HI-PRO

Published

Piazza G, et al. "Apixaban for extended treatment of provoked venous thromboembolism". The New England Journal of medicine. 2025. (epub 2025-08-31):1-10.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

Among adults with a VTE who completed primary treatment with anticoagulation who have a chronic provoking risk factor, is use of apixaban 2.5 mg PO BID associated with fewer recurrent VTE events or more major bleeding events when compared to placebo?

Bottom Line

Among adults with a VTE who completed primary treatment with anticoagulation who have a chronic provoking risk factor, apixaban 2.5 mg PO BID is associated fewer recurrent VTE events and no excess major bleeding events when compared to placebo.

Major Points

The use of anticoagulation for prolonged periods of time for prevention of recurrence of venous thromboembolism (VTE; i.e., pulmonary embolism or proximal deep venous thrombosis) was studied in the [AMPLIFY-EXT] (2013) and [EINSTEIN CHOICE] (2017) trials. These trials found that use of DOACs beyond the initial VTE treatment window (~6 months) was associated with lower risk of recurrent VTE. These trials did not specify the circumstances under which the VTE occurred and only excluded persons who otherwise required long-term anticoagulation. Largely because of these trials, the 2020 American Society of Hematology (ASH) VTE management provided updated definitions for treatment timelines and VTE risk factors. Here, management is defined as as (1) initial treatment, being initial interventions selected at or around the time of VTE diagnosis, (2) primary treatment, or use of anticoagulation for up to 3-6 months or possibly a few months longer, and (3) secondary prevention, or use anticoagulation beyond the initial primary treatment window. VTE events were defined by associated risk factors, with examples including:

• Unprovoked:
  • No risk factors
• Provoked, chronic risk factors:
  • Active cancer
  • IBD
  • Autoimmune disorders, including antiphospholipid antibody syndrome and RA
  • Chronic infections
  • Chronic immobility such as spinal cord injury
• Provoked, major transient risk factors, with risk factors occurring in 3 months prior to VTE occurrence:
  • Surgery with general anesthesia for ≥30 min
  • Hospitalized with limited mobility for ≥3 days because of an acute illness
  • C-section
• Provoked, minor transient risk factors, with risk factors occurring in 2 months prior to VTE occurrence:
  • Surgery with general anesthesia for <30 min
  • Hospitalized for <3 days with acute illness
  • Exogenous estrogen therapy (e.g., OCPs or HRT)
  • Pregnancy and post-partum
  • Bedbound outside of hospital for ≥3 days with an acute illness
  • Leg injury with decreased mobility for ≥3 days

For persons with low bleeding risk, the ASH guidelines suggests the following secondary prevention strategies:

• Unprovoked - Indefinite anticoagulation
• Provoked, chronic risk factor - Indefinite anticoagulation
• Provoked, transient risk factor - Typically no further anticoagulation

There was not clarity about the role of anticoagulation continuation among persons with provoked events, based on available evidence. The 2025 Extended-Duration Low-Intensity Apixaban to Prevent Recurrence in High-Risk Patients with Provoked Venous Thromboembolism (HI-PRO) trial sought to address that. This trial recruited 600 patients with provoked VTE with a "persistent provoking" risk factor (immobility, obesity, HF, chronic lung disease, CKD, autoimmune diseases, or ASCVD) who had completed ≥3 months of primary treatment from a single academic medical center in Boston, MA. Participants were randomized to apixaban 2.5 mg PO BID or placebo in a double blinded fashion. Participants had a mix of provoked, major transient risk factors (e.g., 18% had an acute medical illness that was presumably related to a hospitalization), provoked, minor transient risk factors (e.g., 12% were on OCPs or HRT), and chronic risk factors (e.g., 31% had immobility that was presumably persistent immobility like being wheelchair bound). About half had BMI ≥30 kg/m², 21% had a prior VTE event. At 12 months, use of apixaban was associated with a significant reduction in symptomatic recurrent VTE events when compared to placebo (1.3% vs. 10.0%; HR 0.13; 95% CI 0.04 to 0.36; P<0.001; NNT=11). There were few major bleeding events in either group.

This trial was limited by its single center design, use of clinician judgment for provoking features rather than use of common definitions, and recruiting a population that is probably at higher risk for recurrent VTE than the typical unprovoked VTE population. Further, the definitions of persistent provoking risk factors used in this trial differs from those in the ASH definition of "provoked, chronic risk factors". Ultimately, this trial provides evidence that older "provoked, chronic risk factor" definitions should be expanded to include obesity, HF, chronic lung disease, CKD, and ASCVD. HI-PRO's findings support ASH guideline's recommendation for use of anticoagulation for secondary prevention of VTE in persons with provoked, chronic risk factors. Whether there is clinical utility to continue anticoagulation among persons with VTE who have provoked, transient risk factors without additional provoked, chronic risk factor or remains unresolved.

Guidelines

As of September 2025, no guidelines have been published that reflect the results of this trial.

Design

• Single center, double blinded RCT
• N=600
  • Apixaban (n=300)
  • Placebo (n=300)
• Setting: 1 academic medical center in Boston, MA
• Enrollment: 2020-2023
• Follow-up: 12 months
• Analysis: Intention-to-treat for the primary outcomes
• Primary outcomes:
  • Efficacy: Symptomatic recurrent VTE event
  • Safety: ISTH major bleeding

Population

Inclusion Criteria

• Aged ≥18 years
• DVT, PE, or both
• ≥3 months of usual anticoagulation therapy without any VTE recurrence in that timeframe
• Followed as outpatient in the center in which the trial was recruiting
• ≥1 persistent provoking features:
  • Immobility (e.g., paralysis, bed-bound, in wheelchair)
  • BMI ≥30 kg/m²
  • HF
  • Chronic lung disease (e.g., COPD, asthma, ILD)
  • eGFR <60 mL/min/1.73 m²
  • Autoimmune disease or inflammatory disorder (e.g., inflammatory arthritis, vasculitis, IBD, chronic infection)
  • ASCVD

Exclusion Criteria

• Pregnant or breastfeeding or childbearing potential unable to use effective birth control method during the study
  • WJC editor note: The protocol has extended details about handling childbearing potential on pages 22 & 23
• Active cancer in prior 5 years
• Contraindication to anticoagulation or antiplatelets
• Need for anticoagulation, DAPT, P2y12 inhibition, or high dose aspirin (>81 mg/day)
• Hgb <9 mg/dL, platelet count <100k, creatinine >2.5 mg/dL or CrCl <25 ml/min, ALT or AST >2x ULN, tbili >1.5 ULN
• Platelet disorder
  • WJC editor note: The protocol lists von Willebrand disease as an example, though this is not a platelet disorder.
• Bleeding diathesis or recent active bleeding
• Severe liver disease
• >6 months without anticoagulation or antiplatelet therapy
• Severe thrombophilia requiring use of a vitamin K antagonist such as concern for antiphospholipid antibody syndrome based on laboratory testing
  • WJC editor note: The protocol lists antithrombin III, protein C, and protein S deficiencies as conditions that require a vitamin K antagonist. At our institutions, these conditions are commonly treated with DOACs.
• Life expectancy <12 mo
• Incarceration or compulsorily detained for psychiatric or other illness
• Receiving investigational agent or non-FDA approved agent in prior 30 days
• Hypersensitivity to apixaban or contraindication to use of apixaban

Baseline Characteristics

From the total population

• Demographics: age 60 years, female sex 58%, White race 81%, Black race 12%, Asian race 1%, Hispanic/Latino 9%
• BMI: 31 kg/m²
• Current smoker: 5%
• Medical issues: Prior VTE 21%, DM 12%, HTN 49%, CAD 17%, PAD 4%, stroke/TIA 5%, HF 2%, dyslipidemia 53%, carotid artery disease 2%
• Family history of VTE: 26%
• Aspirin (≤81 mg/day): 21%
• Index event: DVT only 48%, isolated calf DVT 20%, PE only 23%, RV dysfunction (presumably with PE) 13%, PE and DVT 29%
• Provoking factors:
  • Acute medical illness (e.g., asthma, Crohn's, HF, COPD, other inflammatory condition exacerbation): 18%
  • Surgery: 33%
  • Trauma 19%
  • Pregnancy 2%
  • Infection: 16%
  • OCP or HRT: 11%
  • Hospitalization ≤3 months before VTE event: 9%
  • Immobility: 31%
  • Blood transfusion in prior 30 days: <1%
  • Covid-19: 8%
  • Long-haul travel in prior 30 days: 17%
  • Other: 9%
    • Dehydration: 3%
    • Localized inflammatory illness: 2%
    • Covid-19 vaccine: 1%
    • May-Thurner sydnrome: 1%
    • COX-2 inhibitor, JAK inhibitor, or IVIG-associated: 0.5%
    • Nephrolithiasis: <1%

Interventions

• Randomized to a group:
  • Apixaban - 2.5 mg PO BID
  • Placebo

Outcomes

Presented as apixaban vs. placebo. Components of the primary and secondary outcomes are shown by the primary and secondary outcomes for simplicity.

Primary Outcome

Symptomatic recurrent VTE event

1.3% vs. 10.0% (HR 0.13; 95% CI 0.04 to 0.36; P<0.001; NNT=11)

Any PE: 0 vs 3.7%

Isolated subsegmental PE: 0 vs. 0.3%

Any DVT: 1.3% vs. 7.7%

Isolated calf: 0.7% vs. 3.3%

ISTH major bleeding

0.3% vs. 0 (P >0.999)

Secondary Outcomes

CV mortality, nonfatal MI, stroke, TIA, systemic embolism, major adverse limb event, coronary/limb ischemia requiring revascularization

0.7% vs. 1.0% (HR 0.67; 95% CI 0.11 to 3.98)

CV mortality: 0 vs. 0

Nonfatal MI: 0.3% vs. 0

Stroke, TIA, systemic embolism: 0.3% vs. 0.7%

Coronary ischemia requiring revascularization: 0 vs. 0.7%

Limb ischemia requiring revascularization: 0 vs. 0

Clinically relevant nonmajor bleeding

4.8% vs. 1.7% (HR 2.68; 95% CI 0.96 to 7.43; P=0.06)

Additional Outcomes

CV mortality, nonfatal MI, stroke, TIA, systemic embolism, major adverse limb event, coronary/limb ischemia requiring revascularization, or symptomatic recurrent VTE

2.0% vs. 10.7% (HR 0.18; 95% CI 0.07 to 0.43)

Symptomatic recurrent VTE, fatal or nonfatal MI, stroke, TI, systemic embolism

2.0% vs. 10.3% (HR 0.19; 0.08 to 0.44)

All-cause mortality

0.3% vs. 1.0% (no comparisons given)

Subgroup Analysis

Subgroup analyses for the primary VTE outcome and the secondary bleeding outcome appear in the supplemental appendix on pages 18 and 19 These outcomes were stratified by presence of PE as index event, age, sex, CKD, ASCVD, use of aspirin at baseline, number of provoking risk factors, long haul travel as provoking factor, surgery/major trauma/prolonged immobility as provoking factors, or prior VTE other than index event. Select outcomes of interest are presented here.

Symptomatic recurrent VTE event

PE status as index event

No PE: 2.1% vs. 7.5% (HR 0.27; 05% CI 0.08 to 0.98)

Yes PE: 0.6% vs. 12.3% (HR 0.05; 95% CI 0.01 to 0.36)

History of ASCVD

No ASCVD: 1.4% vs. 13.3% (HR 0.10; 95% CI 0.03 to 0.33)

Yes ASCVD: 1.2% vs. 2.2% (HR 0.52; 95% CI 0.05 to 5.73)

Number of provoking factors:

≤2: 0.7% vs. 12% (HR 0.06; 95% CI 0.01 to 0.42)

>2: 1.9% vs. 8.6% (HR 0.21; 95% CI 0.06 to 0.73)

Long-haul travel as provoking risk factor

No: 1.2% vs. 8.9% (HR 0.13; 95% 0.04 to 0.42)

Yes: 2.2% vs. 14.8% (HR 0.14; 95% CI 0.02 to 1.09)

Clinically relevant non-major bleeding

Note: This was not the secondary, not primary, bleeding outcome.

Baseline use of aspirin:

No aspirin: 5.0% vs. 1.3% (HR 3.52; 95% CI 0.99 to 12.46)

Yes aspirin: 5.6% vs. 2.9% (HR 1.98; 95% CI 0.33 to 11.84)

Number of provoking factors:

≤2: 4.4% vs. 2.5% (HR 1.69; 95% CI 0.42 to 6.76)

>2: 5.7% vs. 1.2% (HR 4.75; 95% CI 1.03 to 21.96)

Prior VTE other than index event:

No prior VTE: 4.4% vs. 0.8% (HR 4.94; 95% CI 1.08 to 22.55)

Yes prior VTE: 7.7% vs. 5.2% (HR 1.42; 95% CI 0.34 to 5.95)

Criticisms

• The authors did not use standard definitions of provoking events and instead used judgment of the investigator.
• Single center design with substantial participant recruitment coming from the 2 co-PIs.

Funding

• Sponsored by Bristol-Myers-Squibb-Pfizer alliance, who were seemingly minimally involved. This was presumably an investigator initiated trial.