Extended-Duration Low-Intensity Apixaban to Prevent Recurrence in High-Risk Patients With Provoked Venous Thromboembolism

NCT04168203 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: CV185-745
• Study Type: interventional
• Target: 600
• Locations: 1 country
• Sites: 1

Brief Summary

Design: U.S.-based, single-center, randomized placebo-controlled trial. Brief Treatment Description: Low-intensity apixaban (2.5mg twice daily) for extended-duration secondary prevention of VTE after initial treatment for provoked VTE. Purpose: To establish the safety and efficacy of low-intensity apixaban versus placebo for extended prevention of recurrence after provoked VTE in patients with at least one persistent provoking factor. Population: Outpatients with provoked VTE with at least one persistent provoking factor. Enrollment: 600 subjects Randomization: 1:1 Clinical Site Locations: 1 center (Brigham and Women's Hospital) Study Duration: 36 months; enrollment period of up to 20 months with 12-month follow-up. Primary Safety and Efficacy Outcomes: Primary Safety Outcome: International Society on Thrombosis and Haemostasis (ISTH) major bleeding at 12 months. Primary Efficacy Outcome: Symptomatic, recurrent VTE, defined as the composite of deep vein thrombosis and/or pulmonary embolism at 12 months. Secondary Efficacy Outcome: The composite of death due to cardiovascular cause, nonfatal myocardial infarction, stroke or systemic embolism, critical limb ischemia, or coronary or peripheral ischemia requiring revascularization (major adverse cardiovascular events, including major adverse limb events) at 12 months. Follow-Up: Follow-up will consist of Electronic Health Record (EHR) review at 12-months from study enrollment. Interim Analysis: An interim analysis for the primary safety and efficacy outcomes will be performed when 300 subjects have completed 12-month follow-up.

Conditions

Deep Vein Thrombosis; Pulmonary Embolism; Venous Thromboembolism

Keywords

pulmonary embolism; deep vein thrombosis; venous thromboembolism; secondary prevention; anticoagulation

Outcome Measures

Primary Outcomes (2)

• Frequency of Symptomatic, Recurrent VTE Defined as the Composite of Deep Vein Thrombosis and/or Pulmonary Embolism

  DVT is diagnosed as a newly non-compressible venous segment or segments on ultrasonography or a filling defect on computed tomographic (CT) venography, magnetic resonance (MR) venography, or contrast venography. PE is diagnosed based on new mismatched perfusion defect(s) on ventilation perfusion scan, the presence of a new pulmonary artery filling defect on contrast-enhanced chest CT, a new finding of intraluminal filling defect on invasive pulmonary angiography, or evidence of PE at autopsy.

  12 months

• Frequency of Major Bleeding

  Defined as overt bleeding that is associated with a decrease in the hemoglobin level ≥ 2 g/dL, leads to transfusion ≥ 2 units of packed red blood cells, occurs in a critical site, or contributes to death

  12 months

Secondary Outcomes (1)

• Frequency of the Composite of Death Due to Cardiovascular Cause, Nonfatal Myocardial Infarction (MI), Stroke or Systemic Embolism, Critical Limb Ischemia (CLI), or Coronary or Peripheral Ischemia Requiring Revascularization

  12 months

Other Outcomes (2)

• Frequency of Clinically Relevant Non-major Bleeding

  12 months

• Adherence to the Twice-daily Regimen of Apixaban (and Placebo)

  12 months

Study Arms (2)

Extended Duration Thromboprophylaxis

EXPERIMENTAL

apixaban 2.5 mg orally twice daily for a duration of 12 months

Drug: Apixaban 2.5 MG

Control

PLACEBO COMPARATOR

oral placebo for a duration of 12 months

Drug: Placebo oral tablet

Interventions

Apixaban 2.5 MG DRUG

apixaban 2.5 mg orally twice daily for a duration of 12 months

Extended Duration Thromboprophylaxis

Placebo oral tablet DRUG

placebo oral tables twice daily for a duration of 12 months

Control

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Man or woman
• Age ≥ 18 years
• Objectively-confirmed provoked DVT and/or PE
• Treated for at least 3 months with standard therapeutic anticoagulant therapy
• Has not suffered symptomatic recurrence during prior anticoagulant therapy
• Outpatient follow-up at BWH
• AND have at least one of the following persistent provoking VTE risk factors:
• Persistent immobility (defined as paralysis, other inability to ambulate freely, bed-bound, wheelchair-bound)
• Obesity (defined as BMI ≥ 30 kg/m2)
• Heart failure (systolic, diastolic, or combined)
• Chronic lung disease (COPD, asthma, interstitial lung disease)
• Chronic kidney disease (nephrotic/nephritic syndrome, renal dysfunction with creatinine ≤ 2.5 mg/dL)
• Chronic inflammatory/autoimmune disorder (inflammatory arthritis, vasculitis, inflammatory bowel disease, chronic infection)
• Atherosclerotic cardiovascular disease (coronary, cerebrovascular, or peripheral artery disease) (up to 35% in each study group may have atherosclerotic cardiovascular disease as a qualifying persistent risk factor)
• NOTE: Eligible patients will be allowed to have multiple risk factors, and there will not be a limit as to how many of the above risk factors a subject may have. In addition, we will place no limit on the number of patients included with multiple risk factors. A study population with multiple risk factors is highly representative of the provoked VTE population and will provide the greatest generalizability of the study results to real-world clinical practice. Including patients with single and multiple persistent provoking risk factors will also facilitate enrollment. As noted, there is clinical and research equipoise regarding whether patients with a single or multiple persistent provoking VTE risk factors should receive extended duration thromboprophylaxis for secondary prevention.

You may not qualify if:

• Women who are pregnant or breastfeeding
• Women of child-bearing potential who are unwilling or unable to use an acceptable method of birth control (such as oral contraceptives, other hormonal contraceptives \[vaginal products, skin patches, or implanted or injectable products\], or mechanical products such as an intrauterine device or barrier methods \[diaphragm, condoms, spermicides\]) to avoid pregnancy for the entire study
• Active cancer within the past 5 years
• Contraindication to antithrombotic or antiplatelet therapy
• Requirement for ongoing anticoagulant therapy, dual antiplatelet therapy, P2Y12 inhibition, or aspirin at a dose of \> 81 mg daily
• Hemoglobin level \< 9 mg/dL, a platelet count \< 100,000/mm3, a serum creatinine level \> 2.5 mg/dL, an ALT or AST level \> 2 times the upper limit of the normal range, or a total bilirubin level \> 1.5 times the upper limit of the normal range
• History of bleeding diathesis or have had recent active bleeding
• Active severe hepatobiliary disease
• More than 6 months that have elapsed without taking an anticoagulant or low-dose aspirin
• o NOTE: The risk of recurrent VTE following cessation of anticoagulation rises slowly over the first 3-6 months (26). After this initial period, the cumulative risk of recurrent VTE steepens. Using a limit of no greater than 6 months of interruption in anticoagulation before potential reinitiation of anticoagulation as part of this trial will safely facilitate enrollment as opposed to restricting the population to no greater than 3 months of interruption.
• Known severe thrombophilia (any increased titer antiphospholipid antibody or positive lupus anticoagulant/DRVVT or deficiency of antithrombin, protein C, or protein S) which would indicate long-term full therapeutic anticoagulation with a vitamin K antagonist
• Life expectancy \< 12 months or hospice care
• Prisoners or subjects who are involuntarily incarcerated
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
• Receiving concurrent non-FDA-approved or investigational agents or has received an investigational agent within the past 30 days prior to the first dose of study treatment (with the exception of approved medications being used for an approved indication, e.g., investigating a new dosing regimen for an approved indication)

Sponsors & Collaborators

• Brigham and Women's Hospital: lead

Study Sites (1)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Related Publications (1)

• Piazza G, Bikdeli B, Pandey AK, Krishnathasan D, Khairani CD, Bejjani A, Morrison RH, Hogan H, Rashedi S, Pfeferman M, Lou J, Fanikos J, Porio N, Rosenbaum L, Sobieszczyk P, Lan Z, Gerhard-Herman M, Campia U, Goldhaber SZ; HI-PRO Trial Investigators. Apixaban for Extended Treatment of Provoked Venous Thromboembolism. N Engl J Med. 2025 Sep 25;393(12):1166-1176. doi: 10.1056/NEJMoa2509426. Epub 2025 Aug 30.

  PMID: 40888734 DERIVED

MeSH Terms

Conditions

Venous Thrombosis; Pulmonary Embolism; Venous Thromboembolism

Interventions

apixaban

Condition Hierarchy (Ancestors)

Thrombosis; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Lung Diseases; Respiratory Tract Diseases; Embolism; Thromboembolism

Results Point of Contact

• Title: Physician
• Organization: BWH

gpiazza@bwh.harvard.edu

6177326984

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind, double-dummy
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Director, Thrombosis Research Group

Model Details: 600-patient U.S.-based, single-center, randomized, double-blinded, placebo-controlled study of apixaban 2.5 mg orally twice daily for extended prevention of recurrence after provoked VTE in patients with at least one persistent provoking factor who have completed at least 3 months of standard therapeutic anticoagulation and who have a low risk of bleeding.

Study Record Dates

• First Submitted: November 12, 2019
• First Posted: November 19, 2019
• Study Start: March 1, 2021
• Primary Completion: November 30, 2023
• Study Completion: April 8, 2025
• Last Updated: November 14, 2025
• Results First Posted: September 30, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)