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Uninterrupted Clopidogrel Therapy Before Elective Colonoscopy Will Increase the Risk of Post-polypectomy Bleeding

Information source: Chinese University of Hong Kong
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Gastrointestinal Bleeding

Intervention: clopidogrel (Drug); clopidogrel (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Chinese University of Hong Kong

Official(s) and/or principal investigator(s):
Francis KL Chan, MD, Principal Investigator, Affiliation: CUHK

Overall contact:
Bing Yee Suen, Nursing, Phone: 852 2632 2931, Email: suenbingyee@surgery.cuhk.edu.hk

Summary

This double-blind, randomized trial aims to evaluate whether uninterrupted anti-platelet therapy (clopidogrel) will increase the risk of bleeding associated with removal of polyp during colonoscopy in patients with coronary artery disease.

Clinical Details

Official title: Uninterrupted Clopidogrel Therapy Before Elective Colonoscopy Will Increase the Risk of Post-polypectomy Bleeding

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Delayed post-polypectomy bleeding

Secondary outcome: Immediate post-polypectomy bleeding

Detailed description: Clopidogrel is a potent anti-platelet agent that, when combines with aspirin, is essential in treating acute myocardial infarction and preventing coronary stent thrombosis. However, adding clopidogrel to aspirin has been shown to substantially increase the risk of gastrointestinal bleeding by 70%. This increased bleeding risk is a particular concern for patients requiring colonoscopy. The latter is a gold standard for screening colorectal cancer. This endoscopic procedure is increasingly performed for patients on anti-platelet drugs because coronary artery disease is associated with increased risk of colorectal neoplasia. We have shown that over 30% of patients with coronary artery disease have colorectal neoplasia. Management of patients on clopidogrel who undergo colonoscopy is a clinical dilemma. Continuation of clopidogrel may increase the risk of bleeding associated with endoscopic resection of polyps (post-polypectomy bleeding). This is a potentially serious complication because post-polypectomy bleeding is often delayed, difficult to locate, and may provoke acute coronary syndrome. Conversely, prolonged discontinuation of clopidogrel increases the risk of recurrent myocardial infarction and coronary stent thrombosis. There is a lack of prospective data on the risk of post-polypectomy bleeding attributable to clopidogrel. Current American Society of Gastrointestinal Endoscopy and British Society of Gastroenterology Guidelines recommend withholding clopidogrel for 7 to 10 days in planned high risk endoscopic procedures such as colonoscopic polypectomy. However, this guideline is largely based on retrospective data and expert opinion. In fact, the anti-platelet effect of clopidogrel lasts for about 5 days only. Coronary stent thrombosis has been reported as early as 7 days after stopping clopidogrel. There remains a large gap in our knowledge on the risk of bleeding in patients taking clopidogrel who undergo gastrointestinal endoscopic procedures. No randomized trials have assessed whether clopidogrel should be discontinued before colonoscopy. This randomized trial aims to assess whether uninterrupted clopidogrel therapy during colonoscopy will increase the risk of post-polypectomy bleeding. Irrespective of the outcome, this trial will be the first to provide controlled data on the risk of post-polypectomy bleeding with uninterrupted clopidogrel during colonoscopy. Unfortunately, this important clinical question is not a priority of pharmaceutical companies because clopidogrel will be off patent soon. The outcome of this industry-independent clinical trial may encourage health authorities and international guideline committees to review their recommendations on the management of anti-platelet therapy for high-risk endoscopic procedures. Hypothesis Uninterrupted clopidogrel therapy increases the risk of post-polypectomy bleeding in patients undergoing elective colonoscopy Aim 1. To investigate whether uninterrupted clopidogrel therapy before elective colonoscopy will increase the risk of post-polypectomy bleeding 2. To assess the impact of platelet reactivity on risk of bleeding in patients on clopidogrel therapy undergoing polypectomy 3. To assess the impact of CYP2C19 polymorphism on bleeding events in patients on clopidogrel therapy undergoing polypectomy Study Design This is a double-blind, randomized, controlled trial in which patients receiving clopidogrel for coronary stents who require elective colonoscopy will be randomized to either clopidogrel or its placebo for one week prior to the endoscopic procedure Drug Allocation & Randomization Seven days before scheduled colonoscopy, eligible patients will be instructed to stop taking their prescriptions of clopidogrel. They will be randomly assigned to receive the study drug (clopidogrel) or its placebo for 7 days until the morning of the endoscopic procedure (refer to schematic trial design). The study drug and its placebo will be prepared by the School of Pharmacy at Chinese University of Hong Kong as identical-appearing capsules, according to international good manufacturing practice guidelines for pharmaceuticals. A computer-generated randomization schedule is used to assign patients to the intervention sequences. Concomitant aspirin therapy, if any, will be continued. Randomization is stratified for concomitant use of other anti-platelet drugs. Colonoscopic Procedures This study will be carried out in two regional hospitals that collectively serve a population of 1. 5 million. Around 4,000 colonoscopies are performed annually in each hospital. All patients will have blood test for hemoglobin level, platelet function and CYP2C19 Genotyping before colonoscopy. Experienced colonoscopists will perform colonoscopy under conscious sedation with midazolam and pethidine. Bowel preparation consists of polyethylene glycol taken orally the evening and the morning before procedure together with a minimum of 2 liters of clear fluids. The adequacy of bowel preparation will be documented (poor, fair, good, or excellent). Colonoscopists will be instructed to remove all polyps during the colonoscopic examination. The location and morphologic feature of each polyp will be recorded. The size is measured using an open biopsy forceps (6 mm apart). Each lesion will be fixed in formalin and sent to the pathologist for histologic evaluation. No prophylactic clips or detachable loops will be applied if immediate bleeding is not observed after polypectomy. Intervention for immediate post-polypectomy bleeding including injection therapy alone or in combination with endoclip application, if any, will be recorded. Follow-up assessment All patients will resume their usual prescriptions of clopidogrel after colonoscopy when oral intake is allowed. They will be monitored hourly for hemodynamic instability and any delayed post-polypectomy bleeding for 24 hours. After discharge, a designated research nurse will contact the patients by telephone on Day 2 and Day 7 for symptoms of bleeding. On Day 30, they will return for a full blood count and symptoms of delayed post-polypectomy bleeding. Emergency visits and hospital discharge summaries will be scanned for up to 6 months after colonoscopy for recurrent cardiothrombotic events. A 24-hour hotline will be provided for patients to report any adverse or serious events. Study End Points The primary endpoint is delayed post-polypectomy bleeding. The latter is defined as rectal bleeding, starting after the colonoscope has been retracted from the anus to 30 days after the procedure. Bleeding is considered significant if there is hypotension, a decrease in hemoglobin of ≥2 g/dL from baseline or ≥10 percentage points decrease in hematocrit, requirement of transfusion, prolonged hospitalization, rehospitalization, and hemostatic interventions using endoscopic therapy, angiographic embolization, or surgery. Secondary endpoints include immediate post-polypectomy bleeding and cardiothrombotic events. Immediate post-polypectomy bleeding is defined as bleeding at the time of polypectomy that persists despite continuous irrigation with diluted epinephrine solution for 5 minutes. Interventions for immediate post-polypectomy bleeding include epinephrine injection alone or in combination with endoclip application. The volume of epinephrine and number of endoclips used will be recorded. The study endpoints will be confirmed by an independent blinded adjudication committee. Sample size estimation Sample size estimation is based on the assumptions that the rate of delayed post-polypectomy bleeding in 30 days is 0. 3 percent with clopidogrel interrupted for 7 days [15], and that the rate of delayed bleeding is 3% with uninterrupted clopidogrel therapy [7]. Accordingly, 290 patients undergoing polypectomy in each group will be required to achieve 90% power at 5% significance level using a 2-sided log-rank test (PASS software, NCSS 2008, Kaysville, Utah). The investigators previously showed that 34% of patients with coronary artery disease will have colonic polyps [13]. Thus, The investigators need to perform colonoscopy on 1706 patients receiving clopidogrel to recruit 580 patients (290 per group) with polyps in this study. Statistical analysis The primary analysis will be based on the intention-to-treat population, which is defined as all randomized patients who undergo colonoscopic polypectomy. Demographic and clinical characteristics will be compared between clopidogrel group and placebo group. Homogeneity of the two groups at baseline will be analyzed using the Pearson's chi-square test for categorical data and Student's t-test for continuous variables. All P values and 95% CIs are two-sided. Statistical analyses will be carried out exclusively by an independent statistician. Quality assurance: Data Management Only the research nurse and the PI have access right to the blinded database using their login user names and passwords. Subjects' information is kept anonymous. They are identified by their study numbers to maintain subjects' confidentiality. Quality assurance: Monitoring An independent staff will perform source data verification (a comparison of the data in the CRFs with the subject's medical records at the hospital or practice, and other records relevant to the study).

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. On regular treatment with clopidogrel alone or in combination with other anti-platelet drugs (e. g. aspirin) 2. Elective colonoscopy for asymptomatic screening of bowel cancer or investigation of bowel symptoms (e. g. altered bowel habit, rectal bleeding, anemia, polyp follow-up) 3. Age ≥ 18 4. Written informed consent Exclusion Criteria: 1. Coronary stent of any type placed within 30 days 2. Cardiac-vascular event within 3 months 3. Drug-eluting coronary stent placed within 6 months 4. Terminal illness 5. Concomitant use of anticoagulants 6. Congenital or acquired bleeding diathesis showing clinical bleeding tendency (e. g. hemophilia, decompensated cirrhosis) 7. Pregnancy or women of child-bearing age without regular use of contraception

Locations and Contacts

Bing Yee Suen, Nursing, Phone: 852 2632 2931, Email: suenbingyee@surgery.cuhk.edu.hk

Prince of Wales Hospital, Hong Kong, Hong Kong, China; Recruiting
Francis KL Chan, MD, Phone: 85226323143, Email: fkl@cuhk.edu.hk
Additional Information

Starting date: February 2012
Last updated: August 21, 2015

Page last updated: August 23, 2015

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