Apixaban-PK Trial: Preventing Portal Hypertension Complications in Cirrhosis (APIXABAN-PK)

Apixaban Plus Carvedilol to Prevent Portal Hypertension Complications in Cirrhosis: A Randomized Single-Blind Placebo-Controlled Trial at AIMS, Hyderabad, Pakistan

The APIXABAN-PK trial is a prospective, randomized, single-blind, placebo-controlled study designed to evaluate the efficacy and safety of apixaban in combination with carvedilol versus placebo with carvedilol in preventing portal hypertension-related complications in patients with cirrhosis. Conducted at the Gastroenterology and Hepatology Department and Clinical Trials Unit (CTU) of Asian Institute of Medical Sciences (AIMS) Hospital, Hyderabad, Pakistan, the trial will enroll eligible cirrhotic patients with portal hypertension. Participants will be followed for 12 months to monitor hepatic decompensation events, variceal bleeding, portal vein thrombosis, and mortality, while safety and tolerability of apixaban will be closely assessed. This study aims to provide local evidence for apixaban use in cirrhosis management in Pakistan.

Study Overview

• Status: Recruiting
• Conditions: Hepatic Encephalopathy; Cirrhosis; Ascites; Esophageal and Gastric Varices; Portal Hypertension; Portal Vein Thrombosis
• Intervention / Treatment: Drug: Apixaban; Drug: Carvedilol; Drug: Placebo

Detailed Description

The APIXABAN-PK trial is a prospective, randomized, single-blind, placebo-controlled study conducted at the Asian Institute of Medical Sciences (AIMS) Hospital in Hyderabad, Pakistan. The study aims to evaluate the efficacy and safety of apixaban, a direct factor Xa inhibitor, in combination with carvedilol compared to carvedilol alone (with placebo) for preventing portal hypertension-related complications in patients with cirrhosis.

Patients with confirmed cirrhosis and evidence of portal hypertension (Child-Pugh B 7-10) are eligible. Participants undergo screening, including esophagogastroduodenoscopy (EGD) within six months prior to enrollment. Those with high-risk varices receive endoscopic variceal band ligation to obliteration before randomization to ensure baseline safety.

Eligible participants are randomized in a 1:1 ratio to one of two groups:

Intervention Group: Apixaban 2.5 mg orally twice daily plus carvedilol (titrated according to a protocol-defined schedule).

Control Group: Placebo (matching apixaban) orally twice daily plus carvedilol (titrated according to the same schedule).

Carvedilol is initiated at 6.25 mg once daily and titrated every 2-4 weeks based on heart rate and blood pressure, aiming for a maintenance dose of 12.5 mg twice daily, as tolerated. Dose adjustments are made for hypotension or bradycardia.

All participants are followed for 12 months. Study visits occur at baseline, 2 weeks (safety telephone call), and 1, 3, 6, 9, and 12 months. Assessments include vital signs, laboratory tests (complete blood count, liver and renal function, international normalized ratio), and imaging (abdominal ultrasound with Doppler and transient elastography at specified intervals). Adherence is monitored via pill counts and patient diaries.

The primary outcome is the first occurrence of portal hypertension-related complications (variceal bleeding, ascites, hepatic encephalopathy, portal vein thrombosis, or liver-related death) within 12 months. Secondary outcomes include bleeding events (major and minor), time to first decompensation or hospitalization, all-cause and liver-related mortality, and changes in non-invasive markers of portal hypertension (e.g., liver stiffness, platelet count).

Safety is closely monitored through routine assessments and an independent Data Safety Monitoring Board (DSMB). The DSMB reviews unblinded safety data after 50% of participants have completed 6 months of follow-up, with predefined stopping rules for excessive bleeding or mortality. Adverse events are graded using CTCAE v6.0 criteria.

Statistical analysis will be performed on an intention-to-treat basis. The primary endpoint (time to first complication) will be analyzed using Kaplan-Meier survival curves, log-rank tests, and Cox proportional hazards regression. The study aims to enroll 220 participants to account for anticipated dropout, with 100 participants per arm required to detect a 50% relative risk reduction in the primary outcome (two-sided α = 0.05, power = 80%). Enrollment is planned over 12 months, with a total study duration of 24 months.

This investigator-initiated trial is sponsored by the Asian Institute of Medical Sciences and is registered on ClinicalTrials.gov. Results will be submitted for publication within 12 months of study completion, regardless of outcome, in accordance with ICMJE guidelines.

• Study Type: Interventional
• Enrollment (Estimated): 220
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Fatima Nadeem Dr, Pharm-D, Mphil; Phone Number: +923080744996; Email: fatima.nadeem2401@gmail.com

Study Locations

• Pakistan
  • Sindh
    • Hyderābād, Sindh, Pakistan, 71000
      • Recruiting
      • Asian Institute of Medical Sciences
      • Contact: Dr Fatima; Phone Number: 03080744996; Email: fatima.nadeem229@amalacademy.org
      • Contact: Email: sadikmemon@gmail.com
      • Principal Investigator: Prof.Dr.Sadik Memon, MBBS,MRCP,FCPS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adults aged ≥18 years with diagnosed cirrhosis (any etiology), confirmed by histology, transient elastography (≥12.5 kPa), or consistent clinical/imaging findings.

2. Evidence of portal hypertension, defined by:

   Clinical: presence of varices on endoscopy, ascites, or splenomegaly with thrombocytopenia.

3. Compensated or early decompensated cirrhosis (Child-Pugh B 7-10), with stable liver function defined as no change in Child-Pugh score >1 point in the preceding 3 months.
4. Screening esophagogastroduodenoscopy (EGD) performed within 6 months prior to enrollment. Patients with high-risk varices (large varices, red wale signs, or history of variceal bleeding) must undergo endoscopic variceal band ligation to obliteration before randomization.
5. Able to provide informed consent and comply with study procedures.

Exclusion Criteria:

1. Active gastrointestinal bleeding within 6 weeks prior to enrollment.

2. High bleeding risk:

   • Platelet count <50,000/µL at baseline
   • INR >1.8 (or >2.0 if secondary to cirrhosis without additional coagulopathy)
   • Active peptic ulcer disease
   • History of intracranial hemorrhage or hemorrhagic stroke
   • Known bleeding diathesis
3. Severe renal impairment (eGFR < 30 mL/min/1.73 m²) or on dialysis.
4. Child-Pugh class C or Child-Pugh score ≥10.
5. History of hypersensitivity to apixaban or carvedilol.
6. Pregnancy, breastfeeding, or unwillingness to use effective contraception during the study period.
7. Concurrent anticoagulant or antiplatelet therapy (including aspirin, clopidogrel, warfarin, or other DOACs) that cannot be safely discontinued. A washout period of at least 5 half-lives is required before randomization.
8. Use of NSAIDs, SSRIs, or other medications that significantly increase bleeding risk, unless approved by the PI with clear risk-benefit justification.
9. Active hepatocellular carcinoma (HCC) outside Milan criteria or with vascular invasion.
10. Current or planned liver transplantation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention Group: Apixaban + Carvedilol; Apixaban, Carvedilol	Drug: Apixaban; Apixaban 2.5 mg oral tablet taken twice daily for 12 months. Apixaban is a direct factor Xa inhibitor that blocks thrombin generation and clot formation through inhibition of the coagulation cascade. Dose adjustment: continue 2.5 mg twice daily if eGFR ≥30 mL/min/1.73 m²; if eGFR 15-29 mL/min/1.73 m², continue with close monitoring; if eGFR <15 mL/min/1.73 m², discontinue. Withheld in case of major bleeding or severe hepatic decompensation.; Drug: Carvedilol; Carvedilol oral tablet titrated according to protocol-defined schedule. Initiated at 6.25 mg once daily at baseline. Titrated every 2-4 weeks based on heart rate and blood pressure: 6.25 mg twice daily at week 2, 12.5 mg twice daily at week 4, with target maintenance dose of 12.5 mg twice daily. Dose may be reduced or withheld if heart rate <55 bpm, systolic blood pressure <90 mmHg, or symptomatic hypotension develops.
Placebo Comparator: Control Group: Placebo + Carvedilol; Placebo, Carvedilol	Drug: Carvedilol; Carvedilol oral tablet titrated according to protocol-defined schedule. Initiated at 6.25 mg once daily at baseline. Titrated every 2-4 weeks based on heart rate and blood pressure: 6.25 mg twice daily at week 2, 12.5 mg twice daily at week 4, with target maintenance dose of 12.5 mg twice daily. Dose may be reduced or withheld if heart rate <55 bpm, systolic blood pressure <90 mmHg, or symptomatic hypotension develops.; Drug: Placebo; Placebo oral tablet matching apixaban in appearance, taken twice daily for 12 months. No active ingredient.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
First Occurrence of Portal Hypertension-Related Complications	Time to first occurrence of a composite of portal hypertension-related complications, defined as variceal bleeding, ascites, hepatic encephalopathy, portal vein thrombosis, or liver-related death, within 12 months of randomization.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major and Minor Bleeding Events	Incidence of major and minor bleeding events attributable to apixaban in combination with carvedilol. Major bleeding is defined by ISTH criteria (fatal bleeding, symptomatic bleeding in a critical area, bleeding causing a fall in hemoglobin ≥2 g/dL, or requiring transfusion of ≥2 units of packed red blood cells). Minor bleeding is defined as any overt bleeding not meeting major criteria.	12 months

Collaborators and Investigators

• Sponsor: Asian Institute Of Medical Sciences
• Investigators: Principal Investigator: Sadik Memon, MBBS,MRCP,FCPS, Asian Institute of Medical Sciences; Study Director: Dr. Fatima Nadeem, Pharm-D, Mphil, Asian Institute of Medical Sciences

Publications and helpful links

General Publications

• Simon TG,Singer DE,Zhang Y,Mastrorilli JM,Cervone A,DiCesare E,Lin KJ
• Xu PS,Wang MC,Chen JJ,Wang HY
• Brown RS,Brown KA,Flamm S,Bejarano RE,Rahimi RS,Singal AK,Rockey DC
• Nulan Y,Felli E,Selicean SE,Prampolini M,Berzigotti A,Gracia-Sancho J,Bosch J
• Mullarkey MJ,Ogola GO,Asrani SK,Volk ML
• Süffert LC,de Faria Moraes B,Cançado GGL
• Joshi A,Raja HAA,Roy P,Latif F,Reji RG,Deb N,Mui RK,Shady A

Helpful Links

• Official NCI CTCAE v6.0 criteria for adverse event grading and documentation.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2026
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: March 31, 2026
• First Submitted That Met QC Criteria: April 3, 2026
• First Posted (Actual): April 9, 2026

Study Record Updates

• Last Update Posted (Actual): April 9, 2026
• Last Update Submitted That Met QC Criteria: April 3, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: randomized controlled trial; non-selective beta-blocker; prevention; portal hypertension; cirrhosis; Pakistan; apixaban; carvedilol; liver disease; variceal bleeding; direct oral anticoagulant; portal vein thrombosis; Factor Xa Inhibitor; hepatic decompensation
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Metabolic Diseases; Digestive System Diseases; Gastrointestinal Diseases; Esophageal Diseases; Brain Diseases, Metabolic; Liver Failure; Hepatic Insufficiency; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Fibrosis; Liver Diseases; Hypertension, Portal; Ascites; Esophageal and Gastric Varices; Hepatic Encephalopathy; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amines; Indoles; Alcohols; Propanolamines; Amino Alcohols; Propanols; Heterocyclic Compounds, 3-Ring; Carbazoles; Carvedilol; apixaban
• Other Study ID Numbers: AIMS/ERC/9853/26

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

IPD will not be shared because:

This is a single-center investigator-initiated trial without infrastructure for external data sharing

The protocol and informed consent do not include provisions for sharing IPD with external researchers

Institutional policy does not support IPD sharing for this study

Aggregate results will be published per ICMJE guidelines

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No