α 0.05 and 10% dropout). Exclusion criteria are pregnancy, amedical history of acute bleeding (without cause), venous thrombotic events (VTEs), epilepsy, anticoagulant use and iatrogenic bleeding during surgery (aside from staple line). The primary outcome is postoperative haemorrhage requiring intervention within 30 days postoperatively. Secondary outcome measures are staple line reinforcement, blood loss, duration of surgery, postoperative haemoglobin, vital parameters, minor and major complications, side effects of TXA (nausea, hypotension and VTE), length of hospital stay and directly made costs.

Ethics and dissemination Written informed consent will be obtained from all participants. The protocol has been approved by the Medical Research Ethics Committees United, Nieuwegein, on 7 February 2023 (registration number: R22.102). Results will be disseminated through peer-reviewed publications and conferences.

Trial registration number NCT05464394

  • Bariatric Surgery
  • Thromboembolism
  • Obesity
  • Randomized Controlled Trial
  • Blood bank & transfusion medicine
  • Bleeding disorders & coagulopathies
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi-org.ezproxy.u-pec.fr/10.1136/bmjopen-2023-078853

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    Strengths and limitations of this study

    • This well-designed trial has reintervention as its primary outcome, which requires a large sample size (1524 patients) and distinguishes it from previous research.

    • This is a multicentre randomised controlled trial, which will contribute to improved generalisability of the results.

    • Study participants may experience a direct positive effect of tranexamic acid (TXA).

    • This study focuses solely on the administration of TXA in gastric bypass surgery.

    • Patients with a history of venous thrombotic events are excluded from the study to mitigate the hypothetical risk on thrombotic events associated with the use of TXA.

    Introduction

    Enhanced Recovery After Bariatric Surgery (ERABS) protocols often include short-term thrombosis prophylaxis and short length of hospital stay (LOS), aiming for early patient discharge.1 2 Although ERABS and day-care surgery have many benefits, it may negatively affect the possibility to diagnose haemorrhage due to the short observation window. Over time, haemorrhage has become the most common major complication, while faster mobilisation and ERABS reduce the risk of venous thromboembolic events (VTEs).3 Tranexamic acid (TXA), a plasminogen inhibitor, may reduce the risk of haemorrhage, as studies have already demonstrated its efficacy in reducing haemorrhage in coronary-artery surgery, shoulder and knee arthroplasty, and elective trauma surgery.4–7

    In a non-randomised study involving sleeve gastrectomy patients, TXA administration was associated with a significant reduction in the number of staple line bleeding points requiring intervention compared with the control group (bleeding points: 19 vs 46).8 The authors concluded that TXA can be a safe and cost-effective approach for reducing staple line bleeding. Our research group conducted a blinded explorative randomised controlled trial with 101 patients undergoing sleeve gastrectomy, randomised between TXA and placebo (sodium chloride 0.9%). Patients receiving TXA exhibited more stable vital signs, few minor complications related to haemorrhage and a shorter LOS.9 Additionally, no VTEs were observed in either group. Probably limited by the sample size, no definitive conclusions on reinterventions could be drawn. Previous study data suggest TXA may reduce reintervention rates after bariatric surgery; a reduction in reoperation rate was also demonstrated in cardiac surgery.4 10 11 Due to its potential, low costs and effectiveness in other surgical fields, TXA might be a cost-effective strategy for staple line bleeding prevention in all types of bariatric surgery.

    Previous studies have focused on TXA in sleeve gastrectomy, while haemorrhage rates range from 1.5% to 6.1% in Roux-en-Y gastric bypass (RYGB) and 2.3%–5.1% in one-anastomosis gastric bypass (OAGB).11–17 This trial aims to assess the effectiveness of peroperative administration of TXA in reducing postoperative haemorrhage requiring treatment in patients after RYGB and OAGB.

    Methods and analysis

    This is a multicentre, phase III, parallel-group double-blind randomised controlled trial in six high-volume bariatric centres in the Netherlands. The study will compare the outcomes of TXA vs placebo (allocation ratio 1:1) in patients with morbid obesity undergoing RYGB or OAGB. A summary of the trial registration information can be found in table 1 and online supplemental file 1.

    Supplemental material

    View this table:
    Table 1

    Trial registration information

    Eligibility and exclusion criteria

    Patients aged ≥18 years suitable for bariatric surgery according to national and international guidelines will be invited for study participation.18 19 In order to be eligible to participate, a subject must meet the following inclusion criteria: primary bariatric procedure, good knowledge of the Dutch or English language and written informed consent. Subjects with any of the following criteria will be excluded: pregnancy, iatrogenic bleeding during surgery (with the exception of bleeding originating from the staple line), a medical history of bleeding disorders, Wegener’s disease, sarcoidosis, spontaneous major acute bleeding, VTE (defined as pulmonary embolism or deep vein thrombosis), disseminated intravascular coagulation or any other coagulopathies, epilepsy, colour vision disorders, use of anticoagulant medication and heart failure or other conditions necessitating fluid restrictions.20

    Recruitment

    In the participating hospitals, approximately 500–1000 bariatric procedures are performed annually per centre, in which 40%–90% of patients receive RYGB or OAGB. With an expected inclusion rate of 1 out of 3 eligible patients and a projected 10% dropout rate, we estimate that 1524 patients will be included within a 12–24-month time frame (see ‘Sample size’ section). All eligible patients will receive written information alongside their outpatient clinic appointment, and the coordinating researcher will subsequently inform each patient about the study. Patients who express interest to participate will be asked to provide written informed consent (Appendix 1) and will be given at least 1 week to consider their decision. Recruitment started in April 2023, and closure is expected in September 2024.

    Treatment allocation and blinding

    At the outpatient clinic, the coordinating researcher will obtain informed consent and randomise patients between TXA and placebo, via computer Variable Block Randomisation4 6 8 software by Ciwit BV (Castor Electronic Data Capture (EDC)), with stratification for centre, day-care/overnight stay and type of surgery (figure 1). The patient, surgical team and all other caregivers involved in the patient’s care will be blinded. The coordinating researcher and hospital pharmacy will not engage in patient care and will not be blinded, in order to prepare individual infusion bags and in case unblinding is necessary (see for details online supplemental file 2).

    Supplemental material

    Figure 1
    Figure 1

    Flowchart abbreviations: TXA, tranexamic acid; RYGB, Roux-en-Y gastric bypass; OAGB, one-anastomosis gastric bypass; VTE, venous thrombotic event.

    Interventions

    In the intervention group, patients will receive a single dose of 1500 mg TXA (Cyklokapron) before the procedure’s induction. TXA exhibits a half-life of approximately 2–3 hours, with approximately 90% of the drug being excreted within 24 hours following intravenous administration.21–23 TXA will be dissolved in 100 mL sodium chloride 0.9% and administered intravenously in a time frame of 15–30 min, with a maximum of 100 mg/min. In the control group, patients will receive a placebo infusion containing 100 mL sodium chloride 0.9%, to be administered in the same time frame. The hospital pharmacy will prepare and label the investigational medicinal products according to the relevant Good Manufacturing Practice guidelines.24

    Two blood samples (one EDTA tube) will be obtained through venepuncture: the first in the week prior to surgery and the second between 8 hours and 16 hours after surgery. From both blood samples, haemoglobin testing will be performed in the hospital’s laboratory.

    Patients will receive prophylactic cefazolin (2 grams) in the preoperative area. Immediately thereafter, the study medication (placebo/TXA) will be administered, lasting 15–30 min. TXA has an onset time of 15–30 min, peaking around 2–3 hours.22 23 There is no option for open-label TXA administration during surgery. Induction of anaesthesia is expected to take 5–10 min, using remifentanil (100 µg), propofol titrated to effect (200–300 mg) and rocuronium bromide (30–40 mg). Approximately 25 min later, the first anastomosis will be created. During surgery, the patient receives remifentanil (10–30 mL per hour), propofol titration, morphine (10–15 mg) and ketamine (10–15 mg). For termination of anaesthesia, remifentanil and propofol will be discontinued, and sugammadex (100 mg) will be administered. The mean arterial pressure will be maintained ≥60 mmHg using titrated vasopressors (such as phenylephrine or ephedrine).

    Expert bariatric surgeons will use a staple device (ECHELON FLEX GST) and energy device (Harmonic) to create the gastric pouch and anastomoses. After the gastric bypass is performed without visible leaks, the staple line will be inspected under normotension and an abdominal pressure of 12 mmHg to identify potential haemorrhage. A step-by-step protocol, as described in the study protocol and online supplemental file 3, will be followed to ensure the proper evaluation of the staple line.25 In case of active bleeding along the staple line (blood pumping), reinforcement such as haemostatic clips (Ethicon Ligaclip) or sutures will be used, while fibrin sealant can be applied for passive bleeding (blood oozing). Patients with iatrogenic bleeding from another location than the staple line will be excluded from the study. Blood loss will be quantified by assessing the suction volume in the container and weighing gauzes. Postoperatively, patients will receive intravenous administration of sodium chloride 0.9% (≤500 mL per 24 hours) and (prophylactic) low-molecular-weight heparin (LMWH) 5000 units at least 6 hours after surgery. Patients will continue daily prophylactic LMWH until discharge. Patients will not receive LMWH preoperatively.26 Vital signs are assessed prior to mobilisation to minimise the confounding effects of movement-related pain on vital signs. If postoperative haemoglobin levels decrease by ≥1.5 points or ≥1.0 point with clinical symptoms of haemorrhage (such as light-headedness, fainting or tachycardia), the bariatric surgeon will be consulted, extra haemoglobin monitoring will be performed and additional open-label TXA will be administered if deemed necessary. For blood transfusion, the advanced trauma life support (ATLS) guidelines will be followed in haemodynamically unstable patients, whereas the 4-5-6 rule will be applied in stable patients.27 28 More details are provided in online supplemental file 2. As routine practice for haemorrhage, a CT scan or an endoscopy will be performe,d and diagnostic endoscopy, radiology intervention or laparoscopy will follow if necessary.29–31 Adverse events will be reported to the medical research ethics committee and to the national trial committee.

    Supplemental material

    Outcomes

    The primary outcome measure is postoperative haemorrhage requiring intervention (administration of packed red blood cells or surgical, radiological or endoscopic intervention) within 30 days. Secondary perioperative outcome measures include staple line reinforcement of the anastomosis (eg, (number of) haemostatic staple devices or sutures), use of fibrin sealant, blood loss and duration of primary surgery. Postoperative outcome measures include haemorrhage requiring intervention within 3 days, (delta) haemoglobin, heart rate, blood pressure, pain score (numeric rating scale 0–10),32 major complications within 30 days including the Clavien-Dindo classification (CD)≥III (especially haematemesis and/or melena) as well as blood transfusion (CD II), minor complications within 30 days evaluated with CD≤II, (especially (suspected) haemorrhage for which extra haemoglobin monitoring and/or TXA admission is needed), side effects of TXA (nausea, hypotension, seizures, number of VTE within 30 days), LOS and cost analysis (directly hospital-based expenses: including duration of hospital stay, unplanned revisits, additional diagnostic tests and additional therapeutic interventions within 30 days) (table 2).

    View this table:
    Table 2

    Schedule: assessment, study procedures and follow-up

    Data management

    Participant identification will be protected by using study numbers non-traceable to the patient’s identity. Only members of the research team will have access to the databases. All data will be retained for 25 years. The data, informed consent forms and adverse events will be monitored by a monitor that is appointed by the sponsor hospital’s research department. All primary and secondary outcomes will be prospectively registered in digital case report forms (Castor EDC).

    Withdrawal of patients

    Subjects are free to withdraw from the study at any time for any reason without consequences. The investigator can decide to withdraw a subject from the study for urgent medical reasons. A subject will be replaced if he/she withdraws consent after randomisation prior to surgery. Subjects who withdraw consent after surgery will not be replaced. Data from this latter group will remain in the analysis, and every effort will be made to acquire follow-up data, unless the patient explicitly prefers otherwise. In order to calculate the sample size, we have included an anticipated 10% withdrawal rate of included patients, based on our previous randomised trials (see ‘Sample size’ section).

    Sample size

    The power analysis (power, 80%; alpha, 5% two-sided) resulted in a required sample size of 2×685=1370 patients. We anticipated a dropout rate of 10%, leading to a total sample size of 1524 patients to be included. This is based on the hypothesis that 3.9% of patients require intervention (administration of packed red blood cells or surgical, radiological or endoscopic intervention) due to postoperative haemorrhage.11 14–17 19 Based on previous studies and our published trial, we expect a decrease in postoperative intervention for haemorrhage to 1.4% (a decrease of 2.5%) in patients who receive TXA peroperatively.10 20

    Statistical methods

    Outcomes will be described as absolute numbers with percentages for categorical variables and as means with SD for parameters with normal distribution. For skewed data, log transformation will be used, or median and IQR will be reported. All comparisons between treatment groups are reported as absolute differences or relative risk with 95% CIs and p values. For the primary outcome, differences in intervention rate will be tested using the χ2 test or Fisher exact test, when appropriate. The same analyses will be used for secondary outcomes with categorical data. Differences in continuous data will be tested using the independent sample t-test or Mann-Whitney U test, when appropriate. Linear or logistic regression analysis will be applied for sensitivity analysis. Data will be analysed following intention-to-treat (primary analysis) and per-protocol and as-treated principles (secondary analyses). Statistical significance will be assessed at a threshold of p<0.05 (two-sided). Efforts will be made to prevent missing data by contacting subjects who did not attend their follow-up visit. If needed (if >10% of a variable is missing), multiple imputations will be used for missing data. Statistical analyses will be performed using IBM SPSS V.28 (IBM Corporation, Armonk, New York, USA).

    Patient and public involvement

    Patients were not involved in the study design and were not consulted to develop patient-relevant outcomes. However, the patient association (Obesitas Vereniging) was invited to contribute to the writing and editing of the patient information document for readability and accuracy. The patient association will be provided with the results of the study, which they can disseminate among their members.

    Ethical and dissemination

    This study has obtained approval from the Medical Research Ethics Committees United (MEC-U), Nieuwegein (R22.102), and has been registered on ClinicalTrials.gov (NCT05464394) (online supplemental file 4). The amendment for two extra participating hospitals was approved on 11 July 2023 (A23.177/R22.102) (online supplemental file 5). The study will be conducted in compliance with the standards of Good Clinical Practice (GCP) principles, in agreement with the Declaration of Helsinki, Dutch law and the Medical Research Involving Human Subjects Act (WMO). The principal investigator (JA) will be responsible for patient recruitment, (follow-up) data collection, case report forms and adherence to the study protocol. Activities will be carried out in accordance with local hospital guidelines for data management. Secure collection of data will be performed using electronic data collection software Castor EDC (Ciwit BV, Amsterdam, v.8.51,c), which adheres to regulatory standards including GCP. Physicians (supervising) of the surgical team will notify the subjects about the ongoing study, and the coordinating investigator will inform the subjects about both treatment groups and ask for their consent using standard patient information letter and informed consent form (see ‘Recruitment’ section). Revisions to the protocol must be approved by MEC-U before implementation. Case record forms including data validation checks and change confirmations are created by Ciwit BV, Amsterdam, v.8.51 (Castor EDC), prior to the start of the study. Stratification, randomisation and allocation of individual trial subjects will also be performed via Variable Block Randomisation software by Ciwit BV. Results will be communicated via national and international conferences and publications in peer-reviewed journals.

    Supplemental material

    Supplemental material

    Discussion

    Haemorrhage is the most common major complication in bariatric surgery, varying between 1.5% and 6.1% after RYGB and 2.3%–5.1% after OAGB.11–17 The objective of this study is to assess the effectiveness of TXA in reducing postoperative haemorrhage in patients undergoing gastric bypass surgery.

    Various strategies have been investigated to prevent haemorrhage in bariatric surgery, such as stapler closure time before gastric dissection and different techniques of staple line reinforcement, but these approaches did not significantly reduce haemorrhage rates.33 34 In contrast, TXA has shown favourable outcomes in other surgical fields like cardiothoracic, shoulder and knee surgery.4 35 36 For general (non-topical) fibrinolysis in adults, intravenous TXA at a dosage of 15 mg/kg body weight in a sodium chloride solution is recommended and can be repeated.23 In this study, a fixed dosage of 1500 mg of TXA was chosen, considering the body weights of this population (mostly between 100 and 200 kg). Due to its limited volume distribution and affinity for aqueous environments, TXA is unlikely to provide additional benefits in this population at doses exceeding 1500 mg. A lower dose may reduce its effectiveness.37 Taking into account the half-life of TXA and the creation of anastomoses during surgery, TXA is administered just before surgery to facilitate better monitoring of intraoperative outcomes. As TXA is most effective during the initial hours and haemorrhage within 3 days carries a significant higher reoperation risk, haemorrhage requiring intervention within 3 days after surgery is a secondary outcome.38 39

    TXA administration may increase the risk of VTE, although the precise percentage remains unclear.23 However, in fast-track surgery, VTE incidence is <0.1%, and the previous explorative study comparing TXA with placebo reported no VTE cases.9 26 Furthermore, Fennern et al demonstrated that postdischarge heparin prophylaxis did not reduce VTE but increased bleeding rates significantly.40 Patients with risk factors for VTE (eg, previous VTE, thrombophilia and current anticoagulant therapy) will be excluded to minimise potential differences in VTE incidence between groups. Patients presenting suggestive VTE symptoms will undergo diagnostic testing and treatment if necessary. In order to minimise the variation in the risk of haemorrhage, a standardised thrombotic prophylactic protocol has been implemented. Preoperative thrombotic prophylaxis will not be administered, but postoperative prophylaxis will be administered until discharge, with guidance provided for postoperative mobilisation.41 Thrombotic prophylaxis will be stopped after discharge, as no increase in VTE has been seen in earlier research.26 40

    Various techniques for staple line reinforcement include oversewing, haemostatic clips or synthetic and biological materials (such as tissue sealants or polyglycolide and dehydrated bovine pericardium).42–44 To reduce variation in staple line reinforcement among surgeons, a guideline with a standardised step-by-step plan for reinforcement has been included in the protocol (online supplemental file 3). Moreover, patients will be stratified according to centre, day-care/overnight stay and type of surgery (RYGB or OAGB) to ensure equal distribution of TXA and placebo between groups. All centres aim to perform the surgical procedures according to previously published methods.45 In this study, additional tests such as prothrombin time, partial thromboplastin time and international normalised ratio will not be conducted, consistent with routine clinical practice.

    High-quality studies on the effect of TXA in bariatric surgery are limited. Based on the available literature, we hypothesise a relative risk reduction for haemorrhage of 64%.11 46 47 It should be noted that the present trial might be underpowered to show a lower than expected but potentially clinically relevant relative risk reduction.

    Outcomes will hold relevance for all bariatric clinics, particularly those using the ERABS protocol and conducting day-care surgery. The trial results will be disseminated through future publications.

    Protocol version

    Version 2.0, January 9th 2023

    Ethics statements

    Patient consent for publication

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    Supplementary materials

    Footnotes

    • Contributors JWH'tH and JAA will have full access to the finalised dataset upon completion of the trial. JWH'tH and BJN drafted the first version of this manuscript. JWH'tH, BJN, JP-H, MD, HFZ, EB, MJvD, E-JGB, EJH, SMMdC, BSL, CV and JAA participated in the study design and critically revised the manuscript. JWH'tH, BJN, JP-H, EB, MD and JAA drafted the original study protocol. JAA initiated the trial and is the principal investigator. All authors read and approved the final and revised manuscript and agreed to be accountable for all aspects of the work.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.