Why this study matters
For decades, we’ve used a neat binary: provoked = 3 months of anticoagulation, unprovoked = indefinite therapy. Easy enough to remember.
The HI-PRO trial, presented at ESC 2025, asked whether the “3 months and done” rule holds up in patients who had a transient provoking factor and lingering, chronic risk features.
HI-PRO (ESC 2025)
| Feature | Details |
|---|---|
| Population | 1,720 patients with a provoked VTE (DVT or PE) due to a transient factor plus ≥1 enduring risk factor (obesity, chronic lung disease, inflammatory disorder, active smoking, hormone replacement therapy, CHF) |
| Intervention | After ≥3 months of anticoagulation, randomized to apixaban 2.5 mg BID vs placebo for 12 months |
| Primary Outcome | Symptomatic recurrent VTE (DVT or PE) |
| Results | 1.3% (apixaban) vs 10.0% (placebo); HR 0.13; p<0.001 |
| Major Bleeding | 0.3% (apixaban) vs 0 (placebo) |
| CRNMB (Clinically relevant non major bleed) | 4.8% vs 1.7% (HR 2.68, NS) |
Key nuance
The recurrence reduction is striking: nearly 87% relative risk reduction. BUT HI-PRO doesn’t argue for extended anticoagulation in all provoked VTE, rather only in provoked with persistent risk.
How this contrasts with guidelines
- ASH / CHEST / ACCP: For decades, the recommendation has been 3 months for provoked VTE due to transient risk factors (surgery, trauma, immobilization, prolonged illness).
- Rationale: Bleeding risk rises with longer therapy, so shorter = safer.
- HI-PRO flips that script:
- Major bleeding was exceedingly rare (0.3%), despite extended anticoagulation.
- The absolute recurrence benefit dwarfed the bleeding cost.
- Clinically relevant non-major bleeding (CRNMB) was higher, but manageable.
This highlights a bias in our field: we often see shortening duration as inherently good, but HI-PRO reminds us the true balance is recurrence risk vs real bleeding events, not theoretical risk.
Clinical Pearls
- Not all “provoked” VTEs are equal — ask what provoked it, and what risk factors linger?
- Provoked + enduring risk (obesity, inflammation, chronic disease) → consider extended therapy.
- Low-dose apixaban (2.5 mg BID) offers robust efficacy with very low major bleeding.
- Don’t reflexively stop at 3 months — tailor based on total risk profile.
- Compare absolute numbers: 0.3% major bleed vs 9% fewer recurrences at 1 year.
My take
HI-PRO makes me rethink the dogma I was trained on. I am curious to see how this dovetails into increasing adoption of thrombectomy for larger DVTs, as we learn more about post-thrombotic syndrome and its complications.
This builds on prior extended-therapy trials (AMPLIFY-EXT, EINSTEIN-CHOICE) but is unique in specifically tackling purely the “provoked” population. For fellows, the takeaway is this: for every provoked DVT, assess the underlying risk factors, and treat accordingly.
TLDR
- HI-PRO (ESC 2025): Extended low-dose apixaban after provoked VTE with persistent risk significantly decreased recurrence (1.3% vs 10%), minimal bleeding.
- Guidelines: Still say 3 months for provoked events — but HI-PRO suggests some of these patients warrant extension, as we know, the guidelines will always lag
- Message: Shorter isn’t always safer. Balance recurrence vs real bleeding, not just theoretical risk.
- Clinical pearl: Reassess risk after 3 months — “provoked” isn’t always low-risk.
References
- Agnelli G, Buller HR, Cohen A, et al. Apixaban for Extended Treatment of Venous Thromboembolism (AMPLIFY-EXT). N Engl J Med. 2013;368:699-708.
Full text (NEJM) - Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism (EINSTEIN-CHOICE). N Engl J Med. 2017;376:1211-1222.
Full text (NEJM) - ESC Congress News. HI-PRO: Extended low-dose apixaban lowers recurrence in provoked VTE patients with persistent risk factors. ESC 2025.
ESC Congress 2025 Hot Line Coverage - Arfvidsson S, Schulman S, et al. HI-PRO Trial Design: Extended-duration low-intensity anticoagulation in provoked VTE with persistent risk. Thromb Haemost. 2021;121:345-353.
PubMed Abstract - Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of DVT and PE. Blood Adv. 2020;4(19):4693-4738. Full text (Blood Advances)
- Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315-352.
Full text (CHEST Journal) - ClinicalTrials.gov. HI-PRO: Extended Low-Intensity Apixaban to Prevent Recurrence in High-Risk Patients With Provoked VTE. NCT04168203.
ClinicalTrials.gov Record
