Ascites, Cirrhosis, Esophageal and Gastric Varices, Hepatic Encephalopathy, Portal Hypertension, Portal Vein Thrombosis
Conditions
Keywords
apixaban, carvedilol, cirrhosis, portal hypertension, direct oral anticoagulant, variceal bleeding, hepatic decompensation, portal vein thrombosis, randomized controlled trial, Pakistan, Factor Xa Inhibitor, non-selective beta-blocker, prevention, liver disease
Brief summary
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.
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.
Interventions
DRUGApixaban
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.
DRUGCarvedilol
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.
DRUGPlacebo
Placebo oral tablet matching apixaban in appearance, taken twice daily for 12 months. No active ingredient.
Sponsors
Asian Institute Of Medical Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Subject)
Masking description
This is a single-blind study. Participants are blinded to treatment allocation and receive either apixaban or an identical-appearing placebo. Investigators and pharmacy personnel are not blinded and are aware of the assigned treatment. The allocation list is secured at the Clinical Trials Unit (CTU) and accessible only to authorized unblinded personnel. Masked Parties: Participants (blinded) Outcome assessors (blinded to treatment allocation during outcome adjudication) Data Safety Monitoring Board (DSMB) members (receive unblinded safety data as per DSMB charter) Data analysts (may remain blinded until final analysis per statistical analysis plan) Unmasked Parties: Principal Investigator Co-Principal Investigator / Pharmacy and Drug Accountability Officer Pharmacy personnel responsible for dispensing study medication Unblinding: Unblinding is permitted only in medical emergencies when knowledge of the treatment assignment is necessary for participant management.
Intervention model description
This is a prospective, randomized, single-blind, placebo-controlled trial with parallel assignment. Eligible participants with cirrhosis and portal hypertension (Child-Pugh A or B ≤9) are randomized 1:1 to two arms. Intervention Arm: apixaban 2.5 mg twice daily plus carvedilol titrated to 12.5 mg twice daily. Control Arm: matching placebo twice daily plus carvedilol titrated identically. Randomization uses a computer-generated sequence with permuted blocks; allocation is concealed via centralized web-based system accessible only to unblinded pharmacist. Participants are blinded; investigators and pharmacy personnel are unblinded. All participants are followed 12 months with visits at baseline, 2 weeks (safety call), and 1, 3, 6, 9, and 12 months. Analysis is intention-to-treat. An independent DSMB reviews unblinded safety data after 50% of participants complete 6 months, with predefined stopping rules for excessive bleeding or mortality.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| First Occurrence of Portal Hypertension-Related Complications | 12 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major and Minor Bleeding Events | 12 months | 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. |
Countries
Pakistan
Contacts
CONTACTFatima Nadeem Dr, Pharm-D, Mphil
PRINCIPAL_INVESTIGATORSadik Memon, MBBS,MRCP,FCPS
Asian Institute Of Medical Sciences
STUDY_DIRECTORDr. Fatima Nadeem, Pharm-D, Mphil
Asian Institute Of Medical Sciences
Outcome results
None listed