Apixaban for Extended Treatment of Provoked Venous Thromboembolism (HI-PRO)

Authors, Journal, Affiliations, Type, DOI

• 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; for the HI-PRO Trial Investigators
• Journal: New England Journal of Medicine 2025;393:1166–76
• Affiliations: Thrombosis Research Group, Brigham and Women's Hospital–Harvard Medical School, Boston (single center)
• Type: Randomized, placebo-controlled, double-blind, single-center superiority trial
• DOI: https://doi.org/10.1056/NEJMoa2509426
• Funding: Bristol-Myers Squibb–Pfizer Alliance (research grant only; no role in design, execution, analysis, or reporting)

Overview

HI-PRO addresses a clinical gap in VTE management: patients with provoked VTE (surgery, trauma, immobility, acute illness) who also carry enduring risk factors (obesity, chronic inflammatory disease, chronic lung disease, ASCVD). Current guidelines recommend only 3 months of anticoagulation for provoked VTE, but HI-PRO shows that in the presence of enduring risk factors, 12-month extension with low-dose apixaban (2.5 mg BID) reduces VTE recurrence by 87% (1.3% vs 10.0%; HR 0.13; P<0.001) with a very low rate of major bleeding (0.3% vs 0%). The 10% placebo recurrence rate demonstrates that provoked VTE + enduring risk factors carries recurrence risk approximating unprovoked VTE, challenging the provoked/unprovoked binary.

Keywords

Provoked venous thromboembolism, extended anticoagulation, apixaban, enduring risk factors, recurrence prevention, VTE-PREDICT, low-intensity anticoagulation

Key Takeaways

Trial Design and Population

• Design: Randomized, placebo-controlled, double-blind; single center (Brigham and Women's Hospital, Boston); November 2020–November 2023
• Eligibility: Adults ≥18 years with objectively confirmed VTE after a transient provoking factor (surgery, trauma, acute medical illness, or immobility); completed ≥3 months of anticoagulation; ≥1 enduring risk factor for recurrence
• Enduring risk factors defined as: BMI ≥30, chronic lung disease, chronic inflammatory/autoimmune disorder (most common), ASCVD (capped at ≤35% per group), or combinations
• Exclusions: Active cancer, unprovoked VTE, anticoagulation contraindication, severe hepatobiliary/renal disease, P2Y12 antagonist or aspirin >81 mg/day, recent active bleeding, life expectancy <12 months
• Randomization: 1:1, permuted blocks of 4; blinded; centralized; stratified
• n = 600: 300 apixaban / 300 placebo; 100% follow-up at 365 days
• VTE type: DVT (lower/upper limb), PE (including subsegmental), or both

Baseline Characteristics

• Mean age 59.5 years; 57% female; 19.2% non-White
• Most common provoking factors: surgery (33.5%), immobility (31.3%), trauma (19.2%), acute medical illness (18.3%)
• Most common enduring risk factors: chronic inflammatory/autoimmune disorder (52.2%), BMI ≥30 (48.2%), ASCVD (29.3%), chronic lung disease (22.3%)
• ~20% on low-dose aspirin (81 mg) in both groups throughout follow-up

Intervention

• Apixaban 2.5 mg orally twice daily × 12 months (low-intensity, maintenance-dose regimen)
• Median adherence: 350 days (apixaban) vs 339 days (placebo) of 365 — excellent

Primary Efficacy: Symptomatic Recurrent VTE

• Apixaban 1.3% (4/300) vs Placebo 10.0% (30/300) — HR 0.13; 95% CI 0.04–0.36; P<0.001
• 87% relative risk reduction
• Consistent across all prespecified subgroups: age ≥65, sex, PE index event, CKD, ASCVD, aspirin use, number of provoking factors
• Post hoc: benefit consistent regardless of major vs minor transient provoking factor

Primary Safety: Major Bleeding

• Apixaban 0.3% (1/300) vs Placebo 0% (0/300) — P>0.999 (not significant)
• The single major bleed: 3-mm parafalcine subdural hematoma after fall from horse; no hospitalization, no apixaban discontinuation, no sequelae after neurosurgical consultation

Clinically Relevant Nonmajor Bleeding (CRNMB)

• Apixaban 4.8% (14/294) vs Placebo 1.7% (5/294) — HR 2.68; 95% CI 0.96–7.43; P=0.06 (trend, not powered for this endpoint)
• Most common apixaban CRNMB: vaginal (1.7%), hematuria (1.4%), rectal (1.0%)
• Most common placebo CRNMB: vaginal (1.0%)
• No fatal bleeding in either group

Secondary CV Composite

• CV death, MI, stroke/TIA, systemic embolism, major adverse limb event, or revascularization: 0.7% vs 1.0% (HR 0.67; 95% CI 0.11–3.98) — no difference

Mortality

• 1 death in apixaban arm (progressive dementia); 3 deaths in placebo arm (lung cancer, end-stage lung disease, trauma)
• No cardiovascular or haemorrhagic deaths in either arm

Key Clinical Message

• The 10% placebo recurrence rate refutes the assumption that provoked VTE + enduring risk always carries low recurrence
• Enduring risk factors (obesity, autoimmune, chronic lung disease, ASCVD) identify a "provoked VTE" subpopulation with recurrence risk (~8–10%) approximating unprovoked VTE — warranting extended anticoagulation consideration
• Low-dose apixaban 2.5 mg BID is highly effective with very low major bleeding risk in this population
• CRNMB trend (4.8% vs 1.7%) represents a nuanced risk–benefit trade-off, particularly since all recurrent VTEs in this trial were nonfatal

Limitations of the Document

• Single-center design (Brigham and Women's Hospital): Results may not generalize to other health care systems
• Not powered for CRNMB or subgroup analyses: Potential harm signal (HR 2.68) could be real but underpowered; subgroup treatment effect differences cannot be reliably detected
• Relatively small n=600: Large confidence intervals on secondary endpoints
• No head-to-head vs continued full-dose anticoagulation: Only vs placebo; cannot determine whether 2.5 mg BID or 5 mg BID is superior in this group
• Active cancer excluded: Cannot be extrapolated to cancer-associated VTE
• Limited racial/ethnic diversity: 80% White despite improvements over prior studies
• Enduring risk factor eligibility verified by treating clinician: Possible inconsistency in classification
• Aspirin co-use (~20%): Slightly increases bleeding signal; discontinuation may further improve CRNMB rate

Key Concepts Mentioned

• concepts/Venous-Thromboembolism-Anticoagulation — extended-duration low-dose apixaban in provoked VTE + enduring risk factors
• concepts/Cancer-Associated-VTE — cancer excluded from HI-PRO; separate evidence base

Key Entities Mentioned

• Apixaban — extended low-dose (2.5 mg BID) for 12-month secondary prevention in provoked VTE
• VTE-PREDICT score — mentioned as risk-stratification tool to guide extended anticoagulation decisions

Wiki Pages Updated

• Created wiki/sources/Apixaban-VTE-HIPRO-NEJM-2025.md
• Created/updated wiki/concepts/Venous-Thromboembolism-Anticoagulation.md
• Updated wiki/wikiindex.md
• Updated wiki/sourceindex.md