The OAT Trail: The Obesity Anti-Coagulation Thromboprophylaxis Trial.

Official title

A Prospective, Randomised Controlled Trial Comparing Weight-based Tinzaparin Versus Weight-based Enoxaparin for Peri-operative Thromboprophylaxis in Patients Undergoing Bariatric Surgery: Evaluation of Anti-Xa Levels and Clinical Outcomes.

Overview

Blood clots in the legs or lungs (called venous thromboembolism or VTE) are one of the most serious complications after weight loss surgery. Most blood clots occur after patients go home from hospital, within the first 30 days after surgery. To prevent blood clots, all patients having weight loss surgery receive a daily blood-thinning injection for 21 days after their operation. Two blood-thinning injections are currently used at St Vincent's University Hospital for this purpose: enoxaparin (Clexane®) and tinzaparin (Innohep®). Both belong to a group of medicines called low molecular weight heparins (LMWHs). Patients with obesity process these medicines differently to the general population, and previous studies from our hospital have shown that fewer than 53% of patients achieve adequate blood-thinning levels with either injection when measured by a blood test called an anti-Xa level. Patients will be randomly assigned (like a coin toss) to receive either tinzaparin or enoxaparin for 21 days after their surgery. Both injections are already in routine use at this hospital. A single extra blood sample will be taken on the second day after surgery to measure the anti-Xa level, which tells us whether the injection is providing adequate protection against blood clots. This blood sample will be taken at the same time as routine post-operative blood tests so that no additional blood draws are required. The study will also look at rates of blood clots and bleeding events within 30 days of surgery, and will ask patients to complete a short questionnaire at their six-week follow-up appointment about their experience with the injection.

Detailed description

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality following bariatric surgery, with a reported incidence of symptomatic DVT of 0.4-3% and PE of 0.3-2%. Over 80% of VTE events occur after hospital discharge, within 30 days of surgery. Obesity is an independent risk factor for VTE through venous stasis, a chronic pro-inflammatory and hypercoagulable state, adipokine dysregulation, and endothelial dysfunction. The pneumoperitoneum and reverse Trendelenburg positioning required for laparoscopic bariatric surgery further amplify venous stasis and thrombotic risk intraoperatively.

Low molecular weight heparin (LMWH) is the cornerstone of pharmacological VTE prophylaxis in bariatric surgery. LMWH exerts its anticoagulant effect via antithrombin-mediated Factor Xa inhibition, and pharmacodynamic adequacy can be assessed by measurement of anti-Xa activity. The American Society for Metabolic and Bariatric Surgery (ASMBS) 2021 position statement recommends a target prophylactic anti-Xa range of 0.2-0.4 IU/mL, measured at 4 hours after the third consecutive dose. The pharmacokinetics of LMWH are significantly altered in patients with severe obesity due to increased volume of distribution, altered renal clearance, elevated Factor Xa activity, and aberrant subcutaneous absorption, reducing the predictability of standard dosing regimens in this population.

Our research group at St Vincent's University Hospital (SVUH) has completed two prospective observational pilot studies. The first (Ethics Ref: RS22-017; n=20) examined weight-stratified enoxaparin dosing and found that 52.2% of patients achieved prophylactic anti-Xa levels. The second (Ethics Ref: RS25-035; n=51) examined weight-based tinzaparin (50 anti-Xa IU/kg once daily) and found that 47.1% achieved prophylactic anti-Xa levels - the first study of tinzaparin pharmacokinetics in a bariatric surgery population. A systematic review and meta-analysis conducted by the research team estimated a pooled prophylactic anti-Xa rate of 0.68 for weight-stratified enoxaparin dosing in the published literature. These data directly informed the design and power calculation of this RCT.

To our knowledge, no adequately powered randomised controlled trial has directly compared anti-Xa activity between tinzaparin and enoxaparin in a bariatric surgery population. The OAT-RCT is designed to address this gap using prospective anti-Xa level monitoring as its primary endpoint.

Design: Single-centre, prospective, parallel-group, open-label, randomised controlled superiority trial at SVUH, Dublin, Ireland.

Randomisation: Participants will be randomised 1:1 to Arm A (weight-based tinzaparin 50 anti-Xa IU/kg once daily) or Arm B (weight-stratified enoxaparin: 40 mg twice daily for weight ≤150 kg; 60 mg twice daily for weight \>150 kg) for 21 days post-operatively, commencing on post-operative day 1. Randomisation will be performed using the web-based Sealed Envelope system (www.sealedenvelope.com) with computer-generated block randomisation (block sizes 4 and 6).

Primary endpoint: Proportion of patients achieving a prophylactic anti-Xa level (0.2-0.4 IU/mL) measured at 4 hours (±30 minutes) after the third consecutive LMWH dose on post-operative day 2.

Secondary endpoints: Incidence of clinically significant bleeding events within 30 days (ISTH criteria); incidence of confirmed VTE events (DVT/PE) within 30 days; proportion achieving sub-prophylactic (\<0.2 IU/mL) and supra-prophylactic (\>0.4 IU/mL) anti-Xa levels; correlations between anti-Xa level and BMI, total body weight, and procedure type; adverse drug reactions; patient-reported treatment satisfaction using the TSQM-9 questionnaire at 6 weeks.

Sample size: 180 participants (90 per arm), based on a formal power calculation using G\*Power (z-test: difference between two independent proportions, two-tailed; p1=0.68, p2=0.47; α=0.05; power=0.80; 86 per arm, inflated to 90 per arm to allow for 5% dropout).

Statistical analysis: Primary analysis by intention-to-treat. Chi-squared or Fisher's exact test for the primary endpoint, with between-group difference reported with 95% confidence intervals. Pre-specified subgroup analyses by BMI category, sex, and procedure type. Interim analysis at 50% enrolment reviewed by an independent Data Safety Monitoring Board, with Haybittle-Peto stopping rule (p\<0.001).

Ethics: Ethical approval granted by the SVHG Research Ethics Committee (Ref: RS26-029). The study will be conducted in accordance with the Declaration of Helsinki and ICH GCP guidelines.

Interventions

• Diagnostic test Anti-Xa Activity Monitoring
  A single venous blood sample (\~5 mL, citrated tube) drawn at 4 hours (±30 minutes) after the third consecutive LMWH dose on post-operative day 2, concurrent with routine post-operative bloods. Anti-Xa activity measured using a CE-marked in vitro diagnostic assay at the SVUH Haematology Laboratory. Results are not available in real time and do not influence clinical management. Target prophylactic range: 0.2-0.4 IU/mL per ASMBS 2021 guidance.
• Drug Tinzaparin (Leo)
  Tinzaparin sodium administered subcutaneously once daily at 50 anti-Xa IU/kg total body weight for 21 days post-operatively, commencing on post-operative day 1. Used for pharmacological VTE prophylaxis following laparoscopic bariatric surgery.
• Drug enoxaparin
  Enoxaparin sodium administered subcutaneously twice daily (40 mg for weight ≤150 kg; 60 mg for weight \>150 kg) for 21 days post-operatively, commencing on post-operative day 1. Used for pharmacological VTE prophylaxis following laparoscopic bariatric surgery.

Primary outcome measures

• Proportion of participants achieving prophylactic anti-Xa levels [Time frame: Post-operative day 2 (4 hours after third LMWH dose)]

Secondary outcome measures (8)

• Incidence of clinically significant bleeding events [Time frame: 30 days post-operatively]
• Incidence of venous thromboembolism [Time frame: 30 days post-operatively]
• Proportion achieving sub-prophylactic anti-Xa levels [Time frame: Post-operative day 2 (4 hours after third LMWH dose)]
• Proportion achieving supra-prophylactic anti-Xa levels [Time frame: Post-operative day 2 (4 hours after third LMWH dose)]
• Correlation between anti-Xa level and body habitus [Time frame: Post-operative day 2]
• Adverse drug reactions [Time frame: 30 days post-operatively]
• Patient-reported treatment satisfaction [Time frame: 6 weeks post-operatively]
• Patient-reported treatment adherence and injection site tolerability [Time frame: 6 weeks post-operatively]

Eligibility criteria

Inclusion criteria

• Age ≥18 years
• BMI ≥40 kg/m², or BMI ≥35 kg/m² with at least one obesity-related comorbidity (type 2 diabetes, hypertension, obstructive sleep apnoea, dyslipidaemia, or metabolic dysfunction-associated steatotic liver disease (MASLD))
• Scheduled to undergo laparoscopic bariatric surgery (sleeve gastrectomy or gastric bypass) at St Vincent's University Hospital, Dublin, Ireland
• Capacity to provide written informed consent

Exclusion criteria

• Current therapeutic anticoagulation for any indication Known allergy or hypersensitivity to tinzaparin, enoxaparin, heparin, or any heparin-derived product, including documented heparin-induced thrombocytopaenia (HIT) Any other contraindication to LMWH therapy Severe renal impairment (eGFR <30 mL/min/1.73m²) Known haematological disorder or coagulopathy Pregnancy, breastfeeding, or planning pregnancy during the study period Active major bleeding or high bleeding risk at the discretion of the treating clinician Inability to provide written informed consent Participation in another interventional clinical study within 30 days prior to enrolment

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Basic science

Study locations

Ireland · 1 center

• St Vincent's University Hospital — Dublin

Publications

• Winegar DA, Sherif B, Pate V, DeMaria EJ. Venous thromboembolism after bariatric surgery performed by Bariatric Surgery Center of Excellence Participants: analysis of the Bariatric Outcomes Longitudinal Database. Surg Obes Relat Dis. 2011 Mar-Apr;7(2):181-8. doi: 10.1016/j.soard.2010.12.008. Epub 2010 Dec 29. PMID 21421182
• Chan AW, Tetzlaff JM, Gotzsche PC, Altman DG, Mann H, Berlin JA, Dickersin K, Hrobjartsson A, Schulz KF, Parulekar WR, Krleza-Jeric K, Laupacis A, Moher D. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013 Jan 8;346:e7586. doi: 10.1136/bmj.e7586. PMID 23303884
• World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013 Nov 27;310(20):2191-4. doi: 10.1001/jama.2013.281053. No abstract available. PMID 24141714
• Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010 Mar 23;340:c332. doi: 10.1136/bmj.c332. PMID 20332509
• Atkinson MJ, Sinha A, Hass SL, Colman SS, Kumar RN, Brod M, Rowland CR. Validation of a general measure of treatment satisfaction, the Treatment Satisfaction Questionnaire for Medication (TSQM), using a national panel study of chronic disease. Health Qual Life Outcomes. 2004 Feb 26;2:12. doi: 10.1186/1477-7525-2-12. PMID 14987333
• Schulz KF, Grimes DA. Allocation concealment in randomised trials: defending against deciphering. Lancet. 2002 Feb 16;359(9306):614-8. doi: 10.1016/S0140-6736(02)07750-4. PMID 11867132
• Nutescu EA, Spinler SA, Wittkowsky A, Dager WE. Low-molecular-weight heparins in renal impairment and obesity: available evidence and clinical practice recommendations across medical and surgical settings. Ann Pharmacother. 2009 Jun;43(6):1064-83. doi: 10.1345/aph.1L194. Epub 2009 May 19. PMID 19458109
• Aminian A, Vosburg RW, Altieri MS, Hinojosa MW, Khorgami Z; American Society for Metabolic and Bariatric Surgery Clinical Issues Committee. The American Society for Metabolic and Bariatric Surgery (ASMBS) updated position statement on perioperative venous thromboembolism prophylaxis in bariatric surgery. Surg Obes Relat Dis. 2022 Feb;18(2):165-174. doi: 10.1016/j.soard.2021.10.023. Epub 2021 Nov 1 PMID 34896011

Identifiers

NCT: NCT07559643 · RS26-029

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗