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Learn more: PMC Disclaimer | PMC Copyright Notice BMJ Open . 2026 Mar 30;16(3):e111695. doi: 10.1136/bmjopen-2025-111695 Search in PMC Search in PubMed View in NLM Catalog Add to search Temporary interruption versus maintenance of anticoagulation in polypectomy of colorectal lesions: study protocol for a multicentre randomised non-inferiority clinical trial POLYPHEM Lucía Majano Díaz Lucía Majano Díaz 1 Department of Gastroenterology and Hepatology, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS). Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain Find articles by Lucía Majano Díaz 1, 0 , Enrique Rodríguez de Santiago Enrique Rodríguez de Santiago 1 Department of Gastroenterology and Hepatology, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS). Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain Find articles by Enrique Rodríguez de Santiago , Mucosal Resection and Third-Space Endoscopy SEED Working Group , Mucosal Resection and Third-Space Endoscopy SEED Working Group 1, *, 0 , Henar Núñez Rodríguez Henar Núñez Rodríguez 2 Department of Gastroenterology, Hospital Universitario Río Hortega, Valladolid, Spain Find articles by Henar Núñez Rodríguez 2 , Daniel Pérez Corte Daniel Pérez Corte 3 Department of Gastroenterology, Hospital Universitario San Agustín, Aviles, Spain Find articles by Daniel Pérez Corte 3 , Miguel Ángel de Jorge Turrión Miguel Ángel de Jorge Turrión 4 Gastroenterology Department, Hospital Universitario de Cabueñes, Gijón, Spain Find articles by Miguel Ángel de Jorge Turrión 4 , Maria Pellisé Maria Pellisé 5 Department of Gastroenterology, Clínic Barcelona, Barcelona, Spain Find articles by Maria Pellisé 5 , Julia Martínez Ocón Julia Martínez Ocón 6 Department of Anesthesiology, Hospital Clinic de Barcelona, Barcelona, Spain Find articles by Julia Martínez Ocón 6 , Fausto Riu Pons Fausto Riu Pons 7 Department of Gastroenterology, Hospital del Mar, Barcelona, Spain Find articles by Fausto Riu Pons 7 , José Santiago García José Santiago García 8 Department of Gastroenterology, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Spain Find articles by José Santiago García 8 , Eva Barreiro Alonso Eva Barreiro Alonso 9 Department of Gastroenterology, Hospital Universitario Central de Asturias, Oviedo, Spain Find articles by Eva Barreiro Alonso 9 , Carlos Rodríguez Escaja Carlos Rodríguez Escaja 10 Department of Gastroenterology, Hospital Sierrallana, Torrelavega, Spain Find articles by Carlos Rodríguez Escaja 10 , Andrés Santos Rodríguez Andrés Santos Rodríguez 11 Gastroenterology, Hospital Universitario Principe de Asturias, Alcala de Henares, Spain Find articles by Andrés Santos Rodríguez 11 , Ángel Cañete Ruiz Ángel Cañete Ruiz 12 Department of Gastroenterology, Clínica Rotger Quirónsalud, Palma, Spain Find articles by Ángel Cañete Ruiz 12 , Alfonso Muriel Alfonso Muriel 13 Biostatistics Unit. 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Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain 2 Department of Gastroenterology, Hospital Universitario Río Hortega, Valladolid, Spain 3 Department of Gastroenterology, Hospital Universitario San Agustín, Aviles, Spain 4 Gastroenterology Department, Hospital Universitario de Cabueñes, Gijón, Spain 5 Department of Gastroenterology, Clínic Barcelona, Barcelona, Spain 6 Department of Anesthesiology, Hospital Clinic de Barcelona, Barcelona, Spain 7 Department of Gastroenterology, Hospital del Mar, Barcelona, Spain 8 Department of Gastroenterology, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Spain 9 Department of Gastroenterology, Hospital Universitario Central de Asturias, Oviedo, Spain 10 Department of Gastroenterology, Hospital Sierrallana, Torrelavega, Spain 11 Gastroenterology, Hospital Universitario Principe de Asturias, Alcala de Henares, Spain 12 Department of Gastroenterology, Clínica Rotger Quirónsalud, Palma, Spain 13 Biostatistics Unit. IRYCIS. CIBERESP, Hospital Universitario Ramón y Cajal, Madrid, Spain 14 Department of Medicine, Universidad de Alcalá, Alcala de Henares, Spain 15 Department of Gastroenterology, Hospital San Agustin de Aviles, Aviles, Spain 16 Department of Gastroenterology, Hospital Universitario de Cabueñes, Gijón, Spain 17 Department of Gastroenterology, Hospital Universitario Principe de Asturias, Alcala de Henares, Spain 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. ERdS: Olympus (educational and advisory roles), Apollo Endosurgery (educational activities), Adacyte Therapeutics (advisory), Norgine (congress fee), Creo Medical (advisory), 3D Matrix (research grant) and Casen Recordati (congress fee). AH-d-T: Consultant for Boston Scientific. Speaker for Norgine, Creo Medical, Olympus and Sonoscape. * Dr Enrique Rodríguez de Santiago; [email protected] 0 LMD and ERdS are joint first authors. Received 2025 Sep 30; Accepted 2026 Mar 4; Collection date 2026. Copyright © Author(s) (or their employer(s)) 2026. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group. 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: https://creativecommons.org/licenses/by-nc/4.0/ . PMC Copyright notice PMCID: PMC13052619 PMID: 41916623 Abstract Background Colorectal polypectomy plays a crucial role in reducing mortality from colorectal cancer. Postpolypectomy bleeding is the most common adverse event. Current European guidelines recommend a temporary suspension of anticoagulation for polypectomy, despite the lack of high-quality evidence supporting this practice. Recent data challenge this approach, suggesting that polypectomy without discontinuing anticoagulation is not only safe but may also reduce the incidence of thromboembolic events. Methods and analysis This multicentre, prospective randomised, endoscopist-blinded, investigator-initiated, non-inferiority clinical trial aims to compare the safety of temporary interruption versus maintenance of anticoagulation during polypectomy for colorectal lesions. A total of 481 patients on oral anticoagulant treatment (either vitamin K antagonists or direct oral anticoagulants), and scheduled for an elective colonoscopy for any indication, will be randomised in a 1:1 ratio to each group. Colonoscopy and polypectomy procedures will be conducted by experienced endoscopists at 11 Spanish hospitals. The primary outcome is clinically significant postpolypectomy haemorrhage, while the secondary outcomes involve evaluating the risk of thromboembolic events and other procedural-related variables. Non-inferiority will be assessed in the per-protocol population using an adjusted absolute risk difference margin of 10%. Ethics and dissemination The study protocol was initially approved by the Medical Ethics Committee of Hospital Clínico San Carlos, Madrid, Spain (approval number: 24/330-EC_M). According to Spanish legislation on clinical trials, approval by a single CEIm is sufficient for multicentre studies and is recognised by all participating centres. The decision of the approving ethics committee is therefore applicable to all study sites. All participants will provide written informed consent prior to enrolment. The results of this study will be disseminated through publication in a peer-reviewed scientific journal and presentation at relevant national and international gastroenterology and endoscopy conferences. Trial registration number NCT07185295 . Keywords: Anticoagulation, Thromboembolism, Endoscopy, Gastrointestinal tumours, Cardiovascular Disease, Anaesthesia in cardiology STRENGTHS AND LIMITATIONS OF THIS STUDY. This is a multicentre, prospective, randomised non-inferiority clinical trial designed to address an important evidence gap in periprocedural anticoagulation management during colorectal polypectomy. The study includes both vitamin K antagonists and direct oral anticoagulants, enhancing the external validity and applicability of the results to routine clinical practice. Endoscopist blinding and centralised randomisation reduce performance and selection bias. The primary outcome is patient-centred and clinically relevant, based on internationally accepted definitions of postpolypectomy haemorrhage. Limitations include the expected low number of large colorectal lesions and heterogeneity in anticoagulant type, which will be addressed through stratified randomisation, predefined subgroup and adjusted analyses. Background Polypectomy of colorectal lesions is key in reducing mortality from colorectal cancer, emerging as the most common endoscopic procedure in endoscopy units. 1 Postpolypectomy haemorrhage stands out as the most common adverse event, with an estimated incidence of 0.29% per polyp and 0.44% per colonoscopy in population studies. 2 Anticoagulation represents a major risk factor, with the incidence in these patients ranging from 10% to 20%. 3 , 5 The prevalence of anticoagulated patients undergoing colonoscopy has risen in the last decade due to the ageing population and the expanded implementation of colorectal cancer screening programmes. 6 7 However, the temporary suspension of anticoagulation heightens the risk of thromboembolic events, even in patients with low thrombotic risk. 8 9 Previous studies have shown a 90-day incidence of thromboembolic events of up to 5.4%. 3 10 Furthermore, the morbidity and mortality associated with thromboembolic events has been proven to be significantly higher than endoscopy-related bleeding. 3 Recent cohorts where anticoagulation was maintained during endoscopy reported a 0% risk of thromboembolic events at 30 days. 11 12 Some previous studies of limited sample size have demonstrated the safety of polypectomy without discontinuation of anticoagulation. In a 2019 non-inferiority clinical trial, patients treated with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) underwent cold snare polypectomy without discontinuation of anticoagulation, showing no increase in the risk of bleeding. 12 Observational studies also support the safe performance of hot snare polypectomy without discontinuation of anticoagulation, including mucosectomy procedures. 11 13 14 The latest clinical practice guideline from the Japanese Society of Endoscopy suggests not suspending VKAs for polypectomy, as long as the international normalised ratio (INR) is within the therapeutic range. 8 Although the evidence on DOACs is less robust, the prospective observational ENDOHEM study conducted by our group (n=1602) and other observational studies suggest that there are likely no clinically relevant differences in the risk of bleeding between VKAs and DOACs, 3 6 and DOACs may even have a lower risk of postpolypectomy haemorrhage. 5 10 Additionally, closing the resection defects with haemoclips has seemed to reduce the risk of postpolypectomy haemorrhage in anticoagulated patients. 15 The 2016 American Society of Endoscopy (ASGE), the British Society of Gastroenterology (BSG) and the 2021 European Society of Endoscopy (ESGE) guidelines recommend temporary discontinuation of anticoagulation for polypectomy with a low level of evidence. 16 However, temporary anticoagulation withdrawal has not shown a decreased risk of postpolypectomy bleeding. In fact, postpolypectomy haemorrhage typically occurs after a median of 4–7 days, several days after the resumption of anticoagulation. 17 Considering these complexities, we believe that this multicentre non-inferiority clinical trial is pertinent and constitutes a valuable means of generating high-quality evidence in this field. Methods and design Trial design and population The POLYPHEM (POLYP Hemorrhagic and thromboEMbolic risk balance) trial is a multicentre, prospective, randomised, endoscopist-blinded, investigator-initiated, non-inferiority clinical trial designed to compare temporary interruption versus maintenance of anticoagulation in polypectomy of colorectal lesions. The study will include patients receiving oral anticoagulant treatment (VKAs or DOACs), scheduled for an elective colonoscopy for any indication. Selection criteria are summarised in table 1 . The anticipated recruitment period is approximately 2 years, with an estimated recruitment rate of 20–25 patients per month. The study protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials guidelines. 18 Table 1. Inclusion and exclusion criteria. Inclusion criteria Exclusion criteria Older than 18 years. Undergoing an elective outpatient colonoscopy for any indication. With anticoagulant treatment with VKAs (acenocoumarol or warfarin) or DOACs (dabigatran, edoxaban, apixaban or rivaroxaban) prior to colonoscopy. Concomitant antiplatelet treatment. Age >85 years. Urgent colonoscopy. Labile INR (time in therapeutic range less than 60%) documented in the previous 3 months in patients receiving VKAs. Supratherapeutic INR (>3.5) at the time of the procedure in patients receiving VKAs. Pregnancy. Decompensated liver cirrhosis. Inability, in the opinion of the investigator, to understand the periprocedural anticoagulation regimen. Previously known coagulopathy or bleeding diathesis. Includes thrombocytopenia <50 000/µl in the previous 12 months. Scheduled endoscopic dilation. Severe psychiatric disorder. Removal of colorectal lesion by endoscopic submucosal dissection. Previous diagnosis of renal failure defined as creatinine >2 mg/dL or clearance <30 mL/min. Planned procedure of high haemorrhagic risk in gastroscopy performed simultaneously. Prior inclusion in the trial. Patients can only be included on one occasion. Any clinical situation or concomitant treatment that, in the opinion of the investigator, poses a significant risk of bleeding. Open in a new tab DOACs, direct oral anticoagulants; INR, international normalised ratio; VKAs, vitamin K antagonists. The study will be conducted in 11 tertiary and community hospitals across the national territory. Patient recruitment will occur during outpatient consultations, and the endoscopic procedures will be performed in conventional endoscopy rooms within the endoscopy units. Follow-up will be conducted via telephone or through in-person consultations. Table 2 and figure 1 present the visit calendar and study flowchart . Table 2. Visit schedule. Screening Preprocedure visit Procedure visit Telephone contact on day 7 and review of medical history Telephone contact on month 1 and review of medical history Visit number Visit 0 (V0) Visit 1 (V1) Visit 2 (V2) Visit 3 (V3) Calendar 0–16 weeks from V1 +7 days from V1 (−2/+5 days) +1 month from V1 (−4/+10 days) Evaluation of inclusion and exclusion criteria X Written informed consent X Collection of clinical history data X X X X Randomisation X Colonoscopy±polypectomy X Evaluation of: Postpolypectomy haemorrhage. Thromboembolic events. Other adverse events. X X X Collection of variables for carbon footprint analysis X X Open in a new tab V, visit. Figure 1. Study flowchart of the POLYPHEM trial, showing patient screening, randomisation, intervention allocation and follow-up. BSG, British Society of Gastroenterology; CRF, Case Report Form; DOAC, direct oral anticoagulant; eGFR, estimated glomerular filtration rate; ESGE, European Society of Endoscopy; VKA, vitamin K antagonist. Open in a new tab Study withdrawal criteria encompass instances such as the patient’s withdrawal of consent and/or refusal of treatment, lack of collaboration, the emergence of clinically relevant exclusion criteria affecting safety or a decision by the principal investigator to discontinue the study in the best interest of the patient. Protocol amendments are communicated as necessary to those involved in the trial. The clinical investigators will obtain informed consent during the initial outpatient study visit ( online supplemental file 1 ). The information disseminated and obtained from the implementation of this study is considered confidential and must be treated as such at all times. Study subjects will be identified only by their study subject code. Both the investigators responsible for the clinical trial and a representative of the sponsor or health authorities will have access to the information recorded throughout the study. In the event of publication of the study results, the identity of the volunteers will not be disclosed. Authorship will adhere to International Committee of Medical Journal Editors guidelines. Patient and public involvement Patients and the public were not involved. Intervention and procedures Enrolled patients will undergo randomisation into two groups: the study group, where anticoagulant maintenance will occur and the control group, where anticoagulation will be temporarily suspended. In the study group, patients on VKAs will continue their medication, ensuring that the INR is within the therapeutic range (<3.5) within 24 hours of the intervention. Patients receiving DOACs will only omit the dose on the morning of the procedure, without any additional modifications to their treatment. This strategy is considered pharmacological continuation rather than interruption, as therapeutic anticoagulant levels persist. For the control group, anticoagulation will be temporarily suspended, following the recommendations outlined in the BSG-ESGE 2021 clinical practice guideline. 16 Dosing modifications will be based on the patient’s thrombotic risk, as specified in the guideline (see table 3 ). 16 The investigator will provide a detailed explanation of the anticoagulation procedure to the patient and deliver an informational sheet containing all relevant details. Table 3. Management of anticoagulation in the control group. Thrombotic risk VKA DOAC HIGH Stop VKA 5 days before. * Start LMWH 2 days later: 1 mg/kg every 12 hours. Last LMWH dose 24 hours before the procedure. Check INR <1.5 before colonoscopy. Restart VKA late-night colonoscopy. Restart LMWH in the morning of the day after the procedure: 1 mg/kg every 12 hours. On day+5-7 check INR and need to continue LMWH. Last DOAC dose 3 days before colonoscopy. Restart: Without polypectomy: day of the procedure. With polypectomy: day+2. LOW Stop VKA 5 days before. * Check INR <1.5 before colonoscopy. Restart VKA late-night colonoscopy. Last DOAC dose 3 days before colonoscopy. Restart: Without polypectomy: day of the procedure. With polypectomy: day+2. Open in a new tab * In patients with acenocoumarol withdrawal time will be adapted. DOAC, direct oral anticoagulant; INR, international normalised ratio; LMWH, low molecular weight heparin; VKA, vitamin K antagonist. Polypectomy of colorectal lesions will be performed following clinical practice guidelines by experienced endoscopists (>5000 colonoscopies). 15 19 The choice of electric current type and the polypectomy snare used will be left to the discretion of the performing endoscopist. In accordance with the study protocol, only polyps measuring less than 4 cm identified in the patient will be resected. Polypectomy of lesions >4 cm will be deferred until completion of the 30-day follow-up period to minimise bleeding risk, given the limited safety data for large lesions in anticoagulated patients, the higher risk of clip-closure failure and the recommendation that such lesions be managed electively by specialised endoscopists. 20 The rest of the patient’s polyps smaller than 4 cm with an indication for resection, up to a maximum of 10 polyps, will be removed during the procedure. Prophylactic clipping will be standardised for pedunculated polyps with head >20 mm or pedicle >5 mm and flat-sessile polyps >20 mm. 15 19 An attempt will be made to achieve complete closure of the scar (mucosal apposition of the edges) and interclip distance ≤1 cm. Injection of the stem with epinephrine will also be standardised prior to polypectomy in pedunculated polyps. Haemostatic gels or powders can be used in case of clip closure failure, according to the physician criteria. Outcome variables Primary outcome: occurrence of clinically significant postpolypectomy haemorrhage at 30 days. The definition is patient-centred and based on recommendations from the ASGE, ESGE and the International Society on Thrombosis and Haemostasis. 16 21 22 A patient will be considered to have clinically significant haemorrhage if they present at least one of the following two events: Clinically significant intraprocedural haemorrhage: major bleeding during colonoscopy that requires suspension of the procedure, a drop in haemoglobin >20 g/L, transfusion, interventional radiology, hospital admission, surgery or death. 12 Delayed clinically significant haemorrhage: lower gastrointestinal bleeding that occurs within 30 days after the completion of the colonoscopy and requires an emergency department visit, hospitalisation or an intervention (endoscopy, interventional radiology or surgery). Secondary outcomes: thromboembolic events as defined by the American College of Cardiology and the American Heart Association Task Force on Clinical Data Standards 24 from 5 days prior to the colonoscopy to day+30. 23 We will also record polyp-related and procedural-related outcomes, clinically non-significant intraprocedural haemorrhage (bleeding that persists for more than 1 min, requires endoscopic treatment and does not meet the criteria for clinically significant intraprocedural haemorrhage) and death. As an additional objective, we also aim to explore whether maintaining anticoagulation reduces the carbon footprint (Kg CO2e). Randomisation Eligible patients will be centrally randomised 1:1 into either maintaining or suspending anticoagulation, facilitated by the Research Electronic Data Capture from the Spanish Association of Gastrointestinal Endoscopy (REDCap-SEED) online electronic platform. This tool has electronic randomisation systems validated in previous studies that guarantees allocation concealment. This database complies with current regulations on the Protection of Personal Data (Regulation (European Union) 2016/679 of the European Parliament and of the Council of 27 April 2016, on General Data Protection Regulation (GDPR) and Organic Law 3/2018, of 5 December, on Personal Data Protection and Guarantee of Digital Rights). The randomisation sequence, generated by the statistician before the trial commences, will be implemented on the day of the pre-endoscopy visit by the collaborating investigator doctor. Each centre will use block randomisation, with permuted block sizes known only to the statistician and not disclosed to the participating researchers. Stratification during randomisation will consider the type of anticoagulant drug (VKAs or DOACs) and age (<75 years, ≥75 years). The study monitor will oversee the randomisation process. Blinding Blinding will be implemented for the endoscopists performing the procedures and the statistician. To ensure the integrity of blinding, the roles of collaborating researchers were predefined, clearly separated and non-interchangeable throughout the study. A minimum of three collaborating researchers at each centre is required for this study: the investigator who includes and randomises the patient (aware of the treatment arm), the researcher evaluating the precolonoscopy INR in patients on VKAs and recording the time since the last dose of anticoagulant (aware of the treatment arm), and the endoscopist. The investigator responsible for patient inclusion and randomisation is never involved in the endoscopic procedure. The endoscopists have no role in treatment allocation or periprocedural management decisions. Blinding is operationalised through multiple complementary procedures. First, within the REDCap-SEED platform, user-specific access restrictions are implemented by the platform manager. Investigators assigned the role of endoscopist have masked access, which prevents visualisation of the intervention arm in all electronic case report forms. Only the recruiting investigator and the investigator responsible for periprocedural anticoagulation management have access to treatment allocation data. Second, treatment allocation is not recorded in the patients’ medical records, ensuring that endoscopists cannot infer group assignment from routine clinical documentation. Third, the preprocedural visit, including verification of INR values in patients on VKAs and assessment of adherence to the periprocedural anticoagulation regimen, is conducted by an investigator distinct from the endoscopist. Fourth, patients are explicitly informed that the endoscopist is blinded to the intervention assignment and are instructed not to disclose any information regarding their periprocedural anticoagulation management unless explicitly requested by the medical team for justified clinical reasons. Blinding may be compromised in cases of clinically significant intraprocedural haemorrhage that cannot be controlled endoscopically, is associated with haemodynamic instability or requires urgent intervention. In such instances, the endoscopist will contact the collaborating researcher who has verified the adequacy of the periprocedural regimen. The reintroduction of anticoagulation may be modified at the discretion of the responsible medical team based on the clinical situation. Similarly, blinding may be lifted in the event of any haemorrhagic or thromboembolic event where knowledge of the intervention received is necessary for optimal clinical management, according to the researcher’s criteria. Sample size calculation The sample size calculation is based on the per-protocol population outlined later, considering a one-sided alpha significance level of 0.025, a power of 90% and accounting for a non-inferiority margin of 10%, with an estimated drop-out rate of 5% loss. Drawing insights from the ENDOHEM observational study from our group, which assessed the safety of endoscopy in anticoagulated patients, it is estimated that 60% of patients will undergo polypectomy and the percentage of clinically significant postpolypectomy haemorrhage will be 7% in both groups. 3 12 Consequently, the estimated total sample size is 481 patients (241 per group). Additional details are provided in the Statistical Analysis Plan (SAP) ( online supplemental file : POLYPHEM SAP). Non-inferiority margin The non-inferiority margin was pre-specified as an absolute risk difference of 10 percentage points and was defined during two formal online consensus meetings among the collaborating investigators held prior to trial initiation. This decision was primarily based on the clinical acceptability of the primary safety endpoint (clinically relevant bleeding), considering its usual clinical course, frequent self-limitation, effective endoscopic rescue options and very low mortality in contemporary practice. Formal effect-preservation approaches (fixed-margin, point-estimate or synthesis methods) were not considered appropriate, as no placebo-controlled evidence exists for periprocedural anticoagulation strategies and the endpoint reflects safety rather than efficacy. Secondarily, the selected margin was contextualised within a quantitative risk–benefit framework, acknowledging the potential trade-off with thromboembolic events, which carry substantially greater morbidity and mortality. Full methodological justification and statistical details are provided in the SAP. Statistical analysis A per-protocol and modified intention-to-treat (ITT) analysis will be performed. The per-protocol analysis is considered the primary analysis of the trial. The non-inferiority analysis will be performed by estimating the 95% CI of the adjusted absolute risk difference. To account for the stratified, multicentre design and the expected low event rate, the analysis will use a random intercept (mixed-effects) logistic regression model. The adjusted risk difference and its two-sided 95% CI will be derived from this model using marginal standardisation. If the upper limit of the 95% CI of the adjusted risk difference does not exceed 10%, non-inferiority of the experimental arm will be declared. In the per-protocol analysis, the population will include patients who, after randomisation, fulfilled all the following criteria: correct implementation of the assigned periprocedural anticoagulation regimen, performance of one or more polypectomies and complete 30-day follow-up (or until the ocurrence of the primary outcome). Patients with major protocol deviations in the anticoagulation management, those who did not undergo polypectomy or those with incomplete follow-up for the primary outcome will be excluded from the per-protocol analysis. A modified ITT analysis will be performed as a supportive analysis and will include all randomised patients who initiate anticoagulation discontinuation, analysed according to their assigned group, irrespective of protocol adherence, performance of polypectomy or completion of follow-up. This population will exclude patients who are found to violate eligibility criteria after randomisation or who withdraw consent after enrolment. Missing outcome data will primarily be addressed within the ITT framework. Further statistical details can be found in the SAP. Secondary analysis to compare the incidence of thromboembolic events will be performed using mixed effects logistic regression. The following subgroup analyses have been planned through first-order interactions: polyp size (<10 vs ≥10 mm; <20 vs ≥20 mm), right colon versus left colon, sessile versus pedunculated morphology, polypectomy with diathermy snare versus cold snare and intraprocedural bleeding versus delayed bleeding, clipping (complete closure vs no closure-partial closure), as well as stratification variables. Secondary and subgroup analysis will not adjust p values for multiple comparisons, so they should be considered exploratory. An intermediate analysis will be performed after the inclusion of 50% of the sample to evaluate safety, as required by the Ethics Committee. An external Data Monitoring Committee will evaluate safety and decide if the trial can continue until the planned sample size is reached. No formal statistical stopping rules for safety or efficacy are planned. Based on an overall clinical review of bleeding and thromboembolic events, this committee will be responsible for recommending continuation, modification or termination of the trial for safety reasons. The carbon footprint analysis will be conducted by the company Outcomes 10 using modelling tools. The primary variable will be the kilogram equivalent of carbon dioxide from the intervention up to 30 days postintervention. To estimate this variable, the average resource use in each study arm will be calculated based on the carbon footprint-related variables collected during the trial. This resource use will be weighted according to its corresponding carbon footprint, estimated from bibliographic references and the ScopeCO2 tool. The full SAP is provided as online supplemental materials . Monitoring The External Data Monitoring will be in charge of an external Clinical Research Organisation (Outcomes 10) virtually and with onsite visits. Adverse events will be collected by the investigators and reported by the Clinical Research Organisation in charge of the trial. The sponsor will prepare annual periodic safety reports in accordance with the recommendations outlined in the International Council for Harmonisation E2F guideline and will submit them to the regulatory authorities following the schedule established by the current legislation. Discussion The POLYPHEM trial is designed to address critical gaps in anticoagulation management during colorectal lesion polypectomy. The hypothesis suggests that maintaining anticoagulation may not only be as safe as interrupting it but also potentially advantageous in reducing the risk of thromboembolic events. Despite the current guidelines for temporary discontinuation of anticoagulation during polypectomy, the level of evidence supporting this practice is low. 15 16 These guidelines are rooted in the intuitive notion that temporary suspension might mitigate bleeding associated with polypectomy. However, emerging evidence challenges this perspective. Early restart and continuous maintenance of anticoagulation do not seem to increase the risk of bleeding, 3 14 with postpolypectomy haemorrhages typically occurring after a median of 4–7 days, postresumption of anticoagulation. 17 Notably, restarting delayed anticoagulation after polypectomy has been associated with a higher risk of thromboembolic events without a corresponding reduction in postpolypectomy haemorrhage. 20 Balancing the risk of postpolypectomy haemorrhage against the increased risk of thromboembolic events during temporary suspension of anticoagulation is challenging. Thromboembolic events are associated with heightened morbidity, long-term disability and extended hospital stays. In contrast, the majority of postpolypectomy haemorrhages are classified as mild or moderate, with up to 50% resolving without the need for colonoscopy. 17 Recognising this, maintaining anticoagulation could potentially mitigate the risk of thromboembolic events. 8 11 There are additional benefits to not stopping anticoagulation, including the simplification of periprocedural anticoagulant management. Furthermore, obviating bridging therapy with heparin in patients with VKAs and high thrombotic risk, 8 16 which independently increases the risk of postpolypectomy haemorrhage, does not provide a clear benefit in reducing the risk of thrombotic events. 8 16 24 25 Finally, in up to 30–60% of patients no intervention is performed during the colonoscopy, making anticoagulation suspension unnecessary. 3 Multiple studies have demonstrated the safety of polypectomy without discontinuation of anticoagulation. To enhance patient safety and minimise the risk of delayed haemorrhage, the trial standardises the application of haemoclips and epinephrine injection in specific scenarios following current recommendations. 15 Moreover, polypectomy of lesions >40 mm will be deferred for 30 days and will be performed after the end of the study. This decision is based on three reasons: (1) polyp size is one of the main risk factors for postpolypectomy haemorrhage and safety data for large lesions in anticoagulated patients are limited, 16 (2) polypectomy of these large lesions is recommended to be performed on a scheduled basis and removed by specialised endoscopists, 26 (3) and size >40 mm is a predictor of closure failure with clips. 20 In the subgroup of patients receiving DOACs, the anticoagulant dose will not be administered on the morning of the colonoscopy. This practice aims to avoid the peak of anticoagulant activity, typically occurring between 0.5–5 hours postdose, as recommended by the Japanese clinical practice guideline. 8 Importantly, the omission of a DOAC dose is not considered a suspension of anticoagulation. This decision is supported by evidence indicating that the anticoagulant effect of these drugs persists for a range of 1–3 days 8 . 16 27 In conclusion, the POLYPHEM trial is positioned to provide valuable insights into the safety and potential benefits of maintaining anticoagulation during polypectomy of colorectal lesions. By directly comparing this approach with temporary anticoagulation suspension, the trial addresses an important evidence gap and has the potential to inform more rational and individualised periprocedural anticoagulation strategies. Beyond safety outcomes, a simplified management approach may improve endoscopy workflow efficiency by reducing preprocedural visits and anticoagulation-related testing, while also enhancing patient-centred outcomes by minimising treatment disruption and anxiety related to anticoagulation interruption. Together, these findings could contribute to safer, more efficient and more patient-focused care in colorectal lesion polypectomy. Ethics and dissemination This study will be conducted in accordance with the principles of the Declaration of Helsinki and applicable national and European regulations. The study protocol was approved by the Ethics Committee for Research with Medicinal Products (CEIm) of Hospital Clínico San Carlos, Madrid, Spain (approval number: 24/330-EC_M). According to Spanish legislation on clinical trials (Law 14/2015 of 24 July), approval by a single CEIm is sufficient for multicentre studies and is recognised by all participating centres. The decision of the approving ethics committee is therefore applicable to all study sites. When a new centre is activated, the study will be notified to the corresponding local ethics committee in accordance with national regulatory requirements, without the need for a new ethics approval. Regulatory approval documents and ethics committee decision letters are provided as onlinesupplemental files 2 6 . All participants will provide written informed consent prior to enrolment in the study. Confidentiality of participant data will be ensured throughout the trial, and all data will be handled in compliance with current data protection regulations. A model informed consent form is provided as Supplementary Information ( online supplemental file 1 ). The results of this study will be disseminated through publication in peer-reviewed scientific journals and presentation at relevant national and international conferences in the fields of gastroenterology and endoscopy. Limitations The main limitations of the study are that we anticipate a low number of large colorectal lesions (>2 cm), and the heterogeneity in the type of anticoagulant drug. To partially overcome these limitations, a subgroup analysis is planned for the first one; and for the second one, stratified randomisation and adjusted analyses have been planned to control its possible impact. Trial status Protocol V.04, September/2025. (Protocolo 2024–5 12 194-27-00_V04). Planned timeline: Patient inclusion and follow-up: October 2024–October 2026. Analysis phase and dissemination of results: October–December 2026. The study is estimated to be completed 30 months after approval. Supplementary material online supplemental file 1 bmjopen-16-3-s001.pdf (244.9KB, pdf) DOI: 10.1136/bmjopen-2025-111695 online supplemental file 2 bmjopen-16-3-s002.pdf (84.5KB, pdf) DOI: 10.1136/bmjopen-2025-111695 online supplemental file 3 bmjopen-16-3-s003.pdf (165.2KB, pdf) DOI: 10.1136/bmjopen-2025-111695 online supplemental file 4 bmjopen-16-3-s004.pdf (26.2KB, pdf) DOI: 10.1136/bmjopen-2025-111695 online supplemental file 5 bmjopen-16-3-s005.pdf (99.5KB, pdf) DOI: 10.1136/bmjopen-2025-111695 online supplemental file 6 bmjopen-16-3-s006.pdf (187.6KB, pdf) DOI: 10.1136/bmjopen-2025-111695 online supplemental file 7 bmjopen-16-3-s007.pdf (572.3KB, pdf) DOI: 10.1136/bmjopen-2025-111695 Footnotes Funding: The study has been funded by Instituto de Salud Carlos III (ISCIII) through the project PI23/01309 (Health R&D&I Projects, Strategic Health Action 2021–2023) and co-funded by the European Union. Spanish Association of Gastroenterology (AEG) 'Gonzalo Miño Grant 2023. Prepub: Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online ( https://doi.org/10.1136/bmjopen-2025-111695 ). Provenance and peer review: Not commissioned; externally peer reviewed. Patient consent for publication: Not applicable. Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. References 1. Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med. 2012;366:687–96. doi: 10.1056/NEJMoa1100370. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 2. Derbyshire E, Hungin P, Nickerson C, et al. Post-polypectomy bleeding in the English National Health Service Bowel Cancer Screening Programme. Endoscopy. 2017;49:899–908. doi: 10.1055/s-0043-113442. [ DOI ] [ PubMed ] [ Google Scholar ] 3. 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Supplementary Materials online supplemental file 1 bmjopen-16-3-s001.pdf (244.9KB, pdf) DOI: 10.1136/bmjopen-2025-111695 online supplemental file 2 bmjopen-16-3-s002.pdf (84.5KB, pdf) DOI: 10.1136/bmjopen-2025-111695 online supplemental file 3 bmjopen-16-3-s003.pdf (165.2KB, pdf) DOI: 10.1136/bmjopen-2025-111695 online supplemental file 4 bmjopen-16-3-s004.pdf (26.2KB, pdf) DOI: 10.1136/bmjopen-2025-111695 online supplemental file 5 bmjopen-16-3-s005.pdf (99.5KB, pdf) DOI: 10.1136/bmjopen-2025-111695 online supplemental file 6 bmjopen-16-3-s006.pdf (187.6KB, pdf) DOI: 10.1136/bmjopen-2025-111695 online supplemental file 7 bmjopen-16-3-s007.pdf (572.3KB, pdf) DOI: 10.1136/bmjopen-2025-111695 Articles from BMJ Open are provided here courtesy of BMJ Publishing Group ACTIONS View on publisher site PDF (516.3 KB) Cite Collections Permalink PERMALINK Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases Cite Copy Download .nbib .nbib Format: AMA APA MLA NLM Add to Collections Create a new collection Add to an existing collection Name your collection * Choose a collection Unable to load your collection due to an error Please try again Add Cancel Follow NCBI NCBI on X (formerly known as Twitter) NCBI on Facebook NCBI on LinkedIn NCBI on GitHub NCBI RSS feed Connect with NLM NLM on X (formerly known as Twitter) NLM on Facebook NLM on YouTube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov Back to Top