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].

Apixaban, a direct factor Xa inhibitor, offers a potential advantage by providing sustained anticoagulation throughout the critical maturation period [7]. Its predictable pharmacokinetics, oral administration, and favorable safety profile make it an attractive agent for short-term use in this setting [8]. By reducing microthrombotic events during the first 4-6 weeks following AVF creation, apixaban could potentially improve maturation rates. However, this potential benefit must be weighed against the increased risk of bleeding, hematoma formation, and wound complications that could negatively impact fistula maturation [9].

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:

Clinical examination Duplex ultrasound: vein diameter, flow volume, depth, stenosis assessment Assessment of maturation per "Rule of 6s" Study drug completion (last dose on Day 42) Adverse event monitoring Study drug compliance check (pill count) 5.10.6. Postoperative Month 3 (Day 90 ± 7): Clinical examination Duplex ultrasound Assessment of patency First cannulation date recorded (if applicable) 5.10.7. Postoperative Month 6 (Day 180 ± 14): Clinical examination Assessment of patency Cannulation success and dialysis adequacy recorded 6. Outcome Measures

Primary Outcome Measure:

Proportion of patients with successful AVF maturation at 6 weeks (as defined in section 5.7).

Secondary Outcome Measures:

Proportion of patients with successful AVF maturation at 3 months. Primary patency rates at 6 weeks, 3 months, and 6 months. Mean vein diameter (mm) at 6 weeks by duplex ultrasound. Mean flow volume (mL/min) at 6 weeks by duplex ultrasound. Incidence of early thrombosis (≤6 weeks). Incidence of clinically significant bleeding. Incidence of clinically significant hematoma. Mean time to first successful cannulation (in days). Proportion of patients successfully using AVF for hemodialysis at 6 months. 7. Data Analysis (Statistical Analysis) Data will be entered into and analyzed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA) and R statistical software (R Foundation for Statistical Computing, Vienna, Austria).

Analysis Populations:

Intention-to-Treat (ITT): All randomized patients (primary analysis population).

Per-Protocol (PP): Patients who completed 6 weeks of study drug with ≥80% compliance.

Safety Population: All patients who received at least one dose of study drug. Descriptive Statistics: Categorical variables (e.g., gender, fistula type, comorbidities) will be presented as frequencies and percentages. Continuous variables (e.g., age, vessel diameter, flow volume) will be checked for normality using the Shapiro-Wilk test and presented as mean ± standard deviation (SD) or median with interquartile range (IQR), as appropriate. Baseline characteristics will be compared between groups to assess balance after randomization.

Primary Outcome Analysis:

For the primary outcome (AVF maturation at 6 weeks), the Chi-square test will be used to compare proportions between the two groups (ITT population). Results will be presented as risk ratio (RR) with 95% confidence interval (CI).

Number Needed to Treat (NNT) will be calculated as 1 / absolute risk reduction.

Secondary Outcome Analyses:

Patency rates at 6 weeks, 3 months, and 6 months will be compared using the Chi-square test. Patency over time will be analyzed using Kaplan-Meier survival curves and compared using the log-rank test.

Continuous outcomes (vein diameter, flow volume, time to cannulation) will be compared using the independent samples t-test (for normally distributed data) or the Mann-Whitney U test (for non-normally distributed data).

Incidence of complications (bleeding, hematoma) will be compared using the Chi-square test or Fisher's exact test, as appropriate.

Subgroup Analyses:

Pre-specified subgroup analyses will be performed for:

Fistula type (radiocephalic vs. brachiocephalic vs. brachiobasilic) Diabetes status (present vs. absent) Surgeon experience (senior vs. junior) Intraoperative heparin use (yes vs. no) Interaction tests will be performed to assess for differential treatment effects across subgroups.

Multivariable Analysis:

Logistic regression analysis will be performed to identify independent predictors of AVF maturation, adjusting for potential confounders including age, diabetes, vessel diameter, surgeon experience, and treatment group. Results will be presented as adjusted odds ratios (OR) with 95% CI.

Safety Analysis:

All adverse events will be tabulated by group and compared using Fisher's exact test. Serious adverse events will be reported to the Data Safety Monitoring Board (DSMB) and ethics committee.

Significance Level: A p-value of < 0.05 will be considered statistically significant for all primary and secondary analyses. No adjustment for multiple comparisons will be made for secondary outcomes, which will be considered exploratory.

Interim Analysis: An interim analysis for safety (bleeding events) will be conducted by an independent DSMB after enrollment of 50% of patients. Stopping rules will be pre-specified (e.g., significantly higher major bleeding in apixaban group with p < 0.001).

8. Ethical Considerations The study protocol will be submitted for approval to the Institutional Ethics Committee (IEC) or Institutional Review Board (IRB) of the participating hospitals.

The study will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable regulatory requirements.

All participants will provide written informed consent after a thorough explanation of the study procedures, risks, benefits, and the investigational nature of the study drug.

A Data Safety Monitoring Board (DSMB) will be established to oversee patient safety and review interim analyses.

Patient confidentiality and anonymity will be strictly maintained by assigning unique study codes to all participants. All data will be stored in password-protected databases accessible only to study investigators.

Clinical trial registration will be completed prior to patient enrollment (ClinicalTrials.gov or other public registry).

Insurance coverage for trial-related injuries will be arranged per institutional requirements.

9. Expected Outcomes and Implications Investigators hypothesize that short-term apixaban therapy (2.5 mg twice daily for 6 weeks) initiated post-AVF creation will significantly improve maturation rates by reducing early microthrombotic events during the critical remodeling phase. Investigators anticipate an absolute improvement in maturation rate of approximately 20% (from 60% to 80%) at 6 weeks. The investigators also expect a small but acceptable increase in minor bleeding and hematoma rates, with no significant increase in major bleeding requiring intervention.

If the hypothesis is confirmed, this trial would provide the first Level 1 evidence supporting short-term anticoagulation to improve AVF outcomes. The findings could establish a new standard of care: routine short-term apixaban therapy following AVF creation to maximize maturation success. Given that apixaban is already widely available, affordable, and familiar to clinicians, this intervention could be rapidly implemented into clinical practice, potentially improving vascular access outcomes for thousands of ESRD patients worldwide.

If the hypothesis is refuted (no benefit or unacceptable bleeding risk), the trial will provide important safety data and prevent the widespread adoption of an ineffective or harmful practice.

Inclusion Criteria:

• Age ≥ 18 years.
• Diagnosis of ESRD (eGFR < 15 mL/min/1.73m² or already on dialysis) with plans for hemodialysis.
• Planned primary upper extremity AVF creation (radiocephalic, brachiocephalic, or brachiobasilic).
• Suitable vessels on preoperative duplex ultrasound (artery ≥ 2 mm, vein ≥ 2.5 mm without tourniquet).
• Ability to provide informed consent.

Exclusion Criteria:

• Known bleeding diathesis or hypercoagulable state.
• Current therapeutic anticoagulation (any indication).
• Current dual antiplatelet therapy.
• History of intracranial hemorrhage.
• Known allergy or hypersensitivity to apixaban.
• Inability to comply with study protocol or follow-up.

IPD will be shared of patient registration number, Age, Sex, co-morbidities, Pre-op vein mapping data, post-op AVF flow and site at 1, 3 and 6 weeks. Data regarding complications of primary fistula failure, hematoma and infection will be made available.

Made available from 1st july 2027 for 1 year