Materials and methods
cancers of the abdomen, disorder of haemostasis, bleeding, chronic renal failure, thrombosis, intraoperative bleeding, death, WBH.8, tumours, ICH, cancer, digestive cancer, Digestive cancers, diabetes, cardiovascular disease, CRF, thrombotic
BLEEDING, CHRONIC RENAL FAILURE, CRF, REGRESSION, EVENTS, INTRAOPERATIVE BLEEDING, THROMBOSIS, DEEP VEIN THROMBOSIS, CANCER, RESPIRATORY FAILURE, BLIND, POLYCYTHAEMIA, RENAL FAILURE, DIGESTIVE CANCER, DISEASE, COMPLICATIONS, THROMBOEMBOLIC EVENT, TUMOURS, EVENT, HEPARIN-INDUCED THROMBOCYTOPENIA, DISEASE, SECONDARY, DISORDER OF HAEMOSTASIS, BSE
This is a prospective, comparative, randomized study, conducted in a single centre during four years and nine months: from October 12, 2015, to July 08, 2020.1. Patients:Included patients were: 1) over 18 years of age with proven, known or newly diagnosed, operable digestive cancer regardless of its nature, location, or stage, 2) and all patients who underwent emergency or elective surgery. Non-included patients were: 1) participating in another study, 2) patients with prior unfractionated heparin impregnation in the last 30 days, 3) patients with chronic renal failure with creatinine clearance<30 ml/min, 4) patients with a known history of peripheral and/or deep vein thrombosis occurring within three months prior to study inclusion, 5) patients under anticoagulation treatment within the last three months, 6) patients with a known disorder of haemostasis, 7) patients unwilling to participate in this study or unable to understand its objectives, 8) and patients with a pregnancy occurring during the study were not included. The follow-up of the included patients was done according to the CONSORT guidelines [2. Disease:Digestive cancers (oesophagus, stomach, small bowel, colon, rectum, hepatobiliary and pancreas) in an early or advanced stage, complicated or not, were included. Extra-digestive cancers of the abdomen and patients with tumours without histological confirmation were not included.3. Treatment:According to randomization the patient received Branded Enoxaparin (BE) (Lovenox4. Outcome measures:The primary endpoint was any asymptomatic thromboembolic event, assessed by a systematic Doppler ultrasound of the vessels of the lower limbs between day-7 and day-10 post surgery. This evaluation was done in a blinded fashion. The sonographer was not aware of the patients’ randomization. The secondary endpoints were the occurrence of a symptomatic thrombotic event, the occurrence of incident heparin-induced thrombocytopenia, the occurrence of bleeding events and mortality.5. Calculation of sample size and randomizationThe occurrence of subclinical thrombosis postoperatively after digestive cancer surgery is estimated to be 18% [The database used the same validated electronic data capture system (DACIMA), which complies with FDA 21 CFR part 11 (Food and Drug Administration 21 Code of Federal Regulations part 11), HIPAA (Health Insurance Portability and Accountability Act) & ICH (International Conference on Harmonization) requirements.6. Compliance, Protocol Violation, Patient follow-upCompliance was defined as the number of days enoxaparin was taken. Days not taken were reported in relation to the previously planned number of days of intake and were secondarily translated into percentage. It was considered "nonadherence" if the rate of non-take days ≥20%. Protocol violation was defined by any selected patient who had "nonadherence" to study treatment ≥20%, randomization allocation error, and Doppler ultrasound performed outside the 7- to 10-day postoperative interval.Several follow-up visits were performed. An inclusion visit verified the eligibility of patients and included them if they met the selection criteria. The patient is hospitalized for seven to 10 days. Ultrasound and clinical control were performed between post-operative day seven to 10.A 30-day follow-up visit for a clinical check-up and closure of the study was planned for each patient.7. Data collection:Eighty eight variables were culled, divided into: 1) Inclusion criteria: age over 18 years, proven cancer, indication for surgical treatment, preventive administration of Enoxaparin BSE or BE, 2) Demographic variables: age, gender, weight, height, body mass index (BMI), comorbidities (history of thrombosis, diabetes, cardiovascular disease, respiratory failure, renal failure, corticosteroid therapy, immunosuppression, polycythaemia, postpartum); 3)Preoperative variables: date of disease discovery, nature of the cancer, site, extension work-up, biology, preoperative chemotherapy, preoperative radiotherapy, 4) Intraoperative variables: operative time, nature of the procedure, type of anaesthesia, intraoperative bleeding; and 5) Postoperative variables: treatment (dose, date of administration, duration), biological follow-up during the study, Doppler ultrasound (date, result), subclinical and clinical thromboembolic events, bleeding event, heparin-induced thrombocytopenia, death, follow-up visit (1 month), All data have been collected by WD and WBH.8. Statistical analysis:All data were entered into SPSS® statistical software (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.).Qualitative variables were expressed by their frequency and percentages. Quantitative variables were mentioned by the mean and standard deviation when the distribution was Gaussian and by the median with extremes and interquartile range when the distribution variable was not Gaussian.The comparison of BSE versus BE groups was performed by independent groups Student’s t-test or the non-parametric Mann-Whitney U test for continuous variables. Categorical variables were compared by Pearson’s chi-squared test or Two-sided Fisher’s exact test, when appropriate. The margin of equivalence, estimated as the difference in frequencies, was between -0.20 and +0.20 (difference in proportion is 0.20). The real difference would be 0.00. The calculation assumes the performance of a one-sided Student’s t-test. The 95% confidence intervals were compared graphically with the equivalence margin interval. The value of p≤0.05 was considered the threshold for significance.We performed a prognostic study to identify independent predictors of clinical and subclinical thrombosis. We performed a crude bivariate analysis using appropriate statistical tests. Factors that were accompanied by a value of p≤0.05 were entered into a Backward logistic regression model. Each retained factor was accompanied by its relative risk and 95% confidence interval with the p value.9. Disclosure, Trial registrationThe Médis laboratory provided the BE treatment and sponsored the practice of Doppler ultrasound exams. The study was carried out in accordance with the current version of the Helsinki Declaration (52nd WMA General Assembly, Edinburgh, Scotland, October 2000). The clinical trial was conducted in accordance with the guidelines of the International Conference on Harmonization (ICH) on Good Clinical Practice (GCP). All patients provided written informed consent to participate in the study before being included.The patient information sheet details the procedures involved in the study (objectives, methodology, potential risks, expected benefits) and the investigator explains them to each patient. The patient signed the consent form to indicate that the information had been explained and understood. The patient was then given time to review the information presented before signing and dating the informed consent form to indicate that he fully understood the information and volunteered to participate in the study. The trial was registered on CLINICALTRIALS.GOV under the number NCT02444572.10. Practical conduct:After patient’s admission in the surgical department B of Charles Nicolle Hospital, a number was assigned to the medical record. The intern in charge of the patient wrote the patient’s medical record, specifying the address and telephone number, under the supervision of the resident and the senior physician in charge. Once it was verified that the patient was eligible to be included in the study, a balanced randomization was done on the same day using the DACIMA software. The person in charge of randomization was CD (one of the authors). The treatment was started eight hours after the end of the operation if there was no bleeding.Once the ultrasound was done between the seventh and 10th postoperative day, the patient was discharged except when he/she had complications requiring a prolonged hospitalization. The randomization is set automatically by the validated IWRS (DACIMA tool). The allocation sequence was designed at the CRF development step before study kick-off. The data-manager who performed the CRF building, and the randomization sequence allocation wasn’t involved in the study management. The data collection at site level was performed by study coordinators and investigators who were aware about the allocated treatment after running the IWRS, when eligibility criteria were verified, and the subject had been available for randomization. As the protocol was an open labeled randomized, rater blind, clinical trial, only the ultrasounds specialist was unaware about the treatment allocation. The person performed the randomization were involved in the data collection.