Effect of Apiban Therapy on AVF Maturation in ESRD Patients

End-stage renal disease (ESRD) is a growing global health burden, and the creation of a native arteriovenous fistula (AVF) is the gold standard for vascular access in patients requiring hemodialysis \[1\]. AVFs offer superior longevity, fewer infectious complications, and lower mortality rates compared to central venous catheters or synthetic grafts \[2\]. However, a significant limitation to their widespread success is the high rate of early failure, primarily due to failure to mature (FTM). FTM occurs in 20-40% of AVFs, rendering them unusable for dialysis \[3\].

The maturation process is a complex physiological response to the newly created arteriovenous anastomosis, requiring adequate arterial inflow, venous outflow, and vessel remodeling \[4\]. Thrombosis during this critical maturation period remains a major cause of early AVF failure \[5\]. While systemic intraoperative heparin (as discussed in the referenced review) provides transient anticoagulation during the immediate perioperative period, it has a half-life of only 1-2 hours and does not provide prolonged protection during the weeks following surgery when maturation is occurring \[6\].

To date, no randomized controlled trial has specifically evaluated the role of short-term, protocol-directed apixaban therapy initiated at the time of AVF creation and continued through the maturation period. This study aims to determine whether perioperative and short-term apixaban therapy improves AVF maturation rates without significantly increasing bleeding complications.

2\. Research Question (PICO) Population: Adult patients (≥18 years) with ESRD undergoing primary upper extremity AVF creation (radiocephalic, brachiocephalic, or brachiobasilic).

Intervention: Short-term therapeutic apixaban initiated immediately postoperatively and continued for 6 weeks during the maturation period.

Comparison: Placebo (matching oral tablets) administered on the same schedule. Outcome: AVF maturation rate (clinical and ultrasonographic) at 6 weeks post-operatively.

3\. Study Objectives Primary Objective: To determine whether short-term (6-week) apixaban therapy, initiated postoperatively, improves the rate of successful AVF maturation at 6 weeks compared to placebo.

Secondary Objectives:

To compare AVF patency rates (primary) at 6 weeks and 3 months between the two groups.

To compare the incidence of postoperative complications, specifically bleeding, hematoma formation, and wound infection, between the two groups.

To compare venous diameter and flow volume (by duplex ultrasound) at 6 weeks between the two groups.

To compare the time to first successful cannulation for hemodialysis between the two groups.

4\. Hypotheses Null Hypothesis (H0): There is no significant difference in the rate of successful AVF maturation at 6 weeks between ESRD patients receiving short-term apixaban and those receiving placebo.

Alternative Hypothesis (H1): There is a significant difference in the rate of successful AVF maturation at 6 weeks between ESRD patients receiving short-term apixaban and those receiving placebo.

5\. Methodology 5.1. Study Design: A prospective randomized, double-blind, placebo-controlled trial. 5.2. Study Setting and Duration:

The study will be conducted in the Departments of Vascular Surgery at Combined Military Hospital, Lahore. The study duration will be 8 months, including:

6-month recruitment period 8-week treatment and follow-up period for the last enrolled patient

1- months for data analysis and manuscript preparation 5.3. Sample Size Calculation: Based on previous literature, the expected AVF maturation rate at 6 weeks in the control group is approximately 60% \[3,10\]. To detect a clinically significant absolute improvement of 20% in maturation rate (from 60% to 80%) in the apixaban group, with a power of 80% and a two-sided alpha error of 0.05, a minimum of 82 patients per group is required. Accounting for a 10% loss to follow-up and 5% discontinuation of study drug, the total sample size needed is 190 patients (95 per group) .

5.6. Apixaban Dosing and Perioperative Protocol 5.6.1. Study Drug Administration Protocol: Timeline Apixaban Group Placebo Group Rationale Preoperative (Day -1) No study drug No study drug Avoid intraoperative bleeding Intraoperative No study drug; standard heparin (50-80 IU/kg) at surgeon discretion No study drug; standard heparin (50-80 IU/kg) at surgeon discretion Standardize intraoperative care Postoperative (Day 0-1) No study drug (24 hours) No study drug (24 hours) Ensure hemostasis

Postoperative Day 1-42 Apixaban 2.5 mg twice daily Placebo twice daily 6-week treatment period

Postoperative Day 43 onwards No study drug No study drug Assess off-treatment durability

5.6.2. Apixaban Dosing Rationale: A fixed dose of apixaban 2.5 mg twice daily will be used for all patients in the intervention group.

This dose represents the approved reduced dose for patients with two of three criteria: age ≥80 years, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL \[11\].

For this trial, the 2.5 mg twice daily dose is selected for all patients to:

Minimize bleeding risk in the postoperative population Provide uniform, simplified dosing Maintain therapeutic effect for thromboprophylaxis (equivalent to VTE prevention dosing) Avoid dose adjustments based on renal function

5.6.3. Criteria for Study Drug Discontinuation:

The study drug will be permanently discontinued if any of the following occur:

* Clinically significant bleeding requiring transfusion or surgical intervention * Major hematoma (\>5 cm or requiring evacuation) * Severe adverse event attributed to study drug * Patient withdrawal of consent * Thrombosis of AVF (study drug stopped, patient managed per standard of care) * Need for therapeutic anticoagulation for another indication

5.7. Operational Definitions:

Successful AVF Maturation at 6 Weeks: Defined as a fistula suitable for hemodialysis cannulation, meeting the "Rule of 6s" at 6 weeks post-operatively:

Flow: ≥ 500 mL/min (assessed by duplex ultrasound). Diameter: Vein diameter ≥ 6 mm (assessed by duplex ultrasound). Depth: ≤ 6 mm from the skin surface (assessed by ultrasound). Length: A straight segment of at least 6 cm available for cannulation. Primary Patency: The interval from AVF creation to any intervention to maintain or restore patency.

Early Thrombosis: Thrombosis occurring within the first 6 weeks postoperatively.

Clinically Significant Bleeding: Bleeding requiring prolonged hospitalization (\>24 hours beyond planned discharge), blood transfusion, or surgical exploration.

Clinically Significant Hematoma: A hematoma \>5 cm in diameter or requiring prolonged hospitalization, blood transfusion, or surgical evacuation.

Time to Maturation: The time from AVF creation to the date of first successful two-needle cannulation for a full dialysis session.

5.9. Randomization and Blinding:

Randomization: Patients will be randomized in a 1:1 ratio to apixaban or placebo using a computer-generated random sequence with variable block sizes (4, 6, and 8). Randomization will be stratified by:

Fistula type (radiocephalic vs. brachiocephalic vs. brachiobasilic) Diabetes mellitus (present vs. absent) Blinding: Patients, surgeons, outcome assessors, and data analysts will be blinded to group allocation.

5.10. Study Protocol: 5.10.1. Preoperative Visit (Day -7 to -1): Screening and enrollment Written informed consent Demographics, medical history, medication review Laboratory tests: CBC, coagulation profile, serum creatinine, liver function tests Duplex ultrasound mapping of upper extremity vessels Randomization assignment 5.10.2. Surgical Procedure (Day 0): AVF creation by experienced vascular surgeon Standardized surgical technique per institutional protocol Intraoperative heparin (50-80 IU/kg) administered at surgeon discretion (recorded) Operative details recorded: fistula type, anastomosis technique, vessel diameters, surgeon level 5.10.3. Postoperative Day 1 (24 hours post-surgery): Assessment for bleeding, hematoma, and immediate thrill/palpable pulse Initiation of study drug (apixaban 2.5 mg or placebo twice daily) Patient education on study drug administration Discharge planning (most patients discharged day 1-2) 5.10.4. Postoperative Week 2 (Day 14 ± 3): Clinical assessment: wound healing, thrill, bruit Adverse event monitoring Study drug compliance check (pill count) Laboratory monitoring: CBC, serum creatinine 5.10.5. Postoperative Week 6 (Day 42 ± 5):

PRIMARY ENDPOINT: